NZ794398A - Combined Therapies For Atherosclerosis, Including Atherosclerotic Cardiovascular Disease - Google Patents
Combined Therapies For Atherosclerosis, Including Atherosclerotic Cardiovascular DiseaseInfo
- Publication number
- NZ794398A NZ794398A NZ794398A NZ79439817A NZ794398A NZ 794398 A NZ794398 A NZ 794398A NZ 794398 A NZ794398 A NZ 794398A NZ 79439817 A NZ79439817 A NZ 79439817A NZ 794398 A NZ794398 A NZ 794398A
- Authority
- NZ
- New Zealand
- Prior art keywords
- subject
- therapy
- ldl
- pcsk9
- risk
- Prior art date
Links
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Abstract
Provided herein are combinations of therapies that provide for the treatment, including regression, of atherosclerosis and/or improvement of cardiovascular outcomes. Generally described, this includes a first, non-PCSK9 LDL-C lowering agent (such as a statin or other non-PCSK9 LDL-C lowering therapy), combined with a second, PCSK9 inhibitor therapy (such as a PCSK9 antibody or anti-RNA). The application of both therapies, at adequately elevated levels so as to reduce the LDL-C level of the subject to very low levels, for an adequate period of time, has been determined to provide an added benefit of further protection from atherosclerosis and improve a subject's cardiovascular outcomes. ), combined with a second, PCSK9 inhibitor therapy (such as a PCSK9 antibody or anti-RNA). The application of both therapies, at adequately elevated levels so as to reduce the LDL-C level of the subject to very low levels, for an adequate period of time, has been determined to provide an added benefit of further protection from atherosclerosis and improve a subject's cardiovascular outcomes.
Description
Provided herein are combinations of therapies that provide for the treatment, ing
regression, of atherosclerosis and/or improvement of cardiovascular outcomes. Generally
described, this includes a first, non-PCSK9 LDL-C lowering agent (such as a statin or other non-
PCSK9 LDL-C lowering therapy), combined with a second, PCSK9 inhibitor therapy (such as a PCSK9
antibody or anti-RNA). The application of both ies, at adequately elevated levels so as to
reduce the LDL-C level of the subject to very low , for an adequate period of time, has been
determined to provide an added benefit of further protection from atherosclerosis and improve a
subject's cardiovascular outcomes.
NZ 794398
COlVfl31NED THERAPIES FOR ATHEROSCLEROSIS INCLUDING
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE
RELATED APPLICATIONS
This application claims priority to US. Provisional Applications Ser. No.
62/421685, filed er 14, 2016, Ser. No. 874, filed March 15, 2017, Ser No.
62/515117, filed June 5, 2017, Ser. No. 62/581244, filed November 3, 2017, and Ser. No.
62/584600, filed November 10, 2017, each of which is hereby incorporated by reference in
their ties.
SEQUENCE LISTING AND TABLES IN ELECTRONIC FORMAT
The present application is being filed along with a Sequence Listing in
electronic format. The Sequence Listing is provided as a file entitled APMOL018WOTXT,
last saved November 13, 2017, created on November 8, 2017, which is 88,325 bytes in size.
The information in the electronic format of the ce Listing is incorporated herein by
reference in its entirety.
BACKGROUND
Field
The present invention relates to combined therapies for the treatment of
atherosclerosis, including atherosclerotic cardiovascular disease.
DescriQtion of the Related Art
There are a number and variety of LDL lowering therapies ble in
cholesterol management that have been developed over the last couple of decades. These
compounds, and s of using these nds, have been found to be effective at
lowering LDL-C levels in various ts to various levels.
SUMMARY
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method comprises a) identifying a subject that is on a first therapy, wherein
the first therapy ses a non-PCSK9 LDL—C ng therapy, and b) administering a
second therapy to the subject. The second therapy comprises a PCSK9 inhibitor y.
Both the first and second therapies are administered to the subject in an amount and time
sufficient to reverse coronary atherosclerosis in the subject, and the first y is not the
same as the second therapy.
In some embodiments, the first therapy is selected from at least one of: a
statin, including but not limited to atorvastatin (LIPITOR®), cerivastatin, fluvastatin
L), lovastatin (MEVACOR, ALTOPREV), mevastatin, pitavastatin, pravastatin
(PRAVACHOL), rosuvastatin, rosuvastatin calcium (CRESTOR) and simvastatin (ZOCOR);
ADVICOR (lovastatin + niacin), CADUET astatin + dine); a selective
cholesterol absorption inhibitor, including but not limited to ezetimibe (ZETIA), a Lipid
Lowering Therapy (LLT) including but not limited to fibrates or fibric acid derivatives,
including but not limited to gemfibrozil (LOPID), fenofibrate (ANTARA, A,
TRICOR, DE) and clofibrate (ATROMID-S); a Resin including but not d to
cholestyramine (QUESTRAN, AN LIGHT, PREVALITE, LOCHOLEST,
LOCHOLEST LIGHT), cholestipol (CHOLESTID) and cholesevelan HCl (WELCHOL)
and/or a combination thereof, including but not limted to VYTORIN (simvastatin +
ezetimibe).
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method comprises a) identifying a subject that has a LDL-C level of less than
70 mg/dL, and b) administering an anti-PCSK9 lizing antibody to the subject, in an
amount sufficient and time sufficient to lower the LDL-C level to less than 60 mg/dL.
In some embodiments, a method of decreasing percent atheroma volume
(PAV) in a subject is provided. The method comprises a) identifying a subject that has
received at least a moderate level of treatment by a statin, and b) stering an anti-
PCSK9 neutralizing antibody to the subject in an amount sufficient and time sufficient to
lower the LDL-C level to less than 100, e.g., less than 90 mg/dL, y decreasing a
percent atheroma volume (PAV) in the subject.
In some embodiments, a method of decreasing total ma volume
(TAV) in a subject is provided. The method comprises a) identifying a subject that has
received at least a moderate level of treatment by a statin, and b) administering an anti-
PCSK9 neutralizing dy to the subject in an amount sufficient and time sufficient to
lower the LDL-C level to less than 100, e.g., less than 90 mg/dL, thereby sing a total
ma volume in the subject.
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method ses a) administering an optimum statin treatment to a subject,
wherein the subject has coronary atherosclerosis, and b) administering an amount of an anti-
PCSK9 neutralizing antibody to the subject at the same time.
In some embodiments, a method of ng ry atherosclerosis is
provided. The method comprises a) identifying a statin-intolerant subject, b) administering at
least a low dose statin treatment to the statin-intolerant subject, and c) administering an
amount of an anti-PCSK9 neutralizing antibody to the subject, thereby treating ry
atherosclerosis.
In some ments, a method of providing regression of coronary
atherosclerosis is provided, the method comprises providing a subject that is on an optimized
level of a statin, and administering to the subject an anti-PCSK9 neutralizing antibody, at a
level adequate to regress coronary atherosclerosis, wherein regression is any change in PAV
or TAV less than zero.
In some embodiments, a method of decreasing a LDL-C level in a subject
beneath 80 mg/dL is provided. The method comprises administering an anti-PCSK9
neutralizing antibody to a subject. The subject has coronary atherosclerotic disease. The
subject is on an optimized statin therapy for at least one year, and a LDL-C level in the
subject decreases to an average value that is h 80 mg/dL for the at least one year.
In some embodiments, a method of reducing a ve risk of a
cardiovascular event by at least 10% is provided. The method ses administering a
PCSK9 neutralizing antibody to a subject that is on at least a moderate intensity of a statin, in
an amount sufficient to lower a LDL-C level of the subject by about 20 mg/dL.
In some ments, a method of reducing an amount of atherosclerotic
plaque in a subject is provided. The method comprises administering to a subject having
WO 89912
atherosclerotic plaque a monoclonal antibody to human PCSK9. The subject is also
receiving optimized statin therapy, and the combination therapy thereby s the amount
of atherosclerotic plaque in the subject.
In some embodiments, a method of reducing disease progression is
provided. The method comprises identifying a subject with a LDL-C level of no more than
60 mg/dL, administering at least a moderate intensity of a statin therapy to the subject, and
administering evolocumab at a level sufficient to decrease the LDL-C level of the subject to
mg/dL, thereby reducing disease progression.
In some embodiments, a method of combining evolocumab and a statin
therapy to produce greater LDL-C lowering and regression of coronary atherosclerosis at a
dose that is well tolerated is provided. The method comprises administering at least a
moderate ity of a statin therapy to a subject, administering an adequate amount of
evolocumab to the subject such that the t’s LDL-C levels drop to no more than 40
mg/dL, and maintaining the t’s LDL-C levels at no more than 40 mg/dL for at least
one year.
In some embodiments, a method of treating ry atherosclerosis is
provided. The method comprises a) fying a subject that has a LDL-C level of less than
70 mg/dL, and b) administering a PCSK9 inhibitor to the subject, in an amount sufficient and
time sufficient to lower the LDL-C level to less than 60 mg/dL.
In some embodiments, a method of decreasing percent atheroma volume
(PAV) in a subject is provided. The method comprises a) identifying a subject that has
received at least a moderate level of treatment by a non-PCSK9 LDL-C lowering agent, and
b) administering a PCSK9 inhibitor to the subject in an amount sufficient and time sufficient
to lower the LDL-C level to less than 100 mg/dL, e.g., less than 90 mg/dL, thereby
decreasing a percent atheroma volume (PAV) in the subject.
In some embodiments, a method of decreasing total atheroma volume
(TAV) in a subject is provided. The method comprises a) identifying a subject that has
received at least a moderate level of treatment by a non-PCSK9 LDL-C lowering agent and
b) stering a PCSK9 inhibitor to the subject in an amount ient and time ient
to lower the LDL-C level to less than 100 mg/dL, e.g., less than 90 mg/dL, thereby
decreasing a total atheroma volume in the subject.
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method comprises a) administering an optimum non-PCSK9 LDL-C lowering
therapy to a subject, wherein the subject has ry atherosclerosis, and b) administering
an amount of a PCSK9 inhibitor to the subject at the same time.
In some embodiments, a method of ng coronary atherosclerosis is
provided. The method comprises a) identifying a -intolerant subject, b) administering a
low intensity statin treatment or no statin treatment to the statin-intolerant subject, and c)
administering an amount of a PCSK9 inhibitor to the subject, thereby treating coronary
sclerosis.
In some embodiments, a method of providing regression of ry
atherosclerosis is provided. The method comprises providing a subject that is on an
optimized level of a non-PCSK9 LDL-C lowering agent and administering to the subject a
PCSK9 inhibitor, at a level adequate to regress coronary atherosclerosis. Regression is any
change in PAV or TAV less than zero.
In some embodiments, a method of decreasing a LDL-C level in a subject
beneath 80 mg/dL is provided. The method comprises administering a PCSK9 inhibitor to a
subject. The subject has ry atherosclerotic disease. The subject is on an optimized
non-PCSK9 LDL-C lowering therapy for at least one year. A LDL-C level in the subject
decreases to an average value that is beneath 80 mg/dL for the at least one year.
In some embodiments, a method of reducing an amount of atherosclerotic
plaque in a subject is provided. The method comprises administering to a subject having
atherosclerotic plaque a PCSK9 inhibitor. The subject is ing optimized non-PCSK9
LDL-C ng y, thereby reducing the amount of atherosclerotic plaque in the
subject.
In some embodiments, a method of reducing e progression is
provided. The method comprises identifying a subject with a LDL-C level of no more than
60 mg/dL, administering at least a te ity of a non-PCSK9 LDL-C lowering
therapy to the subject, and administering a PCSK9 inhibitor at a level sufficient to decrease
the LDL-C level of the subject to 30 mg/dL, thereby reducing disease progression.
In some embodiments, a method of ing a PCSK9 inhibitor therapy
and a non-PCSK9 LDL-C lowering therapy to produce greater LDL-C lowering and
regression of ry atherosclerosis at a dose that is well tolerated is provided. The
method comprises administering at least a moderate ity of a non-PCSK9 LDL-C
lowering therapy to a subject, administering an adequate amount of a PCSK9 inhibitor to the
subject such that the subj ect’s LDL-C levels drop to no more than 40 mg/dL, and ining
the subject’s LDL-C levels at no more than 40 mg/dL for at least one year.
In some ments, a method of treating a subject that is unable to
tolerate a full eutic dose of a non-PCSK9 LDL-C lowering agent is provided. The
method comprises fying said subject and administering a PCSK9 inhibitor to the
subject until a LDL terol level of the subject ses beneath 60 mg/dL.
In some embodiments, a method of treating a subject that is unable to
te a full therapeutic dose of a statin is ed. The method comprises identifying said
subject and administering a PCSK9 inhibitor to the subject until a LDL cholesterol level of
the subject decreases beneath 60 mg/dL.
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method comprises a) fying a subject that has a LDL-C level of less than
70 mg/dL and b) administering a non-PCSK9 LDL-C lowering agent to the subject, in an
amount sufficient and time sufficient to lower the LDL-C level to less than 60 mg/dL.
In some embodiments, a method of treating atherosclerotic cardiovascular
disease is provided. The method comprises a) identifying a subject that is on a first therapy,
wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy, and b)
administering a second therapy to the subject. The second therapy comprises a PCSK9
inhibitor therapy, wherein both the first and second therapies are administered to the subject
in an amount and time sufficient to reduce a risk of atherosclerotic cardiovascular disease in
the subject. The first therapy is not the same as the second therapy. The risk is a) a
composite for cardiovascular death, myocardial tion, stroke, hospitalization for unstable
angina, or coronary revascularization or b) a composite for cardiovascular death, myocardial
infarction, or stroke, or c) cardiovascular death, or d) fatal and/or non-fatal MI, or e) fatal
and/or non-fatal stroke, or f) transient ischemic attack, or g) hospitalization for unstable
angina, or h) elective, urgent, and/or emergent coronary revascularization.
In some embodiments, a method of reducing a risk of a cardiovascular
event is provided. The method comprises a) fying a subject that is on a first therapy,
wherein the first therapy comprises a SK9 LDL-C lowering therapy, and b)
administering a second therapy to the subject. The second y comprises a PCSK9
inhibitor, wherein both the first and second therapies are stered to the subject in an
amount and time sufficient to reduce a risk of a cardiovascular event in the t. The first
therapy is not the same as the second therapy. The risk is a) a composite for cardiovascular
death, myocardial infarction, stroke, alization for unstable , or coronary
revascularization or b) a composite for cardiovascular death, myocardial infarction, or stroke,
or c) cardiovascular death, or d) fatal and/or non-fatal MI, or e) fatal and/or non-fatal stroke,
or f) ent ischemic attack, or g) hospitalization for unstable angina, or h) elective, urgent,
and/or nt coronary revascularization.
In some embodiments, a method of reducing a risk of urgent coronary
revascularization is provided. The method comprises a) identifying a subject that is on a first
therapy, wherein the first therapy comprises a SK9 LDL-C lowering therapy, and b)
administering a second therapy to the subject. The second y comprises a PCSK9
inhibitor therapy. Both the first and second therapies are administered to the subject in an
amount and time sufficient to reduce the risk of atherosclerotic cardiovascular disease in the
subject, and wherein the first therapy is not the same as the second therapy.
In some embodiments, a method of reducing a risk of a cardiovascular
event is provided. The method comprises a) identifying a t with cardiovascular
disease, and b) administering a PCSK9 inhibitor to the subject in an amount and over time
sufficient to reduce a risk of at least one of cardiovascular death, non-fatal dial
infarction, non-fatal stroke or transient ischemic attack (TIA), coronary revascularization, or
hospitalization for unstable angina.
In some embodiments, a method of lowering LDL-C levels in a subject is
provided. The method comprising administering: a) a first therapy to a subject, wherein the
first therapy comprises a SK9 LDL-C lowering therapy, and b) administering a
second y to the subject, wherein the second therapy comprises a PCSK9 inhibitor.
Both the first and second therapies are administered to the subject for at least five years, and
the first therapy is not the same as the second therapy, and wherein the subject’s LDL-C level
is maintained beneath 50 mg/dL.
In some embodiments, a method of reducing a risk of a cardiovascular
event is ed. The method comprises a) identifying a subject that is on a first therapy,
the first therapy comprises a non-PCSK9 LDL-C lowering therapy. The method further
comprises b) administering a second y to the subject. The second therapy comprises a
PCSK9 inhibitor. Both the first and second therapies are administered to the subject in an
amount and time sufficient to reduce a risk of a cardiovascular event in the subject. The first
therapy is not the same as the second y. The risk is at least one of cardiovascular
death, myocardial infarction, stroke, alization for unstable angina, or ry
revascularization.
In some embodiments, a method of treating a subject is provided. The
method ses fying a subject with peripheral artery disease (“PAD”) and reducing
a level of PCSK9 activity in the subject.
In some embodiments, a method of reducing a risk of an e limb
event in a subject is provided, the method comprises reducing a level of PCSK9 activity in a
subject, wherein the subject has PAD.
In some embodiments, a method of reducing a risk of a major
cardiovascular adverse event (“MACE”) is provided. The method comprises stering a
non-statin LDL-C lowering agent to a subject and administering a statin to the subject. The
subject has PAD. In some embodiments, a method of reducing a risk of PAD and/or CAD
and/or cerebrovascular disease is provided. The method comprises administering a non-
statin LDL-C lowering agent to a t and administering a statin to the subject.
In some ments, a method of reducing a risk of a major adverse
limb event (“MALE”) is provided. The method comprises administering a atin LDL-C
lowering agent to a subject and administering a statin to the subject. The subject has PAD.
In some embodiments, a method of reducing a risk of a cardiovascular
event is provided. The method comprises providing a first therapy to a subject. The first
therapy comprises a non-PCSK9 LDL-C lowering therapy. The method further comprises
providing a second therapy to the subject. The second therapy comprises a PCSK9 inhibitor.
The first and second therapies are administered to the subject, and wherein the subject has a
Lp(a) level of 11.8 mg/dL to 50.
In some embodiments, a method of reducing a risk of a major vascular
event in a subject is provided. The method comprises 1) identifying a subject that has at least
one of: (a) a recent MI, (b) multiple prior MS, or (c) multivessel disease. The method further
comprises 2) providing a first therapy to a subject, wherein the first therapy comprises a non-
PCSK9 LDL-C lowering therapy. The method further comprises 3) providing a second
therapy to the subject, wherein the second therapy comprises a PCSK9 inhibitor, y
reducing a risk that the subject will have a major vascular event.
In some embodiments, a method of treating coronary atherosclerosis is provided that
comprises administering, to a subject who has a LDL-C level of greater than 70 mg/dL a
PCSK9 inhibitor in an amount sufficient and over a time period sufficient to lower the LDL-
C level to less than 40 mg/dL. In some ments, a method of reducing a risk of a
cardiovascular event is ed that comprises administering, to a subject who has a LDL-C
level of greater than 70 mg/dL, a PCSK9 inhibitor in an amount sufficient and over a time
period sufficient to lower the LDL-C level to less than 40 mg/dL.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the disposition of the patients during the GLAGOV
study.
Figure 2 depicts the mean (::standard error) percent change in LDL-C in
patients treated with placebo es) and evolocumab (triangles) during the study.
Figure 3 s the prespecified subgroup analysis of the primary end
point, the change in percent atheroma volume (PAV) from baseline to 78-week follow-up.
Results are eXpressed as least square meanistandard error LDL-C, nsity lipoprotein
cholesterol, non-HDL-C, non-high-density lipoprotein terol, PCSK9, proprotein
convertase subtilisin keXin type 9; TAV, total atheroma volume.
Figure 4A depicts the change in percent atheroma volume (PAV, left
panel) and percentage of patients demonstrating regression of PAV (right panel) in the
placebo ) and umab (black) treatment groups, fied according to baseline
LDL-C.
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Figure 4B depicts the change in total atheroma volume (TAV, left panel)
and percentage of patients demonstrating regression of TAV (right panel) in the placebo
(white) and evolocumab (black) treatment , stratified according to baseline LDL-C.
Figure 4C s the data from an exploratory subgroup of subjects
having a ne LDL-C <70 mg/dL.
Figure 4D depicts the data from an exploratory subgroup have a baseline
LDL-C of <70 mg/dL,
Figure 5 depicts the local regression (LOESS) curve illustrating the
association (with 95% ence intervals) between achieved LDL-C levels and the change
in percent atheroma volume in all patients oing serial IVUS evaluation.
Figure 6 depicts some sequence aspects of some embodiments of PCSK9
inhibitors. The highlighted regions denote the variable regions.
Figure 7 depicts some sequence aspects of some ments of PCSK9
inhibitors. The highlighted regions denote the variable regions.
Figure 8 depicts some sequence s of some embodiments of PCSK9
inhibitors (Figure 8 is related to Figure 10).
Figure 9 depicts some sequence aspects of some embodiments of PCSK9
inhibitors (Figure 9 is d to Figure 11).
Figure 10 depicts some sequence aspects of some embodiments of PCSK9
inhibitors (Figure 10 is related to Figure 8).
Figure 11 depicts some sequence aspects of some embodiments of PCSK9
inhibitors (Figure 11 is related to Figure 9).
Figure 12 depicts some sequence s of some embodiments of PCSK9
inhibitors.
Figure 13 depicts some constant domain sequence aspects of some
embodiments of PCSK9 inhibitors.
Figure 14A depicts an amino acid sequence of the mature form of PCSK9
with the pro-domain ined.
Figures 14B1-14B4 depict the amino acid and nucleic acid sequences of
PCSK9 with the pro-domain underlined and the signal sequence in bold.
Figure 15 is a graph depicting LDL cholesterol levels over time.
Figures 16A and 16B are graphs depicting the cumulative incidence of
cardiovascular events. Shown are the cumulative event rates for the primary end point (the
ite of cardiovascular death, myocardial tion, stroke, hospitalization for unstable
angina, or coronary revascularization; A) and the key secondary efficacy end point
(the composite of cardiovascular death, myocardial infarction, or , B).
Figure 17 is a trial consort diagram for FOURIER.
Figure 18 is a graph depicting LDL cholesterol values over time. Data are
in fixed cohort of 11077 patients who had all measurements through 120 weeks, did not
discontinue study drug, and did not change concomitant background lipid lowering therapy.
Shown are median values with 95% confidence intervals in the two arms. To convert the
values for cholesterol to oles per liter, multiply by 0.02586.
Figure 19 is a series of graphs displaying s lipid parameters.
Displayed are mean changes at 48 weeks except for triglycerides and Lp(a), which are
median changes. Errors bars denote 95% C1.
Figure 20 is two graphs showing the landmark analyses for the primary
endpoint.
Figure 21 depicts two graphs showing the landmark analyses for the
secondary endpoint.
Figure 22 s the efficacy in various subgroups.
Figure 23 depicts the hazard ratio ) per 1 mmol/L reduction in
LDL-C.
a is a graph ing the primary composite endpoint
(cardiovascular death, myocardial infarction, stroke, unstable angina, coronary
revascularization) by treatment (evolocumab in dark, placebo in r) in patients with
(solid lines) and without (dashed lines) symptomatic PAD.
b is a graph depicting the key secondary composite nt
(cardiovascular death, myocardial infarction, stroke) by treatment (evolocumab in dark,
placebo in lighter) in patients with and without symptomatic PAD.
a is a graph depicting the major adverse limb events (composite of
acute limb ischemia, major amputation or urgent revascularization) by treatment
(evolocumab in dark, placebo in lighter) in all randomized patients.
b is a graph depicting the major adverse limb events (composite of
acute limb ischemia; major amputation or urgent revascularization) by treatment
cumab in dark; placebo in lighter) in patients with symptomatic PAD.
is a graph depicting the composite of major adverse
cardiovascular events (MACE; cardiovascular death, myocardial infarction or ) and
major adverse limb events (MALE; acute limb ischemia; major amputation or urgent
revascularization) by ent (evolocumab in dark; placebo in lighter) in patients with and
without symptomatic PAD.
is a graph depicting the relationship between achieved LDL-C
and major adverse limb events (MALE; acute limb ischemia; major amputation or urgent
revascularization).
are graphs ying cardiovascular outcomes at 2.5 years in
placebo patients by symptomatic PAD at baseline.
is a graph depicting CV death; MI; or stroke at 2.5 years in a
o patient by disease state.
is a graph depicting cardiovascular outcomes at 2.5 years in
placebo patients by symptomatic PAD and no MI/stroke at baseline.
is a graph depicting limb outcomes at 2.5 years in placebo
patients by symptomatic PAD and no MI or stroke at baseline.
is a graph depicting LDL cholesterol by ent group in
patients with symptomatic lower extremity PAD.
A is a graph depicting the primary endpoint in patients with PAD
hdloronke
B is a graph depicting CV death; MI; or stroke in patients with
PAD and no MI or stroke.
C is a graph depicting major adverse limb events in patients with
PAD and no MI or stroke.
is a graph depicting MACE or MALE in patients with PAD and
no MI or stroke.
is a graph ing achieved LDL-C and MACE or MALE in
patients with PAD.
is a graph depicting achieved LDL-C and MACE or MALE in
patients with PAD and no MI or stroke.
depicts a GLAGOV trial schematic.
depicts a cross-sectional lumen and formula for ining
percent atheroma volume.
depicts graph showing plaque progression and percent atheroma
volume as a function of the number of risk factors present.
depicts a FOURIER trial .
depicts graphs depicting the primary results for the FOURIER
trial for placebo vs mab.
is a graph depicting the risk of CVD, MI or stroke based on time
fronihdl
is a graph depicting the risk of CVD, MI, or stroke based on the
number of prior MIs.
is a graph depicting the risk of CVD, MI, or stroke based on the
ce of multivessel disease.
are graphs depicting the risk of CVD, MI, or stroke based on time
from prior MI.
are graphs depicting the risk of CVD, MI, or stroke based on time
from prior MI and number of prior MIs.
are graphs depicting the risk of CVD, MI, or stroke based on time
from prior MI and presence of multivessel disease.
is a graph depicting the benefit of evolocumab therapy in subjects
with no risk features.
is a graph depicting the benefit of evolocumab y in subjects
with 1 or more risk feature.
is a graph depicting the benefit of evolocumab therapy (for CVD,
MI or ) in subjects with high-risk MI features.
is a graph depicting the benefit of evolocumab therapy (for CVD,
MI or ) in subjects with high-risk MI features.
is a graph depicting the three year KM rate of CV death, MI or
stroke for low, intermediate, or high TIMI risk score.
is a set of graphs depicting the total primary endpoints prevented
(a) and the primary endpoint events using Wei, Lin Weissfeld model.
FIGs. 54A and 54B are set of graphs depicting the types 54A and sizes
54B of MI reduced with evolocumab in FOURIER.
is a graph depicting the adjusted event rate by average
postbaseline non-HDL-C up to time-to-event endpoint.
DETAILED DESCRIPTION OF THE PREFERRED ElVHBODIMENT
Statins can be used for managing patients with clinically manifest
coronary heart disease23’24. However, many ts are not able to achieve optimal LDL-C
ng25 or experience cardiovascular events despite statin y.26 Furthermore, some
ts report inability to tolerate full therapeutic doses of statins.27 uate LDL-C
reduction and high residual risk suggests that additional therapies are required to deliver
more effective cardiovascular tion. Elucidating the role of PCSK9 in regulation of
hepatic LDL receptor expression has provided an attractive target for therapeutic modulation.
The fact that PCSK9 levels rise in response to statin administration further supports the
eutic potential of PCSK9 inhibitors to reduce residual cardiovascular risk in -
treated patients.28
Provided herein are results from a clinical trial (reported in Example 1), in
which patients d with a non-PCSK9 LDL-C lowering agent (e.g., a statin) and a PCSK9
inhibitor (e.g., evolocumab)(or in a some cases, a PCSK9 tor alone), ed benefits
on LDL-C, atheroma volume and atheroma regression that was onal to the benefit from
statin treatment alone.
The presently disclosed trial results (Example 1) provided an opportunity
to evaluate the impact of a PCSK9 inhibitor in a number of settings. By studying the effect
of a PCSK9 inhibitor on atheroma volume, it provided the first evaluation of PCSK9
inhibition on an efficacy endpoint beyond LDL-C (and/or other lipids, such as ApoB, Lp(a),
etc.), providing evidence that LDL-C lowering (and/or other lipids) affects e activity
within the vessel wall. Interestingly, the benefits were observed at a LDL-C level well below
that typically encountered in studies of te or high-intensity statin monotherapy and
represents the first evidence of efficacy in patients who were predominantly treated with
either moderate or high-intensity statin therapy.
In light of the presently disclosed study, provided herein are one or more
“combined therapies” for the treatment of atherosclerosis (including, e.g., ry artery
disease (CAD)). The “combined therapies” or “combination therapies” combine at least two
different therapies so as to achieve a very low LDL-C level such that the subject receiving
both therapies will have a reduced risk of atherosclerosis (e.g., CAD and/or PAD and/or
cerebrovascular disease). As ed in more detail below, while, individually, each of the
two types of therapy to be combined has been known before, their combination, to e
the very low level of LDL-C lowering benefit, which in turn provides for the treatment of
atherosclerosis, has not been demonstrated previously. While there are a variety of le
combinations of therapies for the “combined therapy” approach provided herein, the term
denotes a first therapy that can be any non-PCSK9 directed therapy (e.g., a statin) that lowers
LDL-C levels, and a second therapy that can be a PCSK9 specific ent (a PCSK9
inhibitor, for example, a neutralizing antibody to PCSK9 and/or antisense RNA to .
Not only are these two therapies to be combined, but in some embodiments, the level of the
therapies are set such that LDL-C levels can be decreased well below other typical goals
attempted for cholesterol lowering therapies (to e a very low level of LDL-C), and
maintained for a duration adequate for addressing atherosclerosis, including coronary artery
disease. Furthermore, as detailed herein, given the value of such low levels of LDL-C in a
subject, other, mbined therapies are also provided herein. Such single ies do not
need to employ a second agent to lower LDL-C levels to the extremely low and highly
beneficial levels (such as less than 50, 40, 30, or 20 mg/dL of LDL-C), and can employ a
single agent, such as a PCSK9 neutralizing antibody, such as evolocumab. Such a statin-free
therapy can be especially useful in situations where the subject is intolerant to statins. In
other embodiments, the subject is not rant to statins, but a single therapy is used
regardless.
Interestingly, the gs presented herein contradict the results and
assumptions made in previous studies, such as ID, from which it was hypothesized
that lowering LDL-C below 60.8 mg/dL may not have any regression benefit. In st to
the findings from ASTEROID, the results ted herein show that regression does not
plateau at 60 mg/dL. Instead, the results in Example 1 show that one can obtain surprisingly
beneficial regression of atherosclerosis by lowering LDL-C lower than 60 mg/dL. Indeed,
the results demonstrate a benefit from achieving LDL-C levels beneath 60 mg/dL, down to
levels as low as 25 mg/dL and 20 mg/dL.
In addition, the t disclosure also provides the results and discoveries
of the FOURIER study (e.g., Example 17). These finding trate the effectiveness of
combined therapies (such as evolocumab on cardiovascular outcomes when combined with a
non-PCSK9 therapy (such as a statin)) in subjects with atherosclerotic cardiovascular disease.
The following section provides a brief set of definitions for the present
disclosure, followed by a detailed description of s particular embodiments and s,
followed by a set of examples.
tions and Embodiments
It is to be understood that both the ing general description and the
following detailed description are exemplary and explanatory only and are not restrictive of
the invention as claimed. In this application, the use of the singular includes the plural unless
specifically stated otherwise. In this application, the use of “or” means “and/or” unless stated
otherwise. Furthermore, the use of the term “including”, as well as other forms, such as
“includes” and “included”, is not limiting. Also, terms such as “element” or nent”
encompass both ts and ents comprising one unit and elements and
components that comprise more than one subunit unless specifically stated otherwise. Also,
the use of the term “portion” can include part of a moiety or the entire moiety.
The section headings used herein are for organizational purposes only and
are not to be construed as limiting the subject matter described. All documents, or portions
of documents, cited in this application, including but not limited to patents, patent
applications, articles, books, and treatises, are hereby expressly incorporated by reference in
their entirety for any e. As utilized in ance with the present disclosure, the
ing terms, unless otherwise indicated, shall be understood to have the following
meanings:
“Combined therapies,” or “combination therapies,” as the terms are used
herein, are meant to denote a first therapy that can be any SK9 LDL-C ng
therapy that lowers LDL-C levels (using for example, a statin), and a second therapy that can
be a PCSK9 inhibitor therapy (using, for example, a neutralizing antibody to PCSK9 and/or
nse RNA to PCSK9). The combined therapy will employ a non-PCSK9 LDL-C
lowering agent and a PCSK9 inhibitor agent. The combined therapies can also have their
benefit from lowering other non-LDL terol particles as well. Such ments can
also be itly called out as “non-PCSK9 lipid lowering therapies”.
The term “regression” or “reversal” denotes that one or more of the
symptoms and/or aspects of the disorder has been reversed. “Regression” can be defined as
any se in PAV or TAV from baseline.
The term “very low LDL-C ” s LDL-C levels beneath 40
mg/dL. In some embodiments, very low encompasses 25 mg/dL or lower.
“PCSK9 inhibitor” denotes a molecule or therapy that inhibits PCSK9
activity to y lower LDL-C (and/or other lipids, such as non-HDL-C, ApoB, Lp(a), etc.)
levels. This can include neutralizing antibodies to PCSK9 and anti-sense molecules to
PCSK9, for example. A PCSK9 tor therapy denotes a method that uses a PCSK9
inhibitor agent.
“A non-PCSK9 LDL—C lowering agent” denotes a molecule that lowers
LDL-C levels through a y other than through PCSK9. A non-PCSK9 LDL-C
lowering therapy denotes a method that employs a non-PCSK9 LDL-C lowering agent.
Examples of non-PCSK9 LDL-C lowering agents include statins (aka HMG CoA reductase
inhibitors), atorvastatin (LIPITOR®), cerivastatin, fluvastatin (LESCOL), lovastatin
(MEVACOR, ALTOPREV), mevastatin, pitavastatin, pravastatin (PRAVACHOL),
rosuvastatin, rosuvastatin calcium (CRESTOR) and simvastatin (ZOCOR), ADVICOR
(lovastatin + niacin), CADUET astatin + amlopidine); selective cholesterol absorption
inhibitors, ezetimibe (ZETIA), a Lipid Lowering Therapy (LLT) fibrates or fibric acid
derivatives, ing gemfibrozil (LOPID), fenofibrate (ANTARA, LOFIBRA, ,
TRIGLIDE) and clofibrate (ATROMID-S); a Resin (aka bile acid sequestrant or bile acid-
binding drugs), cholestyramine (QUESTRAN, QUESTRAN LIGHT, PREVALITE,
LOCHOLEST, LOCHOLEST LIGHT), cholestipol (CHOLESTID) and cholesevelan HCl
(WELCHOL) and/or a combination thereof, including but not limted to VYTORIN
(simvastatin + ezetimibe). The term “non-PCSK9 LDL-C ng agent” encompasses
agents that do more than just reduce LDL-C. In some embodiments, the methods involving
“non-PCSK9 LDL-C lowering agents” provided herein can instead be practiced with a “non-
PCSK9 lipid lowering agent”, which is an agent that lowers the lipid in a subject, without
specifically lowering LDL-C.
The term “proprotein convertase subtilisin keXin type 9” or “PCSK9”
refers to a polypeptide as set forth in SEQ ID NO: 1 and/or 3 in Figures 14A, 14B1-B4.
“PCSK9” has also been referred to as FH3, NARCl, HCHOLA3, proprotein convertase
subtilisin/keXin type 9, and neural sis regulated convertase l. The PCSK9 gene
encodes a proprotein convertase protein that belongs to the proteinase K subfamily of the
secretory subtilase family. The term “PCSK9” denotes both the proprotein and the product
generated following autocatalysis of the proprotein. When only the autocatalyzed product is
being referred to (such as for an antibody that selectively binds to the cleaved PCSK9), the
protein can be referred to as the e,3) (4 cleaved”, ssed” or e” PCSK9. When
only the inactive form is being referred to, the protein can be ed to as the “inactive”,
“pro-form”, or “unprocessed” form of PCSK9.
The term “PCSK9 activity” includes the ability of PCSK9 to reduce the
availability of LDLR and/or the ability of PCSK9 to increase the amount of LDL in a subject.
The term “isolated protein” means that a subject protein (1) is free of at
least some other proteins with which it would normally be found, (2) is essentially free of
other proteins from the same source, e. g., from the same species, (3) is eXpressed by a cell
from a different species, (4) has been ted from at least about 50 percent of
polynucleotides, lipids, carbohydrates, or other materials with which it is associated in
nature, (5) is operably associated (by nt or noncovalent interaction) with a polypeptide
with which it is not associated in , or (6) does not occur in nature. lly, an
“isolated protein” constitutes at least about 5%, at least about 10%, at least about 25%, or at
least about 50% of a given sample. Genomic DNA, cDNA, mRNA or other RNA, of
synthetic origin, or any combination thereof can encode such an isolated protein. Preferably,
the isolated protein is substantially free from ns or polypeptides or other contaminants
that are found in its natural environment that would ere with its therapeutic, diagnostic,
prophylactic, research or other use.
An antibody is said to “specifically bind” its target antigen when the
dissociation constant (K1) is 510'7 M. The antibody specifically binds antigen with “high
affinity” when the Kd is :5 x 10'9 M, and with “very high affinity” when the Kd is 55x 10'10
M. In one embodiment, the antibody has a Kd of £1 0'9 M. In one embodiment, the off-rate is
<1 x 105. In other ments, the antibodies will bind to human PCSK9 with a Kd of
n about 10'9 M and 10'13 M, and in yet another ment the antibodies will bind
with a Kd £5 x 10'“). As will be appreciated by one of skill in the art, in some embodiments,
any or all of the antibodies can specifically bind to PCSK9.
An antibody is “selective” when it binds to one target more tightly than it
binds to a second target.
The term “antibody” refers to an intact immunoglobulin of any isotype,
and includes, for instance, chimeric, humanized, human, and bispecific dies. An intact
antibody will generally comprise at least two full-length heavy chains and two full-length
light chains. Antibody sequences can be derived solely from a single species, or can be
“chimeric,” that is, different portions of the antibody can be d from two different
s as described further below. Unless ise indicated, the term “antibody” also
includes antibodies comprising two substantially full-length heavy chains and two
substantially full-length light chains provided the antibodies retain the same or similar
binding and/or function as the antibody comprised of two full length light and heavy chains.
For example, antibodies having 1, 2, 3, 4, or 5 amino acid residue substitutions, insertions or
deletions at the N—terminus and/or C-terminus of the heavy and/ or light chains are included
in the definition provided that the dies retain the same or similar binding and/or
function as the antibodies comprising two full length heavy chains and two full length light
chains. Furthermore, unless explicitly ed, antibodies include, for example,
monoclonal dies, onal antibodies, chimeric antibodies, humanized dies,
human antibodies, bispecific antibodies, and synthetic antibodies. In some sections of the
present disclosure, examples of antibodies are described herein in terms of the hybridoma
line number as “number/letter/number” (e.g., 21B12). In these cases, the exact name
denotes a specific monoclonal antibody derived from a specific hybridoma having a specific
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light chain variable region and heavy chain variable region. In some embodiments, the
antibody can include one or more of the ces in 13.
Typical antibody structural units se a tetramer. Each such tetramer
typically is composed of two identical pairs of polypeptide chains, each pair having one fulllength
“light” (in certain ments, about 25 kDa) and one full-length “heavy” chain (in
certain embodiments, about 50-70 kDa). The amino-terminal portion of each chain typically
includes a variable region of about 100 to 110 or more amino acids that typically is
sible for antigen recognition. The carboxy-terminal portion of each chain typically
defines a constant region that can be responsible for effector function. Light chains are
typically classified as kappa and lambda light chains. Heavy chains are typically fied
as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG,
IgA, and IgE, respectively. IgG has several subclasses, ing, but not limited to, IgGl,
IgG2, IgG3, and IgG4. IgM has sses including, but not limited to, Ing and IgM2.
IgA is similarly subdivided into subclasses including, but not limited to, IgAl and IgA2.
Within full-length light and heavy chains, typically, the variable and constant regions are
joined by a “I” region of about 12 or more amino acids, with the heavy chain also including a
“D” region of about 10 more amino acids. See, e.g., Fundamental Immunology, Ch. 7 (Paul,
W., ed., 2nd ed. Raven Press, NY. (1989)) (incorporated by reference in its entirety for all
purposes). The variable regions of each light/heavy chain pair typically form the antigen
binding site.
The variable regions typically eXhibit the same general structure of
relatively conserved ork regions (FR) joined by three hyper variable regions, also
called complementarity determining regions or CDRs. The CDRs from the two chains of
each pair typically are aligned by the framework regions, which can enable binding to a
specific epitope. From N—terminal to C-terminal, both light and heavy chain le regions
typically comprise the s FRl, CDRl, FR2, CDR2, FR3, CDR3 and FR4. The
ment of amino acids to each domain is typically in accordance with the definitions of
Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health,
Bethesda, Md. (1987 and 1991)), or Chothia & Lesk, J. Mol. Biol, 196:901-917 (1987),
Chothia et al., Nature, 342:878-883 (1989).
In some ments, instead of a full length antibody, a “fragment” or
“antigen binding fragment” of an antibody is provided. As used herein and unless otherwise
specified, an “antibody fragment” refers to the Fab, Fab’, 2, and Fv fragments that
contain at least one CDR of an immunoglobulin that is sufficient to confer specific antigen
binding to the target protein, such as PCSK9. Antibody fragments may be ed by
recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies.
In some embodiments, an dy heavy chain binds to an n in the
absence of an antibody light chain. In certain embodiments, an antibody light chain binds to
an antigen in the absence of an antibody heavy chain. In certain ments, an antibody
binding region binds to an antigen in the absence of an antibody light chain. In certain
embodiments, an antibody g region binds to an n in the absence of an antibody
heavy chain. In certain embodiments, an individual variable region specifically binds to an
antigen in the absence of other variable s.
In certain embodiments, definitive delineation of a CDR and identification
of residues comprising the binding site of an antibody is accomplished by solving the
structure of the antibody and/or solving the structure of the antibody-ligand compleX. In
certain embodiments, that can be accomplished by any of a variety of techniques known to
those skilled in the art, such as X-ray crystallography. In certain embodiments, various
methods of analysis can be employed to identify or approximate the CDR regions. Examples
of such methods include, but are not limited to, the Kabat definition, the Chothia definition,
the AbM definition, the AHo definition, and the contact definition.
The Kabat definition is a rd for numbering the residues in an
antibody and is typically used to identify CDR regions. See, e. g., Johnson & Wu, Nucleic
Acids Res, 28: 214-8 (2000). The a definition is similar to the Kabat definition, but
the Chothia tion takes into account ons of n structural loop regions. See,
e.g., Chothia et al., J. Mol. Biol, 196: 901-17 (1986), Chothia et al., , 342: 877-83
(1989). The AbM definition uses an integrated suite of computer programs produced by
OXford Molecular Group that model antibody structure. See, e. g., Martin et al., Proc Natl
Acad Sci (USA), 86:9268-9272 (1989), “AbMTM, A Computer Program for Modeling
Variable Regions of Antibodies,” OXford, UK; OXford Molecular, Ltd. The AbM definition
models the tertiary structure of an antibody from primary sequence using a combination of
knowledge ses and ab initio methods, such as those described by ala et al., “Ab
Initio n Structure Prediction Using a Combined Hierarchical Approach,” in
PROTEINS, Structure, Function and Genetics Suppl, 3:194-198 (1999). The AHo definition
is a residue numbering scheme based on spatial alignment of known three-dimensional
structures of immunoglobulin domains (See, e. g., Honegger and Plueckthun, J. Mol. Biol,
309:657-670 (2001). The contact definition is based on an analysis of the available
compleX crystal structures. See, e.g., MacCallum et al., J. Mol. Biol., 5:732-45 (1996).
By convention, the CDR regions in the heavy chain are typically referred
to as H1, H2, and H3 and are numbered sequentially in the direction from the amino us
to the carboxy us. The CDR regions in the light chain are typically referred to as L1,
L2, and L3 and are numbered sequentially in the direction from the amino terminus to the
carboxy terminus.
The term “light chain” includes a full-length light chain and nts
thereof having sufficient le region sequence to confer binding icity. A full-
length light chain includes a variable region domain, VL, and a constant region domain, CL.
The variable region domain of the light chain is at the amino-terminus of the polypeptide.
Light chains include kappa chains and lambda chains.
The term “heavy chain” includes a full-length heavy chain and fragments
thereof having sufficient variable region sequence to confer binding specificity. A full-
length heavy chain es a variable region domain, VH, and three constant region
domains, CH1, CH2, and CH3. The VH domain is at the amino-terminus of the polypeptide,
and the CH domains are at the carboxyl-terminus, with the CH3 being closest to the carboxy-
terminus of the polypeptide. Heavy chains can be of any isotype, ing IgG (including
IgG1, IgG2, IgG3 and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM and
A bispecific or bifunctional antibody typically is an artificial hybrid
antibody having two different heavy/light chain pairs and two different binding sites.
ific antibodies can be ed by a variety of methods including, but not limited to,
fusion of hybridomas or linking of Fab' fragments. See, e. g., Songsivilai et al., Clin. Exp.
Immunol., 79: 315-321 (1990), Kostelny et al., J. Immunol., 148:1547-1553 (1992).
Some species of mammals also produce antibodies having only a single
heavy chain.
Each individual immunoglobulin chain is lly composed of several
“immunoglobulin domains,” each consisting of roughly 90 to 110 amino acids and having a
teristic folding pattern. These domains are the basic units of which antibody
polypeptides are composed. In humans, the IgA and IgD isotypes contain four heavy chains
and four light chains; the IgG and IgE isotypes contain two heavy chains and two light
chains; and the IgM isotype contains five heavy chains and five light chains. The heavy
chain C region typically comprises one or more s that can be responsible for or
function. The number of heavy chain constant region domains will depend on the isotype.
IgG heavy chains, for example, contain three C region domains known as CH1, CH2 and CH3.
The antibodies that are provided can have any of these isotypes and subtypes. In n
embodiments of the present invention, an CSK9 antibody is of the IgGl or IgG2 or
IgG4 subtype.
The term “variable region” or “variable domain” refers to a portion of the
light and/or heavy chains of an antibody, typically including approximately the amino-
terminal 120 to 130 amino acids in the heavy chain and about 100 to 110 amino terminal
amino acids in the light chain. In certain embodiments, variable regions of different
antibodies differ extensively in amino acid sequence even among antibodies of the same
species. The le region of an antibody typically determines specificity of a particular
antibody for its target
The term “neutralizing antibody” as used in “anti-PCSK9 neutralizing
antibody” refers to an antibody that binds to a target and prevents or reduces the biological
activity of that target. This can be done, for example, by ly blocking a binding site on
the target or by binding to the target and altering the target’s ability to bind through indirect
means (such as structural or energetic alterations in the target). In assessing the binding
and/or specificity of an antibody or immunologically functional fragment thereof, an
antibody or nt can substantially inhibit binding of a target to its g partner when
an excess of antibody reduces the quantity of binding partner bound to the ligand by at least
about 1-20, 20-30%,30-40%, , , 60-70%, 70-80%, , 85-90%, 90-
95%, 95-97%, 97-98%, 98-99% or more (as measured in an in vitro competitive binding
. In the case of PCSK9 antibodies, such a neutralizing molecule can sh the
y of PCSK9 to bind the LDLR. In some embodiments, the neutralizing ability is
terized and/or described via a competition assay. In some embodiments, the
neutralizing ability is described in terms of an IC50 or EC50 value. In some embodiments, the
antibodies lize by binding to PCSK9 and preventing PCSK9 from binding to LDLR (or
reducing the ability of PCSK9 to bind to LDLR). In some embodiments, the antibodies
neutralize by binding to PCSK9, and while still ng PCSK9 to bind to LDLR,
preventing or reducing the PCSK9 mediated degradation of LDLR. Thus, in some
embodiments, a neutralizing antibody can still permit PCSK9/LDLR binding, but will
prevent (or reduce) subsequent PCSK9 involved degradation of LDLR. In some
embodiments, neutralizing results in the lowering LDL-C (and/or other lipids, such as non-
HDL-C, ApoB, Lp(a), etc.).
An “antigen g protein” is a protein comprising an antigen binding
fragment that binds to an antigen and, optionally, a ld or framework portion that allows
the antigen binding fragment to adopt a conformation that promotes g of the antigen
binding protein to the antigen. In some embodiments, the antigen is a PCSK9 n or a
fragment thereof. In some ments, the antigen binding fragment comprises at least one
CDR from an dy that binds to the antigen, and in some embodiments comprises the
heavy chain CDR3 from an antibody that binds to the antigen. In some embodiments, the
antigen binding fragment comprises all three CDRs from the heavy chain of an antibody that
binds to the antigen or from the light chain of an antibody that binds to the antigen. In still
some embodiments, the antigen binding fragment comprises all six CDRs from an antibody
that binds to the antigen (three from the heavy chain and three from the light chain). The
antigen binding fragment in certain embodiments is an antibody fragment.
The term “compete” when used in the context of antibodies that e
for the same epitope means competition between antibodies as determined by an assay in
which the antibodies being tested prevents or inhibits (e.g., reduces) specific binding of a
reference antibody (e.g., a ligand, or a reference antibody) to a common antigen (e.g., PCSK9
or a fragment thereof). Numerous types of competitive binding assays can be used to
determine if one antibody es with another, for example: solid phase direct or indirect
radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA),
sandwich competition assay (see, e. g., Stahli et al., 1983, Methods in Enzymology 9:242-
253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. l.
mz3614-3619) solid phase direct labeled assay, solid phase direct labeled sandwich assay
(see, e. g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor
Press); solid phase direct label RIA using I-125 label (see, e. g., Morel et al., 1988, Molec.
Immunol. @745), solid phase direct biotin-avidin EIA (see, e.g., Cheung, et al., 1990,
Virology @546-552), and direct labeled RIA (Moldenhauer et al., 1990, Scand. J.
l. flz77-82). Typically, such an assay involves the use of purified antigen bound to a
solid surface or cells bearing either of these, an unlabelled test antibody and a labeled
reference antibody. Competitive inhibition is measured by determining the amount of label
bound to the solid surface or cells in the presence of the test antibody. Usually the test
antibody is present in excess. Antibodies identified by competition assay include antibodies
binding to the same epitope as the reference antibody and antibodies binding to an adjacent
epitope sufficiently proXimal to the epitope bound by the reference antibody for steric
hindrance to occur. Additional details ing methods for determining itive
binding are provided in the examples herein. Usually, when a competing antibody is present
in excess, it will inhibit (e. g., reduce) specific binding of a reference antibody to a common
antigen by at least , 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75% or 75% or
more. In some instances, g is inhibited by at least , 85-90%, 90-95%, 95-97%,
or 97% or more.
As used , “substantially pure” means that the described s of
molecule is the predominant species present, that is, on a molar basis it is more abundant than
any other individual species in the same e. In certain embodiments, a substantially
pure le is a composition n the object species comprises at least 50% (on a
molar basis) of all macromolecular species present. In other embodiments, a substantially
pure composition will comprise at least 80%, 85%, 90%, 95%, or 99% of all macromolecular
species present in the composition. In other embodiments, the object species is ed to
essential homogeneity n contaminating species cannot be detected in the composition
by conventional detection s and thus the composition consists of a single detectable
macromolecular species.
The term “biological sample”, as used herein, includes, but is not limited
to, any quantity of a substance from a living thing or formerly living thing. Such living
things e, but are not limited to, humans, mice, monkeys, rats, rabbits, and other
animals. Such substances include, but are not limited to, blood, serum, urine, cells, organs,
tissues, bone, bone marrow, lymph nodes, and skin.
The term “pharmaceutical agent composition” (or agent or drug) as used
herein refers to a chemical compound, composition, agent or drug capable of inducing a
desired therapeutic effect when ly stered to a patient. It does not necessarily
require more than one type of ingredient.
The term “therapeutically effective amount” refers to the amount of a
therapeutic substance or therapeutic substances (e.g., PCSK9 inhibitor, a non-PCSK9 LDL-C
lowering agent (such as a statin or other non-PCSK9 LDL-C lowering therapy), and a
PCSK9 inhibitor and a non-PCSK9 LDL-C lowering agent). This will be an amount
ient to produce a eutic se in a mammal. Such therapeutically effective
amounts are readily ascertained by one of ordinary skill in the art.
The terms “patient” and “subject” are used interchangeably and include
human and non-human animal subjects as well as those with formally sed disorders,
those without formally recognized disorders, those receiving medical attention, those at risk
of developing the disorders, etc.
The term “treat” and “treatment” includes therapeutic treatments,
lactic ents, and applications in which one reduces the risk that a subject will
develop a disorder or other risk factor. ent does not require the complete curing of a
disorder and encompasses ments in which one reduces symptoms or underlying risk
factors. Treatment encompasses regression.
The term “prevent” does not require the 100% elimination of the
ility of an event. Rather, it denotes that the likelihood of the occurrence of the event
has been reduced in the presence of the compound or method.
The phrase “percent atheroma volume (PAV),” can be calculated as
follows:
2(EEA/Ima — Lumenarea)
PAV = X100
ZEEMarea
EEMareal is the cross-sectional area of the external elastic membrane and
Lumenareal is the cross-sectional area of the lumen. A change in PAV can be ated as the
PAV at any ular time minus the PAV at baseline.
Normalized “total atheroma volume” (TAV), can be calculated as follows:
TA V —
— 2KEEA/I#LWMW)XMedian number ofimages in cohort
Normallzed
Number OfImages m Pullback
The average plaque area in each image was multiplied by the median
number of images analyzed in the entire cohort to compensate for differences in segment
length between subjects. Change in normalized TAV can be calculated as the TAV at any
particular time minus the TAV at baseline.
The term “moderate-intensity” non-PCSK9 LDL-C lowering therapy
(such as a statin or other non-PCSK9 LDL-C lowering therapy) denotes lowering LDL-C by
imately 30% to <50%.
The term “high-intensity” non-PCSK9 LDL-C lowering therapy (such as a
statin or other non-PCSK9 LDL-C lowering therapy) therapy s lowering LDL-C by
approximately 350%.
The term “optimal” or ”optimized” or “maximized” or al” non-
PCSK9 LDL-C lowering y (such as a statin or other SK9 LDL-C lowering
therapy) denote a dose of the non-PCSK9 LDL-C lowering therapy (such as a statin or other
non-PCSK9 LDL-C lowering therapy) that has been administered so as to allow the subject
to reach their LDL-C lowering goal. When the subject is on at least some amount of a non-
PCSK9 LDL-C lowering therapy (such as a statin or other non-PCSK9 LDL-C lowering
therapy), the subject can be described as one receiving a non-PCSK9 LDL-C lowering
therapy (such as a statin or other non-PCSK9 LDL-C lowering therapy).
In some embodiments, any of the definitions or classifications employed
for any of the levels or disorders identified in Example 17 (including the supplement) can be
employed in other R related embodiments or in non-FOURIER embodiments. The
placement of those characterizations of disorders etc. at the end of Example 17 is to clarify
that these were the tions ed for the FOURIER study. While such definitions
(from Example 17) need not be applied to all embodiments provided herein in all scenarios, it
is plated that such definitions can be applied to any of the embodiments provided
herein, unless designated otherwise or at odds with other definitions. Unless explicitly stated
that the definitions as applied in Example 17 are to apply, the various terms will have their
plain and ordinary g within any claims. Standard ques can be used for
recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g.,
electroporation, lipofection). Enzymatic reactions and purification techniques can be
performed according to manufacturer's ications or as commonly accomplished in the
art or as described herein. The foregoing techniques and procedures can be generally
performed according to conventional methods well known in the art and as described in
various general and more specific references that are cited and discussed throughout the
present specification. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual
(2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. (1989)), which is
orated herein by reference for any purpose. Unless specific definitions are provided,
the latures utilized in connection with, and the laboratory procedures and techniques
of, analytical chemistry, tic organic chemistry, and medicinal and pharmaceutical
chemistry described herein are those well-known and commonly used in the art. Standard
techniques can be used for chemical syntheses, chemical analyses, pharmaceutical
preparation, formulation, and delivery, and treatment of patients.
Combined TheraQies [or the Reduction of Atherosclerosis and ImQroving Cardiovascular
Outcomes in Patients with Cardiovascular Disease
Reducing low-density lipoprotein cholesterol (LDL-C) with inhibitors of
3-hydroxymethylglutaryl coenzyme ase (statins) is common for management for
patients with atherosclerosis. Analysis of data within individual statin trials and through
meta-analyses ts a possible consistent onship n achieving lower LDL-C
levels and reduction in major adverse vascular eventsl’2 In parallel, trials using
intravascular ultrasound (IVUS) have studied the effect of statins on coronary atherosclerosis
and demonstrated a linear relationship between achieved LDL-C levels and reduction in
atheroma burden.3'6 However, major clinical outcome trials and IVUS studies have explored
a range of LDL-C levels, only extending to a mean of approximately 60 mg/dL.3’5
Proprotein tase isin kexin type-9 (PCSK9) plays a pivotal
role in LDL-C metabolism by preventing LDL or recycling to the hepatic surface,
thereby limiting removal of LDL particles from the ation.7'9 onal antibodies
against PCSK9 profoundly lower LDL-C as well as other lipids such as L-C, ApoB
and Lp(a), when administered alone or in combination with statinslo’11 l studies have
demonstrated the feasibility of using the combination of statins and PCSK9 inhibitors to
achieve much lower LDL-C levels than previously studiedlo’11 However, no trials to date
have explored whether LDL-C lowering with a PCSK9 inhibitor reduces the rate of
progression of coronary sclerosis and no data exist assessing whether achieving very
low LDL-C levels via combination therapy results in incremental benefits in ng disease
progression compared with statins alone.
Presented herein (in Example 1) are the results of the Global Assessment
of Plaque Regression with a PCSK9 Antibody as Measured by ascular Ultrasound
(GLAGOV) trial, which assessed two principal scientific questions: whether PCSK9
inhibition impacts atherosclerosis and/or reduces progression of atherosclerosis and whether
achieving very low LDL-C levels with the combination of statins (representative of non-
PCSK9 LDL-C ng therapies) and a PCSK9 inhibitor (e.g., evolocumab) provide
incremental value in further reducing the progression of coronary e as measured by
IVUS.
Given the s of this study (in Example 1), the present application
provides for various embodiments involving combined ies. This is based, in part, upon
the observation that reducing low-density lipoprotein cholesterol (LDL-C) with moderate
and/or high intensity statin therapy (a SK9 LDL-C lowering agent) reduces
progression of atherosclerosis (e.g., coronary atherosclerosis) in proportion to achieved LDL-
C levels and that proprotein convertase subtilisin kexin type-9 (PCSK9) inhibitors further
produce incremental LDL-C lowering in statin-treated patients. The results in Example 1
below trate that the addition of a PCSK9 inhibitor, e.g., evolocumab, compared with
statin monotherapy (a representative e of a non-PCSK9 LDL-C lowering agent),
produced greater LDL-C lowering and significant regression of coronary atherosclerosis at a
dose that was well tolerated. Thus, ed herein are combination therapies that involve a
PCSK9 inhibitor and a non-PCSK9 LDL-C lowering agent. In some embodiments, the
combined therapies can be used for subjects with atherosclerotic cardiovascular disease to
e the subject’s cardiovascular outcome.
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method can include identifying a subject who is on a first therapy that
includes a SK9 LDL-C ng agent (e.g., a lipid lowering treatment, such as a
statin or other non-PCSK9 LDL-C lowering therapy). The method can further include
administering a second y to the subject. The second therapy comprises administering a
PCSK9 inhibitor to the subject, such as an anti-PCSK9 neutralizing antibody. Both the first
and second ies are administered in an amount and time sufficient to reverse coronary
atherosclerosis in the subject (in ation). The PCSK9 inhibitor decreases a level of
LDL-C in the subject. The first therapy is different from the second therapy. For example,
in some embodiments, the first therapy is not an anti-PCSK9 antibody treatment, but is any
other LDL-C lowering agent (such as a statin or other non-PCSK9 LDL-C lowering therapy).
In some ments, the first therapy is not an antibody treatment. In some embodiments,
the combined therapies can be used for ts with atherosclerotic cardiovascular disease to
e the subject’s cardiovascular e.
In some embodiments, the first therapy can be any non-antibody, LDL-C
lowering therapy. In some embodiments, the first therapy is ed from at least one of:
ezetimibe (Zetia) or a statin. In some embodiments, the first therapy is an optimized and/or
maximally tolerated statin therapy. In some embodiments, the subject’s LDL level decreases
to a level beneath 80 mg/dL from the first therapy and then decreases further from the second
y. In some embodiments, both treatments together result in lowering LDL-C levels at
least to 80 mg/dL.
In some ments, a method of treating coronary atherosclerosis is
provided. The method comprises identifying a subject that has a LDL-C level of less than 70
mg/dL, and administering an anti-PCSK9 neutralizing antibody to the subject, in an amount
sufficient and time sufficient to lower the LDL-C level to less than 60 mg/dL. In some
embodiments, the subject has been sed with a cardiovascular disease.
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method comprises identifying a subject that has a LDL-C level of less than 70
mg/dL, and administering a PCSK9 inhibitor to the subject, in an amount sufficient and time
sufficient to lower the LDL-C level to less than 60 mg/dL. In some embodiments, the subject
has been diagnosed with a cardiovascular disease.
In some embodiments, a method of treating coronary atherosclerosis is
provided. The method comprises identifying a subject that has a LDL-C level of less than 80
mg/dL, and administering a PCSK9 inhibitor (such as an anti-PCSK9 neutralizing antibody)
to the subject, in an amount sufficient and time sufficient to lower the LDL-C level to less
than 60 mg/dL.
In some embodiments, a method of treating coronary sclerosis is
provided. The method comprises administering a PCSK9 inhibitor y (such as an anti-
PCSK9 neutralizing antibody) to the subject who is receiving a non-PCSK9 LDL-C lowering
therapy (e.g., an optimized statin therapy), in an amount sufficient and time sufficient to
lower the LDL-C level to less than 80 mg/dL. In some embodiments, the result is achieved
ing at least one year of continuous treatment of both the statin y and the
antibody therapy. In some embodiments, the subject has further been identified by being
diagnosed with coronary atherosclerosis disease or at a high risk of developing with ry
sclerosis disease. In some embodiments, the therapies can be used for subjects with
atherosclerotic cardiovascular disease to improve the subject’s cardiovascular outcome.
In some ments, a method of decreasing percent atheroma volume
in a subject is provided. The method comprises 1) identifying a subject that has received at
least a moderate-intensity ent by non-PCSK9 LDL-C lowering agent (e.g., a statin),
and 2) administering a PCSK9 inhibitor (e.g., an anti-PCSK9 neutralizing antibody) to the
subject in an amount ient and time sufficient to lower the LDL-C level to less than 100
mg/dL, e.g., less than 90 mg/dL. This can thereby decrease the percent atheroma volume
(PAV) in the subject. In some embodiments, the amount and time sufficient is sufficient to
lower the LDL-C level to less than 40 mg/dL. In some embodiments, the time period is at
least one year and the amount of each of the compounds is as provided herein.
In some embodiments, a method of sing total atheroma volume
(TAV) in a subject is provided. The method comprises 1) identifying a subject that has
received at least a moderate level of treatment by a non-PCSK9 LDL-C lowering agent (e.g.,
a statin), and 2) administering a PCSK9 inhibitor (e.g., an anti-PCSK9 neutralizing dy)
to the subject in an amount sufficient and time sufficient to lower the LDL-C level to less
than 100 mg/dL, e.g., less than 90 mg/dL. This can thereby decrease the total atheroma
volume (TAV) in the subject. In some ments, the amount and time sufficient is
WO 89912
ient to lower the LDL-C level to less than 40 mg/dL. In some embodiments, the time
period is at least one year and the amount of each of the compounds is as provided . In
some embodiments, the subject has been diagnosed with a cardiovascular disease.
In some embodiments, both TAV and PAV are reduced in the subject. In
some embodiments, the decrease of PAV is at least 0.1 t, for example, 0.1, 0.2, 0.3,
0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1,1.1,1.2,1.3,1.4,1.5,1.6,1.7,1.8,1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5%
decrease of PAV is achieved. In some embodiments, the decrease of TAV is at least 0.1
t, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1,1.1,1.2,1.3,1.4,1.5,1.6,1.7,
18,19, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,
4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6%
decrease of TAV is achieved. In some embodiments, the noted decrease is achieved within
about 3 years, 2 years, 18 months, or 1 year. In some embodiments, the PAV is decreased by
at least 1% following 18 months of treatment. In some embodiments, the PAV is decreased
by at least 2% ing 18 months of treatment. In some embodiments, the TAV is
decreased by at least 1% following 18 months of treatment. In some embodiments, the TAV
is decreased by at least 2% following 18 months of treatment. In some embodiments, the
TAV is decreased by at least 3% following 18 months of treatment. In some ments,
the TAV is decreased by at least 4% following 18 months of treatment. In some
embodiments, the TAV is decreased by at least 5% following 18 months of treatment. In
some ments, the TAV is decreased by at least 6% following 18 months of treatment.
In some embodiments, a method of ng coronary atherosclerosis
comprises 1) administering an optimum non-PCSK9 LDL-C lowering therapy (e.g., a statin
therapy) to a subject, wherein the subject has coronary atherosclerosis and 2) administering
an amount of a PCSK9 inhibitor (e.g., an anti-PCSK9 neutralizing antibody) to the subject at
the same time. The steps can occur in order, at the same (or overlapping) time, or in a
different order.
In some ments, a method of treating coronary atherosclerosis
comprises 1) fying a statin-intolerant subject, 2) administering at least a low intensity
statin treatment to the statin-intolerant subject, and 3) administering an amount of an anti-
PCSK9 neutralizing antibody to the subject, thereby treating coronary atherosclerosis. The
steps can occur in order, at the same (or overlapping) time, or in a different order. In some
WO 89912
embodiments, a moderate dose statin therapy is administered. In some embodiments, a high
dose statin therapy is administered.
In some embodiments, any of the methods ed herein, including the
combination therapies and the therapies where one is lowering LDL-C levels with a single
therapy (and/or non-HDL-C levels) to very low levels, involve ng LDL-C by 5, 10, 15,
, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125,
130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 mg/dL, or r decrease in LDL-C
(and/or non-HDL-C, which values are ed s by +30).
In some embodiments, a method of providing regression of coronary
atherosclerosis comprises providing a subject that is on an optimized SK9 LDL-C
lowering therapy (e.g., an zed level of a statin) and administering to the subject a
PCSK9 inhibitor (e.g., an anti-PCSK9 neutralizing antibody) at a level adequate to regress
coronary atherosclerosis, wherein regression is any change in PAV or TAV less than zero.
The steps can occur in order, at the same (or overlapping) time, or in a different order.
In some ments, a method of decreasing a LDL-C level in a subject
beneath 80 mg/dL is provided. The method comprises administering a PCSK9 inhibitor
(e.g., an anti-PCSK9 neutralizing antibody or RNAi to PCSK9) to a subject, wherein the
subject has coronary atherosclerotic disease, wherein the t is on a non-PCSK9 LDL-C
lowering therapy (e.g., an optimized statin therapy) for at least one year, and wherein a LDL-
C level in the subject decreases to an average value that is beneath 80 mg/dL for the at least
one year. The steps can occur in order, at the same (or overlapping) time, or in a different
order. In some ments, the t’s LDL levels decrease to an average value that is
beneath 60 mg/dL for the at least one year, for example, 55, 50, 45, 40, 35, 30, 25, 20 mg/dL
or lower for at least one year.
In some embodiments, a method of reducing a relative risk of a
cardiovascular event by at least 10% is provided. The method comprises administering a
PCSK9 inhibitor (e.g., a PCSK9 neutralizing antibody) to a subject that is on at least a
moderate intensity of a non-PCSK9 LDL-C lowering agent (e.g., a statin), in an amount
sufficient to lower a LDL-C level of the subject by about 20 mg/dL.
In some embodiments, the cardiovascular event is one selected from the
group of non-fatal myocardial infarction, myocardial infarction (MI), stroke/Transient
Ischemic Attack (TIA), angina, arterial revascularization, coronary revascularization, fatal
and non-fatal stroke, hospitalization for Congestive Heart Failure (CHF), ry Heart
Disease (CHD) deaths, ry death. In some embodiments, the combined therapy can
reduce and/or slow the progression of sclerosis, slow the progression of coronary
atherosclerosis, slow the progression of atherosclerosis in patients with CHD, and slow the
progression of atherosclerosis in patients with CHD. In some embodiments, the combined
therapy can reduce and/or slow atherosclerotic cardiovascular disease (ASCVD), CAD/CHD,
cerebrovascular dz, and/or Peripheral Artery Disease (PAD). In some embodiments, any one
of the methods provided herein regarding combined therapies can be used to reduce the risk
of any one or more these events. In some embodiments, any patient or subject at risk of one
of these events is the subject identified as one to receive the combined therapy.
In some embodiments, the t is one with at least one of the following:
an elevated LDL-C level, HoFH, HeFH, and nonfamilial hypercholesterolemia. In some
embodiments, the subject is one with a primary hyperlipidemia (heterozygous familial and
non-familial) or mixed dyslipidemia or homozygous familial hypercholesterolemia. In some
embodiments, a subject that has been identified as being at risk of a cardiovascular event is
fied as one to receive the combined therapy. In some embodiments, the subject to
e the combined therapy is one that has at least one or more of: a) ed total-
cholesterol (t—C), b) elevated LDL-C, c) elevated Apo B, d) elevated Lp(a), and/or e) elevated
cerides (TG), f) elevated L-C and/or g) low HDL-C and has a primary
hyperlipidemia ozygous familial and nonfamilial) and/or mixed dyslipidemia. In some
embodiments, the subject has one or more of type 1 diabetes, type 2 diabetes, metabolic
syndrome, prediabetes, and/or HIV/AIDS.
In some embodiments, the combination therapy provided herein can be
used to reduce the risk of or treat at least one or more of the following: CV death, non-fatal
myocardial infarction, non-fatal stroke or transient ischemic attack (TIA), coronary
revascularization, and alization for unstable angina.
In some embodiments, the combination therapy provided herein can be
used in ts with clinically evident atherosclerotic cardiovascular (CV) disease (e.g.,
prior MI, stroke or symptomatic PAD), to reduce the risk of one or more of: CV death, non-
fatal myocardial infarction, tal stroke or transient ischemic attack (TIA), coronary
revascularization, and hospitalization for unstable . In some embodiments, the
combination therapy can be used in patients that are hospitalized for HF (heart failure).
In some embodiments, the combination therapy provided herein can be
used in patients with clinically evident atherosclerotic vascular (CV) disease, to reduce
the risk of one or more of CV death, non-fatal myocardial tion, non-fatal stroke or
ent ischemic attack (TIA), coronary revascularization, and hospitalization for unstable
angina. In some embodiments, the combination therapy can be used in patients that are
hospitalized for HF.
In some embodiments, the combination therapy provided herein can be
used in patients with clinically evident atherosclerotic cardiovascular (CV) disease (e.g.,
prior MI, stroke or symptomatic PAD plus 1 major or 2 minor additional CV risk s), to
reduce the risk of CV death, tal myocardial infarction, non-fatal stroke or ent
ischemic attack (TIA), coronary revascularization, and hospitalization for unstable angina.
In some embodiments, the combination therapy can be used to
treat/prevent/reduce the risk of primary hyperlipidemia and/or mixed dyslipidemia (e.g.,
heterozygous familial hypercholesterolemia (HeFH), nonfamilial hypercholesterolemia,
mixed dyslipidemia, al atherosclerotic cardiovascular disease (CVD) or high risk
patients t ASCVD (subclinical ASCVD)), coronary atherosclerosis, and/or
cardiovascular disease (e.g., CV death, tal myocardial infarction, tal stroke or
transient ischemic attack (TIA), coronary revascularization, and hospitalization for unstable
angina).
In some embodiments, a method of reducing an amount of atherosclerotic
plaque in a subject is provided that comprises administering to a subject having
atherosclerotic plaque a PCSK9 inhibitor (e.g., a monoclonal dy PCSK9, e.g., an anti-
PCSK9 neutralizing antibody). The subject is receiving an optimized non-PCSK9 LDL-C
lowering therapy (e.g., an optimized statin therapy), thereby reducing the amount of
atherosclerotic plaque in the subject. In some embodiments, the method further comprises
identifying the subject who is in need of reducing their amount of atherosclerotic plaque.
The steps can occur in order, at the same (or overlapping) time, or in a different order.
In some embodiments, a method of ng disease ssion is
provided. The method can comprise 1) identifying a subject with a LDL-C level of no more
than 80 mg/dL, 2) administering at least a high and/or moderate intensity of a non-PCSK9
LDL-C lowering therapy (e.g., a statin therapy) to the subj ect, and 3) administering a PCSK9
inhibitor (e.g., evolocumab) at a level sufficient to decrease the LDL-C level of the subject to
mg/dL, thereby ng disease progression. The steps can occur in order, at the same
(or pping) time, or in a different order. In some embodiments, the t has had a
heart attack. In some embodiments, the subject has a LDL-C level of no more than 60
mg/dL.
In some embodiments, a method of reducing disease progression is
provided. The method comprises fying a subject with a LDL-C level of no more than
80 mg/dL, administering at least a moderate intensity of a statin therapy to the t, and
administering evolocumab at a level sufficient to decrease the LDL-C level of the subject to
mg/dL, thereby reducing disease progression. In some embodiments, a ntensity of a
Mafinthaapyisused
In some embodiments, a method of combining evolocumab and a statin
therapy to produce greater LDL-C lowering and sion of coronary sclerosis at a
dose that is well tolerated is provided. The method comprises administering at least a
moderate intensity of a statin therapy to a subject, administering an adequate amount of
evolocumab to the subject such that the t’s LDL-C levels drop to no more than 40
mg/dL, and maintaining the subject’s LDL-C levels at no more than 40 mg/dL for at least
one year. In some embodiments, a high-intensity of a statin therapy is used.
In some embodiments, te-intensity non-PCSK9 LDL-C lowering
therapy (such as a statin or other non-PCSK9 LDL-C lowering therapy) denotes lowering
LDL-C by approximately 30% to <50%. In some embodiments, high-intensity non-PCSK9
LDL-C lowering therapy (such as a statin or other non-PCSK9 LDL-C lowering therapy)
therapy s lowering LDL-C by approximately 350%.
In some embodiments, a method of combining a PCSK9 inhibitor (e.g.,
evolocumab) and a non-PCSK9 LDL-C lowering therapy (e.g., a statin therapy) to e
greater LDL-C lowering and regression of coronary atherosclerosis at a dose that is well
tolerated is provided. The method can comprise l) administering a high and/or moderate-
intensity of a non-PCSK9 LDL-C lowering y (e.g., a high and/or moderate-intensity
statin therapy) to a subject, 2) administering an adequate amount of a PCSK9 inhibitor (e.g.,
evolocumab) to the subject such that the t’s LDL-C levels drop to no more than 40
ngMLflmd3nmmmmmgmembfidkLDL£HmflsMnommemmHmngMLfixmdwfi
one year. The steps can occur in order, at the same (or overlapping) time, or in a different
order
In some embodiments, a method of treating a subject that is unable to
wbmwamflmmmwmflmefiafimnmmmww.NwmfidemmfiakbMfimgme
subject; and administering a PCSK9 inhibitor (e.g., an anti-PCSK9 neutralizing antibody) to
the subject until a LDL terol level of the subject decreases beneath 60 mg/dL. In some
embodiments, the method comprises identifying the subject; and administering a PCSK9
inhibitor (e.g., an anti-PCSK9 neutralizing antibody) to the subject until a LDL cholesterol
level of the subject decreases beneath 80 mg/dL.
In some embodiments, ing upon the t, the first therapy is a
non-PCSK9 dependent, LDL-C lowering therapy. That is, it involves the use of a non-
PCSK9 LDL-C lowering agent. In particular, while the non-PCSK9 LDL-C lowering agent
will lower LDL-C levels, it does not do so through PCSK9. In some embodiments, the first
therapy is not an anfibody therapy. In sonJe eanodnnentg the firsttherapy can be an
antibody therapy, wherein the antibody does not bind to PCSK9. The non-PCSK9 LDL-C
lowering agent/therapy is not a PCSK9 neutralizing antibody ent. In some
embodiments, the non-PCSK9 LDL-C lowering therapy is a small molecule ent that
can lower LDL-C levels in a subject. In some embodiments, the non-PCSK9 LDL-C
lowering therapy is a lipid ng therapy that excludes PCSK9 driven lipid ng
therapies. In some embodiments, the SK9 LDL-C lowering therapy is one or more
of: niacin; ezetimibe; or a statin (aka HMG CoA reductase inhibitors), atorvastatin
OR®), cerivastatin, fluvastatin (LESCOL), lovastatin (Mevacor, ALTOPREV),
mevastatin, pitavastatin, pravastatin (PRAVACHOL), rosuvastatin, rosuvastatin calcium
(CRESTOR) and simvastatin (ZOCOR). s are also found in combination tions
including: ADVICOR (lovastatin + niacin), CADUET (atorvastatin + amlopidine); selective
cholesterol absorption inhibitors, ezetimibe (ZETIA), a Lipid Lowering Therapy (LLT)
fibrates or fibric acid derivatives, including rozil (LOPID), fenofibrate (ANTARA,
A, TRICOR, TRIGLIDE) and clofibrate (ATROMID-S); a Resin (aka bile acid
sequestrant or bile acid-binding drugs), cholestyramine (QUESTRAN, QUESTRAN LIGHT,
PREVALITE, LOCHOLEST, LOCHOLEST LIGHT), tipol (CHOLESTID) and
cholesevelan Hcl (WELCHOL) and/or a ation thereof, including but not limited to
VYTORIN (simvastatin + ezetimibe). In some embodiments, the non-PCSK9 LDL-C
lowering therapy comprises a te or a high intensity statin therapy. In some
embodiments, the non-PCSK9 LDL-C ng therapy comprises a maXimally tolerated
dose of the . A moderate-intensity therapy denotes lowering LDL-C by approximately
to <50%. A high-intensity therapy denotes lowering LDL-C by 350%. In some
ments, the first therapy, the non-PCSK9 dependent therapy lowers lipid levels
generally, and non-HDL-C levels specifically. Thus, it is also contemplated that non-PCSK9
dependent lipid lowering therapies can be used as a first therapy, even though the therapy
may alter more than just LDL-C levels and/or not emphasize LDL-C levels.
In some embodiments, the non-PCSK9 LDL-C lowering therapy (which
can be the statin treatment) is an amount of statin that is at least as effective as a dose of
atorvastatin of 20 mg daily or an equivalent to atorvastatin at an equivalent amount. In some
embodiments, the amount of the statin is at least as effective as a dose of atorvastatin of at
least 40 mg daily or an equivalent to statin at an equivalent amount. In some
embodiments, the statin is at least one of atorvastatin, simvastatin, statin, pravastatin,
lovastatin, and pitavastatin. In some embodiments, the statin is at least one of atorvastatin at
, 40, or 80 mg; simvastatin at 40 or 80 mg; rosuvastatin at 5, 10, 20, or 40 mg; pravastatin
at 80 mg, lovastatin at 80 mg, or pitavastatin at 4 mg. In some embodiments, the subject is
receiving or taking at least statin 40 or 80 mg; rosuvastatin 10, 20, or 40 mg; or
simvastatin 80 mg. In some embodiments, the amount of statin administered is the
maXimally tolerated amount of statin. In some embodiments, the amount of statin is
equivalent to at least atorvastatin 20 mg/day. In some embodiments, the amount of statin is
equivalent to at least atorvastatin 40 .
In some embodiments, the statin is a monotherapy. In some ments,
the subject is also on an additional lipid lowering therapy (and thus can be on a statin, a
PCSK9 antibody, and a third treatment). In some embodiments, the additional lipid lowering
therapy is niacin, ezetimibe, or both niacin and ezetimibe. The present treatments are not
only options for the first therapy, but, of , also embodiments for the lipid lowering
ies and/or the statin therapies provided herein. In some embodiments, the additional
therapy can be an inhibitor to ASGRl, such as an antibody to ASGRl or an ASGRl siRNA.
In some embodiments, the additional y can be an inhibitor to LDLR, such as an
antibody to LDLR or an LDLR siRNA. In some embodiments, the additional y can be
an inhibitor to Lp(a), such as an antibody to Lp(a) or an Lp(a) siRNA. In some
embodiments, the additional therapy can be one or more of: a Lp(a) antagonist (e.g., peptide,
mAb, and/or siRNA), an antibody or tor of ANGPTL4 and/or ANGPTL3, an inhibitor
of PNPLA3 (e.g., siRNA), an inhibitor of ASGRl, an inhibitor of ASGR2 (siRNA), an
inhibitor of ApoC3 (e.g., siRNA), a GLP-1 or t, and/or a GIPR antagonist.
In some embodiments, the non-PCSK9 LDL-C lowering therapy (which
can be a statin treatment) can be administered at any level sufficient to lower cholesterol in
the blood. In some embodiments, the non-PCSK9 LDL-C lowering therapy (which can be a
statin treatment and/or a LLT) is administered in an amount and time to achieve the l
level of LDL lowering in the blood. In some ments, any one or more of the above
statins is administered daily.
In some embodiments, the second therapy, the PCSK9 LDL-C lowering
agent, the PCSK9 inhibitor, the atin LDL-C lowering agent can be any therapy that
lowers LDL-C levels through PCSK9. This can also be described as involving a PCSK9
inhibitor. Such PCSK9 inhibitors can include antibodies evolocumab (CAS Reg. No.
12569375; WHO No. 9643, IND No. 105188) (REPATHA®), alirocumab
(PRALUENT®), zumab, REGN728, RG7652, LY3015014, LGT209, 1D05
88,234), 1B20 (US8,188,233). In some embodiments, the antibody is a lizing
antibody. In some embodiments, the anti-PCSK9 neutralizing antibody is evolocumab. In
some embodiments, the inhibitor is an anti-PCSK9 antibody that contains one or more
(including all 6) of the CDRs from the antibody constructs shown in any one or more of
FIGs. 6-12. In some embodiments, the PCSK9 inhibitor is an anti-PCSK9 antibody that
contains one or more of the amino acid heavy and/or light chains of FIGs. 6-12. In some
embodiments, antibodies that e any one or more of the CDRs of the antibodies noted
herein can be employed. In some embodiments, antibodies that include the heavy and light
chain variable regtions of the antibodies noted herein can be employed. In some
embodiments, the antibody is at least 95, 96, 97, 98, 99% identical in amino acid sequence to
an antibody denoted herein. In some embodiments, the anti-PCSK9 antibody is selected
WO 89912 2017/061346
from the antibodies in US8,062,640 (e.g., HCVR/LCVR = SEQ ID NOS:90/92),
1,184 (e.g., REGN728, HCVR/LCVR = SEQ ID NOS3218/226), US8,080,243 (e.g.,
bococizumab, HCVR/LCVR = SEQ ID Nos254/53), US8,188,234 (e.g., 1D05, HCVR/LCVR
= SEQ ID Nos:ll/27), US8,188,233 (e.g., lB20, HCVR/LCVR = SEQ ID Nos:ll/27),
LGT209 in US8,7lO,l92, US2011/0142849, and US2013/0315927, and RG7652 in
US2012/0195910, LY30lSOl4 in US8,530,4l4 (HCVR/LCVR = SEQ ID 8). In some
embodiments, the PCSK9 inhibitor includes the ic double stranded sequence of ALN-
PCSsc (from US7,605,251, US8,809,292, US9,260,718 and US8,273,869). The entireties of
each of which is hereby incorporated by reference including the disclosure of the specifically
referenced PCSK9 inhibitors. Such PCSK9 inhibitors can also e RNAi therapies, such
as siRNA and ALN—PCSsc. Also contemplated herein are PCSK9 lipid lowering agents that
can lower other lipids (apart from LDL-C). Of course, the above “second therapy,” the
“PCSK9 LDL-C lowering agent,” the “PCSK9 inhibitor,” and/or the “non-statin LDL-C
lowering agent” can lower both LDL-C as well as other lipids. Further contemplated are
PCSK9 lipid lowering agents, which can lower lipids generically. All of the embodiments
provided in the present paragraph can be employed for one or more of the combination
therapies provided herein. Furthermore, for the embodiments provided herein that do not
require a combination of therapies (such as those that provide an especially large reduction in
LDL-C or L-c via a single agent), the present therapeutics can be used for those
embodiments as well (even though there is no “second therapy” in that context).
The amount of the non-PCSK9 LDL-C lowering therapy administered can
be enough to achieve the desired result, when combined with the PCSK9 inhibitor y
for an adequate period of time.
In some embodiments, at least 50, 60, 70, 75, 80, 90, 100, 110, 120, 130,
140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310,
320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450 mg of a PCSK9
inhibitor (such as a neutralizing antibody) is administered to the subject. In some
embodiments, evolocumab is administered in an amount of at least 140 mg, for example, at
least 150 mg, 300 mg, 400 mg or at least 420 mg. In some embodiments, the amount of the
anti-PCSK9 neutralizing antibody is at least 140 mg, for example, at least 150 mg, 300 mg,
400 mg or at least 420 mg.
WO 89912
In some embodiments, the PCSK9 inhibitor (e.g. neutralizing antibody,
e.g., evolocumab), is stered at a frequency of at least once a week, at least once a
month, at least once every two weeks, once every three months, or at least once a week.
In some embodiments, the non-PCSK9 LDL-C ng therapy and/or
PCSK9 inhibitor ies can be administered as they would normally be administered for
mgInwmemmmmmmmJMSmmmewammmmMywbmwdmmgefirme
subject. In n embodiments, the route of administration of the two ingredients in the
combined therapy is in accord with known methods, e.g. orally, through injection by
intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular,
intramuscular, subcutaneously, intra-ocular, intraarterial, intraportal, or intralesional routes;
by sustained release s or by implantation devices.
In some embodiments, the PCSK9 inhibitor (e.g., neutralizing antibody,
e.g., evolocumab), is administered at least monthly to the subject for at least one year. In
some embodiments, it is administered for at least 0.5, 12, 18, 24, 30, 36, 42, 48, 54, 60 or
more months.
In some embodiments, the LDL-C level of the subject on the combined
therapy decreases by at least 40%, for example 40, 45, 50, 55, 60, 65, 70, 75, 80, 85% or
niore.
In some embodiments, the subject has been treated with a stable non-
PCSK9 LDL-C lowering agent (e.g., statin) dose for at least four weeks and has a LDL-C
280 mg/dL or between 60 and 80 mg/dL with one major and/or three minor cardiovascular
risk factors. The major risk factor can be at least one of: non-coronary atherosclerotic
vascular disease, myocardial infarction or hospitalization for unstable angina in the preceding
2 years or type 2 diabetes mellitus. The minor risk factor can be at least one of: current
tte smoking, hypertension, low levels of high-density lipoprotein cholesterol (HDL-C),
family history of premature coronary heart disease, or high ivity C-reactive protein (hs-
CRP) Z2mg/L or age 250 years in men and 55 years in women.
In some embodiments, providing regression of coronary atherosclerosis
denotes a se in PAV and/or TAV. In some embodiments, the decrease in PAV is at
least 0.1 percent, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4,
1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, or 2.5% decrease of PAV is achieved. In some
embodiments, the decrease of TAV is at least 0.1 percent, for example, 0.1, 0.2, 0.3, 0.4, 0.5,
0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,
2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,
, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1,
7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3,
9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10% decrease of TAV is achieved.
In some embodiments, the combined therapy provides for a ion in a
risk of atherosclerosis, coronary atherosclerosis, atherosclerotic cardiovascular disease, a
ry artery disease (CAD), cardiovascular event, non-fatal myocardial infarction
coronary ularization, PAD, and/or cerebrovascular disease for the subject. In some
embodiments, the combined therapy provides for a reduction in risk of the occurrence of one
or more of: death from any cause, CHD deaths, vascular death, angina, myocardial
tion (MI), stroke, fatal and non-fatal stroke arterial revascularization procedures,
coronary revascularization procedures, hospitalization for CHF, and/or unstable angina.
In some embodiments, the combined therapies provides for an LDL-C
level in the subject to be decreased h 80 mg/dL, for example, beneath 70, 60, 50, 40,
, 20 mg/dL.
In some embodiments, any of the above embodiments (or other
embodiments provided herein) regarding atherosclerosis can be applied to improving
vascular outcomes in patients with atherosclerotic cardiovascular disease. Such
embodiments can employ similar y approaches (e.g., a combined therapy), in that the
subject can be on two therapies, one of which is, for example a non-PCSK9 inhibitor, such as
a statin, while the other is, for example, a PCSK9 inhibitor, such as evolocumab. The non-
PCSK9 LDL-C lowering therapy will lower LDL-C levels.
In some ments, the cardiovascular method can comprise the
inhibition of PCSK9 with evolocumab in a subject who is on a statin therapy. This can result
in a lowered LDL cholesterol to 30 mg/dL and a reduced risk of cardiovascular events. In
some embodiments, this is achieved with no significant safety de.
In some embodiments, a method of treating atherosclerotic cardiovascular
disease is ed. The method can comprise a) identifying a subject that is on a first
therapy, wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy. The
WO 89912
method can further comprise b) administering a second therapy to the subject. The second
therapy comprises a PCSK9 inhibitor therapy. Both the first and second therapies are
administered to the subject in an amount and time sufficient to reduce a risk of
atherosclerotic cardiovascular disease in the subject. The first therapy is not the same as the
second y, and the risk is a) a composite for cardiovascular death, dial infarction,
stroke, hospitalization for le angina, or coronary revascularization or b) a ite
for cardiovascular death, myocardial infarction, or stroke, or c) cardiovascular death, or d)
fatal and/or non-fatal MI, or e) fatal and/or non-fatal stroke, or f) transient ischemic attack, or
g) hospitalization for unstable angina, or h) elective, urgent, and/or emergent coronary
ularization.
In some embodiments a method of reducing a risk of a vascular
event is provided. The method comprises a) identifying a subject that is on a first therapy,
wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy. The method can
further se b) administering a second therapy to the subject. The second therapy
comprises a PCSK9 inhibitor. Both the first and second therapies are administered to the
subject in an amount and time sufficient to reduce a risk of a cardiovascular event in the
subject. The first therapy is not the same as the second therapy. The risk is a) a composite
for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or
coronary revascularization or b) a composite for cardiovascular death, myocardial tion,
or stroke, or c) cardiovascular death, or d) fatal and/or non-fatal MI, or e) fatal and/or non-
fatal stroke, or f) transient ic attack, or g) hospitalization for unstable angina, or h)
elective, , and/or emergent ry revascularization.
In some embodiments, a method of reducing a risk of urgent coronary
revascularization is provided. The method comprises a) identifying a subject that is on a first
therapy, wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy. The
method r comprises b) administering a second therapy to the subject. The second
therapy comprises a PCSK9 inhibitor therapy. Both the first and second ies are
administered to the subject in an amount and time sufficient to reduce the risk of
atherosclerotic cardiovascular disease in the subject. The first therapy is not the same as the
second therapy.
-43 _
In some embodiments, a method of reducing a risk of a cardiovascular
event is provided. The method comprises a) identifying a subject with cardiovascular
disease, and b) administering a PCSK9 inhibitor to the subject in an amount and overtime
sufficient to reduce a risk of at least one of cardiovascular death, non-fatal myocardial
tion, non-fatal stroke or transient ischemic attack (TIA), coronary revascularization, or
hospitalization for le angina.
In some embodiments, a method of reducing a risk of a cardiovascular
event is provided. The method comprises a) identifying a subject that is on a first therapy,
wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy; and b)
administering a second therapy to the subject, wherein the second therapy comprises a
PCSK9 inhibitor. Both the first and second therapies are administered to the subject in an
mmmfimmfimmmmdmflommmMHMUfammmWWMMethMMsmfia.flwfimt
therapy is not the same as the second therapy, and the risk is the composite of coronary
revascularization, myocardial infarction, cerebral ar accident.
In some ments, a method of reducing a risk of a vascular
event is provided. The method comprises a) identifying a subject that is on a first therapy,
wherein the first therapy ses a non-PCSK9 LDL-C lowering therapy, and b)
administering a second therapy to the subject, wherein the second therapy comprises a
PCSK9 inhibitor. Both the first and second ies are stered to the subject in an
amount and time sufficient to reduce a risk of a cardiovascular event in the subject, and
wherein the first therapy is not the same as the second therapy, and wherein the risk is the
composite of fatal MI and/or non-fatal MI and fatal and/or tal coronary
revascularization.
In some embodiments the risk is any one or more of, combination of, or
composite of coronary revascularization, myocardial infarction, cerebral vascular accident.
In some embodiments the risk is any one or more of, combination of, or composite of fatal
MI and/or tal MI and fatal and/or non-fatal ry revascularization.
In some embodiments, the combined therapy (or any of the monotherapies
provided herein) is continued for more than siX months, for example, 7, 8, 9, 10, ll, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,
39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,
64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or more
months, following which, the risk of a cardiovascular event, such as vascular death,
myocardial infarction, stroke, hospitalization for unstable angina, or coronary
revascularization has decreased at least 5, 10, 15, 20, 25 or greater t. In some
embodiments, the risk is the composite of these disorders (the first occurrence of any one of
those, in combination). In some embodiments, the risk is for the combination of these
disorders. In some embodiments, the risk is for each of the disorders tely. In some
embodiments, the risk is for cardiovascular death, myocardial infarction, or stroke only (but
as a composite). In some embodiments, the combined risk of all of these has decreased at
least 5, 20, 25% or more, at 6, 7, 8, 9,10,11,12,13,14,15,16,17,18,19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65,66, 67, 68,69, 70,71,
72,73,74,75,76,77,78,79,80,81,82,83,84(n1norennnnhs Insonuaanbodnnenm,the
reduced rate is the composite of these disorders (the first occurrence of any one of those, in
combination). In some embodiments, the risk is for the combination of these disorders. In
some embodiments, the risk is for each of the disorders separately. In some embodiments,
the risk is for cardiovascular death, myocardial infarction, or stroke only (but as a
composite). In some ments, the risk deceases from about 16% during the first year of
therapy to about 25% after the first year of therapy.
In some embodiments, the ed therapy (or any of the monotherapies
ed herein) is continued for more than siX months, for example, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19,20,21,22,23,24,25,26,27,28,29, 30, 31, 32,33, 34, 35,36, 37,38,
39,40,41,42, 43, 44,45, 46,47,48,49, 50, 51, 52, 53,54, 55, 56, 57,58, 59, 60,61, 62,63,
64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or more
months, following which, the risk of a cardiovascular event, such as cardiovascular death,
dial tion, or stroke has decreased at least 5, 10, 15, 20, 25 or greater percent. In
some embodiments, the risk is the composite of these disorders (the first occurrence of any
one of those, in combination). In some embodiments, the risk is for the combination of these
disorders. In some embodiments, the risk is for each of the disorders separately. In some
embodiments, the combined risk of all of these has decreased at least 5, 10, 15, 20, 25% or
more, at 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22,23, 24, 25,26, 27, 28,29,
, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,
55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,
80, 81, 82, 83, 84 or more months. In some embodiments, the reduced rate is the composite
of these disorders (the first occurrence of any one of those, in combination). In some
embodiments, the risk is for the combination of these disorders. In some ments, the
risk is for each of the disorders separately. In some embodiments, the risk deceases from
about 16% during the first year of therapy to about 25% after the first year of y.
In some embodiments, any of the methods provided herein related to
reducing risk can exclude reducing the risk of cardiovascular death over more than 12
months and less than 36 months when separate from dial infarction and stroke. In
some embodiments, any of the methods provided herein related to reducing risk can exclude
reducing the risk of cardiovascular death over more than 12 . In some embodiments,
any of the methods provided herein related to reducing risk can include reducing the risk of
cardiovascular death over more than 36 months.
In some embodiments, the combination therapy (or any of the
erapies provided herein) allows for a significant reduction in the risk of
cardiovascular events, with, for example, a 15% reduction in the risk of the primary
composite end point of vascular death, myocardial infarction, stroke, hospitalization
for unstable angina, or coronary revascularization (either a) individually or b) as a composite
(any one of which, but as a combination) and a 20% reduction in the risk of the clinically
stringent key secondary end point of cardiovascular death, myocardial infarction, or stroke
(either a) dually or b) as a ite (any one of which, as a combination)). In some
embodiments, combination therapy reduces a risk of myocardial infarction by 27%, stroke by
21%, and coronary revascularization by 22%. In some embodiments, the primary end point
is a ite (e.g., the first of any one of which, in combination) of time to cardiovascular
death, dial infarction, stroke, coronary revascularization, or hospitalization for
unstable angina, whichever occurs first. Thus, in some embodiments, the method allows one
to reduce the risk of (or increase the time to) cardiovascular death, myocardial infarction,
stroke, coronary revascularization, or alization for unstable angina, whichever occurs
first. In some embodiments, the method allows one to decrease the composite (e.g., the first
of any one of which, in combination) of time to cardiovascular death, myocardial infarction,
stroke, coronary revascularization, or hospitalization for unstable angina, whichever occurs
first.
In some embodiments, the method allows one to reduce the risk of (or
increase the time to) cardiovascular death, myocardial infarction, or stroke, whichever occurs
first. In some embodiments, the method allows one to decrease the composite (e.g., the first
of any one of which, in combination) of time to cardiovascular death, myocardial infarction,
or stroke, ver occurs first.
In some embodiments, the methods provided herein result in lowering
LDL cholesterol by a significant . In some embodiments, the reduction is at least
50%, for e 59% from a median of 92 to 30 mg/dL (from 2.4 to 0.8 mmol/L). This
effect can be sustained over 3 years t evidence of ation.
In some embodiments, the subject who is to receive an ed
cardiovascular outcome, is (l) on a statin with a potency equivalent to atorvastatin 20 mg
daily or greater (see, e.g., table 17.4), and (2) while on that regimen have an LDL-C 270
mg/dl or a non-HDL-C 2100 mg/dl. In some embodiments, the subject to be d has a
non-HDL-c levels that is at least as high as a corresponding level of LDL-C. In some
embodiments, this means any LDL-C level provided herein, +30 mg/dLl (as a conversion
factor from L-c to LDL-c). Non-HDL-C denotes its art ized meaning, and
denotes cholesterol minus HDL-C. It includes LDL-C, VLDL-C mined roughly as
tg/5) and Lp(a). As shown in , lowering of non-HDL-C, down to approximately 30
mg/dL) reduces the event rate, and thus risk that the subject will have a wide variety of
events. As shown in , reducing non-HDL-C to such very low levels (e.g., less than
50, 40, 30, 20, etc.) lows the event rate of: the primary, secondary, CVD, MI, stroke, pevasc,
and alization for unstable angina (“HUA”) of the subject. The primary and secondary
endpoints are those as d in FOURIER. The primary endpoint is: cardiovascular death,
MI, stroke, hospitalization for unstable angina, or coronary revascularization. The secondary
endpoint was the composite of CV death, MI or stroke. Subjects at risk of any of the
indications (or subparts thereof) shown in can benefit from the methods provided
herein. Furthermore, any of the indications that have a benefit described herein from
lowering a subject’s LCL-C level, can also have their progress tracked by monitoring non-
HDL-C levels. That is, it is also contemplated that each LDL-C lowering method can also
(or in the alternative focus on) the lowering of non-HDL-C. One of skill in the art will
appreciate the overlap between the two approaches, as LDL-C is a component of non-HDL-
In some embodiments, the subject has ally evident atherosclerotic
cardiovascular disease. In some embodiments, this is defined as a history of myocardial
infarction, history of non-hemorrhagic stroke, or symptomatic peripheral artery disease, and
additional characteristics that placed them at higher cardiovascular risk (such as those
outlined in the mental section of Example 17). In some ments, the subject has
had a fasting LDL cholesterol 270 mg/dL or a non-HDL cholesterol of 2100 mg/dL on an
optimized stable lipid-lowering therapy, preferably a high intensity statin, but must have been
at least atorvastatin 20 mg daily or equivalent, with or t ezetimibe. In some
embodiments, such subjects, following identification, can receive the combined y and
obtain improved cardiovascular outcomes.
In some ments, the method allows for a reduction in the risk or
occurrence of the composite of (e.g., the first of any one of which, in ation)
cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or
coronary ularization. In some embodiments, the risk is significantly reduced when
P<0.05. In some embodiments, there is a reduction in the risk of ence of the composite
of (e.g., the first of any one of which, in combination) cardiovascular death, myocardial
infarction, stroke, hospitalization for le angina, or coronary revascularization.
In some embodiments, the method allows for a reduction in the risk or
occurrence of the composite (e.g., the first occurrence of any one of which, in combination)
of cardiovascular death, myocardial infarction, or stroke. site denotes the first
occurrence (e.g., time to) of an item listed within a group of events. “Composite risk” or
other similar term denotes the risk to the time to the first of the events within the list. Thus,
a composite risk for cardiovascular death, myocardial infarction, or stroke would describe the
risk of first occurrence of any one of those three, considered in combination. In some
embodiments, there is a reduction in the risk of ence of the composite of
cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke or
coronary revascularization. In some embodiments, there is a reduction in the risk of
occurrence of the composite of cardiovascular death, myocardial infarction, or stroke. As
used herein, the term “composite” will control how the meaning of a list of items is to be
reted.
In some ments, the combined use of a non-PCSK9 inhibitor and a
PCSK9 inhibitor can icantly reduce the rate of: death, myocardial infarction, stroke,
coronary revascularization, or hospitalization for unstable angina. In some embodiments, the
reduced rate is the composite of these disorders (the first occurrence of any one of those, in
combination). In some ments, the magnitude of the risk reduction can r
increase over time, from 12% (95% CI 3 to 20) in the first year to 19% (95% CI 11 to 27)
beyond the first year, for example. Likewise for the secondary endpoints described herein in
regard to the FOURIER results, the risk reduction went from 16% (95% CI 4 to 26) in the
first year to 25% (95% CI 15 to 34) beyond the first year (see Figure 20 and Example 17
Supplemental Results). In some embodiments, the combined therapy allows for a hazard
ratio in a first year of reduced risk of 0.84 (95% CI, 0.74-0.96) for cardiovascular death,
myocardial infarction, or stroke (as a composite). In some embodiments, the combined
therapy allows a hazard ratio beyond the first year of reduced risk of 0.75 (95% CI, 0.66-
0.85) for cardiovascular death, myocardial infarction, or stroke (as a composite). In some
embodiments, the combined therapy allows for a hazard ratio in a first year of reduced risk of
0.88 (95% CI, .97) for vascular death, myocardial infarction, stroke,
hospitalization for unstable angina, or coronary revascularization (as a composite). In some
embodiments, the combined therapy allows for a hazard ratio beyond the first year of
reduced risk of 0.81 (95% CI, 0.73-0.89) for cardiovascular death, dial infarction,
stroke, hospitalization for unstable angina, or coronary revascularization (as a composite).
In some embodiments, the combined therapy allows for a hazard ratio as
shown in Table 17.2b, from ing a combined therapy method as outlined herein.
Table 17.2b
Hazard Ratio (95% CI)
Outcome
In first year Beyond first year
Primary end point 0.88 0.97) 0.81 (0.73-0.89)
Key secondary end point 0.84 (0.74-0.96) 0.75 (0.66-0.85)
Cardiovascular death 0.96 (0.74-1.25) 1.12 (0.88-1.42)
Myocardial infarction 0.80 (0.68-0.94) 0.65 (0.55-0.77)
Hospitalization for unstable angina 0.97 (0.77-1.22) 0.99 (0.75-1.30)
CTTC composite endpoint 0.87 (0.79-0.97) 0.78 (0.71-0.86)
coronary heart death’ ML 15.0mm”
0.86 (0.76-0.97) 0.76 (068-0. 86)
stroke, or urgent revascularization
ry heart death, MI, or stroke 0.84 (0.73-0.95) 0.73 (0.65-0.83)
Fatal or nonfatal MI or stroke 0.81 (0.70-0.93) 0.67 0.77)
In some embodiments, the combined therapy allows for a hazard ratio of
0.96 (0.74-1.25) in the first year for vascular death.
In some embodiments, the ed therapy allows for a hazard ratio of
0.80 (0.68-0.94) in the first year for Myocardial infarction. In some embodiments, the
combined therapy allows for a hazard ratio of 0.65 (0.55-0.77) beyond the first year for
Myocardial infarction.
In some ments, the combined therapy allows for a hazard ratio of
0.97 (0.77-1.22) in the first year for Hospitalization for unstable angina. In some
embodiments, the combined therapy allows for a hazard ratio of 0.99 (0.75-1.30) beyond the
first year for alization for unstable angina.
In some embodiments, the combined therapy allows for a hazard ratio of
0.83 (0.63-1.08) in the first year for Stroke. In some embodiments, the combined therapy
allows for a hazard ratio of 0.76 (0.60-0.97) beyond the first year for Stroke.
In some embodiments, the combined therapy allows for a hazard ratio of
0.84 0.96) in the first year for Coronary ularization. In some embodiments, the
combined therapy allows for a hazard ratio of 0.72 (0.63-0.82) beyond the first year for
Coronary reyascularization.
In some embodiments, the combined therapy allows for a hazard ratio of
0.84 (0.71-1.00) in the first year for urgent coronary revascularization. In some
embodiments, the combined therapy allows for a hazard ratio of 0.63 (0.52-0.75) beyond the
first year for urgent coronary revascularization.
In some embodiments, the combined therapy allows for a hazard ratio of
0.86 (0.72-1.03) in the first year for elective coronary revascularization. In some
embodiments, the combined therapy allows for a hazard ratio of 0.81 (0.68-0.97) beyond the
first year for elective coronary ularization.
In some embodiments, the combined therapy allows for a hazard ratio of
0.87 0.97) in the first year for CTTC composite endpoint. In some embodiments, the
combined therapy allows for a hazard ratio of 0.78 0.86) in the second year for CTTC
composite endpoint.
In some embodiments, the combined therapy allows for a hazard ratio of
0.86 (0.76-0.97) in the first year for Coronary heart death, MI, ischemic stroke, or urgent
ularization as a composite. In some embodiments, the combined therapy allows for a
hazard ratio of 0.76 (0.68-0.86) in the second year for Coronary heart death, MI, ischemic
stroke, or urgent revascularization as a composite.
In some embodiments, the combined therapy allows for a hazard ratio of
0.84 (0.73-0.95) in the first year for Coronary heart death, MI, or stroke (as a composite). In
some ments, the combined therapy allows for a hazard ratio of 0.73 (0.65-0.83) in the
second year for Coronary heart death, MI, or stroke (as a composite).
In some embodiments, the combined y allows for a hazard ratio of
0.81 (0.70-0.93) in the first year for Fatal or nonfatal MI or stroke (as a composite). In some
embodiments, the combined therapy allows for a hazard ratio of 0.67 (0.59-0.77) in the
second year for Fatal or nonfatal MI or stroke (as a composite).
In some embodiments, “reducing the risk” denotes at least one of a)
increasing an amount of time to the first of any one of cardiovascular death, myocardial
tion, stroke, hospitalization for unstable angina, or coronary revascularization (as a
composite or individually or in combination), or b) sing an amount of time to the first
of any one of vascular death, myocardial infarction, or stroke (as a composite or
individually or in combination). In some embodiments, a reduction in the risk can be
achieved throughout the treatment period, for example, at month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or month 12 or beyond (as a composite or individually or in combination).
In some embodiments, the method can result in a 17% reduction in risk of
the key secondary endpoint in patients who start with a median LDL cholesterol from 126,
which is then lowered by evolocumab to 43 mg/dL and a 22% reduction in risk in patients
who start with a median LDL cholesterol of 73, which is then lowered by evolocumab to 22
mg/dL.
In some embodiments, there is a 21% to 27% reduction in a risk of
myocardial infarction, stroke and coronary revascularization (as a composite, individually, or
as a combination).
In some embodiments, there is a 17% ion in risk of cardiovascular
death, myocardial infarction, or stroke in a subject, wherein the subject has an initial median
LDL cholesterol of 126 mg/dL (as a ite, individually, or as a combination). In some
embodiments, the final median LDL cholesterol level of the subject is 43 mg/dL.
In some embodiments, there is a 22% reduction in risk of vascular
death, myocardial infarction, or stroke in a subject, wherein the subject has an initial median
LDL cholesterol of 73 mg/dL(as a composite, dually, or as a combination). In some
embodiments, the final median LDL cholesterol level of the subject is 22 mg/dL.
In some embodiments, the method reduces the composite of myocardial
infarction, stroke, or cardiovascular death in patients with established atherosclerotic
cardiovascular disease (ASCVD). In some embodiments, the method comprises
administering evolocumab to a subject having ASCVD and who is on a standard background
therapy ding, for example, statins, ing in a combined therapy). In some
embodiments, the result is that the t’s risk of cardiovascular events ing
myocardial infarction, ischemic stroke, and cardiovascular death decreases. In some
embodiments, the subject’s quality-adjusted life-year (QALY) increases. The quality—
adjusted life year or quality~adiusted life—year (QALY) is a generic measure of disease
burden, including both the quality and the quantity of life lived.
In some embodiments, lifetime cardiovascular event rates can be about
179 per 100 patients with standard background therapy, but can drop down to about 135 with
the addition of evolocumab (in a combined therapy). In some embodiments, lifetime
cardiovascular event rates can be about 140 to 130 to 120 per 100 patients when standard
ound y is combined with an antibody therapy, such as evolocumab (for a
combined therapy). In some embodiments, the treatment is administered to patients with
low-density lipoprotein (LDL) terol of dL In some embodiments, the 2-year
WO 89912
risk for first event (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death)
is less than 13.9%, for subjects on the antibody and standard ound therapy (e.g., on a
combined therapy), for example, between 13.9 and 7, 13 and 7, 12 and 7, 11 and 7, 10 and 7,
9 and 7, 8 and 7.4%.
In some embodiments, the individual non-fatal myocardial infarction, non-
fatal ic stroke, and coronary revascularization respective risk reductions can be 21%,
26% and 16% in the first year and 36%, 25% and 28% beyond year 1 on a combined therapy.
In some embodiments, the lifetime QALY can be 7.23 with standard
background therapy and can increase to 7.62 with evolocumab (in a combined therapy), with
the difference in health effects of 0.39 QALY. In some embodiments, the increase can be at
least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6 QALY upon the administration of evolocumab (in a combined
therapy). In some embodiments, the QALY itself can be more than 7.23 upon administration
with evolocumab, e.g., 7.23, 7.25, 7.3, 7.35, 7.4, 7.45, 7.5, 7.55, 7.6, 7.7, 7.8 or more.
In some ments, the method provides a decrease in the rate of
subsequent events, health state utilities (the y of the life-years) and cardiovascular
disease events and procedures costs by reducing nonfatal events, even in the absence of
direct survival t.
In some embodiments, evolocumab, when added to standard ound
therapy, including high or te intensity statin therapy, in patients with established
ASCVD provides a 15% relative risk reduction in the composite of vascular death,
myocardial infarction, stroke, hospitalization for unstable angina, or coronary
ularization over a median follow-up of 2.2 years. In some embodiments, there can be a
% risk reduction in the composite of cardiovascular death, myocardial infarction, or stroke.
In some embodiments, a greater magnitude of clinical benefits can be observed after the first
year of treatment with evolocumab.
In some embodiments, the method provides an ental reduction in
cardiovascular events, corresponding to reductions in hospitalizations, and revascularizations
resulting from the addition of evolocumab (in a combined therapy).
In some embodiments, the patient has established ASCVD. In addition,
the patient would, with other currently available lipid-modifying therapies including
lly tolerated statins, benefit from additional LDL cholesterol lowering. Such a
patient can e evolocumab, which can facilitate improved clinical outcomes for the
subject. In some embodiments, the ed therapy is administered to a patient with
ASCVD who is at a particularly high risk for events based on al s, formal risk
scores, arid/or use of a higher LDL cholesterol.
{£1250} The table below outlines the baseline characteristics of the atherosclerotic
cardiovascular disease U.S. patient population from NHANES. In some embodiments, any
one or more of the items below can be used to assist in identifying subjects at higher risk of
atherosclerotic cardiovascular disease.
LDL-C Z 70 ngdL LDL-C Z 100 ngdL
A e, ears, mean SD 66 11 64 12
SeX, male, % 61% 59%
Race, %
White 78% 74%
Black or African American 8% 11%
Asian or other 14% 14%
Cardiovascular risk factors, %
Hypertension 74% 77%
Diabetes mellitus 26% 27%
Current tte use 26% 20%
History of vascular disease, %
Established cardiovascular disease 14% 29%
dial infarction 52% 44%
Stroke 34% 27%
Ezetimibe use, % 7% 5%
Lipid parameters at parent study baseline
LDL-C, mg/dL 104 (28) 130 (27)
LDL 70—99 mg/dL, % 59% 0%
LDL 2100 mg/dL, % 41% 100%
HDL-C, m /dL 50 12 48 ll
Triglycerides, mg/dL 138 74 164 85
Abbreviations: HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density
lipoprotein-cholesterol; SD, standard deviation.
In some embodiments, the combined therapy allows for an improvement
tion) in the population event rates per 100 patients (Standard Background Therapy vs.
Evolocumab plus Standard Background Therapy), as outlined in the table below.
WO 89912
Evolocumab +
SOC SOC
-year Horizon
Rate of Non-fatal MI 18 29
Rate of Non-fatal IS 18 26
Rate of CV death 23 25
Rate of revascularization 27 38
Rate of MI, IS or CV death 58 79
Risk of MI, IS or CV death
% 44% 55%
Lifetime Horizon
Rate of Non-fatal MI 41 65
Rate of Non-fatal IS 43 58
Rate of CV death 51 56
Rate of revascularization 58 79
Rate of MI, IS or CV death 135 179
Risk of MI, IS or CV death
% 74% 83%
Abbreviations: CV, cardiovascular; IS, ischemic stroke; MI, myocardial infarction; SOC,
standard of care.
In some embodiments, a method of ng a risk of urgent coronary
ularization can comprise a) identifying a subject that is on a first therapy, wherein the
first therapy comprises a non-PCSK9 LDL-C lowering therapy, and b) administering a
second therapy to the subject, wherein the second therapy comprises a PCSK9 inhibitor
therapy. Both the first and second therapies are administered to the subject in an amount and
time sufficient to reduce the risk of atherosclerotic cardiovascular disease in the subject, and
n the first therapy is not the same as the second therapy. In some embodiments, the
risk is not vascular death over more than 12 months and less than 36 months separate
from myocardial infarction and stroke.
In some embodiments, a method of ng a risk of a vascular
event is provided. The method comprises a) identifying a subject with cardiovascular
disease, and b) administering a PCSK9 inhibitor to the subject in an amount and overtime
sufficient to reduce a risk of at least one of cardiovascular death, non-fatal myocardial
infarction, tal stroke or transient ischemic attack (TIA), coronary revascularization, or
hospitalization for unstable angina. In some embodiments, the subject with cardiovascular
e is on a non-PCSK9 LDL-C lowering therapy, wherein the non-PCSK9 LDL-C
lowering therapy is not a same therapy as the PCSK9 inhibitor. Both the non-PCSK9 LDL-C
ng y and the PCSK9 inhibitor are administered to the subject in an amount and
time sufficient to reduce a risk of a cardiovascular event in the subject. In some
embodiments, the SK9 LDL-C lowering therapy ses a statin. In some
embodiments, the risk is not cardiovascular death over more than 12 months and less than 36
months separate from myocardial infarction and stroke.
In some embodiments, a method of lowering LDL-C levels in a subject is
provided. The method comprising administering: a) first therapy to a subject, wherein the
first therapy comprises a non-PCSK9 LDL-C lowering therapy, and b) a second therapy to
the subject, wherein the second therapy ses a PCSK9 inhibitor. Both the first and
second therapies are administered to the subject for at least five years, and the first therapy is
not the same as the second therapy. In some embodiments, the subject’s LDL-C level is
maintained beneath 50 mg/dL.
In some embodiments, a method of reducing a risk of a cardiovascular
event is provided. The method comprises a) identifying a subject that is on a first therapy,
wherein the first therapy ses a non-PCSK9 LDL-C lowering therapy, and b)
administering a second therapy to the subject. The second therapy comprises a PCSK9
inhibitor. Both the first and second therapies are administered to the subject in an amount
and time sufficient to reduce a risk of a cardiovascular event in the subject. The first therapy
is not the same as the second therapy. The risk is at least one of myocardial infarction,
stroke, hospitalization for le angina, or ry revascularization.
In some embodiments, the subject to e the combined therapy for an
improved cardiovascular outcome has least 1 major risk factor or at least 2 minor risk factors
below:
Major Risk Factors:
0 diabetes (type 1 or type 2)
0 age 2 65 years at randomization (and S 85 years at time of informed
consent)
0 MI or morrhagic stroke within 6 months of screening
0 additional diagnosis of myocardial infarction or non-hemorrhagic
stroke excluding qualifying MI or non-hemorrhagic strokeal
0 current daily cigarette smoking
0 history of symptomatic PAD (intermittent cation with ABI
< 0.85, or eral arterial revascularization procedure, or
tion due to atherosclerotic disease) if le by MI or stroke
history
Minor Risk s:
0 history of non-MI related coronary revascularizational
o residual coronary artery disease with 2 40% stenosis in 2 2 large
vessels
0 Most recent HDL-C < 40 mg/dL (1.0 mmol/L) for men
and < 50 mg/dL (1.3 mmol/L) for women by central laboratory before
randomization
0 Most recent hsCRP > 2.0 mg/L by central laboratory before
randomization
0 Most recent LDL-C 2 130 mg/dL (3.4 mmol/L) or non-HDL-C
2 160 mg/dL (4.1 mmol/L) by central laboratory before randomization
o metabolic syndromeb
In some embodiments, the subject to receive the ed therapy for an
improved cardiovascular outcome has: a most recent fasting LDL-C 2 70 mg/dL
(2 1.8 mmol/L) or non-HDL-C 2 100 mg/dL (2 2.6 mmol/L) after 2 2 weeks of stable lipid
lowering therapy per discussion in Example 17, and/or a most recent fasting triglycerides S
400 mg/dL (4.5 mmol/L) by l laboratory before randomization.
PeriQheral Artery Disease
In some embodiments, one or more of the various treatment approaches
provided herein can be used in a subject who has, or is at risk of developing peripheral artery
disease (“PAD”). The application of a combination therapy to such a subject is outlined in
Example 18. By way of context, the presence of peripheral artery disease (PAD) is a marker
of a malignant vascular phenotype with event rates exceeding those of other stable
populations with atherosclerosis, particularly in the setting of polyvascular disease. (Suarez
C, Zeymer U, Limbourg T, et al. Influence of polyvascular disease on cardiovascular event
rates. Insights from the REACH Registry. Vase Med 2010; 15(4): 259-65. Criqui MH,
Aboyans V. Epidemiology of peripheral artery e. Circ Res 2015, 116(9): 1509-26.
Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for Prevention of Ischemic Events After
Myocardial Infarction in Patients With Peripheral Artery Disease. J Am Coll Cardiol 2016;
67(23): 2719-28.) Thus, patients with symptomatic PAD are at heightened risk of major
adverse cardiovascular events (MACE) including myocardial tion, stroke and
cardiovascular death. (Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC Guidelines on
the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the
European y for Vascular Surgery (ESVS): Document covering atherosclerotic disease
of extracranial d and vertebral, mesenteric, renal, upper and lower extremity arteries
Endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and
Treatment of eral Arterial Diseases of the European y of Cardiology (ESC) and
of the European Society for Vascular y (ESVS). Eur Heart J 2017, Gerhard-Herman
MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of ts
With Lower Extremity Peripheral Artery Disease: A Report of the American College of
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Circulation 2016.) In on, patients with PAD suffer significant morbidity from major
adverse limb events (MALE) including acute limb ischemia, urgent peripheral
ularization and major amputation. (Kumbhani DJ, Steg PG, Cannon CP, et al. Statin
therapy and long-term adverse limb outcomes in patients with eral artery disease:
insights from the REACH registry. Eur Heart J 2014; 35(41): 2864-72, Jones WS,
Baumgartner I, Hiatt WR, et al. Ticagrelor Compared With Clopidogrel in Patients with Prior
Lower ity ularization for Peripheral Artery Disease. Circulation 2016; Bonaca
MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease:
results from TRA2{degrees}P-TIMI 50. Circulation 2013; 127(14): 1522,9, 1529el-6.)
Although lipid-lowering therapy has been correlated in reducing MACE in
stable patients with ry heart disease or atherosclerosis risk factors, there have been few
well-powered prospective randomized trials of low-density lipoprotein LDL cholesterol
) reduction specifically in patients with PAD. (Aung PP, Maxwell HG, Jepson RG,
Price JF, Leng GC. Lipid-lowering for peripheral arterial disease of the lower limb.
Cochrane Database Syst Rev 2007, (4)(4): CD000123.) Moreover, these trials have not
specifically looked at the ability of LDL-C lowering to reduce the risk of MALE, an
important cause of morbidity in patients with PAD. (Kumbhani DJ, Steg PG, Cannon CP, et
al. Statin therapy and erm adverse limb outcomes in patients with peripheral artery
disease: insights from the REACH registry. Eur Heart J 2014, 35(41): 2864-72, Aronow
WS, Nayak D, Woodworth S, Ahn C. Effect of simvastatin versus placebo on treadmill
se time until the onset of intermittent claudication in older patients with peripheral
arterial disease at six months and at one year after treatment. Am J Cardiol 2003, 92(6): 711-
2, Mohler ER,3rd, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves
walking ce in patients with peripheral arterial disease. Circulation 2003, 108(12):
, Spring S, Simon R, van der Loo B, et al. High-dose atorvastatin in peripheral arterial
disease (PAD): effect on endothelial function, intima-media-thickness and local progression
of PAD. An open randomized lled pilot trial. Thromb Haemost 2008; 99(1): 182-9;
Schanzer A, Hevelone N, Owens CD, Beckman JA, Belkin M, Conte MS. Statins are
independently ated with reduced mortality in patients undergoing infrainguinal bypass
graft surgery for critical limb ischemia. J Vasc Surg 2008; 47(4): 774-81.) Lastly, as PAD
has often been used simply as a risk enhancer, little is known about PAD patients without
prior MI or stroke. a MP, a BM, Creager MA, et al. Vorapaxar in patients with
peripheral artery disease: results from TRA2{degrees}P-TIMI 50. Circulation 2013,
127(14): 1522,9, 1529el-6. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-
lowering for eral arterial disease of the lower limb. Cochrane Database Syst Rev 2007,
(4)(4): CD000123, Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus Clopidogrel in
Symptomatic Peripheral Artery Disease. N Engl J Med 2016; Anand S. et al. <br
/>COMPASS PAD- vascular OutcoMes for People using agulation StrategieS
trial: Results in Patients with Peripheral Artery Disease. European Society of Cardiology
Hotline 2017.)
FOURIER was a very large cardiovascular outcomes trial of the PCSK9
inhibitor evolocumab and enrolled patients with atherosclerotic disease, in either the
coronary, cerebrovascular or peripheral arterial bed. FOURIER thus allowed one to test the
following hypotheses: (1) ts with PAD would be at greater risk of MACE relative to
patients with coronary or cerebrovascular disease t PAD; (2) consistent relative risk
reductions in MACE with umab would translate to larger te risk reductions in
patients with PAD relative to those without; and (3) LDL-C reduction with evolocumab
would significantly reduce MALE with benefits extending to very low levels of LDL-C. This
is examined and its application confirmed in Example 18 below.
As detailed in Example 18 below, patients with symptomatic lower
extremity PAD are at heightened risk of major e cardiovascular and limb risks.
Combination therapies, such as Evolocumab added to statin therapy, significantly and
ly reduced the risk of MACE, even in patients with PAD and no prior MI or stroke.
Likewise, combination ies, such as the addition of evolocumab to a statin, reduced the
risk of major adverse limb events, and the relationship between achieved LDL-C and lower
risk of limb events extended down to very low achieved levels of LDL. These benefits come
with no apparent safety concerns. Thus, LDL-C reduction to very low levels is useful in
patients with PAD, regardless of a history of MI or stroke, to reduce the risk of MACE and
MALE.
In some embodiments, a method of treating a subject is provided. The
method comprises identifying a subject with peripheral artery disease and reducing a level of
PCSK9 ty in the t.
In some embodiments, a method of reducing a risk of an adverse limb
event in a subject is provided, the method comprises reducing a level of PCSK9 ty in a
subject, wherein the subject has peripheral artery e.
In some embodiments, a method of ng a risk of a major
cardiovascular adverse event ”) is provided. The method comprises administering a
non-statin LDL-C lowering agent to a subject and administering a statin to the subject. The
subject has PAD.
In some embodiments, a method of reducing a risk of a major adverse
limb event (“MALE”) is provided. The method comprises administering a non-statin LDL-C
lowering agent to a subject and administering a statin to the t. The t has
peripheral artery disease (“PAD”).
For any of the preceding embodiments regarding PAD, MACE, MALE, or
the ation thereof, any of the combination therapies and/or compositions provided in
the present application can be employed.
For any of the preceding embodiments regarding PAD, MACE, MALE, or
the combination thereof, any of the following aspects are also contemplated (as well as any
appropriate aspects ed elsewhere in the present specification).
In some embodiments, the subject is r administered a non-PCSK9
LDL-C lowering therapy. In some embodiments, the SK9 LDL-C lowering therapy
comprises a statin. In some embodiments, any of the non-PCSK9 LDL—C lowering therapies
provided herein can be employed. In some embodiments, the amount of the statin can be at
least atorvastatin 20 mg daily or equivalent, titrated to e LDL-C reduction per regional
guidelines. In some embodiments, the amount of the statin can be at least equivalent to
atorvastatin 40 mg daily or higher.
In some embodiments, the adverse limb event is ed from the group
consisting of at least one of: acute limb ischemia, major amputation and urgent peripheral
revascularization.
In some embodiments, the subject has no history of myocardial infarction
or . Despite this, the subject still receives a t from the therapy. In some
embodiments, the subject has a history of myocardial infarction and/or stroke and will still
e a benefit from the therapy. In some embodiments, the subject has not had a prior MI
or stroke. In some embodiments, the subject has had a prior MI or stroke.
In some embodiments, the subject is identified to receive therapy if the
subject had intermittent claudication and an ankle brachial index of <0.85, if they had a prior
peripheral procedure (lower extremity revascularization or amputation), or if they had both.
In some embodiments, the therapy provides a reduction in a risk of a
composite of cardiovascular death, myocardial tion, , hospital admission for
unstable angina, or coronary revascularization.
In some embodiments, reducing a level of PCSK9 activity in a subject is
achieved via an antibody to PCSK9. In some embodiments, any PCSK9 inhibitor or PCSK9
LDL-C lowering agent or therapy can be used. In some embodiments, any PCSK9 inhibitor
or PCSK9 LDL-C lowering agent or therapy provided in the present specification can be
employed. In some embodiments, the PCSK9 LDL-C lowering agent comprises an dy.
In some embodiments, the PCSK9 LDL-C lowering agent comprises evolocumab. In some
embodiments, the amount of the PCSK9 LDL-C ng agent administered is as outlined
within the present specification. In some embodiments, the amount of the PCSK9 LDL-C
lowering agent will be sufficient such that, when combined with the non-PCSK9-LDL-C
lowering agent, the subject’s LDL-C level is lowered to less than 70, 60, 50, 40, 30, 20, or 10
mg/dL. In some embodiments, the amount of evolocumab administered is between 100 and
840, for example 120 and 700, 140 and 600, 140 and 500, 140 and 420, 210 and 630, 140, or
420 mg. In some embodiments, the amount of evolocumab stered is 140 mg, once
every two weeks or 420 mg once a month. In some embodiments, a combination therapy (as
ed herein, can be administered to a subject who has a LDL-C level of greater than 70
mg/dL, to reduce the subject’s LDL-C level to a very low level, for example, less than 60,
such as less than: 55, 50, 45, 40, 35, 30. 25, 20, 15, or 10 mg/dL or lower (including any
range between any two of the preceding values. This method can be d to any one of
more of the indications and/or goals provided herein, including, but not limited to, reducing a
risk of: a major vascular event, a cardiovascular event, major cardiovascular adverse event,
major adverse limb event, adverse limb event, PAD, fatal MI and/or non-fatal MI and fatal
and/or tal coronary revascularization, composite of: a) coronary revascularization, b)
myocardial infarction, and c) cerebral vascular accident, composite of: a) cardiovascular
death, b) myocardial infarction, c) stroke, d) hospitalization for unstable angina, or e)
coronary ularization, urgent coronary revascularization, at least one of: a)
cardiovascular death, b) myocardial infarction, c) , d) hospitalization for unstable
angina, or e) coronary ularization, or a vascular event by at least 10%. This
method can also be applied to: treating atherosclerotic cardiovascular disease, treating
coronary atherosclerosis, providing regression of coronary atherosclerosis, treating a subject
that is unable to tolerate a full eutic dose of a statin, treating a subject that is unable to
tolerate a full eutic dose of a non-PCSK9 LDL-C ng agent, combining a PCSK9
inhibitor therapy and a non-PCSK9 LDL-C lowering therapy to produce greater LDL-C
lowering and regression of ry sclerosis at a dose that is well tolerated, reducing
disease progression, reducing an amount of atherosclerotic plaque in a subject, combining
evolocumab and a statin therapy to produce greater LDL-C lowering and sion of
coronary sclerosis at a dose that is well tolerated, decreasing a LDL—C level in a
subject beneath 80 mg/dL, decreasing total atheroma volume (TAV) in a subject, decreasing
percent atheroma volume (PAV) in a subject, for lowering LDL-C level, and for reducing
disease progression or any combination thereof. Thus, in some embodiments, any of the
combination therapies provided herein can be employed for any of these applications, to a
subject with a LDL-C level of at least 70 mg/dL, at a level effective to lower the subject’s
IJILJCIeveIU)a knvleveloflessthan,60,55,50,45,40,35,30,25,20,15,or UJto
achieve one or more of these aspects. With respect to the referenced combination therapy,
this can be any described herein, including, a first therapy (e.g., a non-PCSK9 LDL-C
lowering agent, a statin, an optimized amount of a statin) with a second therapy (e.g., a
PCSK9 LDL-C lowering agent, a PCSK9 inhibitor, a non-statin LDL—C lowering agent, a
anti-PCSK9 neutralizing antibody, evolocumab). In some embodiments, this therapy can be
wmmmwmmmmmfimmmMMgamflmwflstMgmmmmMym
some embodiments, d of a subject receiving the combination therapy if their LDL-C
level is above 70 mg/dl (or other value provided ), they can e it from an
alternative indicator, such as non-HDL, which can be, (for 70 mg/dL) r than or equal to
100(ofnonJIDI)
In some ments, a ion in risk to a subject is greater in a
t having PAD, than in a subject who does not have PAD.
In some embodiments, the subject has PAD, and following the therapy, the
subject has a reduced the risk of MACE, MALE, or MACE and MALE.
In some embodiments, MALE is a composite of acute limb ischemia
(ALI), major amputation (above the knee, AKA or below the knee BKA, excluding forefoot
or toe), or urgent revascularization (thrombolysis or urgent vascular intervention for
ischemia. In some embodiments, MACE is a composite of CV death, MI or stroke.
In some embodiments, the subject’s LDL—C level is reduced to at least 50
mg/dL, for example, less than 50, 40, 30, 25, 20, 15, or 10 mg/dL. In some embodiments, the
cardiovascular risk is reduced at least 10%, for example, at least 10, 15, 20, 25, 30, 35, 40,
45, or 50% reduction in cardiovascular risk.
In some embodiments, the risk of MALE, following therapy, is reduced at
least 10%, for example at least 10, 15, 20, 25, 30, 35, 40, 45, or 50% reduction in risk. In
some embodiments, the risk of MACE, following therapy, is reduced at least 10%, for
example at least 10, 15, 20, 25, 30, 35, 40, 45, or 50% reduction in risk. In some
embodiments, the risk of MALE and MACE is reduced at least 5%, for example, at least 5,
, 15, 20, 25, or 30%.
In some embodiments, the subject to receive therapy is one identified as
having a risk of MACE, MALE, or MACE and MALE. In some embodiments, the subject to
receive therapy is one having a risk of, or actually having, PAD.
In some embodiments, subjects with PAD benefit especially from one or
more of the methods provided herein, as they are in the highest risk patient group. That is,
the subjects who have PAD are considered difficult to treat with other approaches. Thus, the
present approach can be especially advantageous over other, less effective, approaches.
In some ments, the subject is one with PAD and/or one or more or
recent myocardial infarctions .
As depicted in Example 19, in some embodiments, the methods provided
herein are more effective in subjects with fewer such risk factors. For example, in some
ments, the subject to be treated has less than 3 such risk factors, such as 2, 1, or 0 of
these risk factors. In some ments, the risk factors are at least one of PAV, HbA1c
and/or a change in oprotein A-I. In some embodiments, undesirable systolic blood
pressure can be a risk . In some embodiments, factors associated with a greater
propensity to g plaque progression, included the presence of additional genic
factors, and thus, in some embodiments, the subject to be treated does not have too many
additional atherogenic factors (e.g., less than 3, 2, 1, or has none).In some embodiments, any
of the combination therapies ed herein can be employed to assist subjects with recent
and/or multiple myocardial infarctions. In some embodiments, the MI is within 4 or more
weeks. In some embodiments, the MI is within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, or 24 . In some embodiments, the subject has suffered
from more than one MI, for example, 2, 3, 4 or more MIs. In some embodiments, the subject
has essel disease. In some embodiments, the subject has some combination of 1)
recent MI (within 2 years), 2) multiple MIs (more than 1), and/or essel disease. In
some embodiments, a subject with one or more of these, who then receives a therapy as noted
herein, can then receive a decreased risk in CVD, MI, and/or stroke. In some embodiments,
this additional screening or selection process can be used to identify subject to receive
one or more of the combination therapies provided herein, including, for example, any
of those within the Summary or the claims. In some ments, the risk is decreased by
at least 1%, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12,13,14,15,16,17,18,19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30%, or more. In some ments, a subject having a
recent or multiple MIs is administered (or continues to receive) a first therapy, wherein
the first y comprises a non-PCSK9 LDL-C lowering therapy and a second therapy is
also administered to the subject. The second therapy comprises a PCSK9 inhibitor therapy.
In some embodiments, both the first and second therapies are administered to the subject in
an amount and time sufficient to reverse ry atherosclerosis in the subject.
As demonstrated in the results in Example 20, in some embodiments, any
of the methods provided herein can be applied selectively to ts with a Lp(a) level of
greater than 11.8 mg/dL. In some embodiments, the subject has a Lp(a) level of more
than 11.8 mg/dL, and thus, can receive an even greater benefit for plaque regression. In
some embodiments, the t has a Lp(a) level of at least (or n any two of the
following) 11.8,12, 13,14, 15,16, 17, 18, 19, 20, 25, 30, 35, 40, 45 or 49 or 50 mg/dL.
In some embodiments, the Lp(a) is more than 30 mg/dL. In some embodiments, this
additional screening or selection process can be used to identify a subject to receive one
or more of the combination therapies provided herein, including, for example, any of
those within the Summary or the claims. In some embodiments, the method to be
applied, after the subject is identified as having a Lp(a) level above 11.8 mg/dL (but
optionally below 30 mg/dL) is to provide (or continue ing) a first therapy, wherein
the first therapy comprises a non-PCSK9 LDL-C lowering therapy and to administer a
second therapy to the subject. The second therapy ses a PCSK9 inhibitor therapy. In
some embodiments, both the first and second therapies are administered to the subject in an
amount and time sufficient to e coronary atherosclerosis in the subject. In some
embodiments, both the first and second therapies are administered to the subject in an
amount and time sufficient to reduce plaque formation.
In some embodiments, any of the following numbered arrangements can
be employed.
1. A method of treating coronary atherosclerosis, the method comprising:
a. identifying a subject that is on a first therapy, wherein the first therapy
comprises a non-PCSK9 LDL-C lowering therapy, and
b. administering a second therapy to the subject, wherein the second
therapy comprises a PCSK9 inhibitor y, n both the first
and second therapies are administered to the subject in an amount and
time sufficient to reverse coronary atherosclerosis in the subject, and
n the first therapy is not the same as the second therapy.
2. The method of arrangement 1, wherein the first therapy is selected from at
least one of: a statin, including but not limited to atorvastatin (LIPITOR®), statin,
tatin (LESCOL), lovastatin (MEVACOR, ALTOPREV), mevastatin, pitavastatin,
pravastatin (PRAVACHOL), rosuvastatin, rosuvastatin calcium OR) and simvastatin
(ZOCOR); ADVICOR (lovastatin + niacin), CADUET (atorvastatin + amlopidine); a
selective cholesterol absorption inhibitor, including but not d to ezetimibe (ZETIA), a
Lipid Lowering Therapy (LLT) including but not d to fibrates or fibric acid derivatives,
ing but not limited to gemfibrozil (LOPID), fenofibrate (ANTARA, LOFIBRA,
TRICOR, TRIGLIDE) and clofibrate (ATROMID-S); a Resin including but not limited to
cholestyramine RAN, QUESTRAN LIGHT, PREVALITE, LOCHOLEST,
EST LIGHT), cholestipol (CHOLESTID) and cholesevelan HCl (WELCHOL)
and/or a combination thereof, including but not limited to N statin +
ezetimibe).
3. The method of any of the numbered arrangements in this section, wherein the
first therapy is an optimized statin therapy.
4. The method of any of the numbered arrangements in this section, wherein the
subject’s LDL level decreases to a level beneath 80 mg/dL.
. A method of treating coronary atherosclerosis, the method comprising:
a. identifying a subject that has a LDL-C level of less than 70 mg/dL,
b. administering an anti-PCSK9 neutralizing antibody to the subject, in
an amount sufficient and time sufficient to lower the LDL-C level to
less than 60 mg/dL.
6. The method of any of the numbered arrangements in this section, wherein the
subject has further been identified by being diagnosed with coronary atherosclerosis disease.
7. A method of decreasing percent atheroma volume (PAV) in a subject, the
method comprising:
a. fying a subject that has ed at least a moderate level of
treatment by a statin; and
b. b) administering an anti-PCSK9 neutralizing antibody to the subject in
an amount sufficient and time sufficient to lower the LDL-C level to
less than 100 mg/dL, e.g., less than 90 mg/dL, y decreasing a
percent atheroma volume (PAV) in the subject.
8. The method of any of the numbered arrangements in this section, n the
amount and time sufficient is ient to lower the LDL-C level to less than 40 mg/dL.
9. A method of decreasing total atheroma volume (TAV) in a subject, the
method comprising:
a. identifying a subject that has received at least a moderate level of
treatment by a statin; and
b. administering an anti-PCSK9 neutralizing antibody to the subject in an
amount sufficient and time sufficient to lower the LDL-C level to less
than 100 mg/dL, e.g., less than 90 mg/dL, thereby decreasing a total
atheroma volume in the subject.
. The method of any of the ed arrangements in this section, wherein the
amount and time sufficient is ient to lower the LDL-C level to less than 40 mg/dL.
11. The method of any of the numbered ements in this section, wherein
stering the anti-PCSK9 neutralizing antibody to the subject decreases a percent
atheroma volume in the subject.
12. The method of any of the numbered arrangements in this section, wherein a
decrease of at least 0.1 percent is achieved in the PAV.
13. The method of any of the numbered arrangements in this section, wherein the
decrease is achieved within 18 months.
14. The method of any of the numbered arrangements in this section, wherein the
PAV is sed by at least 1% following 18 months of treatment.
. The method of any of the numbered ements in this n, wherein the
PAV is decreased by at least 2% following 18 months of treatment.
16. A method of treating coronary sclerosis, the method comprising:
a. administering an optimum statin treatment to a subject, wherein the
subject has coronary atherosclerosis; and
b. administering an amount of an anti-PCSK9 neutralizing antibody to
the subject at the same time.
17. A method of treating coronary atherosclerosis, the method comprising:
a. identifying a statin-intolerant subj ect;
b. administering at least a low dose statin treatment to the statin-
intolerant subject; and
c. administering an amount of an anti-PCSK9 neutralizing antibody to
the subject, thereby ng ry atherosclerosis.
18. A method of providing regression of coronary sclerosis, the method
comprising:
providing a subject that is on an optimized level of a statin; and
stering to the subject an anti-PCSK9 neutralizing antibody, at a level
adequate to regress coronary atherosclerosis, wherein regression is any change in
PAV or TAV less than zero.
19. A method of sing a LDL-C level in a subject beneath 80 mg/dL, the
method comprising: administering an anti-PCSK9 neutralizing antibody to a subject, wherein
the subject has ry atherosclerotic disease, wherein the subject is on an zed statin
therapy for at least one year, and wherein a LDL-C level in the subject decreases to an
average value that is beneath 80 mg/dL for the at least one year.
. The method of any of the numbered arrangements in this section, wherein the
subject decreases to an average value that is beneath 60 mg/dL for the at least one year.
21. The method of any of the numbered arrangements in this n, n the
subject decreases to an average value that is beneath 40 mg/dL for the at least one year.
22. A method of reducing a relative risk of a cardiovascular event by at least 10%,
the method comprising administering a PCSK9 neutralizing antibody to a subject that is on at
least a moderate intensity of a statin, in an amount sufficient to lower a LDL-C level of the
t by about 20 mg/dL.
23. The method of arrangement 22, wherein the cardiovascular event is one
ed from the group of selected from the group of non-fatal myocardial infarction,
myocardial infarction (MI), stroke/TIA, angina, arterial revascularization, coronary
revascularization, fatal and non-fatal , hospitalization for CHF, CHD deaths, coronary
death, cardiovascular.
24. A method of reducing an amount of atherosclerotic plaque in a subject, the
method comprising stering to a subject having atherosclerotic plaque a monoclonal
antibody to human PCSK9, wherein the subject is receiving optimized statin therapy, y
reducing the amount of atherosclerotic plaque in the subject.
. The method of arrangement 24, further comprising, identifying a subject who
is in need of reducing the amount of atherosclerotic plaque in the subject.
26. A method of reducing disease progression, the method comprising:
identifying a subject with a LDL-C level of no more than 60 mg/dL,
administering at least a moderate intensity of a statin therapy to the subject;
administering evolocumab at a level sufficient to decrease the LDL-C level of
the subject to 30 mg/dL, thereby reducing disease progression.
27. The method of any of the numbered arrangements in this n, wherein the
subject has had a heart .
28. A method of combining evolocumab and a statin therapy to produce greater
LDL-C lowering and regression of ry atherosclerosis at a dose that is well tolerated,
the method comprising:
administering at least a moderate ity of a statin therapy to a subj ect;
administering an adequate amount of evolocumab to the subject such that the
subject’s LDL-C levels drop to no more than 40 mg/dL, and
ining the t’s LDL-C levels at no more than 40 mg/dL for at least
one year.
29. A method of treating coronary sclerosis, the method comprising:
a. fying a subject that has a LDL-C level of less than 70 mg/dL,
b. administering a PCSK9 inhibitor to the t, in an amount sufficient
and time sufficient to lower the LDL-C level to less than 60 mg/dL.
. A method of decreasing percent ma volume (PAV) in a subject, the
method comprising:
a. identifying a t that has received at least a moderate level of
treatment by a non-PCSK9 LDL-C lowering agent, and
b. administering a PCSK9 inhibitor to the subject in an amount sufficient
and time sufficient to lower the LDL-C level to less than 100 mg/dL,
e.g., less than 90 mg/dL, thereby decreasing a percent atheroma
volume (PAV) in the subject.
31. A method of decreasing total atheroma volume (TAV) in a subject, the
method comprising:
a. identifying a subject that has received at least a moderate level of
treatment by a non-PCSK9 LDL-C lowering agent, and
b. administering a PCSK9 inhibitor to the subject in an amount sufficient and
time sufficient to lower the LDL-C level to less than 100 mg/dL, e.g., less
than 90 mg/dL, thereby decreasing a total atheroma volume in the subject.
32. A method of treating coronary atherosclerosis, the method comprising:
a. administering an optimum non-PCSK9 LDL-C lowering therapy to a
subject, wherein the subject has coronary atherosclerosis; and
b. administering an amount of a PCSK9 inhibitor to the subject at the
same time.
33. A method of treating coronary atherosclerosis, the method comprising:
a. identifying a statin-intolerant subj ect;
b. administering at least a low intensity statin treatment to the statin-
intolerant subject; and
c. administering an amount of a PCSK9 inhibitor to the subject, thereby
treating coronary atherosclerosis.
34. A method of providing regression of coronary atherosclerosis, the method
comprising:
providing a subject that is on an optimized level of a non-PCSK9 LDL-C
lowering agent; and
administering to the subject a PCSK9 inhibitor, at a level adequate to regress
coronary atherosclerosis, wherein regression is any change in PAV or TAV less than
zero.
. A method of sing a LDL-C level in a t beneath 80 mg/dL, the
method comprising: stering a PCSK9 inhibitor to a subject, wherein the subject has
coronary atherosclerotic disease, wherein the subject is on an optimized non-PCSK9 LDL-C
lowering y for at least one year, and wherein a LDL-C level in the subject decreases to
an average value that is beneath 80 mg/dL for the at least one year.
36. A method of reducing an amount of atherosclerotic plaque in a subject, the
method comprising administering to a subject having atherosclerotic plaque a PCSK9
inhibitor, wherein the subject is receiving zed non-PCSK9 LDL-C lowering therapy,
thereby reducing the amount of atherosclerotic plaque in the subject.
37. A method of reducing disease progression, the method comprising:
identifying a subject with a LDL-C level of no more than 60 mg/dL,
stering at least a moderate intensity of a SK9 LDL-C ng
therapy to the subj ect; and
administering a PCSK9 inhibitor at a level sufficient to decrease the LDL-C
level of the t to 30 mg/dL, thereby reducing disease progression.
38. A method of combining a PCSK9 inhibitor therapy and a non-PCSK9 LDL-C
lowering therapy to produce greater LDL-C lowering and regression of coronary
atherosclerosis at a dose that is well tolerated, the method comprising:
stering at least a moderate intensity of a non-PCSK9 LDL-C lowering
therapy to a subj ect;
administering an adequate amount of a PCSK9 inhibitor to the subject such
that the subject’s LDL-C levels drop to no more than 40 mg/dL, and
maintaining the subject’s LDL-C levels at no more than 40 mg/dL for at least
one year.
39. A method of treating a subject that is unable to tolerate a full therapeutic dose
of a non-PCSK9 LDL-C ng agent, the method comprising:
identifying said subject; and
administering a PCSK9 inhibitor to the t until a LDL cholesterol level
of the subject decreases beneath 60 mg/dL.
40. The method of any of the numbered arrangements in this section, wherein the
PCSK9 tor comprises any of the 6 CDR sequences depicted in Figures 6-12.
41. The method of any of the ed arrangements in this section wherein the
first therapy comprises a moderate or a high-intensity statin therapy.
42. The method of any of the numbered arrangements in this n sing a
statin at a level of an effective dose of statin of at least 20 mg daily or an equivalent to
atorvastatin at an equivalent amount.
43. The method of any of the numbered arrangements in this section, wherein the
amount of the statin is at least an effective dose of atorvastatin of at least 40 mg daily or an
equivalent to atorvastatin at an equivalent amount.
44. The method of any of the numbered arrangements in this section, wherein the
statin is at least one of atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, and
pitavastatin.
45. The method of any of the numbered arrangements in this section, wherein the
statin is at least one of atorvastatin at 20, 40, or 80 mg, simvastatin at 40 or 80 mg,
rosuvastatin at 5, 10, 20, or 40 mg; pravastatin at 80 mg, lovastatin at 80 mg, or pitavastatin
at 4 mg.
46. The method of any of the numbered arrangements in this n, wherein the
subject is on at least atorvastatin 40 or 80 mg; rosuvastatin 10, 20, or 40 mg, or simvastatin
80 mg.
47. The method of any of the ed arrangements in this section, wherein the
statin is a monotherapy for the statin.
48. The method of any of the numbered arrangements in this section, wherein the
subject is also on an additional lipid lowering therapy.
49. The method of any of the numbered arrangements in this section, n the
additional lipid lowering therapy is niacin, ezetimibe, or both niacin and ezetimibe.
50. The method of any of the ed arrangements in this section, wherein the
PCSK9 inhibitor or the anti-PCSK9 antibody is evolocumab, and wherein umab is
administered in an amount of at least 140 mg.
51. The method of any of the numbered arrangements in this section, wherein
evolocumab is administered in an amount of at least 420 mg.
52. The method of any of the numbered arrangements in this section, wherein the
PCSK9 inhibitor or the anti-PCSK9 antibody is evolocumab, and wherein umab is
administered at a frequency of at least once a month.
53. The method of any of the numbered arrangements in this section, wherein
providing regression of coronary atherosclerosis denotes a se in PAV.
54. The method of any of the ed arrangements in this section, wherein an
LDL-C level in the subject is sed beneath 60 mg/dL.
55. The method of any of the numbered arrangements in this n, wherein an
LDL-C level in the subject is decreased beneath 50 mg/dL.
56. The method of any of the ed arrangements in this section, n an
LDL-C level in the subject is decreased beneath 40 mg/dL.
57. The method of any of the numbered ements in this section, wherein an
LDL-C level in the subject is decreased beneath 30 mg/dL.
58. The method of any of the numbered arrangements in this section, wherein an
LDL-C level in the subject is decreased beneath 20 mg/dL.
59. The method of any of the numbered arrangements in this section, wherein a
risk of a CV death, non-fatal myocardial infarction, non-fatal stroke or transient ischemic
attack (TIA), coronary revascularization, and hospitalization for unstable angina for the
subject is reduced.
60. The method of any of the numbered arrangements in this section, wherein an
amount of the anti-PCSK9 neutralizing antibody is at least 140 mg.
61. The method of any of the numbered arrangements in this section, wherein an
amount of the anti-PCSK9 neutralizing antibody is at least 150 mg.
62. The method of any of the numbered arrangements in this n, wherein an
amount of the anti-PCSK9 neutralizing antibody is at least 300 mg.
63. The method of any of the ed arrangements in this section, wherein an
amount of the anti-PCSK9 neutralizing antibody is at least 400 mg.
64. The method of any of the numbered arrangements in this section, wherein an
amount of the anti-PCSK9 neutralizing antibody is 420 mg.
65. The method of any of the numbered ements in this section, further
sing evolocumab.
66. The method of any of the numbered arrangements in this section, wherein
evolocumab is administered subcutaneously.
67. The method of any of the numbered arrangements in this section, wherein
evolocumab is administered at least monthly to the subject for at least one year.
68. The method of any of the numbered arrangements in this section, wherein a
percent atheroma volume (PAV) in the subject decreases by 0.1 to 2.5%.
69. The method of any of the numbered arrangements in this section, wherein the
normalized total atheroma volume decreases by 0.1 to 10%
70. The method of any of the numbered arrangements in this section, n a
LDL-C level of the subject decreases by at least 40%.
71. The method of any of the numbered arrangements in this section, wherein a
LDL-C level of the t ses by at least 60%.
72. The method of any of the numbered arrangements in this n, wherein the
subject has been treated with a stable statin dose for at least four weeks and has a LDL-C 280
mg/dL or between 60 and 80 mg/dL with one major or three minor cardiovascular risk
factors.
73. The method of any of the numbered arrangements in this section, comprising
an anti-PCSK9 neutralizing antibody.
74. The method of any of the numbered arrangements in this section, n the
anti-PCSK9 neutralizing dy is evolocumab.
75. The method of any of the numbered arrangements in this section, wherein a
major risk factor comprises at least one of: non-coronary atherosclerotic vascular disease,
myocardial infarction or hospitalization for unstable angina in the preceding 2 years or type 2
es mellitus.
76. The method of any of the numbered ements in this section, wherein a
minor risk factor ses at least one of: current cigarette smoking, hypertension, low
levels of high-density lipoprotein cholesterol (HDL-C), family history of premature ry
heart disease, high sensitivity C-reactive protein (hs-CRP) 22mg/L or age 250 years in men
and 55 years in women.
77. A method of treating a subject that is unable to tolerate a full therapeutic dose
of a statin, the method sing:
identifying said subject; and
administering a PCSK9 inhibitor to the subject until a LDL cholesterol level
of the subject decreases beneath 60 mg/dL.
78. A method of treating coronary atherosclerosis, the method comprising:
a. identifying a subject that has a LDL-C level of less than 70 mg/dL,
b. administering a non-PCSK9 LDL-C lowering agent to the subject, in
an amount sufficient and time sufficient to lower the LDL-C level to less
than 60 mg/dL.
79. The method of any of the numbered arrangements in this section, wherein a
high intensity of a statin is administered to the subject.
80. The method of any of the numbered arrangements in this section, wherein the
person has been diagnosed with a cardiovascular disease.
81. The method of any of the numbered arrangements in this section, n
umab is administered every two weeks.
82. A method of treating atherosclerotic cardiovascular disease, the method
comprising:
a. identifying a subject that is on a first y, wherein the first therapy
ses a non-PCSK9 LDL-C lowering therapy, and
b. administering a second therapy to the subject, wherein the second
therapy comprises a PCSK9 inhibitor therapy, wherein both the first
and second therapies are administered to the subject in an amount and
time sufficient to reduce a risk of atherosclerotic cardiovascular
e in the subject, and wherein the first therapy is not the same as
the second therapy, and wherein the risk is a) a composite for
cardiovascular death, myocardial infarction, stroke, hospitalization for
unstable angina, or coronary revascularization or b) a composite for
cardiovascular death, myocardial infarction, or .
83. The method of arrangement 82, wherein the first and second therapies are
continued for at least two years.
84. The method of arrangement 83, wherein a risk of a composite of
cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or
coronary revascularization is decreased by at least 15%.
85. The method of arrangement 82, wherein a risk of a composite of
cardiovascular death, myocardial infarction, or stroke is decreased by at least 20%.
86. A method of reducing a risk of a cardiovascular event, the method
comprising:
a. identifying a subject that is on a first therapy, wherein the first therapy
comprises a non-PCSK9 LDL-C lowering y, and
b. administering a second therapy to the subject, wherein the second
therapy ses a PCSK9 inhibitor, wherein both the first and
second therapies are administered to the subject in an amount and time
sufficient to reduce a risk of a cardiovascular event in the subject, and
wherein the first therapy is not the same as the second therapy, and
wherein the risk is a) a composite for cardiovascular death, dial
infarction, stroke, hospitalization for unstable angina, or coronary
revascularization or b) a composite for cardiovascular death,
myocardial infarction, or stroke.
87. The method of arrangement 86, wherein the cardiovascular event is selected
from at least one of: cardiovascular death, myocardial infarction, , hospitalization for
unstable angina, or ry ularization, and wherein the first and second therapies are
continued for at least two years.
88. The method of arrangement 86, wherein a risk of a composite of
vascular death, dial infarction, stroke, hospitalization for unstable angina, or
coronary ularization is decreased by at least 15%.
89. The method of arrangement 86, wherein a risk of a composite of
cardiovascular death, dial infarction, or stroke is decreased by at least 20%.
90. The method of arrangement 86, wherein a hazard ratio in a first year of
reducing the risk is 0.84 (95% CI, 0.74-0.96) for cardiovascular death, myocardial infarction,
91. The method of arrangement 86, wherein a hazard ratio in a second year of
reducing the risk is 0.75 (95% CI, 0.66-0.85) for cardiovascular death, myocardial infarction,
or stroke.
92. The method of arrangement 86, wherein a hazard ratio in a first year of
reducing the risk is 0.88 (95% CI, 0.80-0.97) for cardiovascular death, myocardial infarction,
stroke, hospitalization for unstable angina, or coronary revascularization.
93. The method of arrangement 86, wherein a hazard ratio in a second year of
ng the risk is 0.81 (95% CI, 0.73-0.89) for cardiovascular death, myocardial infarction,
stroke, hospitalization for unstable angina, or coronary ularization.
94. The method of any one of arrangements 82-93, wherein reducing the risk
denotes at least one of a) increasing an amount of time to the first of any one of
cardiovascular death, myocardial infarction, stroke, hospitalization for unstable , or
coronary revascularization, or b) increasing an amount of time to the first of any one of
vascular death, myocardial infarction, or stroke.
95. The method of arrangement 86, wherein there is a 21% to 27% reduction in
the risk of myocardial infarction, stroke and coronary revascularization.
96. The method of arrangement 86, wherein there is a 17% reduction in risk of
vascular death, myocardial infarction, or stroke in a subject, wherein the subject has an
initial median LDL cholesterol of 126 mg/dL.
97. The method of arrangement 96, wherein a final median LDL cholesterol level
of the subject is 43 mg/dL.
98. The method of arrangement 86, n there is a 22% reduction in risk of
cardiovascular death, dial infarction, or stroke in a t, wherein the subject has an
initial median LDL cholesterol of 73 mg/dL.
99. The method of arrangement 98, wherein a final median LDL cholesterol level
of the subject is 22 mg/dL.
100. A method of reducing a risk of urgent coronary revascularization, the method
comprising:
a. identifying a subject that is on a first therapy, wherein the first therapy
ses a non-PCSK9 LDL-C ng therapy; and
b. administering a second therapy to the subject, wherein the second
therapy comprises a PCSK9 inhibitor therapy, wherein both the first
and second therapies are administered to the t in an amount and
time sufficient to reduce the risk of atherosclerotic cardiovascular
disease in the subject, and wherein the first therapy is not the same as
the second therapy.
101. A method of reducing a risk of a cardiovascular event, the method
comprising:
a. identifying a subject with cardiovascular disease;
b. administering a PCSK9 inhibitor to the subject in an amount and
overtime sufficient to reduce a risk of at least one of cardiovascular
death, non-fatal dial infarction, non-fatal stroke or ent
ischemic attack (TIA), coronary revascularization, or hospitalization
for unstable angina.
102. The method of arrangement 101, wherein the subject with cardiovascular
disease is on a non-PCSK9 LDL-C lowering y, wherein the non-PCSK9 LDL-C
lowering therapy is not a same y as the PCSK9 inhibitor, wherein both the non-PCSK9
LDL-C lowering therapy and the PCSK9 inhibitor are administered to the subject in an
amount and time sufficient to reduce a risk of a cardiovascular event in the subject.
103. The method of arrangement 102, wherein the non-PCSK9 LDL-C lowering
therapy comprises a statin.
104. The method of any one of arrangements , wherein the risk is for the
composite of cardiovascular death, myocardial infarction, or stroke.
105. The method of any one of arrangements 82-103, wherein the risk is for the
composite of cardiovascular death, myocardial tion, stroke, hospitalization for unstable
angina, or coronary revascularization.
106. A method of lowering LDL-C levels in a subject, the method comprising
administering:
a. a first therapy to a subject, wherein the first therapy comprises a non-
PCSK9 LDL-C ng therapy; and
b. administering a second therapy to the subject, wherein the second
therapy comprises a PCSK9 inhibitor, wherein both the first and
second therapies are administered to the subject for at least five years,
and wherein the first therapy is not the same as the second therapy, and
wherein the subject’s LDL-C level is maintained beneath 50 mg/dL.
107. A method of reducing a risk of a cardiovascular event, the method
comprising:
a. identifying a subject that is on a first therapy, wherein the first therapy
comprises a SK9 LDL-C lowering therapy, and
b. stering a second therapy to the subject, n the second
therapy comprises a PCSK9 inhibitor, wherein both the first and
second ies are administered to the t in an amount and time
sufficient to reduce a risk of a cardiovascular event in the subject, and
wherein the first therapy is not the same as the second therapy, and
n the risk is at least one of myocardial infarction, stroke,
hospitalization for unstable angina, or ry revascularization.
108. A method of reducing a risk of a cardiovascular event, the method
comprising:
a. identifying a subject that is on a first therapy, wherein the first therapy
comprises a non-PCSK9 LDL-C lowering therapy, and
b. stering a second therapy to the subject, wherein the second
therapy comprises a PCSK9 inhibitor, wherein both the first and
second therapies are administered to the subject in an amount and time
sufficient to reduce a risk of a cardiovascular event in the subject, and
wherein the first therapy is not the same as the second therapy, and
wherein the risk is the composite of coronary revascularization,
myocardial infarction, cerebral vascular accident.
109. A method of reducing a risk of a cardiovascular event, the method
comprising:
a. identifying a subject that is on a first therapy, wherein the first therapy
ses a SK9 LDL-C lowering therapy, and
b. administering a second therapy to the subject, wherein the second
therapy comprises a PCSK9 inhibitor, wherein both the first and
second therapies are administered to the subject in an amount and time
sufficient to reduce a risk of a cardiovascular event in the subject, and
wherein the first therapy is not the same as the second therapy, and
wherein the risk is the composite of fatal MI and/or non-fatal MI and
fatal and/or non-fatal ry revascularization.
110. A method of treating a subject, the method comprising:
identifying a subject with peripheral artery disease; and
reducing a level of PCSK9 activity in the subject.
111. A method of reducing a risk of an adverse limb event in a subject, the method
comprising: reducing a level of PCSK9 activity in a subject, wherein the subject has
peripheral artery disease.
112. The method of arrangement 111, wherein the subject is r administered a
non-PCSK9 LDL-C lowering y.
113. The method of arrangement 112, wherein the non-PCSK9 LDL-C lowering
therapy ses a statin.
114. The method of arrangement 113, wherein the adverse limb event is selected
from the group consisting of at least one of: acute limb ischemia, major amputation and
urgent peripheral revascularization.
115. The method of arrangement 113, n the t has no history of
myocardial tion or stroke.
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116. The method of arrangement 113, wherein the subject is identified if the
subject had ittent claudication and an ankle brachial index of <0.85, if they had a prior
eral procedure (lower extremity revascularization or amputation), or if they had both.
117. The method of arrangement 113, wherein there is a reduction in a risk of a
composite of cardiovascular death, myocardial infarction, stroke, hospital admission for
unstable angina, or coronary revascularization.
118. The method of any one of arrangements 110-117, wherein reducing a level of
PCSK9 activity in a subject is achieved via an antibody to PCSK9.
119. The method of arrangement 118, wherein the antibody comprises
evolocumab.
120. The method of any one of arrangements 110-119, wherein the ion in
risk to a subject is greater in a subject having PAD, than in a subject that does not have PAD.
121. The method of any one of arrangements 110-119, wherein the subject has
PAD and wherein, following the method, the subject has a reduced the risk of MACE.
122. The method of any one of arrangements 9, wherein the subject has not
had a prior MI or stroke.
123. A method of reducing a risk of a major adverse limb event (“MALE”), said
method comprising:
administering a non-statin LDL—C lowering agent to a subj ect; and
administering a statin to the subject, wherein the subject has
peripheral artery disease (“PAD”).
124. The method of arrangement 123, wherein MALE is a composite of acute limb
ia (ALI), major amputation (above the knee, AKA or below the knee BKA, ing
forefoot or toe), or urgent revascularization (thrombolysis or urgent vascular intervention for
ischenna.
125. A method of reducing a risk of a major cardiovascular adverse event
(“MACE”), said method comprising:
stering a non-statin LDL—C lowering agent to a subj ect; and
administering a statin to the subject, wherein the subject has PAD.
126. The method of ement 125, wherein MACE is a ite of CV death,
MI or stroke.
127. The method of any one of arrangements 110-126, wherein the subject did not
have a prior MI or stroke.
128. The method of any one of arrangements, 110-127, wherein the subj ect’s LDL-
C level is reduced to at least 50 mg/dL.
129. The method of any one of arrangements 8, wherein the subject’s LDL-
C level is reduced to at least 10 mg/dL.
130. The method of any one of arrangements 110-129, wherein a cardiovascular
risk is d at least 10%.
131. The method of any one of arrangements 110-129, wherein a cardiovascular
risk is reduced at least 40%.
132. The method of any one of arrangements 111-124, n the risk of MALE
is reduced at least 10%.
133. The method of any one of arrangements 111-124, wherein the risk of MALE
is d at least 20%.
134. The method of any one of arrangements 110-134, wherein a combined risk of
MALE and MACE is reduced at least 10%.
135. The method of any one of arrangements 110-134, wherein a combined risk of
MALE and MACE is reduced at least 20%.
136. A method of reducing a risk of a cardiovascular event, the method
comprising:
providing a first therapy to a subject, wherein the first y comprises a
non-PCSK9 LDL-C lowering therapy; and
providing a second therapy to the subject, wherein the second y
comprises a PCSK9 inhibitor, wherein both the first and second therapies are
administered to the subject, and wherein the subject has a Lp(a) level of 11.8 mg/dL
to 50.
137. A method of reducing a risk of a major vascular event in a subject, the method
comprising:
1) identifying a subject that has at least one of: (a) a recent MI, (b) multiple
prior MIs, or (c) multivessel disease;
2) providing a first therapy to a t, n the first therapy comprises a
non-PCSK9 LDL-C lowering therapy; and
3) providing a second therapy to the subject, wherein the second therapy
comprises a PCSK9 inhibitor,
thereby reducing a risk that the subject will have a major vascular event.
138. The method of arrangement 137, wherein the major vascular even is selected
from the group consisting of at least one of: CVD, MI, or stroke.
139. The method of arrangement 137 or 138, wherein a recent MI is one that with
within two years.
140. The method of one of arrangements 137-139, wherein the multiple prior MIs
is at least 2.
141. The method of any one of arrangements 137-140, wherein the subject has at
least two of (a) a recent MI, (b) multiple prior MS, or (c) multivessel disease.
142. The method of any one of arrangements137-140, wherein the t has all
three of (a) a recent MI, (b) multiple prior MS, or (c) multivessel disease.
143. The method of any one of arrangement 1, 16, 18, 19, 32, 34, 35, 36, 82, 86,
100, 106, 107, 108, 109, 123, 125, 136, or 137, wherein the first therapy or the non-PCSK9
LDL-C lowering agent or the statin consists of or comprises an zed amount of a statin,
and wherein the second therapy, the PCSK9 LDL-C ng agent, the PCSK9 inhibitor, the
non-statin LDL-C ng agent, or the anti-PCSK9 neutralizing antibody consists of or
comprises evolocumab, alirocumab, or an dy that competes with evolocumab or
alirocumab.
144. The method of any one of arrangements 5, 7, 9, 17, 18, 19, 22, 29, 30, 31, 33,
37, 38, 39, 77, or 101, wherein the second therapy, the PCSK9 LDL-C lowering agent, the
PCSK9 inhibitor, the non-statin LDL-C lowering agent, or the anti-PCSK9 neutralizing
antibody consists of or comprises umab, alirocumab, or an antibody that competes
with evolocumab or alirocumab.
145. The method of arrangements 143 or 144, wherein the statin is at least one of
atorvastatin at 20, 40, or 80 mg; simvastatin at 40 or 80 mg, rosuvastatin at 5, 10, 20, or 40
mg; tatin at 80 mg, lovastatin at 80 mg, or pitavastatin at 4 mg, or wherein the first
therapy or the non-PCSK9 LDL-C lowering agent is ezetimibe.
146. The method of arrangements 143 or 144, wherein the PCSK9 tor or the
anti-PCSK9 antibody is evolocumab, and wherein evolocumab is administered in an amount
of at least 140 mg every two weeks.
147. The method of arrangements 143 or 144, wherein evolocumab is administered
in an amount of at least 420 mg once monthly.
148. The method of arrangements 143 or 144, wherein an amount of the anti-
PCSK9 neutralizing dy is at least 150 mg.
149. The method of any of ements 143 or 144, wherein an amount of the
anti-PCSK9 neutralizing antibody is at least 300 mg.
150. The method of any one of arrangement 1, 16, 18, 19, 32, 34, 35, 36, 82, 86,
100, 106, 107, 108, 109, 123, 125, 136, or 137, wherein the first therapy or the non-PCSK9
LDL-C lowering agent or the statin consists of or comprises an optimized amount of a statin,
and wherein the second therapy, the PCSK9 LDL-C lowering agent, the PCSK9 tor, the
non-statin LDL-C lowering agent, or the anti-PCSK9 neutralizing dy consists of or
comprises evolocumab, and wherein evolocumab is administered in an amount of at least 140
mg every two weeks or 420 mg once monthly.
151. The method of any one of ements 5, 7, 9, 17, 18, 19, 22, 29, 30, 31, 33,
37, 38, 39, 77, or 101, wherein the second therapy, the PCSK9 LDL-C lowering agent, the
PCSK9 tor, the non-statin LDL-C lowering agent, or the anti-PCSK9 neutralizing
antibody consists of or comprises evolocumab, and wherein evolocumab is administered in
an amount of at least 140 mg every two weeks or 420 mg once monthly.
152. The method of the arrangement of 150 or 151, wherein the subject has clinical
sclerotic cardiovascular disease and the method reduces a risk of myocardial infarction,
stroke, and/or coronary revascularization.
153. The method of the arrangement of 150 or 151, wherein the subject has
primary (heterozygous familial and non-familial) hyperlipidemia.
154. The method of one of the arrangements of 3, wherein the evolocumab
is administered via an autoinj ector or on-body infusor with prefilled cartridge.
155. A method of treating atherosclerotic cardiovascular disease and/or primary
(heterozygous familial and non-familial) hyperlipidemia, the method comprising, providing a
ent to a subject, the ent comprising: a statin; and evolocumab, wherein
evolocumab is provided in an amount of at least 140 mg every two weeks or 420 mg once
monthly.
156. A method of treating atherosclerotic cardiovascular disease and/or primary
(heterozygous familial and non-familial) hyperlipidemia; the method comprising: receiving at
least one of: atorvastatin at 20; 40; or 80 mg; simvastatin at 40 or 80 mg; rosuvastatin at 5;
; 20; or 40 mg; pravastatin at 80 mg; lovastatin at 80 mg; or pitavastatin at 4 mg; and
receiving umab in an amount of at least 140 mg every two weeks or 420 mg once
monthly.
157. A method of ng atherosclerotic cardiovascular disease and/or primary
(heterozygous al and non-familial) hyperlipidemia; the method comprising: providing
or administering at least one of: atorvastatin at 20; 40; or 80 mg; simvastatin at 40 or 80 mg;
rosuvastatin at 5; 10; 20; or 40 mg; tatin at 80 mg; lovastatin at 80 mg; or pitavastatin
at 4 mg; and providing or administering evolocumab in an amount of at least 140 mg every
two weeks or 420 mg once monthly.
158. A method of treating coronary sclerosis; the method comprising:
identifying a subject that has a LDL-C level of r than 70 mg/dL; and administering an
anti-PCSK9 neutralizing antibody to the t; in an amount ient and time sufficient
to lower the LDL-C level to less than 40 mg/dL; less than 30 or less than 20 mg/dL.
159. A method of any one of the above arrangements; wherein the indication
and/or goal in any one of the above arrangements is applied instead to at least one of: A)
reducing a risk of at least one of: a major vascular event; a cardiovascular event; major
cardiovascular adverse event; major adverse limb event; adverse limb event; PAD; fatal MI
and/or non-fatal MI and fatal and/or non-fatal coronary revascularization; composite of: a)
coronary revascularization; b) myocardial infarction; and c) cerebral vascular accident;
composite of: a) cardiovascular death; b) dial infarction; c) stroke; d) hospitalization
for unstable angina; or e) coronary revascularization; urgent coronary revascularization; at
least one of: a) vascular death; b) myocardial infarction; c) stroke; d) hospitalization for
unstable angina; or e) coronary revascularization; or a cardiovascular event by at least 10%;
or B) at least one of: treating atherosclerotic cardiovascular e; treating coronary
atherosclerosis; ing regression of coronary atherosclerosis; treating a subject that is
unable to tolerate a full therapeutic dose of a statin; treating a subject that is unable to tolerate
a full therapeutic dose of a non-PCSK9 LDL-C lowering agent, combining a PCSK9
inhibitor therapy and a non-PCSK9 LDL-C lowering therapy to produce greater LDL-C
lowering and sion of coronary atherosclerosis at a dose that is well ted, ng
disease progression, reducing an amount of atherosclerotic plaque in a subject, combining
evolocumab and a statin therapy to produce greater LDL-C lowering and regression of
coronary atherosclerosis at a dose that is well tolerated, decreasing a LDL-C level in a
subject beneath 80 mg/dL, decreasing total atheroma volume (TAV) in a subject, sing
percent atheroma volume (PAV) in a subject, for lowering LDL-C level, and for reducing
disease progression or any combination thereof.
160. Any of the methods of the arrangements provided above that includes a
combination therapy, n a non-PCSK9 lipid lowering therapy or the SK9 LDL-
C lowering agent or the statin is used as the first therapy.
161. A method of ng coronary atherosclerosis comprising a) identifying a
statin-intolerant subject, b) administering a low dose or no dose statin treatment to the statin-
intolerant subject, and c) administering an amount of an anti-PCSK9 neutralizing antibody to
the subject to lower the LDL-C level of the statin intolerant subject to less than 60 mg/dL,
thereby treating coronary atherosclerosis, such as 55, 50, 45, 40, 35, 30, 25, 20, or less
mg/dL.
162. Any of the methods of the arrangements provided above, wherein the
mfljecfisrunkfflDlr(3levelisreducedtolessthan.100,90,80,70,60,50,or40.
163. The method of the arrangement in 162, n a risk of a y,
secondary, CVD, MI, stroke, pevasc, and/or hospitalization for unstable angina (“HUA”) of
the subject is reduced.
164. Thernefluxlofany(nusofananganenm L 16,18,19,32,34,35,36,82,86
100,106, 107,108,109, 123, 125, 136, 137,7,9, 17, 18, 19, 22, 29, 30, 31, 33, 37, 38, 39,
77, or 101, wherein the second therapy, the PCSK9 LDL-C lowering agent, the PCSK9
inhibitor, the atin LDL-C lowering agent, or the anti-PCSK9 neutralizing antibody
comprises at least one of the siX CDRs of umab.
165. The method of arrangement 164, wherein the second therapy, the PCSK9
LDL-C lowering agent, the PCSK9 inhibitor, the atin LDL-C lowering agent, or the
anti-PCSK9 neutralizing antibody comprises all 6 CDRs of evolocumab.
166. The method of arrangement 165, wherein the 6 CDRs are the 6 CDRs in FIGS.
8-11 of the construct designated as 21B12.
167. The method of arrangement 164, wherein the second therapy, the PCSK9
LDL-C lowering agent, the PCSK9 inhibitor, the non-statin LDL-C lowering agent, or the
anti-PCSK9 neutralizing antibody comprises the heavy and light chain amino acid sequence
of evolocumab.
168. The method of arrangement 167, wherein the second therapy, the PCSK9
LDL-C lowering agent, the PCSK9 inhibitor, the non-statin LDL-C lowering agent, or the
anti-PCSK9 neutralizing antibody comprises an evolocumab heavy chain and light chain, as
shown in .
In some embodiments, a method of treating coronary atherosclerosis is provided. The
method ses a) identifying a statin-intolerant subject, b) administering a low dose or no
dose statin treatment to the statin-intolerant subject, and c) administering an amount of at
least one of: a PCSK9 LDL-C ng agent, a PCSK9 inhibitor, a non-statin LDL-C
lowering agent, an anti-PCSK9 lizing antibody, evolocumab, alirocumab, and/or an
antibody that competes with evolocumab or alirocumab to the subject to lower the LDL-C
level of the statin intolerant subject to less than 60 mg/dL, thereby treating coronary
atherosclerosis. In some embodiments, the subject is treated long enough and with enough
anti-PCSK9 neutralizing antibody to lower their LDL-C to 55, 50, 45, 40, 35, 30, 25, 20, or
less mg/dL. In some embodiments, the antibody is evolocumab. When only a single y
is ed, the therapy is not considered to be a “combination therapy” as the term is used
herein. r, any of the embodiments ed herein for combination therapies are also
contemplated for the present very low LDL-C y, as long as they allow for appropriate
modification. In particular, the use of at least one of: a PCSK9 LDL-C lowering agent, a
PCSK9 inhibitor, a atin LDL-C lowering agent, an anti-PCSK9 neutralizing antibody,
evolocumab, alirocumab, and/or an antibody that competes with evolocumab or alirocumab
will result in an exceptionally low LDL-C level in the subject, which will provide for the
noted benefit (for that particular embodiment).
In some ments, a composition for achieving any of the above
methods is provided. In some embodiments, the composition can be a combination of the
first and second therapies. In some embodiments, the therapy can be provided as te
components, and each component can be administered separately or at the same time to the
t. In some embodiments, the ary therapy is administered to the abdomen, thigh,
orupperann.
In some embodiments, one or more of the methods provided herein can be
used to reduce the risk of myocardial infarction, stroke, and coronary revascularization in
adults with clinical atherosclerotic cardiovascular disease.
In some embodiments, one or more of the methods provided herein can be
used as an t to diet, alone or in combination with other lipid-lowering therapies (e.g.,
statins, ezetimibe), for treatment of adults with primary ozygous familial and non-
familial) hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C).
In some embodiments, one or more of the methods provided herein can be
used as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL
apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require
additional lowering of LDL-C. In some embodiments, a SK9 lipid lowering therapy
includes procedures, like apheresis. Thus, in some embodiments, any of the combination
therapies provided herein can include a non-PCSK9 lipid lowering lowering treatment and/or
a statin therapy and/or a PCSK9 therapy. In some embodiments, any of the ation
therapies provided herein can include a non-PCSK9 lipid lowering lowering treatment and/or
a PCSK9 therapy. In some embodiments, any of the combination therapies provided herein
can include a non-PCSK9 lipid ng treatment and/or a statin therapy.
In some embodiments, a 420 mg dose of REPATHA can be administered:
over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or by giving
3 injections consecutively within 30 minutes using the -use prefilled autoinjector or
single-use prefilled syringe.
In some embodiments, for subjects ing a combination therapy for
plaque reduction, the subject has no or relatively few risk factors (as outlined in , for
example and Example 19). In some ments, the subject lacks PAV, HbAlc and
change in apolipoprotein A-I (p=0.0l) that indicate risk or a risky ic blood pressure.
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In some embodiments, the subject to be treated by any of the methods
ed herein has a Lp(a) level between 11.8 and 49 mg/dL. In some embodiments, the
combination therapies provided herein can be applied to a t with a normal Lp(a) level
and the subject can still receive a benefit with respect to reduced atherosclerosis risk, from
the intensive lipid ng results provided by the combination therapy. Thus, the subject
can receive an additional benefit by having their LDL-C level lowered to less than 70, less
than 60, less than 50, less than 40, or, for example less than 30 mg/dL.
In some embodiments the subject receives a greater absolute reduction in
major CV . Support for this conclusion can be found, for example, in Example 22. In
some embodiments, a high risk subject receives a combination therapy, as provided herein
(e.g., a statin and evolocumab) so as to reduce the subject’s LDL-C level to a level lower
than 70, less than 60, less than 50, less than 40, or, for example less than 30 mg/dL. The risk
to an intermediate risk subject (intermediate risk of atherosclerotic CV disease; TRS 2°P
Score=24; 79% of population) can have at least a 1.9% absolute risk reduction (ARR) in CV
death, MI or stroke at 3 yrs with EvoMab compared to Pbo alone. The risk to a high-risk
subject (high risk of atherosclerotic CV e, Score 2 5; 16%) can have a 3.6% ARR in
CV death, MI or stroke (see, e.g., and Example 22).
In some ments, any of the methods provided herein can be
employed to reduce a total number of major vascular events in a subject, not just a risk of a
first event. Support for this can be found in present e 23, for example. In some
embodiments, subjects on one of the ation therapies provided herein can have their
LDL-C level lowered to less than70, less than 60, less than 50, less than 40, or, for example
less than 30 mg/dL, which can in turn reduce a risk of not just a first major cardiovascular
event, but should one occur, it will reduce the risk of any subsequent cardiovascular event.
This can be over 2, 4, 6, 8, 10, 12 months or 1, 1.2, 1.4, 1.6, 1.8, 2, 2, 2.2, 2.4, 2.6, 2.8, 3 or
years or more. In some embodiments, the risk of a subsequent MI, stroke, or coronary
revascularization is decreased both in likelihood of occurrence and in the time to such an
event in the subject.
In some embodiments, any of the methods provided herein can be
employed to reduce a risk of MI across the various subtypes of MI related to plaque rupture,
smaller and larger MIs and both STEMI and , and/or types 1-4. Support for this can
be found in present e 24, for example. In some embodiments, subjects on one of the
combination therapies provided herein can have their LDL-C level lowered to less than 70,
less than 60, less than 50, less than 40, or, for example less than 30 mg/dL, which will allow
for a reduced risk of MI across various es of MI related to plaque rupture, r and
larger MIs and/or both STEMI, NSTEMI, type 1, type 2, type 3, and/or type 4. In some
embodiments, it is especially useful for STEMI, NSTEMI, type 1, and/or type 4 subtypes of
MI. In some embodiments, MS of various troponin thresholds can also be reduced in risk.
In some embodiments, any of the combination methods provided herein are especially useful
for subjects with elevated troponin. As outlined in the example below, in some
embodiments, one can employ the ation y to reduce MIs in ts with large
with Tn210>< ULN. Thus, the methods can be especially advantageous in subjects with
elevated troponin, and this can be used as a screen for ts that will have an additional
benefit from the method (e.g., 10 fold greater level of troponin, for example).
In some embodiments, a method of treating a subject is provided. The
method comprises providing a first therapy to a subject, wherein the first therapy comprises a
non-PCSK9 LDL-C lowering y, and administering a second therapy to the subject,
wherein the second therapy comprises a PCSK9 inhibitor. The subject has a y of stroke
and/or diabetes. The method can be combined with any of the other combination
embodiments provided herein.
For the embodiments provided herein regarding "stroke," the disclosure of
"stroke" discloses all embodiments related to , including "fatal stroke", "non-fatal
stroke", and both "fatal stroke" and "non-fatal stroke". Similarly, the disclosure of “fatal
stroke” also denotes the contemplation of the use of the method in non-fatal strokes or for the
broad use for both as well.
For the embodiments provided herein ing "MI," the disclosure of
"MI" discloses all embodiments related to MI, including "fatal MI", "non-fatal MI", and both
"fatal MI" and "non-fatal MI". Similarly, the disclosure of “fatal MI” also denotes the
contemplation of the use of the method in non-fatal MI or for the broad use for both as well.
For the embodiments provided herein regarding "coronary
revascularization," the disclosure of "coronary revascularization" ses all embodiments
related thereto, including: "urgent coronary ularization", "non-urgent coronary
revascularization", and both "urgent coronary revascularization" and "non-urgent coronary
revascularization". Similarly, the disclosure of “urgent coronary revascularization” also
denotes the contemplation of the use of the method in coronary revascularization or for the
broad use for both as well.
EXAMPLES
Introduction
The present example outlines and ts the results of the Global
Assessment of Plaque sion with a PCSK9 Antibody as Measured by Intravascular
Ultrasound (GLAGOV) trial. This trial assessed l principal scientific questions,
including: whether PCSK9 inhibition reduces progression of atherosclerosis and whether
achieving very low LDL-C levels with the combination of statins and a PCSK9 inhibitor
e incremental value in further ng the progression of coronary disease as
ed by IVUS. The results also demonstrated that the result of the combination therapy
(achieving very low LDL-C levels), not only reduces progression, but can actually reverse
the disorder.
Methods
Study Design
The GLAGOV trial was a randomized, multicenter, -blind,
institutional review boards at each site approved the protocol, and patients ed n
informed consent. The protocol and statistical analysis plan are available at
JAMAnetworkcom and the design of the trial has been described previously. 12
Patients aged 218 years were eligible if they demonstrated at least one
epicardial coronary stenosis 220% on clinically-indicated coronary angiography and had a
target vessel suitable for imaging with 550% visual obstruction. Patients were required to
have been treated with a stable statin dose for at least four weeks and to have a LDL-C 280
mg/dL or between 60 and 80 mg/dL with one major or three minor cardiovascular risk
factors. Major risk factors included non-coronary atherosclerotic vascular disease,
myocardial infarction or hospitalization for unstable angina in the preceding 2 years or type 2
diabetes mellitus. Minor risk factors included current tte smoking, hypertension, low
levels of high-density lipoprotein cholesterol (HDL-C), family y of premature coronary
heart disease, high sensitivity C-reactive protein (hs-CRP) 22mg/L or age 250 years in men
and 55 years in women. By design, patients with an entry LDL-C between 60-80 mg/dL were
limited to 25% of the total patient cohort. A four-week lipid stabilization period was included
for patients not currently taking lipid-modifying therapy at screening. Inclusion of patients
rant to statins was limited to 10% of the total cohort. ts were excluded if they
had uncontrolled diabetes or hypertension or heart failure, renal dysfunction or liver disease.
Patients were asked to identify race according to fixed categories ined by the study
ol, in order to evaluate potential differences in concomitant treatment and disease
progression.
Patients underwent randomization in a 1:1 allocation ratio with a block
size of 4 using an interactive voice response system to treatment with evolocumab 420 mg or
placebo administered monthly via subcutaneous ion for 76 weeks. During the treatment
period, patients underwent clinic visits at weeks 4, 12, 24, 36, 52, 64, 76 and repeat IVUS
imaging at week 78. A al events committee, blinded to treatment assignment,
adjudicated cardiovascular events. An independent, unblinded data monitoring committee,
led by an academic cardiologist, ed al trial safety during the study.
Acquisition and Analysis of Ultrasound Images
Following coronary angiography, ne intravascular ultrasonography
was performed. Previous reports have described the methods of image acquisition and
analys1s.~ 3,5,6,13-18 Imaging was performed in a single artery and screened by a core laboratory.
Patients meeting prespecified requirements for image quality were eligible for
randomization. At week 78, patients underwent a second ultrasonographic ation
within the same artery. Using digitized images, nel, unaware of the treatment ,
performed measurements of the lumen and al elastic membrane in images within a
matched artery segment. Measurement personnel were d to the sequence of imaging
studies (baseline vs. follow up). The accuracy and reproducibility of this method have been
reported previously.3’5’6’13'18
The y efficacy measure, t atheroma volume (PAV), was
calculated as follows:
2(EEA/Ima — Lumenarea)
PAV = X100
ZEEMarea
where EEMareal is the cross-sectional area of the external elastic membrane
and Lumenareal is the cross-sectional area of the lumen. The change in PAV was calculated as
the PAV at 78 weeks minus the PAV at baseline. A secondary measure of efficacy,
normalized total atheroma volume (TAV), was calculated as follows:
TA V —
iannumberofimagesin cohort
Number ofImages in Pullback
where the average plaque area in each image was multiplied by the median
number of images analyzed in the entire cohort to compensate for differences in segment
length between subjects. Change in normalized TAV was calculated as the TAV at 78 weeks
minus the TAV at baseline. Regression was defined as any decrease in PAV or TAV from
baseline.
Efficacy Endgoints
The y efficacy endpoint was the nominal change in PAV from
baseline to week 78 as described above. Secondary efficacy endpoints included, in
sequential order of g, l change in TAV from baseline to week 78 as described
above, any reduction of PAV from baseline and any reduction of TAV from baseline.
Exploratory endpoints ed the incidence of adjudicated events (all-cause mortality,
cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary
revascularization, stroke, transient ischemic attack [TIA], and hospitalization for heart
failure) and change in lipid parameters. Additional exploratory post hoc analyses included
comparison of the change in PAV and percentage of patients undergoing regression of PAV
in those with a LDL-C less than or r than 70 mg/dL at baseline. Locally weighted
polynomial sion (LOESS) curve fitting was performed to examine the association
between achieved LDL-C levels and disease progression.
Statistical Analysis
All statistical analyses were performed using SAS version 9.4 (SAS Inc,
Cary NC). For continuous variables with an approximately normal distribution, means and
standard deviations are reported. For variables not normally distributed, medians and
uartile ranges are reported. IVUS cy parameters are reported as least square
means (95% confidence intervals [CI]) and treatment groups compared using analysis of
covariance (ANCOVA) on rank-transformed data with adjustment for baseline value and
geographic region. On-treatment otein levels are reported as time-weighted means
(95% confidence intervals [CI) and ed using ANCOVA with adjustment for treatment
group and geographic region. eighted averages for each laboratory parameter were
created by the summation of the product between each measurement and time interval
n each visit divided by the total time.
A step down tical approach was applied to investigate the primary
and secondary endpoints. First the primary endpoint was tested at the 0.05 significance level,
then the secondary endpoints tested at the significance level of 0.05 in the sequential order as
listed in Section 4.1.2 in the tical analysis plan. A sensitivity analysis using multiple
tion was performed to impute missing primary endpoint data. The tion model
included variables for treatment group, background statin therapy intensity, region, baseline
LDL, baseline PAV, age and sex as covariates. Subgroup analyses on the primary endpoint
were conducted using subgroups specified in section 7.4 of the statistical analysis plan.
Subgroup by treatment interactions were tested. An additional exploratory analysis was
conducted in patients with baseline LDL-C less than or greater than 70 mg/dL.
For the change in the y efficacy parameter, PAV, a sample size of
356 subjects in each treatment group was required to provide 90% power at a two-sided
alpha of 0.05 to detect a l treatment difference of 0.71% assuming a 2.9% standard
deviation. A difference of 0.5% has been previously reported to distinguish ts who
. . 19 . .
experience cardiovascular events, from those who do not. Assuming a w1thdrawal rate of
%, 950 randomized patients were required. All reported p-values are 2-sided. A p-value
<0.05 was ered statistically significant.
Results
Subject teristics
The disposition of patients enrolled in the study is illustrated in Figure 1.
From May 3, 2013 to January 12, 2015, at 197 centers, 970 patients were randomized and
968 received study drug, 484 to the evolocumab treatment group and 484 to the o
group. 846 patients (87.2%) had evaluable IVUS g at both baseline and follow-up. Of
these patients, 423 were in the placebo group and 423 in the evolocumab group. Mean
eXposure to study drug was 17.6 months. Table 1 reports the baseline characteristics of
randomized patients.
Table 1. Baseline Characteristics of Subjects in the Randomized
Population who Received Study Drug (N=968)
meter umab N=484
-e 598:b O\
Malesn % 72.1%
Whiten % !!!34945694.2% cuS 29.4;1'11.
H oertensionn % 398 82. %
Previous PCIn % 189 39.0%
PreviousMIn % 169 34.9%
Smokingn % 124 25.6%
Diabetesn % 98 20.2%
Baseline statin usen % T 478 98.8%
High intensityn % 280 57.9%
te intensityn % 196 40.5%
Low intensityn % 2 0.4%
aseline ezetimibe usen % 9 2.1%
aseline medicationsn % T —
-_Anti-oolateletthera 454 93.8%
Beta-blocker 362 74.8%
ACE inhibitor 260 53.7%
87 18.0%
Age and BMI expressed as mean::standard deviation. T Baseline statin and ezetimibe use is
defined as subject treated with statin or ezetimibe therapy at the end of the lipid stabilization
period at randomization.
Table 1 (above) outlines the clinical characteristics and concomitant
medications of patients treated with placebo or evolocumab with evaluable imaging at
baseline and follow-up. Results sed as meanistandard deviation for continuous
variables and frequency (percentage) for categorical variables. ACE; angiotensin converting
; ARB; angiotensin receptor blocker; BMI; body mass index; MI; myocardial
infarction; PCI; percutaneous ry intervention.
At the time of randomization; 58.9% were receiving high intensity statin
and 39.4% moderate statin therapy with 1.4% of patients not treated with a . At
ne; patients had a mean LDL-C 27.2 mg/dL and median hsCRP of 1.6
(interquartile range 0.8; 3.4) mg/L. No significant differences in these parameters were
observed between patients who had evaluable follow-up IVUS imaging and those who did
not (see Table 1.1 ).
Table 1.1 Baseline Characteristics of Subjects in the Randomized Population who
Received Study Drug with and without Evaluable Follow-up IVUS Imaging (N=968)
Parameter IVUS (N=846)
g 59.631
Males n (%) 614 (72.6)
White 11 (%) 796 (94.1)
BMI 29.4:50
Diabetes 11 (%) 175 (20.7)
Hypertension 11 (%) 695 (82.2)
Smoking n (%) 32 (26.2) 205 (24.2)
Previous MI 11 (%) 287 (33.9)
IAnti-platelet therapy 115 (94.3) 804 (95.0)
I Beta-blocker 88 (72.1) 644 (76.1)
ACE inhibitor 66 (54.1) 458 (54.1)
ARB 18 (14.8) 161 (19.0)
Age and BMI expressed as standard deviation. T Baseline medication use is defined as
subject treated with statin or ezetimibe therapy at the end of the lipid stabilization period at
randomization.
Biochemical Measurements
Table 2 below summarizes the baseline and on-treatment tory values
for the 846 patients who underwent follow-up IVUS imaging. During 78 weeks of treatment,
time-weighted mean LDL-C levels were 93.0 mg/dL (a 3.9% change from baseline, resulting
in a 90 mg/dL of LDL-C)in the placebo group and 36.6 mg/dL (a -59.8% change from
baseline, resulting in 29 mg/dL of LDL-C)in the evolocumab group (P<0.001), representing
an increase in LDL-C by 0.5 mg/dL in the placebo group compared with a decrease by 56.1
mg/dL in the umab group, n groups difference -56.5 mg/dL (95% CI -59.7, -
53.4, P<0.001). (Figure 2) Evolocumab-treated patients trated greater reductions in
apoB (-38.8 vs. +2.7 mg/dL, between groups difference -40.6 mg/dL [95% CI -42.9, -38.3],
P<0.001), triglycerides (-9.6 vs. +5.6 mg/dL, n groups difference -19.1 mg/dL [95%
CI -27.5, -10.6], P<0.001) and Lp(a) (-3.8 vs. —0.2 mg/dL, between groups difference -6.7
mg/dL [95% CI -7.9, -5.5], P<0.001) and greater increases in HDL-C levels (+4.0 vs. +1.2
mg/dL, between groups difference 2.5 mg/dL [95% CI 1.7, 3.4], P<0.001). Median hsCRP
levels during treatment were 1.4 mg/L (IQR 0.7, 3.0) in the placebo group and 1.4 mg/L
(IQR 0.7, 3.0) in the evolocumab group, P=0.48.
Table 2
On-Treatment Absolute Change
Parameter Placebo Evolocumab P o Evolocumab P Placebo Evolocumab P
N=484 N=484 Value@ N=484 N=484 Value@ N=484 N=484 Value@
Total
166.2 169.1 1.8 (-2.0, -59.0 (-62.8, -
crlgol/efierol 166.1 (34.1) a 108.6 (29.8) <0.001 <0.001
(34.2) (31.5) 5.6) 55.2)
92 4 93 0 0 2 (-2 9 -56 3 (-59 4 -
crlgol/efierol 92.6 (27.5) 0.95 36.6 (23.5) <0.001 <0.001
(26.9) (26.8) 3.4) 53.1)
Baseline On-Treatment Absolute Change
<0.001 3..,.3(2441)
105.1 (82. 5 8.1 (-0.4, -19.1 (-27.5. -
1 20. 8 1.1 (-2.7, -62.3 (-66.0
119. 4 (32.0) 57.7 (28.4) <0.001
(32 2) 4.8) -58.5)
Total/HDL -.-.01( -1.6,-
9)..9(11) 3.7(1.)1 0.10 2.3(0.8)
cholesterol 2004) (4)
100B (m)9/dL)” 81.1 (2.02) 0.55 424(178) <0.001 032162-01'40-2é'32-6"
236.05140'5 2.5 3) 0. 55 151. 6 (23. 4) <0,001 8.5 (6.5, 10.5)
m/dL 5.5
-0.02(-
(860) '0'31'0-331'
poB/A-I 0.59 0.)(18 38 . . <0.001 0.04,-
0.001
hsCRP((mg/L) -0.3(- -0.4(-1.3,
”4 .8 0.6
_C) 0') (.11
Glucose 107.3 109.4
104.0 2(41 110.1 (2.)56
mo/dLT‘Ii . 7.8(53, 10.4)
0.2.,(015
HbA1c(%)‘|l 5.9.(09) 5807 _C) .p.p
Systolic BP 129. 6 131. 9
131.4 (1.49 0.07 131.5( 11.5
mmH . -1.-3(2.90.4)
Diastolic BP 76. 7 78. 5 2. 2 (.1 0, 0.9 (-0.2,
78.0 (9.6) 0. 03 78.6 7(.1)
mmH 1.99
@ P value for between treatment group comparison. Baseline laboratory variables are
presented using means and standard deviation except where indicated. 1 Median and
interquartile range are presented for non-normally distributed parameters and tested using
Wilcoxon rank-sum test. I On-treatment tory parameters are the time-weighted
es (::standard error) of all post-baseline values and estimates are derived from an
ANOVA model with s for treatment group and region. 1) Final measurements are used
for on-treatment values Absolute changes are presented as least square means (95%
confidence intervals). >“When the calculated LDL-C is <40 mg/dL or triglycerides are >400
mg/dL, ultracentrifugation LDL-C was determined from the same blood sample. # Lp(a)
converted from nmol/L to mg/dL by dividing by 2.8. Table 2 shows baseline and time-
weighted average on-treatment values and percentage changes of tory measures and
blood pressure of patients d with o or evolocumab with evaluable imaging at
baseline and -up. Results expressed as meanistandard deviation at baseline and least-
square meanistandard error for on-treatment values. Apo; apolipoprotein; BP; blood
pressure; HbAlc; glycosylated hemoglobin; HDL; ensity lipoprotein; hsCRP; high
sensitivity C-reactive protein; LDL; low-density lipoprotein; Lp(a); lipoprotein (a); PCSK9;
proprotein convertase subtilisin keXin type 9.
Primary and Secondary IVUS Endgoints
Changes in IVUS measures of plaque burden are summarized in Table 3
below. Table 3 es the primary and secondary end points as evaluated on intravascular
ultrasonography at baseline and 78-week follow-up with changes from baseline. s
eXpressed as meaniSD and median (95% confidence interval) for uous variables and
percentage for categorical variables at baseline and follow-up. Change in parameters
eXpressed as least square meanistandard error.
Table 3. Primary and Secondary Study End Points as Evaluated on Intravascular
Ultrasonography.
Between
Evolocumab
ter o (N=423) Group
(N=423)
Differences
Percent Atheroma Volume (%)
MeaniSD 37.2i8.5 36.4i8.7 -0.76 (-1.9, 0.4)
Median ) 37.1 (36.0, 38.0) 36.4 (35.5, 37.5)
Total Atheroma Volume (mm3)
MeaniSD 191 .4i85.7 187.0:r81.8 -4.3 (-15.6, 7.0)
Median (95%CI) 175.8 (164.0, 187.4 174.6 (164.1, 183.1)
Follow-up at 78 weeks
Percent Atheroma Volume (%)_
37.3ir8.2 35.6:r82 -1.7 (-2.8, -0.6)
I__-_
Change from baseline
Between
Percent Atheroma Volume (%) groups P
ValueT
ILSmean 9(5AJCI) -1. 01
0 0.0(5-0.32, 0.4)2 _0.9(5-1.33, -0.)58 <0.001
(-1.,78 0.64)
P value for change from
P=0.78 P<0.001
baseIIne
Total ma Volume (mm3)
ILSmean (9)5%C| -.,3291.4)7 -5.(808-.1,9 3-.4)1 3 25 <0.001
IP value for change from
P'045 P<0. 001 _
baseline
Percentage of opatients with
17.0 (10.4
regression percent 47. 3 4.2 5, 52.0) 64. 2 5.9 7, 68. 9) 23( 6) <0.001
atheroma f % 95% Cl
Percentage of patients with
sion of total atheroma 48.9 (44.2, 53.7) 61.3 (56.8, 66.1) 12.5 (5.9, 19.2) <0.001
volume % 95%Cl
T The p-Value for comparison between treatments for change from baseline were generated
from an analysis of covariance.
The primary efficacy measure, PAV, did not change in the placebo group
(+0.05%, P=O.78 compared with baseline) and decreased by 0.95% in the umab group
(P<0.001 compared with baseline; between groups difference -1.01% (95% CI -1.78, 0.64)
P<0.001). The secondary efficacy measure, TAV, did not change in the placebo group (-0.9
mm3, P=0.45 compared with baseline) and decreased by 5.8 mm3 in the evolocumab group
(P<0.001 ed with baseline; between groups difference -4.9 mm3 [95% CI -7.3, 2.5]
P<0.001). More evolocumab-treated patients exhibited PAV regression with 64.2% vs.
47.3%, P<0.001) and TAV regression with 61.3% vs. 48.9%, P<0.001). For all prespecified
-lOO-
subgroups, there was no statistical evidence of interaction (Figure 3). Specifically, there was
no difference in treatment effect observed in patients fied ing to baseline LDL-C.
Imputation modeling for patients that did not have evaluable IVUS imaging at follow up
demonstrated similar findings with a decrease in PAV with placebo (-0.02%) and
evolocumab (-1.05%), n groups difference -1.03% (95% CI -1.51, -0.55), P<0.001.
Exgloratory PostHoc es
In 144 patients with a baseline LDL-C <70 mg/dL, evolocumab treatment,
compared with placebo, was associated with favorable effects on the change in PAV (-1.97%
vs. , between groups difference -1.62% [95% CI -2.50, -0.74], P<0.001). In this
subgroup, the percentage of patients with regression of PAV for evolocumab compared with
placebo was 81.2% vs. 48.0%, between groups difference 33.2% [95% CI 18.6, 47.7]
1). (Figure 4A, black bars represent statin ed with umab, white bars are
statin monotherapy). The change in PAV for statin monotherapy was 0.05%, the change in
PAV for statin+evolocumab was -0.95% (across all groups treated). A similar ation
was observed for the TAV secondary endpoint. (Figure 4B black bars represent statin
combined with evolocumab, white bars are statin monotherapy). The change in TAV for
statin monotherapy was -0.9%, and the change in TAV for statin + evolocumab was -5.8%
(across all groups treated). The right hand panel of Figure 4A depicts the percent of ts
with PAV regression (the sum of the <70 and 370 is monotherapy: 47.3% regressors, 52.7%
progressors; and statin + evolocumab: 64.3% regressors and 35.7% progressors). The right
hand panel of Figure 4B depicts the percent of subjects with TAV regression.
Figure 4C depicts the data from an exploratory subgroup of subjects
having a baseline LDL-C <70 mg/dL. The mean LDL-C was 70.6 mg/dL for the
monotherapy (a 16.4% change from baseline to end at 65.5 mg/dL) and 24.0 mg/dL for the
combination therapy (a -58.3% change to end at 15.0 mg/dL). Figure 4D s the data
from an exploratory subgroup having a baseline LDL-C of <70 mg/dL, showing the change
in PAV at -0.35% for the statin monotherapy and -1.97% for the combination therapy, with
48.0% showing regression on the monotherapy and 81.2% showing regression on the
combination therapy.
A LOESS plot showed a linear relationship between achieved LDL-C and
PAV progression for LDL-C levels g from 110 mg/dL to as low as 20 mg/dL. (Figure
, plot shows 95% confidence limits).
Exploratory Clinical Events and Laboratory Adverse Events
Table 4 describes centrally adjudicated al events, al adverse
events, laboratory abnormalities and reasons for study discontinuation. Table 4 summarizes
the clinical and laboratory adverse events and reasons for discontinuation in the safety
population. Results eXpressed as frequency (percentage). ULN, upper limit of normal.
Table 4. Clinical and Biochemical Adverse Events and Reasons
for Discontinuation in the Safety Population
N=484 N=484
Cardiovascular events — n (%) i __
Nonfatal myocardial infarction
Nonfatal stroke
Hospitalization for unstable angina
ry revascularization
First major adverse cardiovascular event
Clinically ant adverse events — n (%) __
ion site reaction
Neurocognitive events*
New diagnosis diabetes mellitus*
Abnormality in laboratory value — n (%) T __
Aspartate or alanine aminotransferase >3XULN
Total bilirubin >2XULN
Creatine phosphokinase >5XULN 3 (0.7%) 3 (0.7%)
Creatinine >ULN
Anti-Evolocumab binding antibody N/A 1 (0.2%)
Anti-Evolocumab neutralizing antibody
Discontinuation from treatment — n (%)
Number of patients
o Evolocumab
Parameter
N=484 N=484
Reason for discontinuation
Preference of patient 21 (4.3%) 15 (3.1%)
Adverse event 7 (1 .4%) 15 (3.1%)
Lost to follow-up 2 (0.4%) 3 (0.6%)
Physician decision 2 (0.4%) 3 (0.6%)
Other 2 (0.4%) 3 (0.6%)
T The denominator for both placebo and evolocumab with normal value at baseline is 958.
There were a total of 10 subjects with missing safety laboratory data. 1 Total number of
cardiovascular events included 2 events occurring during the period between the last
scheduled visit and the end of safety assessment . >“Neurocognitive events and new
diagnosis diabetes mellitus as reported by investigators as adverse . N/A: not
applicable.
Although the study was not powered to assess effects on cardiovascular
events, exploratory analysis revealed numerically fewer adverse cardiovascular outcomes
(12.2% vs. 15.3%), non-fatal myocardial infarction (2.1% vs. 2.9%) and coronary
revascularization (10.3% vs. 13.6%) in the evolocumab versus placebo groups.
Administration of evolocumab was well tolerated with no significant excess in rate of
injection site ons (0.4% vs. 0%), myalgia (7.0% vs. 5.8%) and ognitive events
(1.4% vs. 1.2%). The rates of laboratory alities were low in both groups. Only 1
patient (0.2%) developed anti-evolocumab antibodies and none had neutralizing antibodies
ed. Glycosylated hemoglobin levels did not change in either treatment group.
Discussion of Examgle 1
The above trial demonstrated that addition of the PCSK9 inhibitor
evolocumab in patients treated with moderate or ive statin therapy (a combination
therapy) had a favorable effect on progression of coronary atherosclerosis as measured by
IVUS. Both the primary and secondary IVUS efficacy measures showed atherosclerosis
regression during 18 months of therapy in patients d with the combination of
evolocumab and statins and absence of regression in patients treated with a statin alone.
Compared with baseline, for the primary IVUS endpoint, PAV, patients in the placebo
treatment group demonstrated no se in atheroma burden (+0.05%, P=0.78) whereas
patients in the evolocumab group showed a significant reduction in PAV (-0.95%, P<0.001),
between-groups difference of , P<0.00l. Similar results were observed for the
principal secondary endpoint, TAV (between groups ence -4.9mm3, P<0.001). These
gs provide evidence that PCSK9 tion produces incremental benefits on coronary
disease progression in statin-treated patients.
The percentage of patients demonstrating sion of coronary
atherosclerosis, defined as any change in PAV or TAV less than zero was evaluated. Using
this definition, for the primary endpoint, PAV, approximately 47% of patients in the placebo
group experienced regression, compared with 67% of the treatment group receiving the
combination of a statin and PCSK9 inhibitor (between groups ence 17.0%, P<0.001).
Similar results were observed for TAV with more patients ing regression with
combination y, (between groups difference 12.5%, P<0.001). This is the first clinical
trial to show incremental effects on regression in patients who had been treated with
moderate or intensive statin therapy prior to entry into the study. It is also the first
demonstration of a reduction in atherosclerotic disease progression by IVUS for a atin
LDL lowering therapy.
After demonstrating major clinical benefits in multiple large outcomes
trialsl9-22, statins are considered ial in global guidelines for ng patients with
clinically manifest coronary heart disease23,24. However, many patients do not achieve
optimal LDL-C reduction25 or experience cardiovascular events despite statin therapy.27
Furthermore, some patients report inability to tolerate full therapeutic doses of statins.27
Inadequate LDL-C reduction and presence of high residual risk suggests that additional
therapies could be useful. PCSK9 regulation of hepatic LDL receptor expression has
provided a potentially useful target for therapeutic modulation to s residual
cardiovascular risk in statin-treated patients, particularly with the observation that PCSK9
levels rise in response to statin administration.28 In the current trial, almost every patient was
treated with a statin prior to study entry and addition of the PCSK9 tor, evolocumab,
provided incremental reduction in LDL-C levels and ma .
Favorable effects were observed in the Trial summarized in Example 1 on
e progression without an increase in the incidence of myalgias, elevations in hepatic
transaminases or new onset diabetes. However, the number of treated patients was relatively
—104—
small. Subcutaneous injections were well tolerated, with injection site reactions reported in
only two evolocumab—treated patients, a low rate of detection of anti-drug antibodies and no
neutralizing antibodies. These safety findings are consistent with prior ations showing
no apparent excess in adverse events in statin-treated patients achieving very low LDL-C
levels.
Subgroup analyses showed no heterogeneity in the favorable effects of
PCSK9 inhibition on disease progression. Regression with evolocumab was observed
regardless of baseline LDL-C levels. An LDL-C of 70mg/dL represents the most stringent
target level recommended by any global guideline for cholesterol ent.24,25 In patients
with a baseline LDL-C <70 mg/dL, post hoc analysis in the current trial demonstrated
regression in PAV in >80% of patients with combination therapy. This observation is
tive of current treatment guidelines recommending intensive lipid lowering in patients
at high cardiovascular risk.23,24 These findings are reassuring from a safety ctive.
The definitive evidence supporting PCSK9 inhibitors as a clinically
effective therapeutic strategy relies on the ability of these drugs to reduce vascular
adverse events. Prior s have demonstrated an association n both the burden and
rate of progression of coronary sclerosis and cardiovascular outcomes.30,3l While the
current gs of the effect of evolocumab on disease progression are promising,
completion of ongoing large vascular outcome trials of PCSK9 inhibitors can provide
further conformation of the cy and safety of these drugs.
The majority (approximately two-thirds) of patients achieved atheroma
regression, despite achieving very low LDL-C levels with umab. However, the Trial in
Example 1 evaluated patients following 18 months of treatment, a relatively short on of
therapy in comparison with other recent studies of high intensity statin treatment which
treated patients for 24 months. It s possible that a greater percentage of patients would
demonstrate regression at these low LDL levels with more prolonged ent.
The above trial examined the effects of PCSK9 inhibition on disease
progression in patients presenting for a clinically indicated coronary angiogram. It is
assumed that similar effects will be observed in asymptomatic patients with manifest
atherosclerosis. While patient retention (87%) was better than previous IVUS studies, as in
any study, the results may have been influenced by patients who did not complete the trial.
During the two s following the seminal observations that statins
reduce adverse cardiovascular outcomes, there has been an ongoing search to identify
additional therapies that produce incremental clinical benefit. The PCSK9 inhibitor,
evolocumab, d LDL-C to very low levels resulting in marked regression of coronary
sclerosis. While the large outcomes trials of PCSK9 inhibitors are in progress, the
current findings indicate that combining a PCSK9 inhibitor with statins provides substantial
incremental reduction in disease progression over a broad range of baseline LDL levels.
To summarize the results in Example 1, among the 968 treated patients,
(mean age, 59.8 [9.2], 269 [27.8%] women, LDL-C 92.5 mg/dL [27.2]), 846 had evaluable
imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean,
time-weighted LDL-C levels, 93.0 vs. 36.6 mg/dL, difference -56.5 mg/dL (95% confidence
interval [CI] -59.7, -53.4), P<0.001. The y efficacy parameter, PAV increased 0.05%,
with placebo and decreased 0.95%, with evolocumab, difference -l.01% (95% CI -1.78,
0.64), P<0.001. The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3
with placebo and 5.8 mm3 with evolocumab, difference -4.9 mm3 (95% CI -7.3, 2.5),
P<0.001). umab d plaque regression in a greater percentage of patients than
placebo, for PAV, 64.3% vs. 47.3%, P<0.001 and for TAV 61.5% vs. 48.9%, 1.
Among patients with angiographic coronary disease treated with statins,
addition of evolocumab, compared with o, resulted in greater decrease in PAV after 78
weeks Evolocumab was well tolerated with a low incidence of laboratory safety
abnormalities and cardiovascular events. The combined therapy not only prevented disease
ssion, but actually reversed it, in terms of PAV and TAV.
The above results confirm that lower LDL-C levels were observed in the
evolocumab combined therapy group (36.6 vs. 93.0 mg/dL), which was associated with a
reduction in percent atheroma volume for evolocumab (-0.95%), but not o (+0.05%)
and a greater percentage of patients demonstrating plaque regression (64.3% vs. 47.3%).
Thus, addition of the PCSK9 inhibitor, evolocumab, to statin therapy produced greater LDL-
C lowering and ma sion. Furthermore, the data indicates that any treatment that
achieves LDL-C levels as low as 20mg/dL will show a benefit for the subject. In addition,
the above benefits also support an approach where benefits are ed by lowering LDL-C
levels below the lowest levels currently recommended by global guidelines (<70mg/dL). No
-lO6-
safety issues were identified at the mean LDL-C levels of 36.6 mg/dL achieved in the trial,
including: no excess in new onset diabetes, no myalgias, and no neurocognitive adverse
effects.
1. LaRosa IC, Grundy SM, Waters DD, et al. Intensive lipid lowering with
statin in patients with stable coronary disease. N Engl] Med.
2005;352(14):1425-1435.
Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and
safety of more intensive lowering of LDL cholesterol: a meta-analysis of data
from 170,000 participants in 26 randomised trials. Lancet.
2010;376(9753):1670-1681.
Nicholls S], tyne CM, Barter P], et al. Effect of two intensive statin regimens
on ssion of coronary disease. NEngI] Med. 2011;365(22):2078-2087.
Nicholls S], Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol,
and regression of coronary atherosclerosis.]AMA. 2007;297(5):499-508.
Nissen SE, Nicholls S], Sipahi I, et al. Effect of very high-intensity statin therapy
on regression of coronary atherosclerosis: the ASTEROID trial/AMA.
2006;295(13):1556-1565.
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect nsive compared with
moderate lipid-lowering therapy on progression of coronary atherosclerosis: a
randomized controlled trial/AMA. 2004;291(9):1071-1080.
Abifadel M, Varret M, Rabes JP, et al. ons in PCSK9 cause autosomal
dominant hypercholesterolemia. Nature genetics. 2 003;34(2) : 1 54-1 56.
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Maxwell KN, Breslow IL. Adenoviral-mediated expression of Pcsk9 in mice
results in a low-density lipoprotein receptor knockout phenotype. Proc Natl
Acad Sci USA. 2004;101(18):7100-7105.
Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase
neural apoptosis-regulated tase 1 (NARC-1): liver regeneration and
neuronal differentiation. Proc NatIAcad Sci USA. 2003;100(3):928-933.
. on IG, Nedergaard BS, Rogers W], et al. Effect of umab or ezetimibe
added to moderate- or high-intensity statin therapy on LDL-C lowering in
patients with holesterolemia: the LAPLACE-Z randomized clinical trial.
]AMA. 2014;311(18):1870-1882.
11. Blom D], Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of
evolocumab in hyperlipidemia. NEngI] Med. 2014;370(19):1809-1819.
12. Puri R, Nissen SE, Somaratne R, et al. Impact ofPCSK9 inhibition on coronary
atheroma progression: Rationale and design of Global Assessment of Plaque
Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound
V).Am Heart]. 76:83-92.
13. Nissen SE, Nicholls S], Wolski K, et al. Comparison of tazone vs glimepiride
on progression of coronary atherosclerosis in ts with type 2 diabetes: the
PERISCOPE randomized controlled trial/AMA. 2008;299(13):1561-1573.
14. Nissen SE, Nicholls S], Wolski K, et al. Effect of rimonabant on progression of
atherosclerosis in patients with abdominal obesity and ry artery disease:
the STRADIVARIUS randomized controlled trial/AMA. 2008;299(13):1547-
1560.
. Nissen SE, TardifIC, Nicholls S], et al. Effect oftorcetrapib on the progression of
ry atherosclerosis. N Engl] Med. 2007;356(13):1304—1316.
16. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on
coronary atherosclerosis in patients with acute coronary syndromes: a
randomized controlled trial/AMA. 2003;290(17):2292-2300.
17. Nissen SE, Tuzcu EM, Brewer HB, et al. Effect of ACAT inhibition on the
progression of coronary atherosclerosis. N Engl] Med. 2006;354(12):1253-1263.
18. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on
cardiovascular events in patients with coronary disease and normal blood
pressure: the CAMELOT study: a randomized controlled trial. ]AMA.
2004;292(18):2217-2225.
19. ised trial of cholesterol lowering in 4444 patients with coronary heart
disease: the Scandinavian Simvastatin Survival Study (4S). Lancet:
1994;344(8934):1383-1389.
. Prevention of cardiovascular events and death with pravastatin in patients with
coronary heart disease and a broad range of initial cholesterol levels. The Long-
Term ention with Pravastatin in Ischaemic Disease ) Study Group. N
Engl] Med. 1998;339(19):1349-1357.
21. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary
events after myocardial infarction in ts with average cholesterol levels.
Cholesterol and ent Events Trial investigators. N Engl] Med.
1996;335(14):1001-1009.
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22. Shepherd], Cobbe SM, Ford 1, et al. Prevention of coronary heart disease with
pravastatin in men with hypercholesterolemia. West of Scotland Coronary
Prevention Study Group. NEngI] Med. 1995;333(20):1301-1307.
23. Stone N], Robinson IG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the
ent of blood cholesterol to reduce atherosclerotic cardiovascular risk in
adults: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines/Am Coll Cardiol. 2014;63(25 Pt
9-2934.
24. Catapano AL, Graham 1, De Backer G, et al. 2016 S Guidelines for the
Management of Dyslipidaemias: The Task Force for the Management of
Dyslipidaemias of the European y of logy (ESC) and European
Atherosclerosis Society (EAS)Developed with the special contribution of the
European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR).
Eur Heart]. 2016.
. Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal
attainment in statin-treated subjects from 3 data s: a retrospective
analysis.]0urna10fthe American HeartAssociation. 2012;1(6):e001800.
26. Libby P. The forgotten majority: unfinished business in cardiovascular risk
reduction/Am Coll l. 2005;46(7):1225-1228.
27. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and Tolerability of
Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance:
The GAUSS-3 Randomized Clinical Trial.]AMA. 2016;315(15):1580-1590.
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28. , Dewpura T, Raymond A, et al. Plasma PCSK9 levels are significantly
modified by statins and fibrates in humans. Lipids in health and e.
2008,'7:22.
29. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, ald E. Can low-
density lipoprotein be too low The safety and efficacy of achieving very low low-
density lipoprotein with intensive statin therapy: a PROVE I 22 substudy.
]Am Coll Cardiol. 2005;46(8):1411-1416.
. Nicholls S], Hsu A, Wolski K, et al. Intravascular ultrasound-derived measures of
coronary atherosclerotic plaque burden and clinical outcome. ]Am Coll Cardiol.
2010;55(21):2399-2407.
31. Puri R, Nissen SE, Shao M, et al. Coronary atheroma volume and vascular
events during maximally intensive statin therapy. Eur Heart].
2013;34(41):3182-3190.
EXAMPLE 2
Uses of PCSK9 Antibodies and Statins for the reduction of
sclerosis
A human subject at risk of developing atherosclerosis is identified. The
subject is administered a therapeutically effective amount of evolocumab, with a statin at an
optimized level of statin administration. The combined therapy is maintained for at least one
year. Throughout the year, the subject’s LDL-C levels drop h 90 mg/dL, thereby
reducing their risk of atherosclerosis in comparison to patients not receiving the treatment.
EXAMPLE 3
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A patient with clinically t atherosclerotic cardiovascular (CV)
disease is identified. The patient is administered a therapeutically ive amount of
evolocumab, with 40 mg/day of atorvastatin (or an equivalent thereto). The combined
therapy is maintained for at least one year. Throughout the year, the subject’s LDL-C levels
drop beneath 90 mg/dL, thereby reducing their risk of CV death, non-fatal dial
infarction, non-fatal stroke or transient ischemic attack (TIA), and coronary
revascularization.
ED<ALJPII34
A patient with clinically evident atherosclerotic cardiovascular (CV)
disease is fied. The patient is administered 420 mg/month of umab, with 80
mg/day of atorvastatin (or an equivalent thereto). The combined therapy is maintained for at
least one year. The ed therapy y reduces their risk of CV death, non-fatal
myocardial infarction, non-fatal stroke or transient ischemic attack (TIA), coronary
revascularization, and hospitalization for unstable angina.
ED<AAJPII35
A patient having atherosclerotic plaque is identified. The patient is
administered evolocumab, with an amount of a statin that is equivalent to 40, or in the
alternative, 80 mg/day of atorvastatin. The ed therapy is maintained for at least one
year. The combined therapy thereby reduces the patient’s PAV.
ED<AAJPII36
A patient having atherosclerotic plaque is identified. The patient is
administered evolocumab, with an amount of a statin that is equivalent to 40, or in the
alternative, 80 mg/day of atorvastatin. The combined therapy is maintained for at least one
year. The combined therapy y s the patient’s TAV.
ED<AAJPII37
A patient having coronary atherosclerosis is identified. The patient is
receiving a non-PCK9 LDL-C lowering therapy (e.g., a statin). The patient is administered a
PCSK9 inhibitor therapy. The amount and time of the PCSK9 inhibitor therapy (e.g., an
CSK9 neutralizing antibody), combined with the continued application of the non-
PCK9 LDL-C lowering therapy, is sufficient to reverse coronary atherosclerosis in the
subj ect.
ED<AAJPII38
A patient having coronary artery e is identified. The t is
administered an amount of an anti-PCSK9 neutralizing antibody and a maXimally tolerated
dose of a statin. The combined therapy is maintained for at least one year. The combined
therapy thereby reduces the patient’s TAV and PAV.
ED<AAJPII39
A patient having atherosclerosis is identified. The patient is administered
an amount of an anti-PCSK9 neutralizing antibody and a maXimally tolerated dose of a
statin. The combined y is maintained for at least one year such that the patient’s LDL-
C level is maintained beneath 90 mg/dL. The ed therapy thereby reduces the patient’s
TAV and PAV.
PIIEIO
A patient having plaques and/or atherosclerosis is fied. The t
is administered an amount of a PCSK9 inhibitor and a maXimally tolerated dose of a statin.
The combined therapy is maintained for at least one year such that the patient’s LDL-C level
is beneath 60 mg/dL. The combined therapy thereby results in plaque regression and
regression in atherosclerosis.
EDCADAPIJEII
A patient having atherosclerosis is fied. The patient is administered
an amount of a PCSK9 inhibitor and an optimized dose of a statin. The combined therapy is
ined for at least one year such that the patient’s LDL-C level is beneath 60 mg/dL.
The combined therapy thereby results in regression in atherosclerosis.
EXAMPLE 12
-ll3-
A subject at risk of developing atherosclerosis is identified. The subject is
administered an amount of a PCSK9 inhibitor and an optimized dose of a statin. The
combined therapy is maintained for at least one year such that the subject’s LDL-C level is
beneath 60 mg/dL. The combined therapy thereby results in decreasing the risk that the
subject will develop atherosclerosis.
EXAlVlPLE 13
A t having sclerosis is identified. The patient is administered
an amount of a PCSK9 inhibitor in an amount and time such that the patient’s LDL-C level is
maintained beneath 60 mg/dL for at least one year. The therapy thereby results in regression
in atherosclerosis.
EXAlVlPLE 14
A patient having atherosclerotic plaque is fied. The patient is
administered an amount of a PCSK9 inhibitor in an amount and time such that the patient’s
LDL-C level is maintained between 20 mg/dL and 40 mg/dL for at least one year. The
therapy thereby s in regression in the atherosclerotic plaque.
EXAlVlPLE 15
A patient having sclerotic plaque is identified. The patient is
stered an amount of a statin in an amount and time such that the patient’s LDL-C level
is maintained between 20 mg/dL and 40 mg/dL for at least one year. The therapy thereby
results in regression in the atherosclerotic plaque.
EXAlVlPLE 16
A patient having atherosclerotic vascular disease is identified. The
patient is administered an amount of a statin in an amount and time such that the patient’s
LDL-C level is maintained between 20 mg/dL and 50 mg/dL for at least two years. The
therapy y results in a 15% ion in the risk of the composite of cardiovascular
death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary
revascularization and a 20% reduction in the risk of the cardiovascular death, myocardial
infarction, or stroke.
EXAIVIPLE 17
A randomized, double-blind, placebo-controlled trial was conducted
involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol
270 mg/dL or non-HDL 3100 on statin therapy. Patients were randomized to receive
evolocumab (either 140mg every 2 weeks or 420mg monthly) or matching placebo injections
subcutaneously. The primary efficacy endpoint was the composite of cardiovascular death,
myocardial infarction, stroke, hospitalization for unstable angina, or coronary
revascularization, whichever occurs first. The key secondary efficacy endpoint was the
composite of cardiovascular death, myocardial infarction, or stroke, whichever occurs first.
Median up was 2.2 years.
Summary of Results: Evolocumab lowered LDL cholesterol by 59%,
from a median of 92 to 30 mg/dL (P<0.001). Evolocumab significantly reduced the risk of
the primary endpoint [1344 (9.8%) vs. 1563 (11.3%) patients, HR 0.85, 95%CI 0.79—0.92,
P<0.001] and the key secondary endpoint [816 (5.9%) vs. 1013 (7.4%) patients, HR 0.80,
95%CI 0.73—0.88, 1]. Results were consistent across key ups, including those
in the lowest quartile of baseline LDL terol (median 74 mg/dL). The nce of
adverse events including muscle-related, diabetes and ognitive were r in the two
arms.
Summary of Conclusions: Inhibition of PCSK9 with evolocumab on a
background of statin therapy lowered LDL cholesterol to 30 mg/dL and reduced the risk of
cardiovascular events with no major safety concerns. These findings demonstrate that
ts with atherosclerotic cardiovascular disease benefit from LDL cholesterol lowering
below t targets.
The t example outlines the results of a study ed “Further
cardiovascular es Research with PCSK9 Inhibition in subjects with Elevated Risk”
(FOURIER). FOURIER was a dedicated cardiovascular outcomes trial that tested the
clinical cy and safety of evolocumab when added to high or moderate intensity statin
therapy in ts with clinically evident atherosclerotic vascular disease.
DETAILED DISCUSSION OF THE METHODS OF EXAMPLE 17
Study Design
The present example (the “FOURIER ) was a randomized, double-
blind, placebo-controlled multinational clinical trial that randomized patients at 1,242 sites in
49 ies.
Study Population
Eligible patients were between 40 and 85 years of age with ally
t atherosclerotic cardiovascular disease, defined as a history of dial infarction,
non-hemorrhagic , or symptomatic eral artery disease, and additional
characteristics that placed them at higher cardiovascular risk (full eligibility criteria in the
Supplementary Appendix). Patients must have had a fasting LDL cholesterol 270 mg/dL or a
L cholesterol of 2100 mg/dL on an optimized stable lipid-lowering therapy,
preferably a high intensity statin, but must have been at least atorvastatin 20 mg daily or
equivalent, with or without ezetimibe.
Randomization and Study Treatment
Eligible patients were randomized 1:1 to receive either evolocumab (either
140 mg every 2 weeks or 420 mg every month according to patient preference) or matching
placebo injections subcutaneously. ized allocation of study treatment was performed
via a central computerized system with stratification by final screening LDL cholesterol (<85
vs 2 85 mg/dL) and region, and was double-blind.
End Points
The primary efficacy end point was major cardiovascular events defined
as the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for
unstable angina, or coronary revascularization. The key secondary efficacy endpoint was the
composite of cardiovascular death, myocardial infarction, or stroke. Other efficacy endpoints
are listed in the Supplemental section of Example 17. Safety was assessed through collection
of adverse events and l laboratory g (see Supplemental section of Example 17).
Descriptions of the endpoints are in the Supplementary section of Example 17.
-ll6-
Statistical Considerations
The primary efficacy analysis was based on the time from randomized
treatment assignment to the first occurrence of any element of the primary composite
endpoint. If the primary endpoint was icantly reduced (P<0.05), then, in a hierarchical
n, the key secondary endpoint and then cardiovascular death were to be tested at a
icance level of 0.05. See the Supplementary section in Example 17 for further details.
All cy es were conducted on an intention-to-treat basis. Safety evaluations
included all randomized patients who received at least one dose of study treatment and for
whom post-dose data are available. Trial sample size was based on the key secondary
endpoint, and it was estimated that 1630 such end points were required to provide 90%
power to detect a 15% relative risk reduction with evolocumab. (Sabatine MS, Giugliano RP,
Keech A, et a1. Rationale and design of the Further cardiovascular OUtcomes Research with
PCSK9 Inhibition in subjects with Elevated Risk trial. Am Heart J 2016;173:94-101.)
Hazard ratios and 95% confidence intervals were generated using a CoX proportional hazards
model with stratification s as covariates, and P values for time-to-event analyses are
from log-rank tests.
S OF EXAMPLE 17
Patients
A total of 27,564 patients were randomized between February 2013 and
June 2015. The baseline characteristics of the ts in the two arms were well matched and
are shown in Table 17.1.
Table 17.1. Baseline Characteristics of the ts
Characteristics Evolocumab Placebo (N=13.780)
N=13.784
Age - yr 62.5J_r9.1 62.5i8.9
Male sex-no. % 10,397 75.4 10,398 75.5
White race-no. %T 11,748 85.2 11,710 85.0
Weight - kg 85.0i17.3 7.4
Reoion
North America 2,287 16.6 2,284 16.6
Eur0oe 8,666 8,669 62.9
Latin America 913 (6.6) 910 (6.6)
Characteristics Evolocumab Placebo (N=13.780)
N=13.784
Asia Pacific and South Africa 1,918 13.9 1,917 13.9
Toe of atherosclerosisi
M ocardial tion - no. % 11,145 80.9 11,206 81.3
Median time from most recent previous
m ocardial infarction IQR - r 3.4 1.0-7.4 3.3 7
Nonhemorrhao ic stroke 2686 19.5 2651 19.2
Median time from most recent previous
stroke IQR — r 3.2 1.1-7.1 3.3 1.1-7.3
Perioheral arte disease— no. % 1,858 13.5 1,784 12.9
Cardiovascular risk s
H oertension — ta| no. % 11,045/13,784 80.1 11,039/13,779 80.1
Diabetes mellitus — no. % 5,054 36.7 5,027 36.5
Current cioarette use — no./tota| no. % 3854/13,783 28.0 3923/13,779 28.5
Statin use — no. % TT
High intensity 9,585 (69.5) 9,518 (69.1)
Moderate intensi 4,161 30.2 4,231 30.7
Low intensi wn intensit ,or no data 38 0.3 31 0.2
ibe—no. % 726 5.3 714 5.2
Other cardiovascular medications — ta| no. %
Asoirin, P2Y12 inhibitor, or both 12,766/13,772 92.7 12,666/13,767 92.0
Beta-blocker 10,441/13,772 75.8 10,374/13,767 75.4
ACE inhibitor or ARB, a|dosterone antagonist, or
both 10,803/13,772 78.4 10.730/13,767 77.9
Median |ioid measures IQR
LDL cholesterol — mo/dl 92 80-109 92 80-109
Total cholesterol — mo/dl 168 151-188 168 9
HDL cholesterol — mo/dl 44 37-53 44 37-53
Triol cerides — mo/dl 134 101-183 133 99-181
Lio0orotein a — nmol/liter 37 13-166 37 13-164
*There were no nominally signficant differences between the two groups in baseline characteristics with
the exception of weight (P=0.01) and the use of aspirin, a P2le inhibitor, or both (P=0.03). To
convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To t the values for
triglycerides to millimoles per liter, ly by 0.01129. ACE denotes angiotensin-converting enzyme,
ARB antiotensin-receptor blocker, HDL high-density lipoprotein, IQR interquartile range, and LDL low-
density lipoprotein.
TRace was reported by the patients.
iPatients could have more than one type of atheroscloersis.
TT Statin intensity was categorized in accordance with the guidelines of the American e of
Cardiology and American Hearth Association.12
The average age of the ts was 63 years, 25% were women; 81% had
a history of myocardial infarction, 19% prior non-hemorrhagic stroke, and 13% matic
peripheral artery disease. At baseline a total of 69.3% patients were on high intensity statin
therapy (defined as per ACC/AHA guidelines (Stone NJ, Robinson JG, Lichtenstein AH, et
al. 2013 ACC/AHA guideline on the ent of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults: a report of the an College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation 29:S1-45.), see
Supplementary section in Example 17) and 30.4% on te intensity statin y; 5.2%
were also taking ezetimibe. Over the duration of the trial, only 9.8% of patients altered
background lipid-lowering therapy (see Supplemental section in Example 17, Results for
details). Use of secondary preventive therapies was high with 93% of patients taking
antiplatelet therapy, 76% taking beta-blockers, and 78% taking an ACE (angiotensionconverting
enzyme) inhibitor or ARB (angiotensin receptor blocker) and/or an aldosterone
antagonist at trial entry.
A total of 27,525 patients (99.9%) received at least one dose of study drug.
Premature permanent tinuation of study drug occurred in 12.5% of patients (5.7% per
annum), withdrawal of consent in 0.7% (0.3% per annum), and loss to follow up in <0.1%
(0.03% per , with similar rates in the two study groups (Figure 17). The median
duration of -up was 26 months (IQR 22—30) resulting in 59,865 patient years of
follow-up. Ascertainment of the primary end point was complete for 99% of potential
patient-years of follow-up.
Lipid Data
The median baseline LDL cholesterol was 92 mg/dL (IQR 80 to 109
mg/dL). Evolocumab as compared with placebo lowered LDL cholesterol by a mean of 59%
(95% CI 58 to 60, P<0.001) at 48 weeks, for a mean absolute reduction of 56 mg/dL (95% CI
55 to 57) to a median of 30 mg/dL (IQR 19 to 46 mg/dL). The reduction in LDL cholesterol
was maintained over time (Figure 15 and Figure 18). At 48 weeks the LDL cholesterol was
reduced to :70 mg/dL in 87%, 340 mg/dL in 67%, and 325 mg/dL in 42% of the
evolocumab group, as compared with 18%, 0.5%, and <0.1%, respectively in the placebo
group (P<0.001 for all treatment isons). Evolocumab rly lowered related
WO 89912
genic lipid measures, with placebo-controlled ions at 48 weeks of 52% in non-
HDL cholesterol and 49% in apolipoprotein B (P<0.001 for both). See Supplemental Results
in Example 17 and for further details.
Efficacy End Points
Evolocumab significantly reduced the risk of the primary composite end
point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable
angina, or coronary ularization. The primary endpoint occurred in 1344 ts (9.8%)
in the evolocumab arm and 1563 patients (11.3%) in the placebo arm (HR 0.85, 95% CI
0.79—0.92, P<0.001) (Table 17.2a and Figure 16A). For Figures 16A and 16B, the -
Meier rates for the primary endpoint at 1, 2, and 3 years were 5.3% (95% CI 4.9-5.7) vs.
6.0% (95% CI 5.6-6.4), 9.1% (95% CI 8.6-9.6) vs. 10.7% (95% CI 10.1-11.2), and 12.6%
(95% CI 11.7-13.5) vs. 14.6% (95% CI 13.8-15.5), tively for the evolocumab and
placebo arms. The Kaplan-Meier rates for the key secondary endpoint at 1, 2, and 3 years
were 3.1% (95% CI 2.8-3.4) vs. 3.7% (95% CI 3.4-4.0), 5.5% (95% CI 5.1-5.9) vs. 6.8%
(95% CI 6.4-7.3), and 7.9% (95% CI 7.2-8.7) vs. 9.9% (95% CI 9.2-10.7), respectively for
the evolocumab and o arms. P values were calculated using log-rank tests.
Table 17.2a
Outcome Evolocumab Placebo Hazard Ratio P Value*
(N=13,784) (N=13,780) (95% Cl)
no. of patients (%)
Primary end point: cardiovascular death, 1344 (9.8) 1563 (11.3) 0.85 (0.79-0.92) <0.001
myocardial infarction, stroke, hospitalization
for unstable angina, or coronary
revascularization
Key secondary end point: cardiovasculardeath, 816 (5.9) 1013 (7.4) 0.80 (0.73-0.88) <0.001
myocardial infarction, or stroke
Other end points
Cardiovascular death 251 (1.8) 240 (1.7) 105 (0.88-1.25) 0.62
Due to acutem ocardial infarction 25 0.18 30 0.22 0.84 0.49-1.42
Due to stroke 31 0.22 33 0.24 0.94 0.58-1.54
Other cardiovascular death 195 1.4 177 1.3 1.10 0.90-1.35
Death from an cause 444 3.2 426 3.1 1.04 0.91-1.19 0.54
M ocardial infarction 468 3.4 639 4.6 0.73 0.65-0.82 <0.001
Hos italization for unstable an ina 236 1.7 239 1.7 0.99 0.82-1.18 0.89
Stroke 207 1.5 262 1.9 0.79 .95 0.01
Ischemic 171 1.2 226 1.6 0.75 0.62-0.92
Hemorrha lo 29 0.21 25 0.18 1.16 0.68-1.98
Outcome umab Placebo Hazard Ratio PValue*
N=13,784 N=13,780 95% Cl
Unknown 13 0.09 14 0.10 0.93 0.44-1.97
Coronar revascularization 759 5.5 965 7.0 0.78 0.71-0.86 <0.001
Ur ent 403 2.9 547 4.0 0.73 0.64-0.83
Elective 420 3.0 504 3.7 0.83 0.73-0.95
Cardiovascular death or hospitalization for 402 (2.9) 408 (3.0) 0.98 (0.86-1.13) 0.82
worsening heart failure
Ischemic stroke or transient ischemic attack 229 1.7 295 2.1 0.77 .92 0.003
CTTC com osite end ointT 1271 9.2 1512 11.0 0.83 0.77-0.90 <0.001
*Given the hierarchical nature of the statistical g, the P values for the primary and key secondary end
points should be considered significant, s all other P values should be considered atory.
TThe terol Treatment Trialists Collaboration (CTTC) composite end point consists of coronary heart
death, nonfatal MI, stroke or coronary revascularization.
CTTC stands for Cholesterol Treatment Trialists Collaboration and the
composite endpoint of coronary heart death, nonfatal MI, stroke, or coronary
revascularization. Given the chical nature of the statistical testing, the P values for the
primary and key secondary endpoint should be considered statistically significant whereas all
other P values should be considered exploratory.
se, evolocumab significantly reduced the rate of the key secondary
composite end point of cardiovascular death, myocardial infarction, or stroke. The key
secondary endpoint occurred in 816 patients (5.9%) in the evolocumab arm and 1013 (7.4%)
in the placebo arm (HR 0.80, 95% CI 0.73—0.88, P<0.001) (Table 17.2, Figure 16B). The
magnitude of the risk ion in the primary endpoint tended to increase over time, from
12% (95% CI 3 to 20) in the first year to 19% (95% CI 11 to 27) beyond the first year.
Likewise for the key secondary endpoint the risk reduction went from 16% (95% CI 4 to 26)
in the first year to 25% (95% CI 15 to 34) beyond the first year (see Figure 20, Table 17.2b
and Example 17 Supplemental Results).
Table 17.2b
Hazard Ratio (95% CI)
Outcome
In first year Beyond first year
Primary end point 0.88 (0.80-0.97) 0.81 (0.73-0.89)
Key secondary end point 0.84 (0.74-0.96) 0.75 (0.66-0.85)
Cardiovascular death 0.96 (0.74-1.25) 1.12 (0.88-1.42)
Myocardial infarction 0.80 (0.68-0.94) 0.65 (0.55-0.77)
Elective 0.86 (0.72—1.03) 0.81 0.97)
CTTC composite nt 0.87 (0.79-0.97) 0.78 (0.71-0.86)
coronary heart death’ ML 15.0mm”
0.86 (0.76-0.97) 0.76 (068-0. 86)
stroke, or urgent revascularization
Coronary heart death, MI, or stroke 0.84 (0.73-0.95) 0.73 (0.65-0.83)
Fatal or nonfatal MI or stroke 0.81 (0.70-0.93) 0.67 0.77)
Primary end point consists of cardiovascular death, myocardial infarction, stroke,
hospitalization for unstable angina, or coronary ularization. The key secondary end
point consists of cardiovascular death, myocardial infarction, or .
There were 21 to 27% reductions in the risk of MI, stroke and coronary
revascularization, but no observed effect on hospitalization for unstable angina,
hospitalization for ing heart failure, or death from any cause (Table 17.2). The
benefits of evolocumab on the risk of the primary and key secondary composite end points
were largely consistent across major subgroups including age, seX, and type of
atherosclerotic vascular disease (Figure 22). It was also consistent across quartiles of baseline
LDL cholesterol, ranging from patients in the top quartile starting with a median LDL
terol of 126 mg/dL (IQR 116 to 143) down to those in the lowest quartile starting with
a median LDL cholesterol of 74 mg/dL (IQR 69 to 77). The benefit of evolocumab was also
tent across statin intensity, regardless of ezetimibe use and in both the 140 mg every 2
weeks and 420 mg monthly dosing ns (Figure 22).
Safety
No statistically significant between-group differences were seen in the
overall rate of adverse events, serious adverse events, or adverse events thought to be related
to study drug and g to study drug discontinuation (Table 17.3).
Table 17.3
Outcome Evolocumab Placebo
N=13,769 N=13,756
Adverse events — no. of ts %
An 10,664 77.4 10,664 77.4
Serious 3410 24.8 3404 24.7
Thought to be d to the study agent and leading to 226 (1.6) 201 (1.5)
discontinuation of stud reo imen
ln'ection-sitereaction* 296 2.1 219 1.6
Alleric reaction 420 3.1 393 2.9
Muscle-related event 682 5.0 656 4.8
Rhabdom ol sis 8 0.1 11 0.1
ct 228 1.7 242 1.8
Ad'udicated case of new-onsetdiabetesT 677 8.1 644 7.7
Neuroc0onitive event 217 1.6 202 1.5
Laborato resu|ts— no. of oatients/total no. %
Aminotransferase |eve|>3 times the upper limit of the 240/13,543 (1.8) 242/13,523(1.8)
normal rane
Creatinine kinase level>5 times the upper limit of the 95/13,543 (0.7) 523 (0.7)
normal ranoe
Likewise rates of muscle-related, cataract, neurocognitive adverse events
and hagic stroke were not significantly different between the two arms. Injection site
reactions were rare, but more frequent with evolocumab (2.1% vs 1.6%). The vast majority
of reactions (~90% in each arm) were classified as mild and only 0.1% of patients in each
arm stopped study drug because of an injection site reaction. The rates of adjudicated new
onset diabetes were not significantly different n the two arms (HR 1.05, 95% CI 0.94-
1.17). Rates of allergic reactions were also not significantly different (3.1% vs. 2.9%). In the
evolocumab arm, new binding antibodies were detected in 43 patients (0.3%) and
lizing antibodies in none.
DISCUSSION OF RESULTS OF EXAlVlPLE 17
When added to statin therapy, the PCSK9 inhibitor evolocumab lowered
LDL cholesterol by 59% from a median of 92 to 30 mg/dL (from 2.4 to 0.8 mmol/L). This
effect was sustained over 3 years t evidence of attenuation. The present results
m, for the first time in a dedicated cardiovascular outcomes study, that the addition of a
PCSK9 inhibitor to statin therapy significantly reduces the risk of cardiovascular events, with
a 15% reduction in the risk of the primary composite end point of cardiovascular death,
myocardial infarction, stroke, hospitalization for unstable , or coronary
ularization and a 20% reduction in the risk of the harder key secondary end point of
cardiovascular death, myocardial infarction, or stroke. Furthermore, there were no major
safety concerns with evolocumab.
The data from the present example (FOURIER) provide insight into the
benefit of decreasing LDL terol to heretofore unprecedented low levels (as median
values). Previously, significant reductions in major cardiovascular events were seen in the
IT TIMI 22 and TNT trials, in which the more intensive statin arm lowered LDL
cholesterol from approximately 100 to 70 mg/dL. Cannon CP, Braunwald E, McCabe CH, et
al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N
Engl J Med 2004;350:1495-504, and LaRosa JC, Grundy SM, Waters DD, et al. ive
lipid lowering with atorvastatin in ts with stable ry disease. N Engl J Med
2005;352:1425-35.) More ly, the addition of ezetimibe to statin therapy in the
IMPROVE-IT trial lowered LDL cholesterol from 70 to 54 mg/dL and significantly reduced
major vascular events. (Cannon CP, Blazing MA, Giugliano RP, et al. ibe Added to
Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387-97.) In the
present example (FOURIER) there were consistent reductions in cardiovascular events across
the range of baseline LDL cholesterol. Specifically, there was a 17% reduction in risk of the
key secondary endpoint in patients in the top quartile of baseline LDL cholesterol, in whom
evolocumab lowered the median LDL cholesterol from 126 to 43 mg/dL (similar to the level
ed with ezetimibe in patients in the lowest le of admission LDL cholesterol
levels in IMPROVE-IT (Giugliano RP, Cannon C, Blazing M, et al. Baseline LDL-C and
clinical outcomes with addition of ezetimibe to statin in 18,144 patients post ACS. J Am Coll
Cardiol 2015,65zA4.) and a 22% reduction in risk in patients in the lowest quartile of LDL
cholesterol, in whom umab lowered the median LDL cholesterol from 73 to 22 mg/dL.
These observations align well with the effects of evolocumab on coronary sclerotic
plaque volume from the GLAGOV trial, (Nicholls SJ, Puri R, Anderson T, et al. Effect of
Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV
Randomized Clinical Trial. JAMA 2016;316:2373-84) and show that continued
cardiovascular benefit can be accrued even when reducing LDL cholesterol down to the 20-
mg/dL range, levels well below t targets. (Lloyd-Jones DM, Morris PB, Ballantyne
CM, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin
—124—
Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic
vascular Disease Risk: A Report of the an e of Cardiology Task Force
on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016;68:92-125, Landmesser
U, John n M, Farnier M, et al. an y of Cardiology/European
Atherosclerosis Society Task Force sus statement on proprotein convertase
subtilisin/keXin type 9 tors: practical guidance for use in patients at very high
cardiovascular risk. Eur Heart J 2016; Sabatine MS. Proprotein convertase subtilisin/keXin
type 9 (PCSK9) inhibitors: comparing and contrasting guidance across the Atlantic. Eur
Heart J 2017.)
In FOURIER, the magnitude of the risk reduction in the key secondary
endpoint ed to grow over time, from 16% over the first year to 25% beyond 12
months, suggesting that the translation of LDL cholesterol reduction into vascular
clinical benefit requires time. Overall, the number needed to treat to prevent a cardiovascular
death, myocardial or stroke was 74 over 2 years or 50 over 3 years.
Consistent with prior trials of more intensive LDL cholesterol lowering
therapy compared with moderate intensity statin therapy, (Cannon CP, Blazing MA,
ano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N
Engl J Med 2015;372:23 87-97, Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et
al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of
data from 170,000 ipants in 26 randomised trials. Lancet 2010;376:1670-81) there was
no observed effect of additional LDL cholesterol lowering on cardiovascular mortality. Use
of evidence-based vascular pharmacotherapies that lower cardiovascular mortality was
very high in FOURIER, in which the rates of cardiovascular mortality were one third of the
rates in the 4S trial (Scandinavian Simvastatin Survival Study Group. ised trial of
cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian
Simvastatin Survival Study (4S). Lancet 1994;344:1383-89.) The relatively short duration of
the trial may have ded emergence of a cardiovascular mortality benefit. Similar to the
findings in SEARCH and IMPROVE-IT, there was no effect on hospitalization for unstable
angina. The advent of increasingly more sensitive cardiac troponin assays likely makes
cardiac ischemia as the true cause of a hospitalization for chest pain symptoms without
biochemical evidence of myocyte injury increasingly questionable. (Braunwald E, Morrow
DA. Unstable angina: is it time for a requiem? Circulation 2013;127:2452-7.) Lastly, urgent
coronary revascularization appeared to be more modifiable than elective revascularization.
Given these caveats, the magnitude of benefit of evolocumab for reducing
the risk of major coronary events, , and urgent coronary ularization is largely
consistent with the benefit seen with statins on a per mmol/L basis of LDL cholesterol
lowering (Figure 23). These observations are in accord with data from meta-analyses of
clinical trial data of different lipid-lowering interventions showing consistent clinical benefits
per unit reduction of LDL cholesterol. rman MG, Ference BA, Im K, et al. Association
Between ng LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic
Interventions: A Systematic Review and Meta-analysis. JAMA 2016;316:1289-97.)
Likewise these observations are ted from data from a recent Mendelian randomization
study in which variants in PCSK9 and in HMGCR were associated with nearly identical
lower risk of cardiovascular events per unit lower LDL cholesterol. (Ference BA, Robinson
JG, Brook RD, et al. ion in PCSK9 and HMGCR and Risk of Cardiovascular Disease
and Diabetes. N Engl J Med 2016;375:2144-53.)
Achievement of these very low LDL cholesterol levels with evolocumab
did not lead to any notable differences between the two study groups in the rates of adverse
events or study drug tinuation. The rate of evolocumab discontinuation due to adverse
events ascribed to study drug was r to placebo /year vs. O.67%/year) and
compares favorably to the rates seen for atorvastatin 80 mg/d (l.5%/year) and ezetimibe
(l.l%/year) (LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with
atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35 and
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after
Acute Coronary mes. N Engl J Med 2015;372:2387-97.) There was not a statistically
significant increase in new-onset diabetes with evolocumab, although the 95% ence
intervals do not exclude the point tes observed with statins. (Sattar N, Preiss D,
Murray HM, et al. Statins and risk of incident diabetes: a collaborative nalysis of
randomised statin trials. Lancet 2010;375:735-42, Preiss D, Seshasai SR, Welsh P, et al. Risk
of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-
is. JAMA 2011;305:2556-64.) Potential concerns over an increased risk of
neurocognitive adverse events were not borne out in this study. In contrast to recent data for
zumab (a humanized but not fully human monoclonal antibody against ,
(Pfizer Discontinues Global Development of Bococizumab, Its Investigational PCSK9
Inhibitor 2017. (Accessed February 2, 2017, 2017, at website world wide
web.pfizer.com/news/press-release/press-releasedetail
/pfizer_discontinues_global_development_of_bococizumab_its_investigational
_pcsk9_ inhibitor)) for evolocumab binding antibodies were rare, no neutralizing antibodies
were detected, and the overall LDL cholesterol-lowering effect continued without
attenuation. Furthermore, similarly reassuring findings with evolocumab were observed over
4 years in OSLER—l. (Koren MJ, Sabatine MS, ano RP, et al. Long-Term LDL-C
Lowering Efficacy, Persistence, and Safety of Evolocumab in Chronic Treatment of
Hypercholesterolemia: Results up to 4 years from the Open-Label l Extension
Study. JAMA Cardiology 2017:in press).
One consideration of this study was a relatively short duration of -
up compared with other lowering trials, which have averaged approximately 5 years.
(Silverman MG, Ference BA, Im K, et al. Association Between Lowering LDL-C and
Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A atic
Review and Meta-analysis. JAMA 2016;316:1289-97) Although the median follow-up in
FOURIER was originally planned to be approximately 4 years, an event rate that was
imately 50% higher than had been postulated led to a r required duration of
-up to accrue the prespecified number of events. Based on nt increasing efficacy
over time, this shorter duration may have attenuated the overall proportional event reduction
in FOURIER. The relatively short duration of the trial may have also limited the ability to
detect delayed e events. The majority but not all patients received high ity statin
therapy and ezetimibe use was infrequent. However, the benefit of evolocumab was
consistent regardless of the intensity of statin therapy or ezetimibe use.
In conclusion, inhibition of PCSK9 with evolocumab on a background of
statin therapy further lowered LDL cholesterol down to a median 30 mg/dL and reduced the
risk of cardiovascular events without any ting adverse events over the ame
studied. These findings demonstrate that patients with atherosclerotic cardiovascular disease
benefit from LDL cholesterol lowering below current targets.
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Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic
Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force
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Unstable angina: is it time for a requiem? Circulation 2013;127:2452-7, Silverman MG,
Ference BA, Im K, et al. Association Between Lowering LDL-C and Cardiovascular Risk
Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-
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Examgle 1 7 Sugglemental Information
Sugglemental Methods
Statin Intensity
Classification is based on the 2013 ACC/AHA Guideline on the Treatment
of Blood Cholesterol. (Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA
guideline on the treatment of blood cholesterol to reduce sclerotic cardiovascular risk
in adults: a report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. Circulation. Jun 24 2014,129(25 Suppl 45.) Table 17.4
present exemplary ranges.
Table 17.4
Atorvastatin 10 to <40 mg
Rosuvastatin 5 to <20 mg
Simvastatin 20 to <80 mg
Pravastatin 240 mg
atin 240 mg
Fluvastatin 80 mg
Pitavastatin 22 mg
Total daily doses
Endgoints
Additional secondary efficacy end points included: the individual
components of the key secondary endpoint; death by any cause; the composite of
cardiovascular death or hospitalization for heart failure; ry revascularization; and
ischemic stroke or ent ic attack. In addition; the Cholesterol Treatment Trialists
Collaboration composite endpoint of major coronary events (coronary heart death or nonfatal
myocardial infarction); stroke; or coronary ularization was examined. (Cholesterol
Treatment Trialists C; Baigent C; Blackwell L; et al. Efficacy and safety of more intensive
lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26
randomised trials. Lancet. Nov 13 2010;376(9753):1670-1681.)
e events of interest including muscle-related; cataracts; injection
site; allergic and neurocognitive. These adverse events were categorized by the TIMI Safety
Desk according to lower level MedDRA terms. New-onset diabetes was centrally
adjudicated. Central laboratory testing included LDL terol and other lipid parameters
(to which investigators and ts were blinded); liver on tests; creatine kinase,
fasting glucose; HbAlc; and anti-evolocumab antibodies. LDL cholesterol was calculated
using the Friedewald equation; except if <40 mg/dL or if the triglycerides were >400 mg/dL;
in which case LDL cholesterol was measured by preparative ultracentrifugation.
-l3l-
Statistical Considerations
n group differences in lipid parameters were calculated using a
ed measures linear mixed effects model using all measurements from baseline up to the
end of the study and are reported as least squared means. The model included terms for
treatment group, stratification s, scheduled visit and the interaction of treatment with
scheduled visit. In cases where there was insufficient data for the model to run (after 120
weeks), the mean percent change was calculated using the difference between the descriptive
mean changes in the evolocumab and placebo arms. Changes in triglycerides and Lp(a) were
expressed as medians and P values from Wilcoxon ranksum tests.
In terms of the hierarchical efficacy end point analyses, if vascular
death was significantly reduced, then all-cause mortality was to be analyzed at a significance
level of 0.04 and onal secondary endpoints at an overall icant level of 0.01 by
applying the Hochberg method.(Benjamini Y, Hochberg Y. lling the false discovery
rate: a practical and powerful approach to multiple testing. J R Stalist Soc B. 1995;57:289-
300.) The tical analysis plan is available with the full text of this article at NEJM. org.
Patients who discontinued study drug continued to be followed in the
same fashion as adherent patients for outcome events. For patients who withdrew consent or
were lost to follow-up, no imputation was done for events.
Schoenfeld residuals were examined to ensure that proportional s
assumptions were not violated when using Cox modeling.
rk analsyes were performed in which patients who were alive and
in follow-up at the start of the period of interest formed the group at risk. For comparison to
Cholesterol Treatment Trialists Collaborators (CTTC) data, the between group difference in
LDL cholesterol at 48 weeks was calculated as per the approach of the CTTC.( Baigent C,
Keech A, y PM, et al. Efficacy and safety of terol-lowering treatment:
prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
Lancet. Oct 8 2005,366(9493):1267-1278.). The number needed to treat to prevent one
element of the CTTC composite endpoint over 5 years was ated by taking the
annualized incident rate for the CTTC composite endpoint in the placebo arm (5.34%),
multiplying that rate by 5, and applying the relative risk reduction (22%) in the CTTC
endpoint after the first year (analogous to the CTTC approach to quantifying longterm
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benefit),(Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy
and safety of statin therapy. Lancet. Nov 19 2016,388(10059):2532-2561) which yields an
absolute risk reduction of 5.9%, or a number needed to treat of 17.
Inclusion and Exclusion Criteria
Inclusion Criteria
4.1.1 Signed informed consent
4.1.2 Male or female 2 40 to S 85 years of age at signing of informed consent
4.1.3 History of clinically eVident cardiovascular disease as eVidenced by ANY of
the following:
o diagnosis of dial infarction
o diagnosis of morrhagic stroke (TIA does not qualify as stroke
for inclusion)
o symptomatic peripheral arterial disease (PAD), as eVidenced by
intermittent cation with ankle-brachial index (ABI) < 0.85, or
peripheral arterial revascularization procedure, or amputation due to
atherosclerotic disease
Note: the proportion ofsubjects with history ofM1 or non-hemorrhagic stroke
> 5 years prior to screening was to be determined by the sponsor
4.1.4 At least 1 major risk factor or at least 2 minor risk factors below:
Major Risk Factors (1 Reguired):
0 diabetes (type 1 or type 2)
0 age 2 65 years at randomization (and S 85 years at time of informed
consent)
0 MI or morrhagic stroke within 6 months of screening
O additional diagnosis of myocardial infarction or non-hemorrhagic
stroke excluding ying MI or non-hemorrhagic strokeal
current daily cigarette smoking
history of symptomatic PAD (intermittent claudication with ABI
< 0.85, or peripheral arterial ularization ure, or
amputation due to atherosclerotic disease) if eligible by MI or stroke
history
Minor Risk Factors (2 Reguired):
O history of non-MI related coronary reyascularizational
O residual coronary artery disease with 2 40% stenosis in 2 2 large
vessels
Most recent HDL-C < 40 mg/dL (1.0 mmol/L) for men
and < 50 mg/dL (1.3 mmol/L) for women by central laboratory before
randomization
Most recent hsCRP > 2.0 mg/L by central laboratory before
randomization
Most recent LDL-C 2 130 mg/dL (3.4 mmol/L) or non-HDL-C
2 160 mg/dL (4.1 mmol/L) by central laboratory before randomization
0 metabolic syndromeb
4.1.5 Most recent fasting LDL-C 2 70 mg/dL (2 1.8 mmol/L) or non-HDL-C 2 100
mg/dL (2 2.6 ) by central laboratory during ing after 2 2 weeks
of stable lipid ng therapy per discussion below
4.1.6 Most recent g triglycerides S 400 mg/dL (4.5 mmol/L) by central
laboratory before ization
alNote: there is no time limit on additional qualifying medical history.
bDefinition: metabolic syndrome for this protocol is defined as 2 3 of the following
(Alberti et al, 2009):
waist circumference > 102 cm (> 40 in.) for men and > 88 cm (> 35 in.) for women
(Asian men, including Japanese > 90 cm; Asian women, except Japanese > 80 cm;
Japanese women > 90 cm)
triglycerides 2 150 mg/dL (1.7 mmol/L) by central laboratory at final screening
HDL-C < 40 mg/dL (1.0 mmol/L) for men and < 50 mg/dL (1.3 ) for women
by central tory at final screening (Note: ifthe HDL-C level is one ofcriterion
used to make the diagnosis ofmetabolic syndrome, it was not used as a separate risk
factor)
systolic blood pressure (SBP) 2 130 mmHg or diastolic BP (DBP) 2 85 mmHg or
hypertension treated with tion
fasting glucose 2 100 mg/dL (2 5.6 mmol/L) by central laboratory at final screening
Exclusion Criteria
4.2.1 Subject must not be randomized within 4 weeks of their most recent MI or
stroke
4.2.2 NYHA class III or IV, or last known left ventricular ejection on < 30%
4.2.3 Known hemorrhagic stroke at any time
4.2.4 Uncontrolled or recurrent ventricular tachycardia
4.2.5 Planned or eXpected cardiac surgery or revascularization within 3 months after
randomization
4.2.6 Uncontrolled hypertension defined as sitting ic blood pressure (SBP) >
180 mmHg or diastolic BP (DBP) > 110 mmHg
4.2.7 Use of teryl ester transfer protein (CETP) inhibition treatment,
mipomersen, or lomitapide within 12 months prior to ization.
Fenofibrate therapy must be stable for at least 6 weeks prior to final screening
at a dose that is appropriate for the duration of the study in the judgment of the
investigator. Other fibrate therapy (and derivatives) are ited
4.2.8 Prior use of PCSK9 tion treatment other than evolocumab or use of
evolocumab < 12 weeks prior to final lipid screening
4.2.9 Untreated or inadequately treated hyperthyroidism or hypothyroidism as
defined by thyroid stimulating hormone (TSH) < lower limit of normal (LLN)
or > 1.5 times the upper limit of normal (ULN), respectively, and free
thyroXine (T4) levels that are outside normal range at final screening
4.2.10 Severe renal dysfunction, defined as an estimated glomerular filtration rate
(eGFR) < 20 mL/min/1.73m2 at final screening
4.2.11 Active liver disease or hepatic dysfunction, defined as aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the
ULN as determined by l laboratory analysis at final screening
4.2.12 ent of any major organ transplant (e.g., lung, liver, heart, bone marrow,
renal)
4.2.13 Personal or family history of hereditary muscular ers
4.2.14 LDL or plasma apheresis within 12 months prior to randomization
4.2.15 Severe, concomitant non-cardiovascular disease that is eXpected to reduce life
expectancy to less than 3 years
4.2.16 CK > 5 times the ULN at final ing
4.2.17 Known major active infection or major hematologic, renal, metabolic,
gastrointestinal or endocrine dysfunction in the judgment of the investigator
4.2.18 Malignancy (except non-melanoma skin s, cervical in-situ carcinoma,
breast ductal oma in situ, or stage 1 prostate carcinoma) within the last
years
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4.2.19 Subject has received drugs via a systemic route that have known major
interactions with background statin therapy (see Appendix F) within 1 month
prior to randomization or is likely to require such treatment during the study
period
4.2.20 Currently enrolled in another investigational device or drug study, or less than
days since ending another investigational device or drug study(s), or
receiving other investigational s)
4.2.21 Female subject who has either (1) not used acceptable method(s) of birth
control for at least 1 month prior to screening or (2) is not willing to use such
a method during treatment with IP and for an additional 15 weeks after the
end of treatment with IP, unless the subject is sterilized or postmenopausal;
o menopause is defined as 12 months of neous and continuous
amenorrhea in a female 2 55 years old or 12 months of spontaneous
and continuous amenorrhea with a le-stimulating e (FSH)
level > 40 IU/L (or according to the definition of "postmenopausal
range" for the laboratory involved) in a female < 55 years old unless
the subject has undergone ral ectomy
o acceptable methods of preventing pregnancy include not having
intercourse, birth control pills, injections, implants, or s,
intrauterine devices (IUDs), tubal ligation/occlusion, sexual activity
with a male partner who has had a vasectomy, condom or occlusive
cap (diaphragm or cervical/vault caps) used with spermicide
4.2.22 Subject is pregnant or breast feeding, or planning to become nt or to
breastfeed during treatment with IP and/ or within 15 weeks after the end of
treatment with IP
4.2.23 Known sensitivity to any of the active substances or their excipients to be
administered during dosing
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4.2.24 Subject likely to not be available to complete all protocol-required study visits
or procedures, to the best of the subject’s and investigator’s knowledge
4.2.25 History or evidence of any other ally significant disorder, condition or
disease other than those outlined above that, in the opinion of the igator
or Amgen physician, if consulted, may compromise the y of the subject
to give written informed consent, would pose a risk to subject safety, or
interfere with the study evaluation, procedures or tion.
Endpoint ions
A. I. DEATH
A. Definition of Cardiovascular Death
Cardiovascular death includes death resulting from an acute myocardial
infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke,
death due to vascular (CV) procedures, death due to CV hemorrhage, and death due to
other CV causes.
Death due to Acute Myocardial tion refers to a death by any
cardiovascular mechanism (e.g., arrhythmia, sudden death, heart failure, stroke, pulmonary
embolus, peripheral arterial disease) 5 3O daysl (the 30-day cut-off is arbitrary) after a MI
related to the immediate consequences of the MI, such as progressive heart failure or
recalcitrant arrhythmia. There may be assessable mechanisms of cardiovascular death during
this time period, but for simplicity, if the cardiovascular death occurs 5 30 days of the
myocardial tion, it was considered a death due to myocardial infarction.
Acute MI should be verified to the extent possible by the diagnostic
criteria outlined for acute MI (see Definition of Myocardial Infarction) or by autopsy
findings showing recent MI or recent coronary thrombosis.
Death resulting from a procedure to treat a MI taneous coronary
intervention (PCI), coronary artery bypass graft surgery [CABG]), or to treat a complication
resulting from MI, should also be considered death due to acute MI.
Death resulting from an elective coronary procedure to treat myocardial
ia (i.e., chronic stable angina) or death due to a MI that occurs as a direct consequence
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of a CV investigation/procedure/operation should be considered as a death due to a CV
procedure
Sudden Cardiac Death refers to a death that occurs unexpectedly, not
following an acute MI, and includes the following deaths:
a. Death witnessed and occurring without new or worsening symptoms
b. Death witnessed within 60 minutes of the onset of new or worsening
cardiac symptoms, unless the symptoms suggest acute MI
c. Death witnessed and attributed to an identified arrhythmia (e.g.,
captured on an ocardiographic [ECG] recording, witnessed on a
r, or unwitnessed but found on implantable verter-
defibrillator review)
d. Death after unsuccessful itation from cardiac arrest
e. Death after successful resuscitation from c arrest and without
identification of a specific cardiac or non-cardiac etiology
f. Unwitnessed death in a subject seen alive and clinically stable S 24
hours prior to being found dead without any evidence supporting a
specific non-cardiovascular cause of death mation regarding the
patient’s clinical status preceding death should be provided, if
General Considerations
Unless additional information suggests an alternate specific cause of death
(e.g., Death due to Other Cardiovascular Causes), if a patient is seen alive 5 24 hours of
being found dead, sudden cardiac death should be recorded. For patients who were not
observed alive within 24 hours of death, undetermined cause of death should be recorded
(e. g., a subject found dead in bed, but who had not been seen by family for several days).
1. Death due to Heart Failure refers to a death in association with clinically
worsening
symptoms and/or signs of heart failure regardless of HF etiology (see
Definition of Heart Failure Event). Deaths due to heart failure can have various etiologies,
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including single or recurrent myocardial infarctions, ischemic or non-ischemic
cardiomyopathy, ension, or valvular disease.
Death due to Stroke refers to death after a stroke that is either a direct
consequence of the stroke or a cation of the stroke. Acute stroke should be verified to
the extent possible by the diagnostic criteria outlined for stroke (see Definition of Transient
Ischemic Attack and ).
Death due to Cardiovascular Procedures refers to death caused by the
immediate complications of a cardiac procedure.
Death due to Cardiovascular Hemorrhage refers to death related to
hemorrhage such as a non-stroke intracranial hemorrhage (see Definition of ent
Ischemic Attack and Stroke), non-procedural or non-traumatic vascular rupture (e.g., aortic
sm), or hemorrhage causing cardiac ade.
Death due to Other Cardiovascular Causes refers to a CV death not
included in the above categories but with a specific, known cause (e.g., pulmonary embolism
or peripheral arterial disease).
B. Definition of Non-Cardiovascular Death
Non-cardiovascular death is defined as any death with a specific cause
that is not thought to be vascular in nature, as listed in Definition of Cardiovascular
Death. Detailed recommendations on the classification of non-CV causes of death are beyond
the scope of this document. The level of detail required and the optimum classification will
depend on the nature of the study population and the anticipated number and type of non-CV
deaths. Any specific anticipated safety n should be included as a separate cause of
death. The following is a suggested list of non-CV causes of death:
- Pulmonary
- Renal
- Gastrointestinal
- Hepatobiliary
- Pancreatic
- Infection (includes sepsis)
- atory (e.g., Systemic Inflammatory Response Syndrome [SIRS] / Immune
(including autoimmune)
—140—
- Hemorrhage that is neither cardiovascular bleeding or a stroke (See Definition of
Cardiovascular Death and Definition of Transient Ischemic Attack and Stroke)
- Non-CV procedure or surgery
- Trauma
- Suicide
- Non-prescription drug on or overdose
- iption drug reaction or overdose
- Neurological (non-cardiovascular)
- Malignancy
- Other non-CV, in which case specify:
C. Definition of Undetermined Cause of Death
rmined Cause of Death refers to a death not attributable to one of
the above categories of CV death or to a non-CV cause. Inability to classify the cause of
death may be due to lack of information (e.g., the only available information is “patient
died”) or when there is icient supporting information or detail to assign the cause of
death. In general, most deaths should be classifiable as CV or non-CV.
C. II. CARDIAC ISCHEMIC EVENTS ACUTE CORONARY MES
A. Definition of Myocardial Infarction
1. General erations
The term myocardial infarction (MI) should be used when there is
evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia.
In general, the diagnosis of MI es the combination of:
0 Evidence of myocardial necrosis (either changes in cardiac biomarkers or
post-mortem pathological findings); and
0 Supporting information d from the clinical presentation,
electrocardiographic changes, or the results of myocardial or coronary
artery imaging
The totality of the al, electrocardiographic, and cardiac biomarker
information should be considered to determine whether or not a MI has occurred.
Specifically, timing and trends in c biomarkers and electrocardiographic information
require careful analysis. The adjudication of MI should also take into account the clinical
setting in which the event . MI may be adjudicated for an event that has characteristics
of a MI but which does not meet the strict tion because biomarker or
electrocardiographic results are not available.
2. Criteria for Myocardial Infarction
a. Clinical Presentation
The clinical presentation should be consistent with diagnosis of
myocardial ischemia and infarction. Other findings that can support the diagnosis of MI
should be taken into account because a number of conditions are associated with ions
in cardiac biomarkers (e.g., , surgery, pacing, ablation, heart failure, hypertrophic
cardiomyopathy, pulmonary embolism, severe pulmonary hypertension, stroke or
subarachnoid hemorrhage, infiltrative and inflammatory disorders of cardiac , drug
toxicity, burns, critical illness, extreme exertion, and chronic kidney e). ting
information can also be considered from myocardial imaging and coronary g. The
totality of the data may help differentiate acute MI from the background disease process.
b. Biomarker ions
For cardiac biomarkers, laboratories reported an upper reference limit
(URL). If the 99th tile of the upper reference limit (URL) from the respective
laboratory performing the assay is not available, then the URL for myocardial necrosis from
the tory was used. If the 99th percentile of the URL or the URL for myocardial
necrosis was not available, the MI decision limit for the particular laboratory was used as the
URL. Laboratories also reported both the 99th percentile of the upper reference limit and the
MI decision limit. Reference limits from the laboratory performing the assay are preferred
over the manufacturer’s listed reference limits in an assay’s instructions for use. In general,
troponins are preferred. CK-lVfl3 should be used if troponins are not available, and total CK
may be used in the absence of CK-lVfl3 and troponin.
In many s, particularly those in which patients present acutely to
als which are not participating sites, it is not practical to stipulate the use of a single
biomarker or assay, and the locally available results are to be used as the basis for
adjudication. However, if possible, using the same cardiac biomarker assay and preferably, a
core laboratory, for all measurements reduces inter-assay variability.
Since the prognostic significance of different types of myocardial
infarctions (e.g., periprocedural myocardial infarction versus spontaneous myocardial
tion) may be different, people were to consider evaluating outcomes for these subsets
of ts separately.
c. Electrocardiogram (ECG) Changes
Electrocardiographic changes can be used to support or confirm a MI.
Supporting ce may be ischemic changes and confirmatory information may be new Q
waves.
0 ECG manifestations of acute myocardial ischemia (in e of left
ventricular hypertrophy (LVH) and left bundle branch block
(LBBB)):
0 ST elevation
New ST elevation at the J point in two contiguous leads with the cut-
points: 2 0.1 mV in all leads other than leads V2-V3 where the ing cut-points apply: 2
0.2 mV in men 2 40 years (2 0.25 mV in men < 40 years) or Z 0.15 mV in women.
0 ST depression and T-wave changes
New horizontal or down-sloping ST depression 2 0.05 mV in two
contiguous leads and/or new T inversion 2 0.1 mV in two contiguous leads with prominent R
wave or IVS ratio > 1.
The above ECG criteria illustrate patterns consistent with myocardial
ischemia. In patients with abnormal kers, it is ized that lesser ECG
alities may represent an ischemic response and may be accepted under the category of
abnormal ECG findings.
Criteria for pathological Q-wave
0 Any Q-wave in leads V2-V3 2 0.02 seconds or QS compleX in leads
V2 and V3
o Q-wave 2 0.03 seconds and 2 0.1 mV deep or QS complex in leads I,
II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping
(I, aVL; Vl-V6; II, III, and aVF)al
a The same criteria are used for supplemental leads V7-V9, and for the
Cabrera frontal plane lead grouping.
0 ECG changes associated with prior myocardial infarction
0 Pathological Q-waves, as defined above
0 R—wave 2 0.04 seconds in Vl-V2 and R/S 2 l with a concordant positive
T-wave in the absence of a conduction defect
0 Criteria for prior myocardial infarction
Any one of the following criteria meets the diagnosis for prior MI:
0 Pathological Q waves with or without symptoms in the absence of non-
ic causes
0 Imaging evidence of a region of loss of viable myocardium that is d
and fails to contract, in the e of a non-ischemic causes
0 Pathological findings of a prior myocardial tion
d. ST-Segment Elevation MI versus Non-ST-segment Elevation MI
All events meeting criteria for MI* were also classified as either ST-
segment elevation MI (STEMI), non-ST-segment elevation MI (NSTEMI), or unknown.
0 STEMI — To be classified as a STEMI the event must have met all of the
above criteria for myocardial infarction and one of the four ia below.
0 New ST segment elevation at the J point in 22 contiguous leads,
d as: 2 0.2 mV in men (> 0.25 mV in men < 40 years) or Z 0.15
mV in women in leads V2-V3 and/or 2 0.1 mV in other leads. ts
must have had an interpretable ECG (i.e., without evidence of left
ventricular hypertrophy or pre-eXisting left bundle branch block), or
0 New left bundle branch block
0 NSTEMI — To be classified as a NSTEMI the event must have met all of the
above criteria for myocardial infarction and not met criteria for classification
as STEMI. In order to be classified as NSTEMI there must have been
adequate interpretable ECG documentation associated with the event.
0 Unknown — Events which met criteria as specified above for MI but did not
meet criteria for STEMI or NSTEMI. All cases where ECG documentation of
the acute event is missing, inadequate, or uninterpretable were classified as
Unknown.
e. Criteria for universal fication of myocardial infarction
Type 1: Spontaneous myocardial tion
Spontaneous myocardial infarction related to atherosclerotic plaque
rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in
one or more of the coronary arteries leading to decreased myocardial blood flow or distal
et emboli with ensuing myocyte is. The patient may have had underlying severe
CAD but on occasion non-obstructive or no CAD.
Type 2: dial infarction secondary to an ischemic imbalance
In instances of myocardial injury with necrosis where a condition other
than CAD contributes to an imbalance between myocardial oxygen supply and/or demand,
e. g. coronary endothelial dysfunction, coronary artery spasm, coronary sm,
/brady-arrhythmias, anaemia, atory failure, hypotension, and hypertension with
or without LVH.
Type 3: Myocardial infarction resulting in death when biomarker values
are unavailable
Cardiac death with symptoms suggestive of myocardial ischaemia and
presumed new ischemic ECG changes or new LBBB, but death occurring before blood
samples could be obtained, before cardiac kers could rise, or in rare cases cardiac
biomarkers were not collected.
Type 4a: Myocardial infarction related to percutaneous coronary
ention (PC1)
Myocardial infarction associated with PCI is arily defined by
ion of cTn values >5 X 99th percentile URL in patients with normal baseline values
(S99th percentile URL) or a rise of cTn values 220% if the baseline values are elevated and
are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia, or
(ii) new ischemic ECG changes or new LBBB, or (iii) angiographic loss of patency of a
major coronary artery or a side branch or persistent slow or no-flow or embolization, or (iV)
imaging demonstration of new loss of Viable myocardium or new regional wall motion
abnormality are required.
Type 4b: Myocardial infarction related to stent thrombosis
Myocardial infarction associated with stent thrombosis is detected by
coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or
fall of cardiac biomarkers values with at least one value above the 99th percentile URL.
Type 4c: Myocardial infarction d to restenosis
Restenosis is defined as 250% stenosis at coronary angiography or a
complex lesion associated with a rise and/or fall of cTn values >99th percentile URL and no
other significant obstructive CAD of greater severity ing: (i) initially successful stent
deployment or (ii) dilatation of a coronary artery stenosis with balloon lasty (<50%).
Type 5: Myocardial infarction related to coronary artery bypass grafting
(CABG)
Myocardial tion associated with CABG is arbitrarily defined by
elevation of c biomarker values >10 X 99th percentile URL in patients with normal
baseline cTn values (S99th percentile URL). In addition, either (i) new pathological Q waves
or new LBBB, or (ii) angiographic documented new graft or new native coronary artery
occlusion, or (iii) imaging evidence of new loss of Viable myocardium or new regional wall
motion abnormality.
Note: As noted in criterion 2]), although ge states troponin, CKA/IB can be
used with similar cut points.
D. IIB. Coronary Revascularization
1. Percutaneous C0r0na1_'y ention (PCI): Placement of an
lasty guide wire, balloon, or other device (e.g., stent, atherectomy catheter,
brachytherapy delivery device, or thrombectomy catheter) into a native coronary artery or
coronary artery bypass graft for the purpose of mechanical coronary revascularization. In the
assessment of the severity of coronary lesions with the use of intravascular ultrasound, CFR,
or FFR, insertion of a guide wire was N_OT considered PCI.
a. Elective: The procedure can be performed on an outpatient basis or
during a subsequent hospitalization without significant risk of myocardial infarction (MI) or
death. For stable in-patients, the ure is being med during this hospitalization for
convenience and ease of scheduling and NOT because the patient's clinical situation
demands the procedure prior to discharge.
b. Urgent: The procedure should be med on an inpatient basis and
prior to discharge because of significant concerns that there is risk of myocardial ischemia,
MI, and/or death. Patients who are outpatients or in the emergency department at the time
that the cardiac catheterization is requested would warrant hospital admission based on their
clinical presentation.
c. Emergency: The procedure should be med as soon as possible
because of substantial ns that ongoing myocardial ia and/or MI could lead to
death. "As soon as possible" refers to a patient who is of sufficient acuity that one would
cancel a scheduled case to perform this procedure immediately in the next available room
during business hours, or one would activate the on-call team were this to occur during off-
hours.
d. Salvage: The procedure is a last resort. The patient is in cardiogenic
shock when the PCI begins (i.e., the time at which the first guide wire or oronary
device is introduced into a coronary artery or bypass graft for the purpose of mechanical
revascularization) OR within the last ten minutes prior to the start of the case or during the
diagnostic n of the case, the t has also received chest compressions or has been
on unanticipated circulatory t (e.g., intra-aortic balloon pump, extracorporeal
mechanical oxygenation, or cardiopulmonary support).
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C. Definition of Hospitalization for Unstable Angina
Unstable angina requiring hospitalization is defined as
1. Ischemic fort (angina, or symptoms thought to be equivalent) 2 10 minutes
in duration occurring:
0 at rest, or
o in an accelerating pattern with frequent episodes associated with
progressively decreased exercise capacity.
2. Prompting an unscheduled hospitalization within 24 hours of the most recent
ms. alization is an admission to an inpatient unit or a visit to an
emergency department that results in at least a 24* hour stay (or a change in
calendar date if the hospital admission or discharge times are not available).
3. At least one of the following:
a) New or worsening ST or T wave changes on resting ECG (in the
absence of confounders, such as LBBB or LVH)
0 Transient ST elevation (duration < 20 minutes)
New ST elevation at the J point in two uous leads with the cut-
points: 2 0.1 mV in all leads other than leads V2-V3 where the
following cut-points apply: 2 0.2 mV in men 2 40 years (> 0.25 mV
in men < 40 years) or Z 0.15 mV in women.
0 ST depression and T-wave changes
New horizontal or down-sloping ST depression 2 0.05 mV in two
contiguous leads and/or new T inversion 2 0.3 mV in two contiguous
leads with prominent R wave or IVS ratio >1.
b) Definite ce of inducible dial ischemia as demonstrated by:
0 an early positive exercise stress test, defined as ST elevation or 2 2 mm
ST depression prior to 5 mets
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0 stress echocardiography (reversible wall motion abnormality) Q
0 myocardial scintigraphy (reversible perfusion defect), Q
0 MRI (myocardial perfusion deficit under pharmacologic stress),
mbelieved to be responsible for the myocardial ischemic symptoms/signs.
c) Angiographic ce of new or worse 2 70% lesion and/or us
in an epicardial coronary artery that is believed to be responsible for the
myocardial ischemic symptoms/signs.
d) Need for coronary revascularization procedure (PCI or CABG) for the
presumed culprit lesion(s). This ion would be fulfilled if
revascularization was undertaken during the unscheduled
hospitalization, or subsequent to transfer to another institution without
interceding home discharge.
4. Negative cardiac biomarkers and no evidence of acute MI
General Considerations
(1) Escalation of pharmacotherapy for ischemia, such as enous
nitrates or increasing dosages of B-blockers, should be considered supportive but not
diagnostic of unstable angina. However, a typical presentation and admission to the al
with escalation of pharmacotherapy, without any of the additional findings listed under
ry 3, would be insufficient to support classification as hospitalization for unstable
angina.
(2) If subjects are admitted with suspected unstable angina, and
subsequent testing reveals a non-cardiac or non-ischemic etiology, this event should not be
recorded as hospitalization for le angina. Potential ischemic events meeting the
criteria for myocardial infarction should not be cated as unstable angina.
(3) Planned hospitalization or rehospitalization for performance of an
elective revascularization in patients who do not fulfill the criteria for unstable angina should
not be considered a hospitalization for le angina. For example,
0 alization of a patient with stable exertional angina for coronary
raphy and PCI that is ed by a positive outpatient stress test
should not be considered hospitalization for unstable angina.
o Rehospitalization of a patient meeting the criteria for unstable angina that was
stabilized, discharged, and subsequently readmitted for revascularization, does
not constitute a second hospitalization for unstable angina.
(4) A patient who undergoes an ve catheterization where incidental coronary
artery disease is found and who subsequently undergoes coronary
revascularization will not be considered as meeting the hospitalization for
unstable angina end point.
E. IIL IIEAHRTVFAILIHRE
A Heart Failure Event includes alization for heart failure and may
include urgent outpatient visits. HF hospitalizations should remain ated from urgent
visits. If urgent visits are included in the HF event endpoint, the number of urgent visits
needs to be itly presented separately from the hospitalizations. A Heart Failure
Hospitalization is defined as an event that meets ALL of the following criteria:
1. The patient is admitted to the hospital with a primary sis of HF
2. The patient’s length-of-stay in hospital extends for at least 24 hours (or a
change in calendar date if the al admission and discharge times are
unavailable)
3. The patient exhibits documented new or worsening symptoms due to HF on
presentation, including at least ONE of the following:
a) Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea,
paroxysmal nocturnal dyspnea)
b) Decreased exercise tolerance
c) Fatigue
d) Other symptoms of ed gan ion or volume overload
4. The patient has objective evidence of new or worsening HF, consisting of a_t
least TWO physical examination findings a) Q one physical examination
finding and at least ONE laboratory criterion b), including:
a) Physical examination findings considered to be due to heart failure,
including new or worsened:
1) Peripheral edema
2) Increasing abdominal distention or ascites (in the absence of
primary hepatic disease)
3) Pulmonary rales/crackles/crepitations
4) Increased jugular venous pressure and/or hepatojugular reflux
) 83 gallop
6) Clinically significant or rapid weight gain thought to be d
to fluid retention
b) Laboratory evidence of new or worsening HF, if obtained within 24
hours of tation, including:
1) Increased B-type natriuretic peptide (BNP)/ N—terminal pro-
BNP (NT-proBNP) concentrations consistent with
decompensation of heart failure (such as BNP > 500 pg/mL or
NT-proBNP > 2,000 pg/mL). In patients with chronically
elevated natriuretic es, a significant increase should be
noted above ne.
2) Radiological evidence of pulmonary congestion
3) Non-invasive or invasive diagnostic ce of clinically
significant elevated left- or sided ventricular filling
pressure or low cardiac output. For example, echocardiographic
criteria could include: E/e’ > 15 or D-dominant pulmonary
-lSl-
venous inflow pattern, plethoric inferior vena cava with minimal
collapse on inspiration
4) Invasive diagnostic evidence with right heart catheterization
showing a pulmonary ary wedge pressure (pulmonary
artery occlusion pressure) 2 18 mmHg, l venous pressure
2 12 mmHg, or a cardiac indeX < 2.2 m2
. The patient receives initiation or intensification of treatment specifically for
HF, including at least ONE of the ing:
a) Augmentation in oral diuretic therapy
b) Intravenous ic, inotrope, or vasodilator therapy
c) Mechanical or surgical intervention, including
1) Mechanical circulatory support (e. g., intra-aortic balloon pump,
ventricular assist device)
2) Mechanical fluid l (e.g., ultrafiltration, hemofiltration,
dialysis)
An Urgent Heart Failure Visit is defined as an event that meets all of the ing:
1) The patient has an urgent, duled office/practice or emergency
department visit for a primary diagnosis of HF, but not meeting the criteria
for a HF hospitalization
2) All signs and ms for HF hospitalization (i.e., 3) symptoms, 4) physical
examination findings, and 5) laboratory evidence of new or worsening HF, as
indicated above) must be met
3) The patient receives initiation or intensification of treatment specifically for
HF, as detailed in the above section with the exception of oral diuretic
therapy, which will not be sufficient
F. IV. CEREBROVASCULAR EVENTS
A. Definition of Transient Ischemic Attack and Stroke
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The distinction between a Transient Ischemic Attack and an Ischemic
Stroke is the presence of infarction. tence of symptoms is an acceptable indicator of
acute infarction.
Transient Ischemic Attack
Transient ischemic attack (TIA) is defined as a transient episode of focal
neurological
dysfunction caused by brain, spinal cord, or retinal ischemia, without acute
infarction.
Stroke is defined as an acute episode of focal or global ogical
dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage
or infarction.
Classification:
1. Ischemic Stroke
Ischemic stroke is d as an acute episode of focal cerebral, spinal, or
retinal dysfunction caused by infarction of central nervous system tissue.
Hemorrhage may be a consequence of ischemic stroke. In this situation,
the stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic
stroke.
2. Hemorrhagic Stroke
Hemorrhagic stroke is defined as an acute episode of focal or global
al or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid
hemorrhage
3. Undetermined Stroke
Undetermined stroke is defined as an acute episode of focal or global
neurological dysfunction caused by presumed brain, spinal cord, or l vascular injury as
a result of hemorrhage or infarction but with insufficient information to allow categorization
as l or 2.
lity should be measured by a reliable and valid scale in all cases,
typically at each visit and 90 days after the event. For example, the modified Rankin Scale
may be used to s this requirement, as outlined in table 17.5:
TABLE 17.5
Scale Disabili
O No s motoms at all
1 No significant disability despite symptoms; able to carry out all usual duties and
activities
2 Slight disability; unable to carry out all previous activities, but able to look after
own affairs without assistance
3 Moderate disability; requiring some help; but able to walk without assistance
4 Moderately severe lity; unable to walk without assistance and unable to
attend to own bodily needs without assistance
Severe lity; bedridden; incontinent and requiring constant nursing care and
6 Dead
7 Unable to Determine
General Considerations
Evidence of vascular central nervous system injury without recognized
neurological dysfunction including microhemorrhage; silent tion; and silent
hemorrhage; if appropriate; will not be adjudicated as cerebrovascular events for this trial.
Subdural mas are intracranial hemorrhagic events and not strokes
Epidural hemorrhages are intracranial bleeds and not strokes
References:
Hicks KA; Hung HMJ; Mahaffey KW; et a1. Standardized definitions for
cardiovascular and stroke end point events in clinical . November 9; 2012.
G. V. NEW ONSET DIABETES
Diabetes definition
Diabetes us; a group of metabolic disorders; is characterized by
hyperglycemia and abnormal n; fat; and carbohydrate metabolism due to defects in
insulin secretions; inadequate and deficient insulin action on target organs; or both. For the
purpose of clinical adjudication; diabetes will be defined ing to the criteria below;
based on the American Diabetes Association1 and National Diabetes Information
Clearinghouse2 definitions.
Diabetes
—154—
Type 2 es (adult-onset diabetes) is the most common form of
diabetes. Although people can develop type 2 diabetes at any age, even during childhood
type 2 diabetes can develop most often in middle-aged and older people. It is anticipated that
most subjects converting to diabetes during the course of the study will develop type 2.
Acute complications include diabetic ketoacidosis and hyperosmolar
hyperglycemic nonketotic coma (HHNC). Chronic complications included accelerated
vascular disease and can be microvascular or macrovasular. Microvascular complications
include neuropathy, nephropathy and retinopathy. Macrovascular complications include
myocardial tion, stroke, coronary heart disease, and eral vascular e.
Diabetes mellitus is diagnosed on the basis of elevated plasma glucose
levels. The criteria for diagnosis of diabetes within the trial are as any of the ing:
1. Symptoms (e.g. polyuria, polydipsia, polyphagia, ained weight loss) of
diabetes and casual/random (any time of day without regard to time since last meal)
plasma glucose levels of 2200 mg/dL (11.1 mmol/L).
2. Fasting (no c intake for at least 8 hours) plasma glucose (FPG) level 2126
mg/dL (7.0 mmol/L), on 2 occasions separated by at least 24 hours.
3. Two-hour plasma glucose level 2200 mg/dL (11.1 mmol/L) during an oral glucose
tolerance test (OGTT performed as per WHO ia with glucose load of 75 g
anhydrous glucose ved in water).
4. Alc level 26.5% using a NGSP3 certified method and standardized to the Diabetes
Control and Complications Trial (DCCT) assay.
. Use of oral or injected diabetes medication and an established diagnosis of diabetes
mellitus per the medical record. Note that the use of diabetes medication for pre-
diabetes with the intent of preventing diabetes does not meet the tion.
Additional Guidance:
al judgment and the totality of information was used to make the
diagnosis. In general it was expected that more than one of the diagnostic criteria above
would be present unless vocal symptoms/signs are present. For example, a single
fasting glucose of 180 mg/dl prompting initiation of diabetes therapy would meet the ia.
1. If two different tests are used e.g., OGTT and A1c and both te diabetes,
consider the diagnosis confirmed.
2. If the two different tests are discordant, it may be reasonable to request that additional
information be obtained, if available.
Secondary Diabetes Mellitus
Hyperglycemia caused as a result of certain conditions, such as pancreatic
surgery, c pancreatitis, chronic liver disease, or various forms of endocrinopathy, such
as Cushing's syndrome, acromegaly, pheochromocytoma, or aldosteronism, or by medication
use, such as chronic orticoid therapy or hyperglycemia associated with a number of
relatively uncommon genetic conditions. Those events where elevated blood glucose levels
are definitely caused by such conditions should not be considered as new onset diabetes and
should be adjudicated as not an event for the purpose of this trial.
mental Results
A total of 1,209 (8.8%) patients allocated to evolocumab and 1,120 (8.1%)
patients allocated to placebo either switched to a less intensive statin regimen or discontinued
a statin during FOURIER. Conversely, 95 (0.7%) patients allocated to evolocumab and 141
(1.0%) patients allocated to placebo switched to a more intensive statin regimen. Ezetimibe
was started in 67 (0.5%) and 145 (1.1%) patients in the evolocumab and placebo arms,
respectively, during the trial, and 2 patients in the evolocumab arm stopped it.
The placebo-controlled mean LDL cholesterol reduction at 12 weeks was
61.1% (95% CI 60.5-61.7) for ts who chose twice weekly dosing and 56.9% (95% CI
8.6) for those who chose monthly dosing.
The between-group difference in LDL cholesterol at 48 weeks with
imputation for missing values as per the Cholesterol Treatment Trialists Collaboration
approach was 53.4 mg/dL (1.38 mmol/L).
The level of C-reactive protein was 1.7 mg/L (IQR 0.9-3.6) at baseline and
by 48 weeks was 1.4 mg/L (IQR 0.7-3.1) in both arms.
The above definitions in the supplemental section of Example 17 describe
the tions of the terms as used in the FOURIER study. While there are embodiments in
which such definitions can be applied in other scenarios and uses, it is to be understood that,
unless explicitly designated otherwise, the denoted terms have their plain and ordinary
meaning to one of skill in the art. In some embodiments, the definitions supplied in the
supplemental section of Example 17 can be used for the same term in any of the other
embodiments provided herein.
Example 18
In this analysis of FOURIER, the vascular efficacy and safety of
evolocumab was investigated in patients with peripheral artery e (PAD) as well as the
effect of LDL cholesterol lowering with evolocumab on major adverse limb events.
Outline of Methods for Exalee 18:
FOURIER was a randomized trial of umab versus placebo in
27,564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2
years. Patients were identified as having PAD at baseline if they had intermittent claudication
and an ankle brachial index of <0.85 or if they had a prior peripheral vascular procedure. The
primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke,
hospital ion for unstable , or coronary revascularization. The key secondary
endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. An
onal outcome of interest was major e limb events (MALE) defined as acute limb
ischemia (ALI), major amputation or urgent peripheral revascularisation for ischemia.
FOURIER is registered with alTrials “dot” gov, number NCT01764633.
Outline of Findings:
3,642 ts (13.2%) had PAD (1505 with no prior MI or stroke).
umab icantly reduced cardiovascular outcomes consistently in ts with and
without PAD (PEP PAD HR 0.79, 95%CI 0~66—0~94; p=0~0098; no PAD HR 086, 95%
CIO~80—0-93; p=0~0003, p-interaction=0-40). For the key secondary endpoint, the HRs were
073 (059—091; p=0~0040) for those with PAD and 081 (073—090; p<0~0001) for those
without PAD (pinteraction=0~41). Due to their higher risk, patients with PAD had larger
absolute risk reductions for the PEP (3.5% PAD, 1.6% no PAD) and the key secondary
endpoint (3.5% PAD, 1.4% no PAD). Evolocumab reduced the risk of MALE HR 0.58 (95%
CI 0.38 — 0.88, p=0.0093). There was a monotonic relationship between lower achieved
LDL-C and lower risk of limb events (P=0.0049) that ed down to 0.25 mmol/L.
Patients with PAD were at high risk of cardiovascular events and PCSK9 inhibition with
evolocumab significantly reduced that risk with large absolute risk reductions. Moreover,
lowering of LDL-C with evolocumab d the risk of major adverse limb events. These
data show LDL-C lowering in patients with PAD can lead reduce clinical complications of
sclerotic disease across multiple vascular beds.
The findings of the present example show that PCSK9 inhibition with
evolocumab added to background statin therapy lowered LDL cholesterol and icantly
reduced cardiovascular risk with similar efficacy in patients with and without PAD, but
greater absolute risk reduction in patients with PAD. LDL-C reduction with evolocumab
also reduced major adverse limb events including acute limb ischemia, major amputation or
urgent peripheral ularization. The is the first study to show a reduction in major
adverse limb events with PCSK9 inhibition.
Taken together, the data with statins and now with the PCSK9 inhibitor
umab added to a statin show that intensive LDL-C lowering in patients with PAD
provides substantial reductions in the clinical complications of atherosclerotic disease across
multiple vascular beds.
ABBREVIATIONS USED IN EXAlVlPLE 18
ALI — acute limb ischemia
MACE — major e cardiovascular events
MALE — major adverse limb events
MI — myocardial infarction
PAD — peripheral artery disease
AKA — above the knee amputation
BKA — below the knee amputation
METHODS: Study Pogulation
The FOURIER trial design is described in Sabatine MS, Giugliano RP,
Keech A, et al. Rationale and design of the Further cardiovascular Outcomes Research with
PCSK9 Inhibition in subjects with Elevated Risk trial. Am Heart J 2016; 173: 94-101.
Patients with clinically evident atherosclerotic cardiovascular disease ing prior
myocardial infarction, prior ischemic , or symptomatic peripheral artery disease were
ized in a 1:1 ratio to evolocumab or placebo. Patients were eligible to y with
symptomatic peripheral artery disease if they had either: intermittent claudication and an
ankle al index (AB1) < 0.85, a history of a peripheral artery revascularization
ure, or a history of amputation due to atherosclerotic disease. In addition to the
prespecified subgroup based on symptomatic lower extremity PAD, as part of a post-hoc
exploratory analysis a more restricted population, defined as patients with symptomatic lower
extremity PAD but with no history of MI or stroke, was also examined.
Endgoints
The primary efficacy endpoint in FOURIER was major cardiovascular
, defined as the composite of cardiovascular death, MI, stroke, hospitalization for
unstable angina, or ry revascularization. The key secondary endpoint was the
composite of CV death, MI or stroke. Other ary endpoints included the components of
the primary endpoint. Cardiovascular events were adjudicated by a d clinical event
committee (CEC). Limb outcomes were ctively ascertained through igator
reporting on dedicated electronic case report form pages and through adverse event forms.
Limb outcomes were adjudicated by two blinded vascular medicine specialists. r to
other recent trials evaluating medical therapies in patients with PAD, MALE was defined as
the composite of acute limb ischemia (ALI), major amputation (above the knee, AKA or
below the knee BKA, excluding forefoot or toe), or urgent revascularization (thrombolysis or
WO 89912
’15’17 Acute limb ischemia (ALI) required both
urgent vascular intervention for ischemia).
a clinical presentation consistent with acute ischemia including findings on physical
examination and/or imaging. Acute limb ischemia and urgent revascularization for
ischemia were identified by trained vascular medicine specialists blinded to treatment
assignment.3 In addition, all peripheral artery revascularization and amputation procedures
were recorded by the site in the electronic case report form. Analogous to other trials, a
combined endpoint of MACE and MALE was examined. 14’15’18 Prespecified safety
endpoints as defined in the primary analysis were included for the PAD subgroup.19
Statistical Considerations
As part of a prespecified analysis, patients were fied into those with
or without symptomatic lower extremity PAD at baseline as bed above. Baseline
characteristics of the subgroups were compared using on rank sum tests for
continuous data and x2 tests for categorical data. All efficacy analyses of evolocumab versus
placebo were done on an intention-to-treat basis (i.e., all patients who were randomly
assigned were analysed, irrespective of study drug compliance). Safety analyses included all
randomly assigned patients who received at least one dose of study treatment and for whom
post-dose data were available. P values for time-to-event analyses are from log-rank tests;
-Meier event rates were calculated up to 2.5 years. Hazard ratios (IRS) and 95% CIs
for the effect of evolocumab versus o were generated by use of a Cox proportional
hazards model, without adjustment (because of the randomised design) but stratifying by
region and screening LDL-C values. The effect modification by PAD on the cy of
umab was tested by incorporating ction terms into Cox models. For the analysis
of risk of cardiovascular es comparing patients with and without PAD in the placebo
group, a multivariable-adjusted HR was obtained from a Cox model that included the
ing baseline covariates: age, sex, race, BMI, hypertension, diabetes, smoking status,
renal dysfunction, CHF, prior MI, CABG or PCI and prior stroke or TIA. tional
hazards assumptions were not violoated. A repeated measures linear mixed s model
was used to obtain the least square means percentage and absolute reduction in LDL-C
n the two treatment groups. For analyses evaluating the relationship of achieved LDL-
C at one month and outcomes, the relationship between composite efficacy endpoints and
-l60-
achieved LDL cholesterol was plotted using a smoothing function applied to the averages of
estimated event rates at each LDL level based on the unadjusted CoX , as has been
done previously applying the same exclusion criteria. 20 P values below 005 were regarded
as significant. SAS (version 9.4) was used for the statistical analyses.
RESULTS
tions
Of the 27,564 ts ized, 3,642 (13.2%) had a history of
matic lower extremity PAD at baseline. A total of 2,067 patients (56.8%) had a
history of prior peripheral revascularization, 126 (3.5%) had a history of amputation for
vascular cause, and 2,518 (69.3%) had an ABI <0.85 and symptoms of claudication (with
some patients having more than one of these factors). Patients with PAD were older, more
frequently female, and had a greater prevalence of risk factors including hypertension,
current smoking, renal insufficiency and es (Table 18.1). At baseline 89% of patients
were taking antiplatelet therapy, 69% high-intensity statin therapy, 30% moderate-intensity
statin therapy, and 6.6% were taking ezetimibe. Of the PAD subgroup, 1,812 patients
(49.8%) had a history of MI and 545 (15.0%) had a y of stroke, there were 1,505 (41%
of those with PAD and 5% of the total population) who had PAD and no prior MI or stroke.
TABLE 18.1 BASELINE CHARACTERISTICS
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PeriQheral Artery Disease and Risk in Patients Randomized t0 Placebo
Among patients in the placebo arm, patients with PAD as compared with
ts without PAD had higher rates of both the primary endpoint (Kaplan-Meier rate at 2.5
years: 16.8% vs 12.1%, P<0.001) and the key secondary endpoint (13.0% vs 7.6%, P<0.001)
(Table 18.2, Fig. 28). After adjusting for ne differences, patients with PAD ed at
significantly higher risk of the primary endpoint (Adj. HR 1.57, 95% CI 1.36 — 1.80,
p<0.001) and the key secondary endpoint (Adj. HR 1.81, 95% CI 1.53 — 2.14, p<0.001, Table
18.2, ).
TABLE 18.2 RATES AND ADJUSTED HAZARD OF ISCHEMIC EVENTS
IN PLACEBO PATIENTS WITH PAD VS NO PAD
matic No Symptomatic Adjusted HR P-value
PAD N (2.5 yr PAD N (2.5 yr KM (95% Cl)
KM rate n=1.784 rate n=11,996
Primary composite 257 (16.80%) 1,306(12.13%) 1.57 (1 .36-1 .80) <0.001
Key Secondary 195 (13.01%) 818 (7.63%) 1.81 (1.54-2.14) <0.001
Cardiovascular death 55 (3.78%) 185 ) 2.04 (1.48-2.82) <0.001
Myocardial Infarction 115 (7.88%) 524 (4.87%) 1.85 (1 50-230) <0.001
Stroke 50 (3.13%) 212 (2.01%) 1.52 (1.09-2.11) 0.013
Coronary 142 (9.55%) 823 ) 1.45 (1.19-1.75) <0.001
revascularization
All cause mortality 97 (6.66%) 329 (3.01%) 1.94 (1 .52-2.47 <0.001
MALE 40 (2.40%) 19 (0.16%) 11.67 (6.25-21.79) <0.001
ALI or major amputation 25 (1.47%) 15 (0.12%) 7.88 (3.67-16.92) <0.001
ALI 18 (1.06%) 15 (0.12%) 5.92 (2.59-13.53) <0.001
Major amputation 7 (0.41%) 0 (0.00%) - -
Urgent revascularization 20 (1.25%) 6 (0.06%) 22.35 (8.26-60.47) <0.001
Any peripheral 200 (12.40%) 93 ) 14.75 (11.28- <0.001
revascularization 19.29)
DVD, Ml, Stroke, or 228 (15.03%) 834 (7.77%) 2.05 (1.75-2.40) <0.001
PEP — y endpoint composite of CV death, myocardial infarction, stroke, alization for unstable angina
or coronary ularization
Key Secondary — composite of CV death, myocardial infarction or stroke
Symptomatic No Symptomatic Adjusted HR P-value
PAD N (2.5 yr PAD N (2.5 yr KM (95% Cl)
KM rate n=1.784 rate n=11,996
MALE — composite of acute limb ischemia (ALI), major amputation (AKA or BKA), or urgen peripheral
ularization for ischemia
Ml=myocardial tion, AKA=above knee amputation, BKA=below knee amputation, ute limb ischemia
Adjusted for age (65 vs. >=65), sex, race (white vs. non-white), BMI, history of diabetes, history of hypertension,
g status (never, current, former), eGFR (<=60 vs. >60), history of congestive heart e, prior mi, history
of CABG or PCI, and y of non-hemorrhagic stroke or TIA
Note: For any peripheral revascularization, smoking status was collapsed to current smoker vs. rrent
smoker and age was changed to 75 vs. >=75
When stratifying the population with PAD by history of concomitant prior
MI or stroke (polyvascular disease), those with polyvascular disease had higher rates of CV
death, MI or stroke compared to those without (14.9% vs. 10.3%, p=0.0028, ).
Patients with PAD and no prior MI or stroke, however, still had higher rates of CV death, MI
or stroke than patients with prior MI or stroke and no symptomatic PAD (10.3% vs 7.6%,
Adjusted HR 2.07, 95% CI 1.42 — 3.01, p=0.0001, ). When evaluating individual
components CV death appeared especially higher (4.4% vs. 1.9%, p<0.001) although rates of
MI and stroke were also cally higher ().
Patients with symptomatic PAD had higher rates of limb outcomes relative
to those without PAD including MALE (2.4% vs 0.2%, ed HR 11.67, 95% CI 6.25 —
21.79, p<0.001) and the composite of ALI and major amputation (1.5% vs. 0.1%, adjusted
HR 7.88, 95% CI 3.67 — 16.92, p<0.001, Table 18.2). gs were consistent in the
subgroup with PAD and no MI or Stroke vs patients with no PAD ().
LDL-Cholesterol Lowering with Evolocumab
The median LDL-C level at baseline among the symptomatic PAD group
was 94 mg/dL (IQR 81 — 112). At 48 weeks, the least-squares mean percentage reduction in
LDL-C with evolocumab, relative to placebo, was 59% (95% CI 57 to 61, p<0.001) and 57
mg/dL (mean absolute reduction, 95% CI 55 to 60) to a median of 31.0 mg/dL (IQR 19.0 —
49.0, ). The reduction in LDL cholesterol levels was maintained over time ().
Cardiovascular Efficacy with Evolocumab
In patients with prior PAD, umab significantly reduced the primary
endpoint by 21% (2.5-year KM rate 13.3% vs. 16.8%, HR 0.79, 95% CI 0.66 — 0.94,
p=0.0089, Table 18.3, Figure 24A) and the composite of CV death, MI or stroke by 27%
(9.5% vs. 13.0%, HR 0.73, 95% CI 0.59 — 0.91, p=0.0040, Table 18.3, B). The
relative risk ions for both endpoints were consistent in patients with and without PAD
(p-interaction 0.40 and 0.41 respectively), however, due to higher absolute risk in ts
with PAD, the absolute risk reductions for both endpoints were r in those with PAD vs.
those without [absolute risk reduction (ARR) for primary endpoint 3.5% (95% CI 0.8% -
6.2%) in PAD, 1.6% (95% CI 0.7% - 2.5%) without PAD; ARR for CV death, MI or stroke
3.5% (95% CI 1.0% - 6.0%) in PAD, 1.4% (95% CI 0.7% - 2.1%) without PAD]. Relative
and absolute risk reductions were consistent in the population of patients with PAD and no
prior MI or stroke including a 4.9% AR (95% CI 1.0% - 8.8%) in the primary nt and
a 4.8% AR (95% CI 1.2% - 8.4%) in the ite of CV death, MI or stroke translating in
NNT2.5y of21 for each (Table 18.3, A and B.
TABLE 18.3. EFFICACY EVOLOCUMAB IN PATIENTS WITH PERIPHERAL
ARTERY E
Table 2. Efficacy of Evolocumab in Patient with Peripheral Artery Disease
gztizges Symptomatic PAD Symptomatic PAD t prior MI or Stroke
Outcome, n, 2.5 Placebo Evolocumab Hazard p-value Placebo Evolocumab Hazard p-value
yr KM rage (%) N=1,784 N=1,858 Ratio N=748 N=757 Ratio
95% Cl 95% Cl
Primary 257, 16.8% 217, 13.3% 0.79 0.0098 74, 12.6% 51, 7.7% 0.67 0.0283
End oint 0.66-0.94 0.47-0.96
CV Death, MI, 195, 13.0% 152, 9.5% 0.73 0.0040 58, 10.3% 34, 5.5% 0.57 0.0095
Stroke MACE 0.59-0.91 0.38-0.88
CVD 55, 3.8% 58, 4.0% 1.02 18, 4.4% 14, 2.9% 0.78
(0.71-1.48) 1.57)
MI 115, 7.9% 84, 5.2% 0.69 32, 5.7% 21, 2.9% 0.66
(0.52-0.91) (0.38-1.14)
Stroke 50, 3.1% 31, 1.8% 0.59 16, 2.5% 5, 0.7% 0.30
(0.38-0.92) (0.11-0.82)
Ischemic Stroke 47, 2.9% 28, 1.7% 0.57 15, 2.4% 4, 0.5% 0.25
(0.35-0.90) (0.08-0.77)
Coronary 142, 9.6% 119, 7.0% 0.79 42, 6.9% 30, 4.0% 0.70
revascularization 0.62-1.01 0.44-1.13
All death 97, 6.7% 93, 6.2% 0.92 0.58 31, 6.4% 27, 4.9% 0.86 0.58
(0.69-1.23) (0.51-1.45)
MALE 40, 2.4% 27, 1.5% 0.63 0.063 18, 2.60% 8, 1.3% 0.43 0.042
(0.39-1.03) (0.19-0.99)
ALI or major 25, 1.5% 16, 0.9% 0.60 12, 1.8% 4, 0.6% 0.33
am utation 0.32-1.13 0.10-1.01
ALI 18, 1.1% 14, 0.8% 0.73 8, 1.2% 4, 0.6% 0.48
(0.37-1.48) 1.61)
Major 7, 0.4% 3, 0.2% 0.41 4, 0.58% 1, 0.1% 0.26
am utation 0.11-1.57 0.03-2.32
Urgent 20, 1.2% 16, 0.9% 0.75 8, 1.2% 6, 0.9% 0.72
revascularization 0.39-1.45 0.25-2.08
Any peripheral 200, 12.4% 215, 13.2% 1.01 0.88 81, 12.1% 95, 14.9% 1.17 0.30
revascularization 0.84-1.23 0.87-1.57
CV Death, MI, 228, 15.0% 177, 10.9% 0.73 0.0014 75, 12.8% 40, 6.5% 0.52 0.0006
Stroke, ALI, (0.60-0.88) (0.35-0.76)
major amp. or
urgent revasc.
MALE — composite of acute limb ischemia (ALI), major amputation (AKA or BKA), or urgent peripheral ularization for ischemia
Ml=myocardial infarction, AKA=above knee amputation, BKA=below knee amputation, ALI=acute limb ischemia
Maior Adverse Limb Event Reduction with Evolocumab
Overall evolocumab reduced the risk of MALE by 42% (0.45% vs 0.26%.
HR 0.58, 95% CI 0.38 — 0.88, p=0.0093, Table 18.4, A) and the n of efficacy
was consistent across all components of MALE (Table 18.4). In the 3642 patients with PAD,
the pattern of efficacy for MALE was consistent (HR 0.63, 95% 0.39-1.03) but rates were
higher, translating into greater absolute risk reductions (Table 18.3, B) with similar
findings in patients with PAD and no prior MI or stroke (C).
Overall evolocumab d the risk of MALE by 42% (0.45% vs 0.26%.
HR 0.58, 95% CI 0.38 — 0.88, p=0.0093, Table 18.4, A) and the n of efficacy
was tent across all components of MALE (Table 18.4). In the 3642 ts with PAD,
the n of efficacy for MALE was consistent (HR 0.63, 95% 0.39-1.03), but rates were
higher, translating into greater absolute risk reductions (Table 18.3, B) with similar
findings in ts with PAD and no prior MI or stroke (Table 18.3, C).
TABLE 18.4 MAJOR ADVERSE LIlVfl3 OUTCOMES WITH EVOLOCUMAB
Efficacz Outcomes
Outcome Placebo Evolocumab Hazard Ratio p-value
N=13,780 N=13,784 (95% Cl)
n, 2.5yr KM rate 1%) n, 2.5yr KM rate 1%)
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Limb Outcomes
MALE 59, 0.45% 34, 0.27% 0.58 0.0093
0.88)
ALI or major amputation 40, 0.29% 21, 0.17% 0.52
(0.31-0.89)
ALI 33, 0.24% 18, 0.15% 0.55
(0.31-0.97)
Major amputation 7, 0.05% 4, 0.03% 0.57
(0.17-1.95)
Urgent revascularization 26, 0.21% 18, 0.13% 0.69
(0.38-1.26)
Any peripheral revascularization 293, 2.37% 317, 2.59% 1.08 0.33
(0.92-1.27)
Composite ofMACE + MALE
CV Death, Ml, Stroke, MALE 1062, 8.70% 847, 6.91% 0.79 <0.001
{0.72-0.87)
MALE — composite of acute limb ischemia (ALI), major amputation (AKA or BKA), or urgent peripheral
revascularization for ischemia
cardial infarction, AKA=above knee amputation, BKA=below knee amputation, ALI=acute limb ia
ite Outcomes in Patients with PAD
Overall evolocumab reduced the composite of MACE (CV death, MI or
stroke) or MALE (ALI, major amputation or urgent revascularization) by 21% (8.70% vs
6.91%, HR 0.79, 95% CI 0.72 — 0.87, 1). The relative risk reduction was similar in
those with and without PAD (p-interaction 0.39) but due to their higher absolute risk
(placebo rate 15.0% in those with PAD vs 10.9% without PAD) there was a numerically
greater absolute risk reduction at 2.5 years in those with PAD (ARR 4.1%, 95% CI 2.5 —6.7,
) relative to those without PAD (ARR 1.5%, 95% CI 0.7 — 2.2, ). Similarly, in
those with PAD and no prior MI or stroke, there was a significant reduction in the composite
of MACE or MALE (6.5% vs. 12.8%, HR 0.52, 95% CI 0.35 — 0.76, p=0.0006; ARR 6.3%,
NNT 16, ).
Safety of Evolocumab in Patients with PAD
There were no differences in incidence adverse or serious adverse events
with umab relative to placebo in patients with PAD (Table 18.5). There was no excess
of adverse events g to treatment discontinuation (1.3% evolocumab vs 1.5% o,
p=0.57).
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TABLE 18.5. SAFETY OF EVOLOCUMAB IN PATIENTS WITH ERAL
ARTERY DISEASE
o Evolocumab
n=1,780 N n=1,856 N
Adverse events, n 1%)
An 1,408 79.1% 1780 1,481 79.8% 1856
Serious 624 35.1% 1780 601 32.4% 1856
Thought to be d to the study agent and leading to discontinuation of study 27 (1 .5%) 1780 24 (1.3%) 1856
regimen
In'ection-Site reaction 32 1.8% 1780 26 1.4% 1856
Allergic reaction 47 (2.6%) 1780 54 (2.9%) 1856
Muscle-related event 79 4.4% 1780 94 5.1% 1856
Rhabdom oi sis 1 0.1% 1780 2 0.1% 1856
Cataract 43 2.4% 1780 24 1.3% 1856
Ad'udicated case of new-onset es 67 6.7% 996 80 8.3% 963
Neuroco nitive event 31 1.7% 1780 28 1.5% 1856
Laboratory results, n 1%)
Aminotransferase level >3 times theu er limit of the normal ran e 31 1.8% 1747 27 1.5% 1812
Creatine Kinase level >5 times theu er |imite of the normal ran e 15 0.9% 1747 5 0.3% 1812
Note: P-value was calculated by chi-square test
All p—values > 0.05 except l 9:001 19 for cataracts and 0.0201 for CK>5
Association 01 achieved LDL-Cholesterol and risk of MACE and MALE
Overall lower achieved LDL-C was ated with a significantly lower
risk of MALE with a roughly linear relationship down to LDL-C of 10 mg/dL (p=0.0049 for
slope ). There was no apparent inflection or plateau in the relationship between LDL-
C and outcome. This pattern was consistent for the broader composite outcome of MACE or
MALE overall and for patients with PAD () and patients with PAD and no prior MI
or stroke ().
DISCUSSION OFRESULTS
This study demonstrates that patients with symptomatic lower extremity
PAD are at higher risk of both MACE and MALE relative to patients with prior MI or stroke
and no PAD. Evolocumab significantly reduced the risk of MACE in patients with
matic PAD, ing those without prior MI or stroke, and the higher risk in PAD
patients ated into greater absolute risk reductions. Furthermore, LDL-C lowering with
evolocumab reduced the risk of MALE including ALI and major amputation. Thus when
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considering both MACE and MALE, the absolute risk reduction with LDL-C lowering in
patients with PAD was quite robust, with an NNT over 2.5 years of only 25. Lastly, akin to
what has been observed for MACE, there was a monotonic lower risk of MALE with lower
levels of achieved LDL—C, down to 10 mg/dL.
The higher ic risk in patients with symptomatic PAD as compared
14’21’22 This observation, however,
to those without has been recognized. is x as there
is heterogeneity in risk within the broad population of patients with PAD. Those patients
with multiple symptomatic territories (e.g. PAD and prior MI or prior stroke), called
polyvascular disease, are at clearly heightened risk and appear to derive robust reductions in
MACE risk from more intensive antithrombotic therapy. 3’23 For patients with symptomatic
PAD and no prior MI or stroke, the benefits of intensive antithrombotic therapy for MACE
reduction are less compelling with studies showing neutral results or modest efficacy. ”’24
This distinction has practical implications both for clinicians and guidelines where
distinguishing the risks and benefits in patients with PAD and no history of MI or stroke
from those with prior MI or stroke may guide recommendations and treatment decisions and
assist in personalizing treatment selection.4’5
In the current Example, two symptomatic PAD populations have been
shown, a broad population including those with polyvascular disease as well as a restricted
population that has never experienced an acute atherothrombotic event (MI or ). In
contrast to intensive antithrombotic therapies, r, the benefits of intensive lipid
lowering with evolocumab were consistent in both tions. These findings therefore
highlight a distinct population where lipid lowering provides robust benefits and supports the
hypothesis that the biology of MACE risk in this population is responsive to LDL-C
lowering.
There are limited prior ized, controlled data on the effect of LDL-
C lowering on clinical es in PAD. The Heart Protection Study ized 20,536
ts with vascular disease with a total cholesterol of at least 3.5 mmol/L to simvastatin 40
mg daily or placebo and ed 6,748 patients with PAD. Over 5 years of follow up,
simvastatin reduced major vascular events relative to placebo with consistent ve risk
reductions in those with and without PAD. 26
An atory outcome of non-coronary
vascular intervention (including carotid intervention) was also lower with simvastatin. 26
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There was no difference in the risk of amputation with tatin vs. o. Beyond these
observations, there are no well-powered randomised studies showing that achieving lower
LDL-C or that the use of a non-statin agent to a statin is beneficial in PAD. This lack of data
has led some to conclude that until further evidence on the relative effectiveness of different
lipid-lowering agents is available, use of a statin in patients with PAD should be d to
those with a total cholesterol level 23.5 mmol/L, a threshold far higher than in most other
patients with ASCVD. 9
The t Example now adds data from a well-powered randomized trial
that achieving lower LDL-C with a non-statin agent added to high or moderate intensity
statin therapy is beneficial in patients with symptomatic lower extremity PAD, including
those without prior MI or stroke.9
In addition to robust benefits for MACE, the current Example is the first
randomized trial to demonstrate a benefit for intensive LDL-C lowering for MALE risk. The
Heart Protection Study noted a ion in the outcome of non-coronary revascularization
ures; however, this was not specific to etiology and included procedures beyond the
lower extremities such as carotid revascularization.26 Major adverse limb events were not
reported and there was no difference in amputations.26 Prior small studies have described
ial symptomatic benefits with statin therapy but have not been powered for MALE.
““127 Analyses from large registries have observed
an association between lower amputation
rates and statin therapy; however, potential for residual confounding has remained and
intensity of statin therapy or achieved LDL-C was not reported.6’29’30 The current Example
demonstrates that non-statin LDL-C lowering added to statins reduces MALE and that the
benefits extend to very low achieved LDL-C.
The reduction in MALE with evolocumab was consistent for all the
ents, which have now been established as modifiable limb nts in three
randomized trials of more intensive antithrombotic therapy and nts that have been
adopted as elements of primary or key ary endpoints in trials ing patients with
PAD. 3’8’14’15’31 There was no apparent benefit for reducing peripheral revascularizations
including elective procedures for claudication as has been described for other therapies
including cilostazol and vorapaxar.8 Possible explanations for the lack of benefit for this
broad endpoint include that lipid lowering does not improve symptoms or alternatively, it
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does but over a longer period of exposure and therefore was not seen in the relatively short
duration of follow up n 2.2 years) in the current study. Supporting the latter is the
observation that benefits for peripheral revascularization and symptoms with vorapaxar were
not apparent until almost 2 years of exposure and were not icant until 3 years.
In evaluating the overall benefits of preventive therapies in patients with
PAD, recent and g trials have utilized a composite endpoint including both
cardiovascular and limb outcomes. ”’31 This composite provides a global picture of benefit in
patients with PAD against which harms and cost can be weighed. In the current Example, in
patients with PAD and, robust ions in both MACE and MALE resulted in an te
risk reduction at 2.5 years of 4.1% and an NNT of 21. Extending this ation to 5 years,
as is typically done for lipid lowering therapy, translates to a NNT approximately 11. In
contrast to anti-thrombotic therapies, this benefit comes with no safety tradeoff in terms of
bleeding or other adverse events. These considerations may be important to clinicians in
personalizing ive therapies to their patients.
Subgroup analyses were generally utilized to evaluate for consistency of
findings with the overall trial and therefore may be underpowered for efficacy and safety
outcomes. In the current analysis the PAD subgroup was adequately powered to demonstrate
tically significant benefits for the primary endpoint and key secondary. The power to
detect differences in safety events may have been more limited but the pattern of safety was
consistent with the overall trial and are not be anticipated to be modified by the presence of
PAD. Limb outcomes were collected on broad eCRF pages for peripheral outcomes and not
focused specifically on ALI. This may have resulted in under ascertainment of ALI outcomes
but would not bias treatment effects. y, relationships between ed LDL—C and
outcome were not randomized and while adjusted for confounders the potential for residual
confounding remains and should be recognized.
Conclusions
Patients with symptomatic lower extremity PAD are at heightened risk of
major adverse cardiovascular and limb risks. umab added to statin therapy
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significantly and robustly reduces the risk of MACE, even in patients with PAD and no prior
MI or stroke. Likewise, the addition of evolocumab to a statin d the risk of major
adverse limb events (MALE), and the relationship n achieved LDL-C and lower risk
of limb events extended down to very low achieved levels of LDL (e.g., 10 mg/dL). These
benefits come with no apparent safety concerns. Thus, LDL-C reduction to very low levels is
useful in patients with PAD, regardless of a history of MI or stroke, to reduce the risk of
MACE and MALE.
Reference for Example 18
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Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Stork S, Keltai M, Ryden L, Pogosova N,
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Gouni-Berthold I, Lopez-Miranda J, Schiele F, Mach F, Ott BR, Kanevsky E, Pineda AL,
Somaratne R, Wasserman SM, Keech AC, Sever PS, Sabatine MS, FOURIER igators.
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. 2017; .
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27. Giri J, McDermott lVIM, Greenland P, Guralnik JM, Criqui MH, Liu K, Ferrucci L, Green
D, der JR, Tian L. Statin use and functional decline in patients with and without
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Example 19
The present example examines predictors of residual plaque progression
despite achieving low levels of LDL—C with the PCSK9 inhibitor, evolocumab. Intravascular
ultrasound (IVUS) trials have shown that statins slow progression or induce regression of
coronary disease in proportion to the magnitude of LDL-C reduction. In addition to statins,
non-statin LDL-C lowering agents, such as proprotein convertase subtilisin/kexin type 9
(PCSK9) antibodies, have emerged as a new class of drugs that effectively lower LDL-C
levels. For example, in the GLAGOV trial, evolocumab reduced LDL-C levels from 93 to 37
mg/dL and induced greater plaque regression than placebo in statin-treated ts (-0.95%
vs. +0.05%, P<0.0001). depicts the GLAGOV trial schematic for the context of this
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study. While evolocumab induced regression in a greater percentage of patients (64% vs.
36%, P<0.0001); more than one third of subjects with evolocumab still exhibited some
plaque progression despite very low LDL-C levels. The present example es the
factors associated with ongoing disease progression in the setting of evolocumab treatment.
The parameters of the subjects and the study are outlined in Tables 9.5.
depicts a cross-sectional lumen and formula for determining percent atheroma volume.
ts withi a PAV>0 were “progressors” while subjects with a PAV<O were regressors.
Table 19.1
Patient Demographics
Progressors Regressors P value
(n=151) (n=272)
Age, yrs 59.5 59.4 0.94
Female, % 29.8 26.5 0.46
BMI, kg/m2 28.7 28.4 0.19
Hypertension, % 79.5 82.0 0.53
Diabetes mellitus, % 21.9 20.2 0.69
Previous MI, % 34.4 33.1 0.78
Current , % 24.5 26.8 0.60
Baseline statin use, % 98.0 99.3 0.35
High-Intensity, % 59.6 59.9
Moderate-intensity, % 37.7 39.0 0.60
tensity, % 0.7 0.4
B-blocker, % 78.8 72.8 0.17
ACE inhibitor, % 52.3 54.0 0.73
Plaque ssions were observed in 151 (35.7%) of evolocumab-treated
patients. No differences in clinical demographics were observed between progressors and
regressors (Table 19.1).
Table 19.2
Risk factor control 1
Progressors Regressors (n=272) P value
n=151
LDL cholesterol, mg/dL
Baseline 94.4 91.2 0.24
On-treatment 37.8 34.3 0.14
Risk factor l 1
ssors Regressors (n=272) P value
n=151
Change -58.3 -57.9 0.89
HDL cholesterol, mg/dL
Baseline 46.6 46.6 0.99
On-treatment 49.6 51.4 0.16
Change 2.0 3.8 0.008
Triglycerides, mg/dL
Baseline 121.0 117.5 0.66
On-treatment 107.5 104.3 0.13
Change -11.4 -9.8 0.87
L cholesterol,
mg/dL
Baseline 122.4 117.8 0.17
On-treatment 59.4 55.3 0.15
Chance -65.0 -62.9 0.50
Table 19.3
Risk factor control 2
Progressors Regressors (n=272) P value
n=151
Apolipoprotein B, mg/dL
Baseline 83.7 79.9 0.07
On-treatment 43.7 40.6 0.08
Change -42.7 -41.2 0.44
Apolipoprotein A—1, mg/dL
Baseline 142.8 140.1 0.28
On-treatment 150.0 152.6 0.26
Change 5.5 10.7 <0.001
Apolipoprotein B/A-1 ratio
Baseline 0.60 0.58 0.28
On-treatment 0.30 0.27 0.03
Change -0.32 -0.33 0.80
Lipoprotein (a), mg/dL
Baseline 8.9 14.6 0.09
On-treatment 5.1 8.2 0.22
Chance -3.1 -4.3 0.08
Table 19.4a
Risk factor control 3
Progressors Regressors P value
(n=151) (n=272)
HbA1c, %
Baseline 6.0 5.8 0.03
On-treatment 6.1 6.0 0.20
Change 0.2 0.2 0.09
e, mg/dL
Baseline 106.2 103.1 0.22
On-treatment 110.8 110.5 0.90
Change 6.6 9.3 0.22
hs-CRP, mg/L
Baseline 1.7 1.5 0.60
On-treatment 1.8 1.4 0.09
Change 0.3 -0.5 0.32
Systolic blood pressure,
Baseline 132.8 130.5 0.12
On-treatment 132.0 130.9 0.34
Chan e -2.7 -1.4 0.32
Table 19.4(b)
Regressors (n=2 721 “U cE.=m
LDL cholesterol, mean (95% C11, mg/dL
9441900, 98.91 9121879, 94.41 9N4:1
On-treatment 37.8 133.7, 41.81 34.3 131.8, 36.91 a K. 4:1
-58.31-63.8,-52.71 -62.6,-53.11 Q. 00\e
HDL cholesterol, mean (95% C11, mg/dL -
46.6 144.6, 48.71 46.6 145.1, 48.21
On-treatment 4961476, 51.61 5141499, 52.91 9N ex
2.010.6, 3.41 3.8 12.6, 5.01 9aaOn
Triglycerides, median (11 2R1, mg/dL -
Baseline 121.0 (91.0, 171.01 117.5 92.0 152.0
107.5190.8, 146.01 104.3 (82.3, 139.11 9NW
-11.41-37.0, 14.01 37.8, 10.81 9 an \1
Non-HDL cholesterol, mean (95%CI1, mg/dL
122.4 (117.1, 127. 71 117.8(113.9, 121.71 9 s. \1
On-treatment 59.4 154.6, 64.11 55.3 52.1, 58.51 § N U.
-65.01-71.5,-58.41 -62.91-68.4,-57.31 % U.%.
‘ goligogrotein B, mean 195%CI1, mg/dL -
8371803, 87.01 7991774, 82.31 9 a \1
On-treatment 4371407, 46.81 40.6 138.7, 42.61 9%on
-42.71-46.8,-38.51 -41.21-44.7,-37.71 Q .I:K.I:K
‘ goligogrotein A-1, mean 1, mg/dL
142.81139.0, 146.61 140.1 (137.1,143.11 9Non
On-treatment 150.0 (146.3, 153.81 152.6 (149.9, 155.31 Q NQ
-.52.3 8.8 10.7 8.0 13.4 APOOH
‘ goligogrotein B/A-I ratio, mean (95%CI),
0.60 (0.57, 0.631 0.58 (0.56, 0.60)
On-treatment 0.30 (0.28, 0.331 0.27 0.26 0.29
-0.321-0.35,-0.291 -0.331-0.35,-0.301 § 00%
Ligogrotein (a), median (IQR), mg/dL
-.94.3 48.4 14.6 4.6 62.1
_.12.4 40.8 8.2 2.4 50.7 9NN
-3.1-9.6 -0.6 -4.3 -12.3 -0.9 % §00
e, mean (95%C12, mg/dL t
106.2 (101.4, 111.02 103.1 (100.5,105.62 § NN
On-treatment 110.8 (106.3, 115.42 110.5 (107.5, 113.52
6.6 2.0 11.2 9.3 (5.4, 13.21 § NN
Hemoglobin A1c, mean (95%CI(, % i
-.05.8 6.1
-.15.9 6.2 020
-.20.1 0.3
hs—CRP, median (IQRZ, mg/L t
1.5 (0.8. 3.21
On-treatment
S stolic blood ressure mean 95%C mmH
132.8 (130.4, 135.22 130.5 (128. 7, 132.22
On-treatment 132.0 (130.1, 133.92 130.9 (129.6, 132.22
-2.7 0.1} -l.4 {-36, 0.9L
The values are shown in Tables l9.4-l9.4(b). Changes in levels of LDL-C (-58.3::2.82
mg/dL vs. -57.9::2.4l mg/dL, P=O.89), apolipoprotein B (-42.7::2.l mg/dL vs. -4l.2::1.8
mg/dL, P=O.44) and hsCRP (0.29 vs. -O.46 mg/L, P=O.32) did not differ between the .
Disease progressors demonstrated higher levels of baseline HbAlc (6.0:20.8% VS. 5.8::O.6%,
P=0.03), on-treatment levels of the apolipoprotein B/A-I ratio (0.30:0.15 vs. 0.27:0.12,
P=0.03) and smaller increases in levels of HDL-C (2.0::O.72 mg/dL vs. 3.8::O.61 mg/dL,
P=0.008) and apolipoprotein A-I (5.5::1.63 mg/dL vs. lO.7::1.39 mg/dL, P<0.001) compared
with patients undergoing plaque regression with evolocumab. >l‘Results are expressed as
mean (95% CI) at baseline and least squares mean (95% CI) for on-treatment values. 1‘ Time-
weighted es are used for on-treatment values. Absolute s are presented as least
s means (95% CIs).
Table 19.5
IVUS . ers
Pro - ressors n=151 Re ressors n=272 P value
Baseline
Percent atheroma volume, % 33.1 38.3 <0.001
Total atheroma volume, mm3 167.2 197.9 <0.001
Follow-up at 78 wks
Percent atheroma volume, % 35.2 35.9 0.40
Total atheroma volume, mm3 173.7 185.9 0.05
Change from baseline
t ma volume, % 1.91 -2.33 <0.001
Total atheroma volume, mm3 4.54 -12.11 <0.001
As shown in Table 19.5, progressors had lower percent atheroma volume
at ne (33.1% vs. 38.3%, P<0.001 ) than regressors.
Table 19.6
Determinants of la ue ro ression
OR 95% Cl P value
Baseline percent atheroma volume (%) 0.93 0.90-0.95 <0.001
Baseline HbA1c (%) 1.48 1.10-2.00 0.01
Change in apolipoprotein A—1 (%) 0.98 0.97-0.99 0.01
Baseline s stolic BP mmH 1.01 0.99-1.03 0.06
Despite ing extremely low LDL-C , 36% of patients with
evolocumab still exhibited plaque progression. There were no significant differences in
LDL-C levels between progressors and sors.
depicts the results of the analysis outlined in the tables above.
The graphs in show plaque progression and percent atheroma volume as a function
of the number of risk factors present. An increase in the number of risk factors results in an
increase in the risk of plaque progression, with the greatest increase in risk ing in
subjects with 3 or more risk factors.
Table 19.6 above, summarizes the various risk factors. Factors
ndently associated with ongoing progression were PAV (p<0.00l), HbAlc (p=0.01)
and change in apolipoprotein A-I (p=0.01), while systolic blood pressure was marginally
significant (p=0.06). A greater number of additional atherogenic risk s was ated
with greater propensity to ongoing plaque progression and attenuated atheroma regression.
Factors ated with a greater propensity to ongoing plaque
progression, despite evolocumab treatment, included the presence of additional atherogenic
factors. These finding highlight the value of multifactorial risk modification even in the
setting of very low LDL-C levels in order to prevent atherosclerotic progression in patients
with coronary artery disease.
Examgle 20
REGRESSION OF RY ATHEROSCLEROSIS WITH THE PCSK9 INHIBITOR,
EVOLOCUMAB, IN PATIENTS WITH R LP(A) LEVELS.
Lp(a) levels can predict cardiovascular risk. Proprotein convertase
subtilisin keXin type 9 (PCSK9) inhibitors can reduce Lp(a) by 21-30%. The present study
provides additional insight into the impact of PCSK9 tion on plaque at different Lp(a)
levels. The GLAGOV study ed the effects of the PCSK9 inhibitor, evolocumab, and
placebo for 78 weeks on progression of coronary sclerosis in statin-treated patients
with coronary artery disease. The impact of evolocumab on plaque progression was observed
in patients stratified according to baseline Lp(a) levels.
Evolocumab d percent atheroma volume (PAV) by 0.8% (P<0.001
compared with baseline) and 1.2% (P<0.001 compared with ne) and total atheroma
volume (TAV) by 5.3 mm3 (P<0.001 compared with baseline) and 7.7 mm3 (P<0.001
compared with baseline) in patients with Lp(a) levels below and above the median baseline
Lp(a) level (11.8 mg/dL) respectively.
Patients with higher Lp(a) levels were more likely to demonstrate PAV
regression (70.6% vs 58.7%, P=0.01). Additional analysis demonstrated sing plaque
regression with evolocumab in patients with increasing baseline Lp(a) levels >11.8 mg/dL
(P=0.04), while a similar degree of regression with evolocumab was observed less of
Lp(a) levels <11.8 mg/dL (P=O.35). This greater benefit at higher Lp(a) levels >11.8 mg/dL
just failed to meet statistical icance following adjustment for baseline plaque burden
(P=0.09).
Evolocumab treated patients with a baseline Lp(a) >11.8 mg/dL were less
likely to have diabetes (16.1% vs 25.5%, P=0.02), hypertension (75.4% vs 86.5%, P=0.001),
have lower baseline CRP levels (1.3 vs 1.77 mg/L, P=0.02) and higher on-treatment LDL-C
levels (33.9 vs 32.6 mg/dL, P=0.02). After adjustment for clinical and mical risk
factors, sing Lp(a) levels >11.8 mg/dL a trend towards greater plaque regression with
evolocumab treatment (P=0.07), although this just failed to meet statistical significance.
While evolocumab produced plaque regression in statin-treated patients at
all Lp(a) levels, greater baseline values, even within the normal range, identified ts
likely to derive a greater degree of regression. This ts that Lp(a), even within the
normal range, may identify patients with a more modifiable form of atherosclerosis for
treatment with ive lipid lowering.
Examgle 21
The present example trates that the long-term use of an antibody to
PCSK9 (e.g., evolocumab) can be used to reduce risk of recurrent cardiovascular events in
patients with a history of multiple events and across heart attack types. Additional analysis
found that patients closer to their most recent heart attack experienced substantial risk
reductions with the antibody (e.g., evolocumab). In addition, it is shown that reducing LDL-
C with a PCSK9 antibody (such as umab) significantly and safely reduces risk of
vascular events in ts with peripheral artery disease. Patients with a history of MI
within 2 years of enrollment had absolute risk ions (ARR; 2.9 percent).
The efficacy of evolocumab (in combination with statin therapy) was
evaluated in different myocardial infarction (MI) subgroups. Patients with a history of MI
(N=22,351) were characterized according to the time since their most recent MI event,
number of previous MIs and presence of essel coronary artery disease (CAD).
Treatment with evolocumab resulted in an absolute risk reduction of 2.9 percent in patients
within two years of their most recent MI (N=8,402), 2.6 percent in those with multiple prior
MIs (N=5,282) and 3.4 percent in patients with a history of multivessel CAD (N=5618)
respectively. The design of the study is depicted in and depicts the primary
results.
The analysis was restricted to 22,351 Pts with prior MI. These were
d into subgroups based on three factors: 1) time from qualifying prior MI (min. 4
weeks per protocol) 2) number of prior MS, and 3) presence of residual mutlivessel disease
(340% is in 3 2 vessels. The outcome of interest was: CV death, MI, or stroke. The
analyses considered risk of CV events in o arm in different subgroups and the efficacy
of Repatha in different subgroups.
The baseline teristics of the subjects are shown in table 21.0 and
Table 21.0
Characteristic Prior
22 y ago
N=13,918
(38%)
Age, mean (SD) 60 (9) 63 (9)
Male sex (%)
Hypertensmn (%)
Diabetes mellitus (%)
current smOker (%)
High-intenSity Statin (%) -_
LDL-C, rng/dL (IQR) 90 93
(79-106) (80-110)
Achieved LDL-C at 48 Wk, Ing/dL
(IQR)
The characteristics of the subjects are shown in table 21.1 for the
relationship to the number of prior MIs, depicted in .
Table 21.1
Characteristic 22 Prior 1 Prior MI
N=5285
(24%)
Age, mean (SD) 62 (9) 62 (9)
High-intensity statin (%)
LDL-C, mg/dL (IQR) 92 92
(81-105) (80-108)
Achieved LDL-C at 48 wk,
mg/dL (IQR)
The characteristics of the subjects are shown in table 21.2 for the
relationship to multivessel CAD, depicted in
Table 21.2
Characteristic 1 Prior
MIs N=17,047
(24%)
Age, mean (SD) 62 (9) 62 (9)
Male sex (%)
Hypertensmn (%)
LDL-C, mg/dL (IQR) 92 92
(81-105) 8)
Achieved LDL-C at 48 Wk, mg/dL
(IQR)
For every 1,000 patients treated for three years, evolocumab prevented 22
first y endpoint events and 52 total primary endpoint events. An evaluation of all the
primary endpoint events during the course of the study revealed that the addition of
evolocumab to statin therapy improved clinical outcomes with significant reductions in total
primary endpoint events driven by decreases in MI, , and ry revascularization.
Evolocumab reduced total primary nt events by 18 percent (incidence-rate ratio 0.82,
95 percent CI 0.75-0.90, p<0.00l).
Lowering LDL-C with an dy to PCSK9 (e. g, evolocumab) was
shown to reduce the risk of MI (27 percent,) and a new analysis revealed a robust benefit
across multiple subtypes of MI. Evolocumab was also effective in reducing the risk for MI
regardless of size (significant reductions observed regardless of fold elevations in troponin
) and severity (STEMI or non-STEMI). ent with evolocumab was associated
with a 36 percent reduction in the risk for STEMI, which accounted for one-fifth of Ms in
the study tion.
FIGs. 42-51 depict the results of this study. As shown in FIGS. 42-44,
those with recent MI (less than 2 years, FIGs. 42, 45, and 47), 2 or more MIs ( and
46), or multivessel disease (FIGs. 44 and 47) had an increased t from the combination
therapy provided herein. Indeed, as shown in FIGs. 48-51, the presence of various high-risk
MI features (one or more) allowed for identification of those subjects that would benefit from
a combination therapy (in this example, statin and evolocumab).
Patients (1) closer to their most recent MI, (2) with multiple prior MIs, or
(3) with multivessel disease are at an increased risk for major vascular events. These patients
eXperience substantial relative and absolute risk reductions with intensive LDL-C lowering
with evolocumab. These readily ascertainable clinical features offer an approach to tailoring
y to particular subjects with an increased benefit to those subjects.
Participants in the present example (evolocumab cardiovascular outcomes
study) were prospectively stratified according to their Thrombolysis in Myocardial Infarction
(TIMI) Risk Score for Secondary Prevention to identify those with the greatest potential for
al benefit following treatment with Repatha. tent with previous results, higher
risk was associated with r absolute risk reductions.
-l90-
EXAMPLE 22
Atherothrombotic Risk Stratification and Magnitude of Benefit
of Evolocumab in FOURIER
uction: Evolocumab (EvoMab) significantly reduced the relative
risk of cardiovascular (CV) death, MI or stroke by 20% (absolute risk reduction 2% at 3
years) in patients with atherosclerotic CV disease. However, such patients vary in their risk
for CV events.
Hypothesis: Risk stratification with the TIMI Risk Score for Secondary
Prevention (TRS 2°P) will fy patients who have the st potential for benefit from
EvoMab. Methods: The TRS 2°P was applied prospectively to 27,564 pts with
atherosclerotic CV disease and an LDLC 270mg/dL randomized to EvoMab or placebo (Pbo)
in FOURIER. The baseline risk as well as the relative and absolute risk reductions in CV
death, MI or stroke with EvoMab were calculated by TRS 2°P strata.
s: The 10 point integer-based scheme showed a strong graded
relationship with the rate of CV death, MI or stroke and the individual components (ptrend<
0.0001 for all). Intermediate risk patients (TRS 2°P Score=24; 79% of population) had a
1.9% absolute risk reduction (ARR) in CV death, MI or stroke at 3 yrs with EvoMab
compared to Pbo alone and high-risk patients (Score 2 5; 16%) had a 3.6% ARR, translating
to a number needed to treat for 3 years of 53 and 28, respectively ().
Conclusion: The TRS 2°P identifies high-risk patients with
atherosclerotic CV disease who demonstrate a pattern of greater absolute risk ion in
major CV events with .
EXAMPLE 23
ion in Total Cardiovascular Events with the PCSK9 Inhibitor Evolocumab in
ts with vascular Disease in the FOURIER Trial
H‘ITRODUCTION: Intensive LDL-C lowering with evolocumab
(EvoMab) significantly reduced the risk of major vascular events in patients with stable
atherosclerotic disease treated on ound statin therapy in the FOURIER trial. Although
-l9l-
traditional survival analyses focus on time to first event, from a patient perspective all events
matter.
HYPOTHESIS: EvoMab would significantly reduce total major vascular
events including those after the first event.
S: All PEP events (composite of CV death, MI, stroke,
unstable angina, or coronary revascularization) were evaluated during a median 2.2 yr
follow-up in FOURIER. Negative binomial regression & other sensitivity models were used.
RESULTS: There were 2907 first PEP events and 4,906 total events PEP
events (41% subsequent events) in 27,564 pts, with 1.7:r1.0 (range 1.11) events on average in
those with an event. EvoMab reduced total PEP events by 18% (incidence-rate ratio [R]
0.82, 95% Cl 0.75-0.90, p<0.001), including both first events (HR 0.85 0.92], p<0.001)
and subsequent events (RR 0.74 [0.65-0.85], p<0.001; , panel A). A time to event
model showed similar reductions (, panel B). For every 1000 pts treated for 3 yrs,
EvoMab prevented 22 first PEP events and 52 total PEP . Reductions in total events
were driven by fewer total MIs (RR 0.74, p<0.001), strokes (RR 0.77, p=0.007), and
coronary revascularization (RR 0.78, p<0.001).
SIONS: The addition of evolocumab to statin therapy
improved al outcomes with significant reductions in total PEP , driven by
decreases in MI, stroke, and coronary revascularization, which revealed more than double the
number of events prevented as ed with an analysis of just first events. These data
indicate the long-term use of evolocumab to prevent recurrent CV events.
EXAMPLE 24
Characterization of Types and Sizes of dial Infarction Reduced with
Evolocumab in FOURIER.
Introduction: The FOURIER trial described herein showed that the
PCSK9 inhibitor evolocumab reduced major vascular events compared to placebo in ts
with stable atherosclerotic CV disease, including reducing myocardial infarction (MI) by
27%. The present example reviews the types and sizes of MI in FOURIER.
Hypothesis: Evolocumab reduces spontaneous MI, less of size and
type (NSTEMI or STEMI).
Methods: 27,564 patients were randomized to evolocumab or o
and followed for a median of 26 months. Clinical endpoints were evaluated by the TIMI
clinical events tee which was not aware of treatment assignment. MI was defined
based on the Third Universal MI Definition, and further classified according to MI type
(Universal MI subclass, STEMI vs NSTEMI) and by MI size (peak biomarker). Rates
presented are 3-year KM estimates.
s: A total of 1107 subjects had a total of 1288 Ms. The majority
(68%) of the MIs were atherothrombotic (Type 1), with 15% supply/demand ch MI
(Type 2) and 15% PCI-related (Type 4). Sudden death MI (Type 3) and CABG—related MI
(Type 5) accounted for a total of 21 MIs ( <2%). See A. Evolocumab significantly
reduced the risk of first MI by 27% (4.4 vs 6.3%, P<0.001), Type 1 MI by 32% and Type 4
MI by 35%, with no effect on Type 2 MI (A). Troponin values were available for
1151 Ms. Using fold elevation of Tn, the majority of MIs (689, 60%) were large with
Tn210>< ULN. One fifth of Ms (238, 18%) were STEMI. The benefit of evolocumab was
highly significant and consistent regardless of the size of MI with a 34% reduction in MIs
with < ULN and a 36% reduction in STEMI (B).
Conclusion: LDL-C lowering with evolocumab was highly effective in
reducing the risk of dial infarction. This reduction included a robust benefit across
multiple subtypes of MI related to plaque rupture, smaller and larger MS, and both STEMI
and NSTEMI.
The present example examines the efficacy of intensive LDL-cholesterol
lowering with PCSK9-inhibitor evolocumab in combination with statin treatment in patients
with cerebrovascular disease.
Evolocumab is a monoclonal dy that inhibits proprotein convertase
subtilisin-kexin type 9 (PCSK9), lowers low-density lipoprotein (LDL) cholesterol levels by
approximately 60% and reduced major vascular events in patients with clinically evident
-l93-
cardiovascular disease in a large randomized trial. The present example assists in detailing
specific effects in patients with a history of ischemic stroke.
Methods
FOURIER was a randomized, double-blind, placebo-controlled trial
enrolling 27,564 ts with prior myocardial infarction, prior non-hemorrhagic stroke or
symptomatic peripheral artery disease, additional atherosclerotic risk factors, and LDL
terol levels 270 mg/dl or non HDL terol 3100 mg/Dl on statin therapy. Patients
were assigned to additional treatment with subcutaneous injections of umab 140 mg
bi-weekly or 420 mg monthly or matching placebo. The primary endpoint was the composite
of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or
coronary revascularization.
Results
The trial enrolled 5,337 patients with a history of ic stroke,
representing 19% of all randomized. In these patients with a history of ischemic (non-
hemorrhagic) stroke, mean age was 64, 66% were male. At 48 weeks, mean reduction in
LDL cholesterol levels with evolocumab, as ed with placebo was 59% from 91 mg/dl
to 29 mg/dl. Evolocumab treatment significantly reduced the primary endpoint relative to
placebo (n=259, [9.6%] vs. n=300, [11.3%], hazard ratio 0.85 (95% CI 0.72 — 1.00);
p=0.047). There was no ce of heterogeneity of benefit for reduction of the key
secondary endpoint of cardiovascular death, myocardial infarction, and ischemic or
hagic stroke alone; and reductions of ischemic stroke and transient ischemic attack
combined. Hemorrhagic stroke and ognitive adverse events were not increased.
Conclusions
Inhibition of PCSK9 with evolocumab on a background of statin therapy
in patients with a history of ischemic stroke lowered LDL-cholesterol levels to a median of
29 mg/dl and reduced the risk of cardiovascular events. These findings te that patients
with ic stroke benefit from lowering of LDL cholesterol levels below current targets.
Introduction
Patients who have experienced an ischemic stroke are at high risk of
suffering future ischemic cerebral, cardiac, and peripheral events.l, 1, ii Treatment to lower
LDL-cholesterol with statins and with the combination of statins and ibe have been
shown to reduce the risk of non-hemorrhagic stroke in patients at risk of atherosclerotic
cardiovascular disease.2'3 More ive therapy to reduce plasma levels of LDL-cholesterol
can be achieved with the combination of a statin and evolocumab, a monoclonal antibody
that inhibits proprotein convertase subtilisin-keXin type 9 (PCSK9)4.
The present disclosure includes the result of a randomized clinical trial
with 27 564 patients with prior myocardial tion, prior non-hemorrhagic stroke or
symptomatic eral arterial disease, additional atherosclerotic risk factors, and LDL-
terol levels of 70 mg/dl or higher while receiving high to moderate-intensity statin
therapy, in which all patients were d with either add-on evolocumab or non HDL
terol 3100 mg/dL, placebo in a -blind fashion5'6. The Further cardiovascular
Outcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) trial
showed that evolocumab reduced the median LDL terol level to a median of 30 mg/dl
(inter quartile range 19-46 mg/dl) while the patient d with statins alone remained at a
median level of 90 mg/dl (inter quartile range 80 — 109 mg/dl).6 After a median follow-up of
2.2 years for the entire cohort, there was a significant reduction in cardiovascular events in
the group treated with evolocumab compared to the placebo group. In this report the effect of
this among the subgroup of patients enrolled in the study who had a prior non-hemorrhagic
stroke is examined.
Methods
Patients were recruited at 1242 sites in 49 countries including Europe,
Asia, Australia, North and South America and the South African Republic. To qualify
patients had to be between 40 and 85 years of age and have clinically evident cardiovascular
disease: prior myocardial infarction, prior non-hemorrhagic stroke, or symptomatic
peripheral artery e. rmore, the patients needed to have at least one additional
major or at least additional minor atherosclerotic risk factors. Major risk factors were: 1.
diabetes, 2. age 265 years, 3. MI or stroke < 6 months before screening, 4. Additional
diagnosis of myocardial infarction or non-hemorrhagic stroke ing the qualifying event,
-l95-
. Current daily tte smoking, 6. History of symptomatic peripheral artery disease if
eligible by myocardial infarction or stroke. Minor risk factors were: 1. History of non-
myocardial infarction related coronary revascularization, 2. Residual coronary artery disease
with 240% stenosis in 22 large vessels, 3. Most recent HDL-cholesterol < 40 mg/dl for men
and <50 mg/dl for women, 4. Most recent high-sensitive C-reactive protein (hsCRP) >2.0
mg/L, 5.Most recent LDL-cholesterol 2130 mg/dl or non-HDL cholesterol 2160 mg/dl. After
22 weeks of stable statin therapy LDL cholesterol had to be 270 mg/dl or non-HDL
cholesterol had to be 2100 mg/dl. Furthermore, fasting triglycerides had to be £400 mg/dl, all
lipid measurements had to be performed at a central laboratory.
Leading exclusion ia were qualifying event ing within 4
weeks, previous hemorrhagic stroke, severe heart failure, severe renal e, malignancy
within the past 10 years, active liver disease or hepatic dysfunction, untreated or inadequately
treated hyperthyroidism or hypothyroidism and severe concomitant non-cardiovascular
disease.
Patients were randomly assigned (1:1) subcutaneous evolocumab r
140 mg every 2 weeks or 420 mg every month according to patient preference) or matching
placebo. Study visits were scheduled at 2, 4, and 12 weeks and every 12 weeks thereafter.
The primary study endpoint was the ite of cardiovascular death,
myocardial infarction, ischemic or hemorrhagic stroke, hospitalization for unstable angina, or
coronary ularization. The key secondary endpoint was the composite of vascular
death, myocardial infarction, or ischemic or hemorrhagic stroke. All events were adjudicated
by an independent endpoint tee blinded to treatment allocation and atment lipid
levels. The modified Rankin Score was determined 230 days after the event in patients
suffering a stroke. The up analysis of results obtained in the stroke population was
predefined in the statistical analysis plan.
Results
Of the 27,564 patients randomized between February 2013 through June
2015, 19% (n=5337) had a history of non-hemorrhagic stroke. The median time from the
most recent ischemic stroke to randomization was 3.2 years and 27% of these patients were
randomized less than 1 year after the stroke. Of the patients randomized with a history of
ischemic stroke, 30.1% and 31.3% of patients in the evolocumab and placebo group
respectively also had a history of myocardial infarction. The main baseline characteristics in
patients with a history of ischemic stroke are shown in Table 25.1. Among patients with a
history of ischemic stroke there were no major differences between the two treatment groups.
Compared with ts enrolled without a prior ic stroke, patients with a prior
ischemic stroke were older, more often female, more frequently had a history of
hypertension, diabetes, atrial fibrillation, and ent ischemic attack, and were less often
Caucasian and more often Asian, were less frequently current smokers (Table 25.3).
At the time of randomization, the median olesterol level was 91
mg/dl (interquartile range 79.0 - 108.5) in the evolocumab group and 92 mg/dl (interquartile
range 80 — 110) in the placebo group. After 4 weeks the median LDL-cholesterol level had
dropped to 31 mg/dl (interquartile range 21 — 46 mg/dl) in the umab group. In the
evolocumab group, 20% of patients reached LDL cholesterol levels of < 19 mg/dl at 4 weeks.
At 48 weeks the median level in the evolocumab was 29 mg/dl (interquartile range 18 -48
mg/dl) while in the placebo group the median LDL level was 89 mg/dl (interquartile range 74
-110). HDL cholesterol levels remained vely stable during the trial with median levels
in both treatment groups of 46 mg/dl (interquartile range 38 - 55 mg/dl) at baseline, rising to
49 mg/dl in the umab group and 46 mg/dl in the o group at 48 weeks. In patients
coming back for lipid measurement the effect on LDL-cholesterol remained stable in the two
groups with a 56% mean reduction in the evolocumab group at 48 weeks compared to the
placebo group.
Efficacy
Among the patients enrolled with a history of non-hemorrhagic stroke,
umab significantly reduced the primary composite endpoint of cardiovascular death,
myocardial infarction, ischemic and hemorrhagic stroke, hospitalization for unstable angina,
or coronary revascularization. This endpoint occurred in 259 patients in the evolocumab
group and 300 patients in the placebo group (hazard ratio 0.85, 95% confidence interval 0.72
— 1.00, (p=0.047). The result is similar to that observed for the entire study population. The
secondary endpoints were consistent in ion and magnitude with that ed in the
entire trial cohort. In particular, the key secondary nt of the composite of
cardiovascular death, myocardial infarction or stroke had a hazard ratio 0.80 (95%
confidence interval 0.73 — 0.88, (p<0.00001)), for myocardial infarction, (hazard ratio 0.74,
(95 % CI 0.55 — 1.19); and ischemic or hemorrhagic stroke, hazard ratio 0.90 (95% CI 0.68 —
1.19).
Considering subtypes of cerebrovascular outcome events, hazard ratios
were nominally lower for recurrent cerebral ic events than for cerebral hemorrhagic
events.
The ts of evolocumab with regard to the risk of the primary and key
secondary composite end points were largely consistent across major subgroups of patients
with prior ic stroke, including those based on age, seX, and entry LDL level
The type of primary endpoint events accruing over the course of the trial
differed among patients enrolled with a history of ischemic stroke and those without. In the
l arm, patients with versus without a history of ischemic stroke had a substantially
higher rate of recurrent ischemic and hemorrhagic stroke and a higher rate of vascular
death, and a lower rate of myocardial infarction.
The study treatment was well tolerated among patients enrolled with a
history of ic stroke and there were no differences for any specific adverse event
ry between the treatment groups (Table 25.2). The pattern of adverse events was
similar for patients qualifying for the study with a history of stroke as for those without.
Neurocogntive adverse events were not increased among evolocumab vs placebo patients
(2.0% vs 2.1%) and were also not increased in the subset of among patients achieving very
low levels (<30 mg/dl) of LDL cholesterol.
Discussion
Among patients with a history of ischemic stroke, further lowering of LDL
cholesterol by addition of evolocumab to statin therapy significantly d the risk of
cardiovascular events, with a 15% reduction in the risk of the primary composite endpoint of
cardiovascular death, dial infarction, ischemic and hemorrhagic stroke,
hospitalization for unstable angina, or coronary vascularization. These effects, and those for
all secondary endpoints were consonant with those among the entire study population,
indicating that patients with a prior ic stroke benefitted from evolocumab the same as
patients with other types of atherosclerotic cardiovascular disease. The ischemic stroke
patients allocated to evolocumab reached unprecendented low levels of LDL cholesterol with
one-fifth of ts having LDL cholesterol levels less than 19 mg/dl within one month of
randomization.
These results extend insights regarding the benefit of moderate and
intensive ions of LDL cholesterol level among patients with an ischemic stroke and
atherosclerotic risk factors. In FOURIER, it was found that additional reductions in
cardiovascular event rates among patients with ischemic stroke when LDL terol
levels were further lowered to a median of 29 mg/dl . These observations accord well with
observational studies demonstrating an association of PCSK9 gene polymorphsims and
plasma levels of LDL cholesterol with development and progression of carotid artery intima-
media thickness and atherosclerosis.viii, ix, x
Achievement of very low LDL-cholesterol levels with evolocumab was
not associated with an increase in adverse effects among ischemic stroke patients ed
to the placebo group. In particular, there was no trend of increased rate of hagic
stroke associated with extremely low levels of LDL-cholesterol, even among this subgroup
of patients entering the trial with past ischemic stroke and, by definition, damaged cerebral
vessels. This finding is reassuring given signal from observational studies and ized
trials of other LDL-cholesterol lowering therapies that raised concern that low LDL-
cholesterol levels might be ated with an increased risk of hemorrhagic stroke. In meta-
analyses, statin therapy was ated with non-significant increased risk of hagic
stroke across 21 y and secondary prevention trials (RR 1.15, 95% CI 0.87 — 1.51)
and across 2 trials of secondary prevention specifically in patients with prior symptomatic
cerebrovascular disease (RR 1.71, 95% CI 1.19 — 2.50).X[ Similarly, in a large trial of the
cholesterol absorption inhibitor ezetimibe there was a non-significant trend for increased risk
of hagic stroke (HR 1.38, 95% ci 0.89 — 3 The lack of association between
hemorrhagic stroke and the more extreme lowering of LDL-cholesterol in the current trial
suggests that cholesterol-lowering per se may not increase hemorrhagic stroke risk, and any
hemorrhagic tendencies of statins and ibe may be mediated by other mechanisms such
as those agents’ known pleiotropic, off-target, antiplatelet and antithrombotic effect, which
may differ quantitatively and qualitatively from the pleiotropic antithrombotic profile of
PCSK9 inhibitors.xii, xiii, xiv
The FOURIER trial was powered based on all eligible patients, so the
sample size of patients specifically qualifying with ischemic stroke was modest, and power to
explore subgroup effects among ts enrolled with ischemic stroke was moderate. The
duration of follow-up in the FOURIER trial was relatively short ed to most statin
trials which were on average 5 years in duration. The trial was originally planned to be
approximately 4 years, but the event rate in the control group was approximately 50% higher
than projected, so the prespecified number of events were accrued more quickly.
ation was not collected ing mechanistic subtypes of ic stroke such as
large artery atherosclerosis, small artery atherosclerosis, cardioembolic, and other. But the
requirement for presence of atherosclerotic risk s and for ischemic rather than
hemorrhagic stroke would strongly select for patients with ischemic stroke of atherosclerotic
origin.
In conclusion, among patients with prior ischemic stroke and onal
atherosclerotic risk factors, inhibition of PCSK9 with evolocumab on a background of statin
therapy lowered LDL cholesterol levels to a median of 29 mg/dl, was safe and reduced the
risk of further cardiovascular events, including stroke. These findings indicate that patients
with ischemic stroke and additional atherosclerotic risk factors benefit from lowering LDL
cholesterol levels below current targets.
References for Exalee 25
l. Kernan WN, Ovbiagle B, Black HR, a DM, Chimowitz MI, Ezekoviwitz MD,
et al. Guidelines for the tion of stroke in patients with stroke and transient
ischemic attack. A guideline for healthcare professionals from the American heart
ation/American Stroke Association. Stroke 5:2160-23 6.
2. Cholesterol Treatment Trialists’ (CTT) oration. Efficacy and safety of LDL-
lowering therapy among men and women: meta-analysis of individual data from
174 000 participants in 27 randomized trials. Lancet 2015;385:1397-405.
3. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al.
Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med
201 5,3 72:23 87-97.
4. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al.
Efficacy and safety of evolocumab in reducing lipids and vascular events. N
Engl J Med 2015;372:1500-09.
. Sabatine MS, Giugliano RP, Keech A, Honarpour N, Wang H, Liu T, et al. Rationale
and design of the Further cardiovascular Outcomes Research with PCSK9 Inhibition
in subjects with Elevated Risk trial. Am heart J 2016;173:94-101.
6. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SM, et
al. Evolcumab and clinical es in patients with vascular disease. N Engl J
Med 2017;376:1713-1722.
7. Giugliano RP, Pedersen TR, Park J-G, De Ferrari GM, Giaciong ZA, Ceska R, et al.
Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations
with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the
FOURIER trial. Lancet 2017; http ” //dX.doi “dot” .1016/S0140-
6736(17)32290-0.
8. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more
intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000
participants in 26 ised trials. Lancet 2010;376:1670-81.
Additional References
I Dhamoon
MS, Sciacca RR, Rundek T, Sacco RL, Elkind MS: Recurrent stroke and cardiac
risks after first ischemic : the Northern Manhattan Study. Neurology 2006;66:641—646.
11 Steg Pi}, Bhait DL, Wilson PW, D’Agostino R Sr, (Hun-em EM, Rather J, Liau CS, Hirsch
AT, Mas IL, Ikeda Y, Pencina ME, Goto S: ()nemyear vascular event rates in
outpatients with atherothrombosis. JAM/3i 2007,2971} 197---1206
III Amarenco P, Bogousslavsky J, an A 3rd, Goldstein LB, Hennerici M, Rudolph AE,
Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA; Stroke Prevention by Aggressive
Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke
or transient ischemic attack. N Engl J Med. 2006 Aug 10,3 55(6):549-59.
IV Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart tion Study Collaborative
Group.Effects of cholesterol-lowering with tatin on stroke and other major vascular
events in 20536 people with cerebrovascular e or other high-risk conditions. Lancet.
2004 Mar 6,363(94l l):757-67.
V The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.
Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary
Heart Disease and a Broad Range of Initial Cholesterol Levels. N Engl J Med 1998,
339:1349-1357
VI Sacks FM, Pfeff er MA, Moyé LA, et al. The eff ect of pravastatin on coronary events
after myocardial infarction in patients with average cholesterol . N Engl J Med 1996;
336: 1001—09.
VII Cannon CP, Blazing MA, Giugliano RP, et al. ibe added to statin therapy after
acute coronary mes. N Engl J Med 2015, 372: 2387-97.
VIII Norata GD1, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, Artali
R, Noto D, Cefalu AB, Buccianti G, Averna M, Catapano AL. Effects of PCSK9 variants on
common carotid artery intima media thickness and relation to ApoE s. Atherosclerosis.
2010 Jan;208(l): 177-82.
IX Chan DC, Pang J, McQuillan BM, Hung J, Beilby JP, Barrett PH, Watts GF. Plasma
Proprotein Convertase Subtilisin KeXin Type 9 as a Predictor of Carotid Atherosclerosis in
Asymptomatic Adults. Heart Lung Circ. 2016 May,25(5): 520-5.
X Xie W, Liu J, Wang W, Wang M, Qi Y, Zhao F, Sun J, Liu J, Li Y, Zhao D. Association
between plasma PCSK9 levels and 10-year progression of carotid sclerosis beyond
LDL-C: A cohort study. Int J Cardiol. 2016 Jul 15,215:293-8.
XI co P, Labreuche J. Lipid management in the prevention of stroke: review and
updated meta-analysis of statins for stroke prevention. Lancet Neurology 2009:8:453—463.
XII Oesterle A, Laufs U, Liao JK.Mitsios JV, Papathanasiou AI, Goudevenos JA, Tselepis
AD. The antiplatelet and antithrombotic actions of statins. Pleiotropic s of Statins on
the Cardiovascular . Circ Res. 2017 Jan 6;120(1):229-24.
XIII Pesaro AE, Serrano CV Jr, Fernandes JL, et al. ropic effects of
ezetimibe/simvastatin vs. high dose tatin. Int J Cardiol 2012;158:400-404
XIV Navarese EP, Kolodziejczak M, Kereiakes DJ, Tantry US, or C, Gurbel PA.
Proprotein Convertase Subtilisin/KeXin Type 9 Monoclonal Antibodies for Acute Coronary
Syndrome: A Narrative Review. Ann Intern Med. 2016 May 3,164(9):600-7.
Table 25.1: Baseline characteristics of patients with a history of ischemic stroke
Characteristic umab Placebo
N=2 686 N=2 6 5 1
Mean (SD) Mean (SD)
64-1 (8-7)
83-9 (18-3)
-3 (5-8)
830 (30-3)
7-4 7-5
134-6 15-6
1646 62.1%
1000 37.7%
98-0 26-9
47-8 13-6
147-2 71-4
175-0 32-3
3-8 7-7
Table 25.2 Adverse Events
Evolocumab o
(N=2686) (N=2651)
Number (%) Number (%
Any treatment-emergent adverse event 2 103 (78.4) 2 0 59 (77.8)
Serious treatment-emerent adverse event 741 2 7.6 738 2 7.9
Adverse event leading to tinuation of study 131 (5.0)
Injection site reactions 46 (1.7)
Allergic reactions 89 (3.3) 81 (3.1)
Neuroconitive event 55 2.1
Headache 115 (4.3)
Fatigue 52 (2.0)
New onset diabetes 106 (7.2)
Muscle—relatedevent 112 4.2 110 4.2
Rhabdom ol sis 5 0.2
Table 25.3 Primary and Secondary End Points.
Outcome Evolocumab o Hazard Ratio*
(N: 2686) (N: 2651) (95% CI)
Number Number
(W (W
Primary endpoint: vascular death,
myocardial tion, stroke,
hospitalization for unstable angina, or 259 (9.6) 300 (11.3) 0.85 (0.72 -
coronary revascularization 1.00)
Key secondary endpoint: cardiovascular
death, myocardial infarction or stroke 202 (7.5) 224 (8.4) 0.89 (0.74 -
1.08)
Cardiovascular death 73 (2.7) 65 (2.5) 1.11 (0.80 -
1.56)
Acute myocardial infarction 75 (2.8) 100 (3.8) 0.74 (0.55 -
1.00)
Stroke (ischemic and hemorrhagic) 95 (3.5) 105 (4.0) 0.90 (0.68 -
Coronary revascularization 89 (3.3) 128 (4.8) 0.68 (0.52 -
All-cause death 120 4.5 111 4.2 1.07 X.XX- 4
*These effects in the ischemic stroke subgroup were homogenous With those in the overall trial for all endpoint (Cochran’s
Q heterogeneity p value > 0‘ 10 for all)
—204—
Example 26
The present example provides a method of ng a relative risk of a
vascular event by at least 10%. A subject that is on at least a moderate intensity of a
statin therapy receives a PCSK9 neutralizing antibody in an amount sufficient to lower a
LDL-C level of the subject by about 20 mg/dL. This s the relative risk of a
cardiovascular event by at least 10% in the subject.
Exalee 27
The present example provides a method of decreasing percent atheroma
volume (PAV). A subject is identified who has received at least a moderate level of
treatment by a non-PCSK9 LDL-C lowering agent. The t then receives umab in
an amount ient and time sufficient to lower the LDL-C level to less than 100 mg/dL,
thereby decreasing a percent atheroma volume (PAV) in the subject.
Examgle 28
The t example provides a method of decreasing total atheroma
volume (TAV). A subject is identified who has received at least a moderate level of
ent by a non-PCSK9 LDL-C lowering agent. The subject then receives evolocumab in
an amount sufficient and time sufficient to lower the LDL-C level to less than 100 mg/dL,
thereby decreasing a total atheroma volume (TAV) in the subject.
The present example provides a method of treating coronary
atherosclerosis. One first identifies a statin-intolerant subject. One then sters at least
a low intensity statin treatment to the statin-intolerant subject. One then administers an
effective amount of evolocumab to the subject. This is continued to thereby treat coronary
atherosclerosis.
Examgle 30
The present example provides a method of combining a PCSK9 inhibitor
therapy and a non-PCSK9 LDL-C lowering therapy to produce greater LDL-C lowering and
regression of coronary atherosclerosis at a dose that is well tolerated. One first administers at
least a moderate intensity of a non-PCSK9 LDL-C lowering therapy to a subject. One then
administers an adequate amount of evolocumab to the t such that the t’s LDL-C
levels drop to no more than 40 mg/dL. One then maintains the subj ect’s LDL-C levels at no
more than 40 mg/dL for at least one year to e the noted result.
Examgle 31
The present example provides a method of treating a subject that is unable
to tolerate a full therapeutic dose of a non-PCSK9 LDL-C lowering agent. One identifies the
subject and then administers a PCSK9 inhibitor to the subject until a LDL cholesterol level of
the subject decreases beneath 60 mg/dL.
Examgle 32
The present example provides a method of treating coronary
atherosclerosis. One identifies a subject that has a LDL-C level of less than 70 mg/dL and
administers a non-PCSK9 LDL-C lowering agent to the subject, in an amount sufficient and
time ient to lower the LDL-C level to less than 60 mg/dL.
Examgle 33
The present e provides a method of treating coronary
sclerosis. One identifies a subject that has a LDL-C level of less than 70 mg/dL and
administers a PCSK9 LDL-C lowering agent to the subject, in an amount sufficient and time
sufficient to lower the LDL-C level to less than 40 mg/dL.
Exalee 34
The present example provides a method of lowering LDL-C levels in a
subject. One sters a first therapy to a subject. The first y comprises a .
One then administers a second therapy to the subject. The second therapy comprises a
PCSK9 inhibitor. Both the first and second therapies are administered to the subject for at
least five years, and the subject’s LDL-C level is maintained beneath 50 mg/dL. This thereby
reduces the LDL-C of the subject.
Examgle 35
The present example provides a method of lowering non-HDL-C levels in
a subject. One administers a first therapy to a subject. The first therapy comprises a .
One then administers a second therapy to the t. The second therapy comprises a
PCSK9 inhibitor. Both the first and second therapies are administered to the subject for at
least five years, and the subject’s L-C level is maintained beneath 80 mg/dL. This
thereby reduces the non-HDL-C of the subject.
Examgle 36
The present example provides a method of treating a subject. One first
fies a subject with peripheral artery disease and then reduces the level of PCSK9
activity in the subject by using evolocumab in an amount and for a on adequate to
reduce the risk or PAD.
Examgle 37
The t example provides a method of reducing a risk of an adverse
limb event in a subject. One reduces a level of PCSK9 activity in a subject by administering
evolocumab to the subject. The subject has peripheral artery disease. Following the therapy,
the subject will have a reduce risk of an adverse limb event.
Examgle 38.
The t example provides a method of reducing a risk of a major
adverse limb event (“MALE”). One first administers a non-statin LDL-C lowering agent to a
subject, and then administers a statin to the subject. The subject has peripheral artery disease
(“PAD”). Following the y, the t will have a reduce risk of MALE.
Examgle 39.
The present example provides a method of ng a risk of a major
cardiovascular adverse event (“MACE”). One first administers a non-statin LDL-C lowering
agent to a subject, and then administers a statin to the subject. The subject has PAD.
Following the therapy, the subject will have a reduce risk of MACE.
Exalee 40
The present example provides a method of reducing a risk of a
cardiovascular event. One first provides a first therapy to a subject, wherein the first therapy
comprises a SK9 LDL-C lowering therapy. One also provides a second therapy to
the t, wherein the second therapy comprises a PCSK9 inhibitor. The subject has a
Lp(a) level of 11.8 mg/dL to 40.
Exalee 41
The present example provides a method of reducing a risk of a major
vascular event in a subject. One identifies a subject that has at least one of: (a) a recent MI,
(b) le prior MS, or (c) multivessel disease. One then provides a first therapy to a
subject, wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy. One
then provides a second therapy to the subject, wherein the second therapy comprises a
PCSK9 inhibitor. This reduces a risk that the subject will have a major vascular event.
Exalee 42
The present e provides a method of treating coronary
atherosclerosis. One identifies a subject that has a LDL-C level of greater than 70 mg/dL.
One administers an anti-PCSK9 neutralizing antibody to the subject in an amount sufficient
and time sufficient to lower the LDL-C level to less than 40 mg/dL, or in the alternative, less
than 30 or in the ative, less than 20 mg/dL.
oration by Reference
All references cited herein, ing patents, patent applications, ,
text books, and the like, and the references cited therein, to the extent that they are not
already, are hereby incorporated herein by reference in their entirety. To the extent that any
of the definitions or terms provided in the references incorporated by nce differ from
the terms and discussion provided herein, the present terms and definitions control.
Equivalents
The foregoing written specification is considered to be sufficient to enable
one skilled in the art to practice the invention. The ing description and examples detail
certain preferred embodiments of the invention and be the best mode contemplated by
the inventors. It will be appreciated, however, that no matter how detailed the foregoing may
appear in text, the invention may be practiced in many ways and the ion should be
construed in accordance with the appended claims and any equivalents thereof.
Claims (19)
1. A method of treating coronary atherosclerosis, the method comprising: a. identifying a t that is on a first therapy, wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy; and b. administering a second y to the subject, wherein the second therapy comprises a PCSK9 inhibitor therapy, wherein both the first and second therapies are administered to the subject in an amount and time sufficient to reverse coronary atherosclerosis in the subject, and wherein the first therapy is not the same as the second therapy.
2. A method of treating coronary sclerosis, the method comprising: a. identifying a t that has a LDL-C level of less than 70 mg/dL, b. administering an anti-PCSK9 neutralizing antibody to the subject, in an amount sufficient and time sufficient to lower the LDL-C level to less than 60 mg/dL.
3. A method of sing percent atheroma volume (PAV) in a subject, the method comprising: identifying a subject that has received at least a moderate level of ent by a statin; and administering an anti-PCSK9 neutralizing antibody to the subject in an amount sufficient and time sufficient to lower the LDL-C level to less than 90 mg/dL, thereby decreasing a percent atheroma volume (PAV) in the subject.
4. A method of decreasing total atheroma volume (TAV) in a subject, the method comprising: a. fying a subject that has received at least a moderate level of treatment by a statin; and b. administering an anti-PCSK9 neutralizing antibody to the subject in an amount ient and time sufficient to lower the LDL-C level to less than 90 mg/dL, thereby decreasing a total atheroma volume in the subject.
5. A method of treating coronary atherosclerosis, the method comprising: a. identifying a statin-intolerant subj ect; b. administering at least a low dose statin treatment to the statin- intolerant subject; and c. administering an amount of an anti-PCSK9 neutralizing antibody to the subject, y treating coronary atherosclerosis.
6. A method of reducing an amount of atherosclerotic plaque in a subject, the method sing administering to a subject having atherosclerotic plaque a monoclonal antibody to human PCSK9, wherein the subject is receiving optimized statin therapy, thereby reducing the amount of atherosclerotic plaque in the subject.
7. A method of combining evolocumab and a statin y to produce r LDL-C lowering and regression of coronary atherosclerosis at a dose that is well tolerated, the method comprising: administering at least a moderate intensity of a statin therapy to a subj ect; administering an adequate amount of umab to the subject such that the subject’s LDL-C levels drop to no more than 40 mg/dL, and ining the subject’s LDL-C levels at no more than 40 mg/dL for at least one year.
8. A method of treating coronary atherosclerosis, the method comprising: fying a subject that has a LDL-C level of less than 70 mg/dL; and administering a PCSK9 inhibitor to the subject, in an amount sufficient and time sufficient to lower the LDL-C level to less than 60 mg/dL.
9. A method of decreasing percent ma volume (PAV) in a subject, the method sing: identifying a subject that has received at least a moderate level of treatment by a non-PCSK9 LDL-C lowering agent; and administering a PCSK9 inhibitor to the subject in an amount sufficient and time sufficient to lower the LDL-C level to less than 90 mg/dL, thereby decreasing a percent atheroma volume (PAV) in the subject.
10. A method of decreasing total atheroma volume (TAV) in a subject, the method comprising: identifying a subject that has received at least a moderate level of treatment by a non-PCSK9 LDL-C lowering agent; and administering a PCSK9 inhibitor to the subject in an amount sufficient and time sufficient to lower the LDL-C level to less than 90 mg/dL, thereby decreasing a total atheroma volume in the subject.
11. A method of reducing disease progression, the method comprising: identifying a subject with a LDL-C level of no more than 60 mg/dL, stering at least a moderate intensity of a non-PCSK9 LDL-C lowering therapy to the subj ect; and administering a PCSK9 inhibitor at a level sufficient to decrease the LDL-C level of the subject to 30 mg/dL, thereby reducing disease progression.
12. A method of combining a PCSK9 tor therapy and a non-PCSK9 LDL-C lowering therapy to produce greater LDL-C lowering and regression of coronary atherosclerosis at a dose that is well tolerated, the method comprising: stering at least a moderate ity of a non-PCSK9 LDL-C lowering therapy to a subj ect; administering an adequate amount of a PCSK9 tor to the subject such that the subject’s LDL-C levels drop to no more than 40 mg/dL, and maintaining the subject’s LDL-C levels at no more than 40 mg/dL for at least one year.
13. A method of reducing a risk of a cardiovascular event, the method comprising: identifying a subject that is on a first therapy, wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy, and administering a second therapy to the subject, wherein the second therapy comprises a PCSK9 tor, wherein both the first and second therapies are administered to the subject in an amount and time sufficient to reduce a risk of a vascular event in the subject, and wherein the first therapy is not the same as the second therapy, and wherein the risk is a) a ite for cardiovascular death, myocardial tion, stroke, hospitalization for unstable angina, or ry ularization or b) a composite for cardiovascular death, myocardial infarction, or stroke.
14. A method of reducing a risk of a cardiovascular event, the method comprising: identifying a subject that is on a first therapy, wherein the first therapy comprises a non-PCSK9 LDL-C lowering therapy; and administering a second therapy to the subject, wherein the second therapy comprises a PCSK9 inhibitor, wherein both the first and second therapies are administered to the subject in an amount and time sufficient to reduce a risk of a cardiovascular event in the subject, and wherein the first therapy is not the same as the second therapy, and n the risk is the composite of fatal MI and/or non-fatal MI and fatal and/or tal coronary revascularization.
15. A method of reducing a risk of a major adverse limb event (“MALE”), said method comprising: administering a non-statin LDL-C lowering agent to a subj ect; and administering a statin to the subject, wherein the subject has eral artery disease (“PAD”).
16. A method of reducing a risk of a major cardiovascular adverse event ”), said method comprising: administering a non-statin LDL-C lowering agent to a subj ect; and administering a statin to the subject, wherein the t has PAD.
17. A method of reducing a risk of a vascular event, the method comprising: providing a first therapy to a subject, n the first therapy comprises a SK9 LDL-C lowering therapy; and providing a second therapy to the subject, wherein the second therapy comprises a PCSK9 inhibitor, wherein both the first and second therapies are administered to the subject, and wherein the subject has a Lp(a) level of 11.8 mg/dL to 50.
18. A method of reducing a risk of a major vascular event in a subject, the method comprising: 1) identifying a subject that has at least one of: (a) a recent MI, (b) multiple prior MIs, or (c) multivessel disease; 2) providing a first therapy to a subject, wherein the first therapy ses a non-PCSK9 LDL-C lowering therapy; and 3) providing a second therapy to the subject, wherein the second y comprises a PCSK9 inhibitor, thereby reducing a risk that the subject will have a major vascular event.
19. A method of reducing a risk of a cardiovascular event, comprising administering, to a subject that has a LDL-C level of greater than 70 mg/dL, a PCSK9 inhibitor in an amount ient and time sufficient to lower the LDL-C level to less than 40 mg/dL. —214— How 9f Patients Thmugh the Trial 252$ screened 1382 62d net meet eiigibiiity ia 1245 enmiied 27S enmiied but net randcmized 235 did not meet inciusian/exciusian criteria 32 withdrew infarmed consent 9 ether 9m F‘atients randamized 485 ed t9 receive piacebe 4184 assigned in receive fiwiacumab 2 never received study drug 484 inciuded in safety anaiysis 484 inciuded in safety anaiysis 51 did nut compiete end point ment 51 did not compiete and paint assessment 1 died before finai ascuiar 3 died mime fina! intravascuiar uitrasaund obtained ultraseund 44 fina! intravascuiar uitrasaund not 43 finai intravascuiar ultrascund net obtained obtainéd 16 finai intravascuiar uitrasound not 15 finai intravascular ultrasaund not abie analyzabie 423 inducted in primary anaiysis 4123 inciuded in primary anaiysis SUBSTITUTE SHEET (RULE 26) WO 89912 FiG.2 m 20 m w Piacebo E; o WWW—wmmm-----W-wwmw «’2: ~10
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US62/421,685 | 2016-11-14 | ||
US62/471,874 | 2017-03-15 | ||
US62/515,117 | 2017-06-05 | ||
US62/581,244 | 2017-11-03 | ||
US62/584,600 | 2017-11-10 |
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NZ794398A true NZ794398A (en) | 2022-11-25 |
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