NZ731528B2 - Methods of treating multiple sclerosis - Google Patents
Methods of treating multiple sclerosis Download PDFInfo
- Publication number
- NZ731528B2 NZ731528B2 NZ731528A NZ73152815A NZ731528B2 NZ 731528 B2 NZ731528 B2 NZ 731528B2 NZ 731528 A NZ731528 A NZ 731528A NZ 73152815 A NZ73152815 A NZ 73152815A NZ 731528 B2 NZ731528 B2 NZ 731528B2
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- NZ
- New Zealand
- Prior art keywords
- fumarate
- patient
- pharmaceutical composition
- foregoing
- monoalkyl
- Prior art date
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- RRHXZLALVWBDKH-UHFFFAOYSA-M trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CC(=C)C(=O)OCC[N+](C)(C)C RRHXZLALVWBDKH-UHFFFAOYSA-M 0.000 description 1
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- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
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Abstract
Provided herein are methods of treating multiple sclerosis with a fumarate, wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the foregoing. The methods provided herein improve the safety of treatment by informing and monitoring patients undergoing treatment regarding progressive multifocal leukoencephalopathy, and/or by monitoring lymphocyte count. y acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the foregoing. The methods provided herein improve the safety of treatment by informing and monitoring patients undergoing treatment regarding progressive multifocal leukoencephalopathy, and/or by monitoring lymphocyte count.
Description
METHODS OF TREATING MULTIPLE SCLEROSIS
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims the benefit ofUS. Provisional Patent ation No.
62/080,783, filed November 17, 2014, US. Provisional Patent Application No. 62/140,255, filed
March 30, 2015, and US. Provisional Patent ation No. 62/232,963, filed September 25,
2015, each of which is incorporated herein by reference in its entirety.
1. FIELD
Provided herein are methods of treating multiple sclerosis with a fumarate, such as a
l filmarate, monoalkyl filmarate, a combination of a dialkyl filmarate and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the ing, and a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing. The methods ed herein improve the
safety of treatment by informing and monitoring patients undergoing treatment regarding
progressive multifocal leukoencephalopathy (PML), and/or by monitoring lymphocyte count.
2. BACKGROUND
Multiple sclerosis (MS) is an autoimmune disease with the autoimmune activity
directed against central nervous system (CNS) antigens. The disease is characterized by
inflammation in parts of the CNS, g to the loss of the myelin sheathing around neuronal
axons (demyelination), axonal loss, and the eventual death of neurons, oligodendrocytes and
glial cells. For a comprehensive review ofMS and current therapies, see, e.g., McAlpine’s
Multiple sis, by Alastair Compston et al., 4th edition, Churchill Livingstone Elsevier, 2006.
An estimated 2,500,000 people in the world suffer from MS. It is one of the most
common diseases of the CNS in young adults. MS is a chronic, progressing, disabling e,
which generally strikes its victims some time after adolescence, with diagnosis generally made
n 20 and 40 years of age, although onset may occur earlier. The disease is not directly
hereditary, gh genetic susceptibility plays a part in its pment. MS is a complex
disease with heterogeneous clinical, pathological and immunological phenotype.
There are four major clinical types of MS: 1) relapsing-remitting MS (RR-MS),
2015/060850
characterized by y defined relapses with full recovery or with sequelae and residual deficit
upon recovery; periods between disease relapses characterized by a lack of disease progression;
2) secondary progressive MS (SP-MS), characterized by initial relapsing remitting course
followed by progression with or without occasional relapses, minor remissions, and plateaus; 3)
primary progressive MS ), characterized by disease progression from onset with
occasional plateaus and temporary minor improvements allowed; and 4) progressive relapsing
MS ), terized by progressive disease onset, with clear acute relapses, with or
without full ry; periods n relapses characterized by continuing progression.
Clinically, the illness most often presents as a relapsing-remitting disease and, to a
lesser extent, as steady progression of neurological lity. Relapsing-remitting MS (RR-MS)
presents in the form of recurrent attacks of focal or multifocal neurologic dysfilnction. Attacks
may occur, remit, and recur, gly randomly over many years. Remission is often
incomplete and as one attack follows another, a se downward progression ensues with
increasing permanent neurological deficit. The usual course of RR-MS is characterized by
repeated relapses associated, for the majority of patients, with the eventual onset of disease
progression. The subsequent course of the disease is unpredictable, although most patients with
a relapsing-remitting e will eventually develop secondary progressive disease. In the
relapsing-remitting phase, relapses ate with periods of clinical inactivity and may or may
not be marked by ae ing on the presence of neurological deficits between episodes.
Periods between relapses during the ing-remitting phase are clinically stable. On the other
hand, patients with progressive MS exhibit a steady increase in deficits, as defined above and
either from onset or after a period of episodes, but this designation does not preclude the fithher
occurrence ofnew relapses.
MS pathology is, in part, reflected by the formation of focal inflammatory
demyelinating lesions in the white matter, which are the hallmarks in patients with acute and
ing disease. In patients with progressive disease, the brain is affected in a more global
sense, with diffuse but widespread y axonal) damage in the normal appearing white matter
and massive demyelination also in the grey matter, particularly, in the cortex.
Salts of fumaric acid esters, in combination with dimethyl fumarate (DMF), such as
present in FUMADERM®, have been proposed for the treatment ofMS (see, 6.g. , Schimrigk et
al., Eur. J. Neurol., 2006, l3(6):604-610; Drugs R&D, 2005, 6(4):229-30; US. Pat. No.
992). RM® contains dimethyl filmarate, calcium salt of ethyl en
fumarate, magnesium salt of ethyl hydrogen filmarate, and zinc salt of ethyl hydrogen fumarate
(see, e.g., Schimrigk et al., Eur. J. Neurol., 2006, 13(6):604-610).
TECFIDERA®, dimethyl fiamarate delayed-release capsules for oral use, was
approved in 2013 by the US. Food and Drug Administration for the treatment of subjects with
relapsing forms of multiple sclerosis. TECFIDERA® contains dimethyl filmarate (DMF), which
has the following structure:
The first Phase 3 study, DEFINE (ClinicalTrials.gov identifier NCT00420212),
demonstrated that DMF significantly reduced clinical es, accumulation of lity
progression, and lesion number and volume compared with placebo after two years of treatment.
See, e.g., Gold et al., N. Engl. J. Med., 2012, 367(12): 1098-1 107. These findings were supported
by the results of the second phase 3 study, CONFIRM (ClinicalTrials.gov identifier
51451), which additionally evaluated subcutaneous glatiramer acetate as an active
reference treatment (rater-blind). See, e.g., Fox et al., N. Engl. J. Med., 2012, 367(12):1087-
1097. DMF has demonstrated an acceptable safety profile in the DEFINE and CONFIRM
studies.
There have been case reports of patients with psoriasis, treated with FUMADERM®
or compounded fiamaric acid esters, who developed PML (Ermis et al., N. Engl. J. Med., 2013,
368(17): 1657-1658; van Oosten et al., N. Engl. J. Med., 2013, 368(17): 1658-1659; Sweetser et
al., N. Engl. J. Med., 2013, ): 1659-1658; , Lisa, era and PML — What’s the
story.” Multiplesclerosis.net, April 25, 2013; accessed November 10, 2014).
PML is an opportunistic Viral infection caused by a type of polymavirus called the JC
virus (JCV) that lly only occurs in patients who are immunocompromised, and that usually
leads to death or severe disability. The virus is very common in the general population, occurs in
childhood, and persists for life. JCV seroprevalence of ~33-84% has been demonstrated,
ing on the studies (see A1, WO2007/100770 A2, and
A2). PML is a severe and rapidly progressive viral disease of the central nervous system that
destroys the myelin coating, which protects the nerve cells. PML occurs almost exclusively in
patients who are severely immunocompromised, and is often associated with lymphoproliferative
and other chronic diseases, such as AIDS, Hodgkin’s e, chronic cytic leukemia,
sarcoidosis, tuberculosis, systemic lupus erythematosus, and organ transplantation. Cases of
PML have also been reported in patients with autoimmune disorders who received
immunosuppressive therapy; among these, three patients with rheumatoid arthritis (Sponzilli et
al., Neurology, 1975, 25(7):664-668; Rankin et al., J. Rheumatol., 1995, 22(4):777-779; Durez et
al., Arthritis , 2002, 46(98):536), one of whom was treated with tumor necrosis factor
(TNF) antagonist (Durez et al., Arthritis , 2002, :536). PML also was reported in a
s Disease patient, but the concomitant treatments were not specified (Garrels et al., Am. J.
Neuroradiol., 1996, 17(3):597-600), and in patients treated with natalizumab, a humanized
monoclonal antibody used in the treatment of multiple sclerosis, and Crohn’s disease. In 2005,
the first cases of PML associated with biological immunomodulatory therapy were reported,
initially with zumab and subsequently in association with other agents including
efalizumab, mab, and alemtuzumab (reviewed in: Major et al., Annu. Rev. Med., 2010,
61:35-47).
There is need in the art for safer methods of treating patients with fumarates that take
into account the possibility of contracting PML.
3. SUMMARY
[0013a] The present ion ularly provides for aspects and embodiments as set out in
the s below:
1. The use of a pharmaceutical composition comprising monomethyl fumarate, dimethyl
fumarate or a combination thereof; with the provisos (i) that a fumarate salt is not present in the
pharmaceutical composition and (ii) that no fumarate other than dimethyl fumarate or
monomethyl fumarate is present in the pharmaceutical composition; in the manufacture of a
medicament for treating a patient with multiple sclerosis, wherein the patient has a lymphocyte
count less than 0.5 x 109/L, the treating comprising the steps of:
(a) administration of said pharmaceutical ition;
(followed by 4A)
(b) obtaining a complete blood count including lymphocyte count after 6 months
of repeated administration of said pharmaceutical composition to said patient,
and every 6 to 12 months thereafter; and
(c) interrupting administration of said ceutical composition to said patient
when the patient has a lymphocyte count less than 0.5 x 109/L persisting for
more than six months.
2. The use of clause 1, wherein the fumarate is a combination of yl fumarate and
monomethyl fumarate.
3. The use of clause 1, wherein the fumarate is dimethyl fumarate.
4. The use according to any one of clauses 1 to 3, wherein the stration is done
orally.
. The use according to clause 1, wherein the administration is of 240 mg fumarate
twice daily orally.
6. The use of clause 1, wherein the administration is of 120 mg fumarate twice daily
orally for 7 days, followed by 240 mg te twice daily orally as a nance dose.
7. The use of any one of clauses 1 to 6, wherein the administration is of not greater than
720 mg daily total fumarates.
8. The use of any one of clauses 1 to 6, wherein the administration is of not greater than
480 mg daily total fumarates.
9. The use of any one of clauses 1 to 8, wherein the treating further comprises
monitoring the patient for a sign or symptom tive of progressive multifocal
leukoencephalopathy (PML) in the patient.
(followed by 4B)
. The use of clause 9, wherein the sign or symptom suggestive of PML is selected from
the group consisting of progressive weakness on one side of the body or clumsiness of limbs,
disturbance of vision, and changes in thinking, , and orientation leading to confusion
and personality changes.
11. The use of clause 9 or 10, wherein the patient exhibits a sign or symptom suggestive
of PML, and the treating further comprises withholding the pharmaceutical composition and
performing an appropriate diagnostic evaluation for PML.
12. The use of clause 11, wherein the said ng further comprises informing the
patient that PML has occurred in a MS patient who received fumarate.
13. Use of a pharmaceutical composition comprising dimethyl fumarate, with the o
that a fumarate salt is not present in the pharmaceutical composition, in the manufacture of a
medicament for ng a patient with multiple sclerosis (“MS”), wherein the patient has a
lymphocyte count less than 0.5 x 109/L and wherein the treating comprises the steps of:
(a) administration of said pharmaceutical composition to the patient;
(b) obtaining a complete blood count including lymphocyte count after 6 months
of repeated administering of said pharmaceutical composition to said patient, and
every 6 to 12 months thereafter; and
(c) interrupting administration of the fumarate therapy to said t when the
t has a lymphocyte count less than 0.5 x 109/L that persists for more than six
months.
14. The use of clause 13, wherein the administration of the pharmaceutical ition is
done .
. The use of clause 13, n the administration is of 240 mg dimethyl fumarate
twice daily orally.
(followed by 4C)
16. The use clause 13, wherein the administration is of 120 mg dimethyl fumarate
administered twice daily orally for 7 days, followed by 240 mg dimethyl fumarate
administered twice daily orally as a maintenance dose.
17. The use of any one of clauses 13 to 16, wherein the administration is of not r
than 720 mg daily total dimethyl fumarate.
18. The use of any one of clauses 13 to 16, wherein the administration is of not greater
than 480 mg daily total dimethyl fumarate.
19. The use of any one of clauses 13 to 18, wherein the treating further comprises a step
monitoring the ts for a sign or symptom suggestive of progressive ocal
leukoencephalopathy (PML) in the patient.
. The use of clause 19, wherein the sign or symptom of PML is ed from the group
consisting of progressive ss on one side of the body or clumsiness of limbs,
disturbance of vision, and changes in thinking, memory, and orientation leading to confusion
and personality changes.
21. The use of clause 19 or 20, wherein the patient exhibits a sign or symptom suggestive
of PML, and the treating further comprises withholding the pharmaceutical composition and
performing an appropriate diagnostic evaluation for PML.
22. The use of clause 21, wherein the ng further comprising step of:
informing the patient that PML has occurred in a MS patient who received dimethyl
fumarate.
[0013a] Further aspects and embodiments are sed at paragraphs [0014] to [00112]
below.
(followed by 4D)
Provided herein is a method of treating a patient with multiple sclerosis comprising
(a) administering a fumarate to the patient, wherein the fumarate is a dialkyl fumarate, a
monoalkyl fumarate, a ation of a dialkyl fumarate and a monoalkyl fumarate, a prodrug
of monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically
able salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a
combination of any of the foregoing; and (b) monitoring the patient for a sign or m
suggestive of progressive multifocal ncephalopathy (PML) in the patient.
Provided herein is a method of improving safety in treatment of a patient with
(followed by 5)
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a te for a sign or symptom suggestive of PML in the patient, n the filmarate is
a dialkyl fumarate, a monoalkyl filmarate, a combination of a dialkyl filmarate and a monoalkyl
fumarate, a prodrug of kyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, e, tautomer, or stereoisomer of any of the
foregoing, or a ation of any of the foregoing.
ed herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a fumarate to the patient, wherein the filmarate is a dialkyl te, a kyl
fumarate, a combination of a l te and a monoalkyl filmarate, a prodrug of
monoalkyl filmarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, e, tautomer, or stereoisomer of any of the foregoing, or a ation of any
of the foregoing; and (b) informing the patient that PML has occurred in a patient who received
dimethyl fumarate.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a fumarate to the patient, wherein the filmarate is a dialkyl filmarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, e, tautomer, or stereoisomer of any of the ing, or a combination of any
of the foregoing; and (b) instructing the patient of the importance of contacting the t’s
doctor if the t develops any symptoms suggestive of PML.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis sing informing a patient with multiple sclerosis who is being treated
with a fumarate that PML has occurred in a patient who received dimethyl filmarate, wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a ated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising instructing a patient with multiple sclerosis who is being treated
with a fumarate of the importance of contacting the patient’s doctor if the patient develops any
symptoms suggestive of PML, wherein the fumarate is a dialkyl fumarate, a monoalkyl filmarate,
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a combination of a dialkyl fumarate and a monoalkyl fumarate, a g of monoalkyl fumarate,
a ated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate,
solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the
foregoing.
In one embodiment, the method further comprises withholding treatment with the
fumarate from the patient at the first sign or symptom suggestive of PML in the patient.
In one embodiment, the method further comprises performing a stic tion
for PML in the patient at the first sign or symptom suggestive of PML in the patient.
In one embodiment, the method fiarther comprises administering a therapeutic to the
patient for the treatment for the treatment of PML when the stic evaluation indicates PML
in the patient.
In one embodiment, the method fiarther comprises instructing the patient to continue
to look for new signs and symptoms suggestive ofPML for approximately 6 months following
discontinuation of treatment with the te.
In one embodiment, the method fiarther comprises instructing the patient that typical
ms associated with PML are diverse, progress over days to weeks, and include
progressive ss on one side of the body or clumsiness of limbs, disturbance of vision, and
changes in thinking, memory, and orientation leading to ion and personality changes.
In one embodiment, the method further comprises instructing the patient that
progression of def1cits associated with PML usually leads to death or severe lity over
weeks or months.
In one embodiment, the diagnostic evaluation comprises a test for the presence of JC
viral DNA in the cerebrospinal fluid of the patient.
In one embodiment, the sign or symptom suggestive ofPML is selected from the
group consisting of progressive weakness on one side of the body or clumsiness of limbs,
disturbance of vision, and changes in thinking, , and orientation leading to ion and
personality changes.
In one embodiment, administering is done orally.
In one embodiment, the pharmaceutical composition comprises a therapeutically
effective amount of the fumarate and a pharmaceutically acceptable carrier.
In one embodiment, the pharmaceutical composition is in the form of a tablet or a
capsule.
In one embodiment, the pharmaceutical composition is in the form of an enterically
coated tablet.
In one embodiment, the pharmaceutical composition is in the form of a capsule
containing enterically coated microtablets.
In one embodiment, the fumarate is dimethyl fumarate and/or monomethyl fumarate.
In one embodiment, the fumarate is yl fumarate
In one ment, the administering is of 240 mg twice daily of dimethyl filmarate..
In one embodiment, the stering is of 120 mg dimethyl fumarate twice daily for
7 days, ed by 240 mg dimethyl fumarate twice daily as a maintenance dose.
In one embodiment, the administering is of not greater than 720 mg daily total
fumarates.
In one embodiment, the administering is of not greater than 480 mg daily total
fumarates.
In one ment, the pharmaceutical composition consists essentially of dimethyl
fumarate, and the administering is of not greater than 720 mg daily dimethyl te.
In one embodiment, the pharmaceutical composition consists essentially of dimethyl
fumarate, and the administering is of not greater than 480 mg daily yl fumarate.
In one embodiment, the pharmaceutical composition consists essentially of yl
fumarate.
In one embodiment, the multiple sclerosis is a relapsing form of multiple sclerosis.
ed herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a ceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a ation of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition; and (b) monitoring the patient for a sign or symptom suggestive of PML in the
patient.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate for a sign or symptom suggestive of
PML in the patient; wherein the fumarate is a dialkyl fumarate, a monoalkyl filmarate, a
combination of a l filmarate and a monoalkyl filmarate, a g of monoalkyl filmarate,
a ated form of any of the foregoing, or a ate, solvate, er, or stereoisomer of
any of the foregoing, or a combination of any of the foregoing; with the proviso that a fumarate
salt is not present in the pharmaceutical composition.
ed herein is a method of treating a patient with le sclerosis comprising (a)
administering a pharmaceutical ition comprising a te to the patient; n the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a ated form of any of the foregoing,
or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition; and (b) informing the patient that PML has occurred in a patient who received
dimethyl fumarate.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a ceutical composition comprising a filmarate to the t; wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a clathrate, e, tautomer, or stereoisomer of any of the ing, or a combination of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition; and (b) instructing the patient of the importance of contacting the patient’s doctor if
the patient develops any symptoms suggestive of PML.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising informing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate that PML has occurred in a patient
who received dimethyl te; wherein the fumarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl te and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a clathrate, solvate, tautomer,
or stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the
proviso that a filmarate salt is not present in the pharmaceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sis comprising instructing a patient with multiple sclerosis who is being d
with a pharmaceutical composition comprising a filmarate of the importance of contacting the
patient’s doctor if the patient develops any symptoms tive of PML; wherein the filmarate
is a dialkyl filmarate, a monoalkyl filmarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a ated form of any of the foregoing,
or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl te, a ation of a l filmarate and a
monoalkyl fumarate, a prodrug of kyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the o that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical composition; and (b) monitoring the patient for
a sign or symptom suggestive ofPML in the patient.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate for a sign or symptom suggestive of
PML in the patient; n the fumarate is a dialkyl te, a monoalkyl te, a
combination of a dialkyl filmarate and a monoalkyl filmarate, a prodrug of monoalkyl filmarate,
a deuterated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate,
e, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the
foregoing; with the proviso that an ethyl hydrogen fumarate salt is not t in the
pharmaceutical composition.
ed herein is a method of treating a patient with multiple sclerosis sing (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl te, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or isomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical composition; and (b) informing the patient that
PML has occurred in a patient who received dimethyl te.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
te is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a ation of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical composition; and (b) instructing the patient of
the importance of contacting the patient’s doctor if the patient develops any symptoms
suggestive of PML.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising ing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate that PML has occurred in a patient
who received dimethyl fumarate; wherein the fumarate is a dialkyl te, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a g of
kyl fumarate, a deuterated form of any of the ing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that an ethyl hydrogen fumarate salt is not present in the
ceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising instructing a patient with le sis who is being treated
with a pharmaceutical composition comprising a filmarate of the importance of contacting the
patient’s doctor if the t develops any symptoms suggestive of PML; wherein the filmarate
is a dialkyl filmarate, a monoalkyl filmarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl te, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, er, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the ceutical composition.
Provided herein is a method of ng a patient with multiple sclerosis comprising (a)
stering a pharmaceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl te, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a ation of any of the foregoing; with the proviso that ethyl hydrogen
fumarate calcium salt, ethyl en fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition;
and (b) ring the patient for a sign or symptom tive of PML in the patient.
Provided herein is a method of improving safety in treatment of a patient with
le sclerosis comprising monitoring a patient with le sis who is being d
with a pharmaceutical composition comprising a filmarate for a sign or symptom suggestive of
PML in the t; wherein the fumarate is a dialkyl fumarate, a kyl filmarate, a
combination of a dialkyl filmarate and a monoalkyl filmarate, a prodrug of monoalkyl filmarate,
a ated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate,
e, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the
foregoing; with the proviso that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate
magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate copper salt are
not present in the pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically able salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a ation of any of the foregoing; with the proviso that ethyl hydrogen
te calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not t in the pharmaceutical ition;
and (b) informing the patient that PML has occurred in a patient who ed dimethyl fumarate.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising fumarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that ethyl hydrogen
fumarate m salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not t in the ceutical composition;
and (b) instructing the patient of the importance of contacting the patient’s doctor if the patient
develops any symptoms tive of PML.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising informing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate that PML has occurred in a patient
who received dimethyl fumarate; n the fumarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a g of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the ing, or a combination of any
of the foregoing; with the proviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogen
fumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper
salt are not present in the pharmaceutical ition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising instructing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition sing a filmarate of the ance of contacting the
patient’s doctor if the patient ps any ms suggestive of PML; wherein the filmarate
is a dialkyl filmarate, a monoalkyl filmarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the ing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or isomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that ethyl hydrogen
fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a ceutical composition ting essentially of dimethyl fumarate and/or
monomethyl fumarate to the patient; and (b) monitoring the patient for a sign or symptom
suggestive of PML in the patient.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition consisting essentially of dimethyl fumarate and/or
monomethyl fumarate for a sign or symptom suggestive ofPML in the patient.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical ition consisting essentially of yl fumarate and/or
monomethyl te to the patient; and (b) informing the patient that PML has occurred in a
t who received dimethyl te.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition consisting essentially of dimethyl fumarate and/or
monomethyl fumarate to the patient; and (b) instructing the patient of the importance of
contacting the patient’s doctor if the patient develops any symptoms tive of PML.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising informing a t with multiple sclerosis who is being treated
with a pharmaceutical composition consisting essentially of dimethyl fumarate and/or
monomethyl fumarate that PML has occurred in a t who received dimethyl filmarate.
ed herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising instructing a patient with le sclerosis who is being treated
with a pharmaceutical composition ting essentially of dimethyl fumarate and/or
monomethyl fumarate of the importance of contacting the patient’s doctor if the patient develops
any symptoms suggestive of PML.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
stering a fumarate to the patient, n the filmarate is a dialkyl filmarate, a monoalkyl
fumarate, a combination of a dialkyl te and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a ation of any
of the foregoing; and (b) obtaining a complete blood count including lymphocyte count after 6
months of repeated administering of said pharmaceutical composition to said patient, and every 6
to 12 months thereafter.
Provided herein is a method of treating a t with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl te, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
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or a ate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition; and (b) obtaining a complete blood count including lymphocyte count after 6
months of repeated administering of said pharmaceutical composition to said t, and every 6
to 12 months thereafter.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the t; wherein the
fumarate is a dialkyl fumarate, a kyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical composition; and (b) ing a complete
blood count including lymphocyte count after 6 months of repeated administering of said
pharmaceutical composition to said patient, and every 6 to 12 months fter.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the t; wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl te, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that ethyl hydrogen
te calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition;
and (b) obtaining a complete blood count including lymphocyte count after 6 months of repeated
administering of said pharmaceutical ition to said patient, and every 6 to 12 months
thereafter.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition ting essentially of yl fumarate and/or
monomethyl fumarate to the t; and (b) obtaining a complete blood count including
lymphocyte count after 6 months of repeated administering of said pharmaceutical composition
to said patient, and every 6 to 12 months thereafter.
In one embodiment, the method r comprises interrupting administering of said
pharmaceutical composition to said patient when the patient has a lymphocyte count less than 0.5
x 109/L persisting for more than six months.
In one embodiment, the method further comprises measuring lymphocyte count in
said patient until lymphopenia is ed in said t.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
prior to initiating treatment of the patient with a pharmaceutical composition comprising a
fumarate: (i) performing a complete blood count including lymphocyte count; and (ii) if the
lymphocyte count is found to be below the normal range, considering alternative causes of
penia, and taking corrective measures as appropriate regarding said alternative causes;
and (b) administering said pharmaceutical composition to the patient, wherein the fumarate is a
dialkyl te, a monoalkyl fumarate, a combination of a dialkyl fumarate and a kyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, ate, solvate, tautomer, or isomer of any of the
foregoing, or a combination of any of the foregoing.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
repeatedly administering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a kyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the ing; and (b) obtaining
a complete blood count including lymphocyte count every 3 months after starting therapy of said
patient with said pharmaceutical ition.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; n the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl te and a
monoalkyl fumarate, a prodrug of kyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the ing; and (b) ring the patient closely for
signs or symptoms of appearance ofnew ogical dysfiJnction if the patient experiences
lymphopenia after administering of said pharmaceutical composition.
Provided herein is a method of ing safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with le sclerosis who is being treated
with a pharmaceutical composition comprising a fumarate, and who experiences lymphopenia,
for signs or symptoms of appearance ofnew neurological dysfunction; wherein the filmarate is a
dialkyl filmarate, a monoalkyl te, a combination of a dialkyl te and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing.
Provided herein is a method of treating le sclerosis in a patient who is being
treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical
composition comprising a filmarate; wherein the filmarate is a dialkyl te, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl te, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or isomer of any of the foregoing, or a combination of any
of the foregoing; said method comprising the following steps in the stated order: (a) stopping
administration of said multiple sclerosis e-modifying therapy to said patient; (b)
considering the half-life and mode of action of said multiple sis disease-modifying therapy
in order to avoid an ve immune effect whilst at the same time minimizing the risk of
e reactivation; and (c) administering the pharmaceutical composition comprising the
filmarate to the patient.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) tinuing
stration of interferon or glatiramer acetate to the patient; and (b) immediately after said
discontinuing, starting administering to the patient of a pharmaceutical composition comprising a
fumarate; wherein the fumarate is a dialkyl filmarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a monoalkyl filmarate, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing.
Provided herein is a method of treating a patient with le sis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a monoalkyl te, a combination of a dialkyl te and a
kyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, ate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; and (b) prior to the initial administering of
the pharmaceutical composition comprising the fumarate to the patient, and ically during
treatment of said patient with said pharmaceutical composition comprising the fumarate, having
a blood test done to count the number of white blood cells in the patient; and (c) ering
stopping said treatment with said pharmaceutical ition comprising the fumarate if the
number of white blood cells decreases during said treatment.
Provided herein is a method of treating a patient with multiple sclerosis comprising
(a) prior to initiating treatment of the patient with a pharmaceutical composition comprising a
fumarate: (i) performing a complete blood count including lymphocyte count; and (ii) if the
lymphocyte count is found to be below the normal range, considering alternative causes of
lymphopenia, and taking corrective measures as appropriate ing said alternative causes;
and (b) administering said pharmaceutical ition to the patient, n the fumarate is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl te and a monoalkyl
fumarate, a prodrug of kyl filmarate, a deuterated form of any of the foregoing, or a
clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of
the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
repeatedly administering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of kyl fumarate, a ated form of any
of the foregoing, or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a
combination of any of the ing; with the proviso that a filmarate salt is not present in the
pharmaceutical composition; and (b) obtaining a complete blood count including lymphocyte
count every 3 months after starting therapy of said patient with said pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; n the
fumarate is a l fumarate, a monoalkyl fumarate, a ation of a dialkyl filmarate and a
kyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition; and (b) monitoring the patient closely for signs or symptoms of appearance ofnew
neurological dysfilnction if the patient experiences lymphopenia after administering of said
pharmaceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
le sclerosis comprising monitoring a patient with le sis who is being treated
with a pharmaceutical composition comprising a fumarate, and who experiences penia,
for signs or symptoms of ance ofnew neurological dysfunction; wherein the te is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl
fumarate, a prodrug of monoalkyl te, a deuterated form of any of the foregoing, or a
clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a ation of any of
the foregoing; with the o that a te salt is not present in the pharmaceutical
composition.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical
composition comprising a filmarate; wherein the filmarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl te, a deuterated form of any of the foregoing, or a ate, solvate, tautomer,
or stereoisomer of any of the ing, or a combination of any of the foregoing; with the
proviso that a filmarate salt is not t in the pharmaceutical composition; said method
comprising the following steps in the stated order: (a) stopping administration of said multiple
sclerosis disease-modifying y to said patient; (b) considering the half-life and mode of
action of said multiple sclerosis disease-modifying therapy in order to avoid an additive immune
effect whilst at the same time minimizing the risk of disease reactivation; and (c) administering
the pharmaceutical composition comprising the fumarate to the patient.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) discontinuing
administration of interferon or amer acetate to the patient; and (b) immediately after said
discontinuing, starting administering to the patient of a pharmaceutical composition comprising a
fumarate; wherein the fumarate is a dialkyl filmarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a monoalkyl filmarate, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,
or a combination of any of the foregoing; with the o that a filmarate salt is not present in
the pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
te is a l fumarate, a monoalkyl fumarate, a combination of a dialkyl te and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a clathrate, solvate, tautomer, or isomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
ition; and (b) prior to the initial administering of the pharmaceutical composition
comprising the fumarate to the patient, and periodically during treatment of said patient with said
pharmaceutical composition comprising the fumarate, having a blood test done to count the
number of white blood cells in the t; and (c) considering stopping said treatment with said
pharmaceutical composition comprising the fumarate if the number of white blood cells
decreases during said treatment.
ed herein is a A method of treating a patient with multiple sclerosis comprising
(a) prior to initiating treatment of the patient with a pharmaceutical composition comprising a
fumarate: (i) performing a complete blood count including lymphocyte count; and (ii) if the
lymphocyte count is found to be below the normal range, considering alternative causes of
lymphopenia, and taking corrective measures as appropriate regarding said alternative causes;
and (b) administering said pharmaceutical composition to the t, wherein the te is a
dialkyl te, a monoalkyl fumarate, a combination of a dialkyl fumarate and a kyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
ceutically able salt, clathrate, solvate, tautomer, or stereoisomer of any of the
ing, or a combination of any of the foregoing; with the proviso that an ethyl en
fumarate salt is not present in the pharmaceutical composition.
Provided herein is a method of treating a patient with le sclerosis comprising (a)
repeatedly administering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that an ethyl hydrogen fumarate salt is not present in the ceutical ition; and (b)
obtaining a complete blood count including lymphocyte count every 3 months after starting
therapy of said patient with said pharmaceutical ition.
ed herein is a method of treating a t with multiple sclerosis comprising (a)
administering a pharmaceutical composition comprising a filmarate to the patient; wherein the
fumarate is a dialkyl fumarate, a kyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a ceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a ation of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical ition; and (b) monitoring the patient
closely for signs or ms of ance ofnew neurological dysfianction if the patient
experiences lymphopenia after administering of said pharmaceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a fumarate, and who experiences lymphopenia,
for signs or ms of appearance ofnew neurological dysfunction; wherein the filmarate is a
dialkyl filmarate, a kyl te, a combination of a dialkyl fumarate and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical ition.
Provided herein is a method of treating multiple sclerosis in a t who is being
treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical
composition comprising a filmarate; wherein the filmarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that an ethyl hydrogen fumarate salt is not t in the
pharmaceutical composition; said method comprising the following steps in the stated order: (a)
stopping stration of said multiple sclerosis disease-modifying therapy to said patient; (b)
considering the half-life and mode of action of said multiple sclerosis disease-modifying therapy
in order to avoid an additive immune effect whilst at the same time minimizing the risk of
disease vation; and (c) administering the ceutical composition comprising the
filmarate to the patient.
ed herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) discontinuing
administration of interferon or glatiramer acetate to the patient; and (b) immediately after said
discontinuing, starting administering to the patient of a pharmaceutical composition comprising a
te; wherein the fumarate is a l filmarate, a monoalkyl fumarate, a ation of a
dialkyl fumarate and a monoalkyl filmarate, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the o
that an ethyl hydrogen te salt is not present in the pharmaceutical composition.
Provided herein is a A method of treating a patient with multiple sclerosis comprising
(a) administering a pharmaceutical composition comprising a filmarate to the patient; wherein
the filmarate is a dialkyl filmarate, a monoalkyl filmarate, a combination of a dialkyl fumarate
and a kyl fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the
foregoing, or a pharmaceutically acceptable salt, ate, solvate, tautomer, or stereoisomer of
any of the foregoing, or a ation of any of the foregoing; with the proviso that an ethyl
hydrogen filmarate salt is not present in the pharmaceutical composition; and (b) prior to the
initial administering of the pharmaceutical ition comprising the filmarate to the patient,
and periodically during treatment of said patient with said ceutical composition
comprising the fumarate, having a blood test done to count the number of white blood cells in the
patient; and (c) considering stopping said treatment with said pharmaceutical ition
comprising the fumarate if the number of white blood cells decreases during said treatment.
Provided herein is a method of ng a patient with multiple sis comprising (a)
prior to initiating treatment of the patient with a pharmaceutical composition comprising a
fumarate: (i) performing a complete blood count including lymphocyte count; and (ii) if the
lymphocyte count is found to be below the normal range, considering alternative causes of
lymphopenia, and taking corrective measures as appropriate regarding said alternative causes;
and (b) administering said pharmaceutical composition to the patient, wherein the fumarate is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl
te, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, e, er, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the o that ethyl hydrogen
fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl en fumarate copper salt are not present in the pharmaceutical composition.
Provided herein is a method of ng a patient with multiple sclerosis comprising (a)
repeatedly administering a pharmaceutical composition comprising a te to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a ation of a l
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen filmarate m salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical composition; and (b) obtaining a complete blood count including lymphocyte
count every 3 months after starting therapy of said patient with said pharmaceutical composition.
Provided herein is a method of treating a patient with le sclerosis comprising (a)
stering a pharmaceutical composition sing a filmarate to the patient; wherein the
fumarate is a dialkyl te, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that ethyl hydrogen
fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition;
and (b) monitoring the patient closely for signs or symptoms of appearance ofnew neurological
dysfunction if the patient experiences lymphopenia after administering of said pharmaceutical
composition.
Provided herein is a method of ing safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being d
with a pharmaceutical ition comprising a fumarate, and who experiences lymphopenia,
for signs or symptoms of appearance ofnew neurological dysfunction; wherein the filmarate is a
dialkyl filmarate, a monoalkyl fumarate, a ation of a dialkyl fumarate and a kyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically able salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that ethyl hydrogen
fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl en fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with a le sclerosis e-modifying therapy other than a pharmaceutical
composition comprising a filmarate; wherein the filmarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogen
fumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate copper
salt are not present in the pharmaceutical composition; said method comprising the following
steps in the stated order: (a) stopping administration of said multiple sclerosis disease-modifying
therapy to said patient; (b) considering the half-life and mode of action of said le sclerosis
disease-modifying therapy in order to avoid an additive immune effect whilst at the same time
minimizing the risk of disease reactivation; and (c) administering the ceutical
composition comprising the filmarate to the patient.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) discontinuing
administration of interferon or glatiramer acetate to the patient; and (b) immediately after said
discontinuing, ng stering to the t of a pharmaceutical composition comprising a
te; wherein the fumarate is a dialkyl filmarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a monoalkyl filmarate, a prodrug of kyl te, a ated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not t in the
pharmaceutical composition.
] Provided herein is a method of treating a patient with multiple sclerosis
sing (a) administering a ceutical ition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical composition; and (b) prior to the initial administering of the pharmaceutical
composition sing the filmarate to the t, and periodically during treatment of said
t with said pharmaceutical composition comprising the fumarate, having a blood test done
to count the number of white blood cells in the patient; and (c) considering stopping said
treatment with said pharmaceutical composition comprising the fumarate if the number of white
blood cells decreases during said treatment.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) prior to initiating treatment of the t with a pharmaceutical composition
consisting ially of dimethyl fumarate and/or monomethyl fumarate: (i) performing a
complete blood count including lymphocyte count; and (ii) if the cyte count is found to
be below the normal range, considering alternative causes of lymphopenia, and taking corrective
measures as appropriate regarding said alternative causes; and (b) administering said
ceutical composition to the patient.
Provided herein is a method of treating a t with multiple sclerosis
comprising (a) repeatedly administering a pharmaceutical composition consisting essentially of
dimethyl fumarate and/or monomethyl fumarate to the patient; and (b) obtaining a complete
blood count including lymphocyte count every 3 months after starting therapy of said patient
with said pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition consisting essentially of dimethyl
fumarate and/or monomethyl te to the patient; and (b) ring the t closely for
signs or symptoms of appearance ofnew neurological dysfilnction if the patient experiences
lymphopenia after stering of said pharmaceutical composition.
2015/060850
Provided herein is a method of improving safety in treatment of a patient with
multiple sis comprising monitoring a patient with multiple sclerosis who is being d
with a pharmaceutical ition consisting essentially of yl fumarate and/or
monomethyl fumarate, and who experiences lymphopenia, for signs or symptoms of appearance
ofnew neurological dysfianction.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with a multiple sis disease-modifying therapy other than a pharmaceutical
ition consisting essentially of dimethyl fumarate and/or monomethyl filmarate; said
method comprising the following steps in the stated order: (a) stopping administration of said
multiple sclerosis e-modifying therapy to said patient; (b) considering the half-life and
mode of action of said multiple sclerosis disease-modifying therapy in order to avoid an additive
immune effect whilst at the same time minimizing the risk of e reactivation; and (c)
administering the pharmaceutical composition ting essentially of dimethyl filmarate and/or
monomethyl fumarate.
Provided herein is a method of ng multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) discontinuing
administration of interferon or glatiramer acetate to the patient; and (b) ately after said
discontinuing, starting administering a pharmaceutical composition consisting essentially of
dimethyl fumarate and/or monomethyl fumarate to the patient.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition consisting essentially of dimethyl
fumarate and/or monomethyl filmarate to the patient; and (b) prior to the initial administering of
said pharmaceutical composition to the patient, and periodically during ent of said patient
with said ceutical composition, having a blood test done to count the number of white
blood cells in the patient; and (c) considering stopping said treatment with said pharmaceutical
composition if the number of white blood cells ses during said treatment.
In one embodiment, the method further comprises discontinuing administering of
said pharmaceutical composition to said patient when the patient has a lymphocyte count less
than 0.7 x 109/L that is confirmed on repeat g after 3 months.
In one embodiment, the signs or symptoms of appearance of new neurological
dysfunction comprise motor dysfunction and cognitive or psychiatric symptoms.
In one embodiment, the method further comprises: if PML is suspected,
withholding treatment with said pharmaceutical composition immediately and performing further
evaluations.
In one embodiment, the method r comprises performing an MRI on the
patient before said starting administering to the patient of the pharmaceutical composition
comprising the te.
3. 1 Terminology
In order to provide a clear and consistent understanding of the specification and
claims, the following definitions are provided:
The term “alkanediyl,” as used herein refers to linear or branched alkyl chains
with, for example 1 to 6 carbon atoms. Representative examples of aklanediyl groups include,
but are not limited to -CH2-, -(CH2)2, -CH(CH3)-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2-, -
)-, -C(CH3)2-, -(CH2)4-, -(CH2)2CH(CH3)-, -CH2CH(CH3)CH2-, -CH(CH3)(CH2)2-, -
CH(C2H5)CH2-, -CH2CH(C2H5)-, )2CH2-, CH3)2-, -CH(CH3)CH(CH3), -
CH(C3H7)—, -(CH2)5, -(CH2)3CH(CH3), -(CH2)2CH(CH3)CH2-, -CH2CHCH3(CH2)2-, -
CH2C(CH3)2CH2-, -(CH2)2C(CH3)2-, -(CH2)6-, -(CH2)4CH(CH3)-, -(CH2)3CH(CH3)CH2-, -
CH2CHCH3(CH2)3-, -(CH2)3C(CH3)2-, and -(CH2)2C(CH3)2CH2-.
The term yl,” as used herein, refers to a lent straight or branched
chain hydrocarbon having from two to six carbons and at least one carbon-carbon double bond.
entative examples of l groups include, but are not limited to, -CH=CH2, -CH=CH-
CH3, -CH2-CH=CH-CH3, or —CH(CH3)—CH=CH-CH3.
The term “alkyl,” as used herein, refers to a fillly saturated branched or
unbranched hydrocarbon moiety. In one embodiment, the alkyl comprises 1 to 20 carbon atoms,
1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
Representative examples of alkyl groups e, but are not d to, methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-
methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.
The term “alkynyl,” as used herein, refers to a monovalent ht or branched
chain hydrocarbon having from two to six carbons and at least one -carbon triple bond.
Representative es of alkynyl groups include, but are not limited to, 2-propynyl, 3-butynyl,
2-butynyl, 4-pentynyl, 3-pentynyl.
] The term “aryl,” as used herein, refers to clic, ic or tricyclic
aromatic hydrocarbon groups having, for example, from 5 to 14 carbon atoms in the ring portion.
In one embodiment, the aryl refers to monocyclic and bicyclic aromatic hydrocarbon groups
having from 6 to 10 carbon atoms. Representative examples of aryl groups include, but are not
limited to, phenyl, naphthyl, fluorenyl, and cenyl.
The term “arylalkyl,” as used herein, refers to an acyclic alkyl group in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is
replaced with an aryl group. entative es of arylalkyl groups include, but are not
limited to, benzyl, 2-phenylethan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, or
2-naphthophenylethan-l-yl. In certain embodiments, an arylalkyl group is C7_30 arylalkyl, e.g.,
the alkyl moiety of the arylalkyl group is C140 and the aryl moiety is C6_20. In certain
embodiments, an arylalkyl group is C648 arylalkyl, e.g., the alkyl moiety of the arylalkyl group is
C1_g and the aryl moiety is C640. In certain embodiments, the arylalkyl group is C742 arylalkyl.
The term “alkyl linker,” as used herein, refers to C1, C2, C3, C4, C5 or C6 ht
chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated
aliphatic hydrocarbon groups. In one embodiment, a C1_6 alkyl linker is a C1, C2, C3, C4, C5,or
C6 alkyl linker group. Representative examples of alkyl linkers include, but are not limited to,
moieties having from one to six carbon atoms, such as, methyl (-CH2-), ethyl (-CHZCH2-), n-
propyl (-CHZCHZCH2-), yl (-CHCH3CH2-), n-butyl (-CHZCHZCHZCH2-), s-butyl (-
CHCH3CH2CH2-), i-butyl (-C(CH3)2CH2-), n-pentyl (-CH2CH2CH2CH2CH2-), s-pentyl (-
CHCH3CH2CH2CH2-), or n-hexyl (-CH2CH2CH2CH2CH2CH2-). The term ituted alkyl
linker” refers to alkyl linkers having substituents replacing one or more hydrogen atoms on one
or more s of the hydrocarbon backbone. Such substituents do not alter the sp3-
hybridization of the carbon atom to which they are attached and include those substituents listed
below in the ion of the term “substituted.”
The term “carbocycle,” as used herein, refers to any stable monocyclic, bicyclic
or tricyclic ring having the specified number of carbons, any of which may be saturated or
unsaturated. In one embodiment, a C344 carbocycle is intended to include a monocyclic, ic,
tricyclic, or spirocyclic (mono- or polycyclic) ring having 3, 4, 5, 6, 7, 8, 9, 10, ll, l2, 13, or 14
carbon atoms. Representative examples of carbocycles include, but are not limited to,
cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl,
cycloheptyl, cycloheptenyl, adamantyl, ctyl, cyclooctenyl, cyclooctadienyl, fluorenyl,
phenyl, naphthyl, indanyl, adamantly, ydronaphthyl, octahydropentalene, ocatahydro-lH-
indene, bicyclo[2.2.2]octane, spiro[3.4]octane, spiro[4.5]decane, spiro[4.5]deca-l,6-diene, and
dispiro[2.2.4.2]dodecane. In one embodiment, the bridge linking to non-adjacent carbon atoms
to form a tricyclic ring is a C1 or C2 bridge. When a ring is bridged, the substituents recited for
the ring may also be present on the bridge.
The term “cycloalkyl,” as used herein, refers to a saturated or partially unsaturated
cyclic alkyl group. Representative examples of lkyl groups include, but are not limited to,
cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In one embodiment, a cycloalkyl
group is C345 cycloalkyl, €3-12 cycloalkyl, or C3_g cycloalkyl.
The term “cycloalkylalkyl,” as used herein, refers to an acyclic alkyl group in
Which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon
atom, is replaced with a cycloalkyl group. In certain embodiments, a cycloalkylalkyl group is
C4_30 cycloalkylalkyl, and, for example, the alkyl moiety of the lkylalkyl group is C140 and
the cycloalkyl moiety is C3_20. In another embodiment, a cycloalkylalkyl group is C3_20
cycloalkylalkyl, and, for example, the alkyl moiety of the cycloalkylalkyl group is C1_g and the
cycloalkyl moiety is C342. In a particular embodiment, a cycloalkylalkyl group is C442
cycloalkylalkyl.
The term rium enrichment ”, as used herein, refers to the ratio
between the isotopic abundance and the natural abundance of deuterium in a given sample of a
compound.
The term rium oration percentage,” as used herein, refers to the
percentage of the molecules having ium at a particular position in a given sample of a
compound out of the total amount of the molecules including deuterated and non-deuterated.
The terms “deuterated methyl” and “deuterated ethyl,” as used herein, refer to a
methyl group and ethyl group, respectively, that ns at least one deuterium atom. Examples
of deuterated methyl include —CDH2, -CD2H, and —CD3. es of deuterated ethyl include,
but are not limited to, —CHDCH3, -CD2CH3, H2, -CH2CD3.
The term “halogen,” as used herein, refers to fluoro, chloro, bromo, or iodo.
The term “heteroalkyl,” as used herein, by itself or as part of another substituent
WO 81355
refers to an alkyl group in which one or more of the carbon atoms (and certain associated
hydrogen atoms) are independently ed with heteroatomic groups. Examples of
heteroatomic groups e, but are not limited to, -O-, -S-, -O-O-, -S-S-, -O-S-,—NR’, =N—N=, -
N=N—, -N=N—NR’-, -PR’-, -, -POR’-, -O-P(O)2-, -SO-, -SOz-, and -Sn(R’)2-, where each R’
is independently hydrogen, C1_6 alkyl, tuted C1_6 alkyl, C642 aryl, substituted C642 aryl, C7-
18 arylalkyl, substituted C748 kyl, C3_7 cycloalkyl, tuted C3_7 cycloalkyl, C3_7
heterocycloalkyl, substituted C3_7 heterocycloalkyl, C1_6 heteroalkyl, substituted C1_6 heteroalkyl,
€6-12 heteroaryl, substituted C642 heteroaryl, €7-18 heteroarylalkyl, or substituted €7-18
heteroarylalkyl. In one embodiment, a C1_6 heteroalkyl, means, for example, a C1_6 alkyl group
in which at least one of the carbon atoms (and certain associated hydrogen atoms) is replaced
with a heteroatom. In a particular embodiment, a C1_6 heteroalkyl, for example, includes groups
having five carbon atoms and one heteroatom, groups having four carbon atoms and two
heteroatoms, etc. In one embodiment, each R’ is independently hydrogen or C1_3 alkyl. In
another ment, a heteroatomic group is -O-, -S-, -NH-, -N(CH3)-, or -SOz-. In a specific
embodiment, the heteroatomic group is -O-.
The term “heteroaryl,” as used herein, refers to, for example, a 5-14 membered
monocyclic-, bicyclic-, or lic-ring system, having 1 to 10 heteroatoms independently
selected from N, O, or S, wherein N and S can be optionally oxidized to various oxidation states,
and wherein at least one ring in the ring system is aromatic. In one embodiment, the heteroaryl is
monocyclic and has 5 or 6 ring members. Representative examples of monocyclic heteroaryl
groups include, but are not limited to, l, thienyl, filranyl, pyrrolyl, pyrazolyl, imidazoyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, zolyl, thiadiazolyl and tetrazolyl. In
another embodiment, the heteroaryl is bicyclic and has from 8 to 10 ring members.
Representative examples of bicyclic heteroaryl groups include indolyl, benzofiaranyl, quinolyl,
isoquinolyl indazolyl, indolinyl, isoindolyl, indolizinyl, benzamidazolyl, quinolinyl, 5,6,7,8-
tetrahydroquinoline, and 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.
The term “heteroarylalkyl,” as used herein, refers to an acyclic alkyl group in
which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon
atom, is replaced with a heteroaryl group. In n embodiments, a heteroarylalkyl group is C7-
12 heteroarylalkyl, and, for example, the alkyl moiety of the arylalkyl group is C1_2 and the
heteroaryl moiety is C640.
The term “heterocycle,” as used herein, refers to any ring structure (saturated or
partially rated) which contains at least one ring heteroatom (e.g., N, O or S). Examples of
heterocycles e, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene,
piperidine, piperazine and tetrahydrofuran.
The term “heterocycloalkyl,” as used herein, refers to a saturated or unsaturated
cyclic alkyl group in which one or more carbon atoms (and certain associated hydrogen atoms)
are independently replaced with one or more heteroatoms; or to a parent aromatic ring system in
which one or more carbon atoms (and certain associated hydrogen atoms) are independently
replaced with one or more heteroatoms such that the ring system no longer contains at least one
ic ring. Representative examples of heteroatoms to replace the carbon ) e,
but are not limited to, N, P, O, S, and Si. Representative examples of heterocycloalkyl groups
include, but are not d to, epoxides, azirines, thiuranes, imidazolidine, morpholine,
piperazine, piperidine, pyrazolidine, pyrrolidine, and quinuclidine. In one embodiment, a
cycloalkyl group is C540 heterocycloalkyl, C5_g cycloalkyl. In a specific
embodiment, a heterocycloalkyl group is C5_6 heterocycloalkyl.
The term "heterocycloalkylalkyl," as used herein, refers to an acyclic alkyl group
in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon
atom, is ed with a heterocycloalkyl group. In certain embodiments, a
heterocycloalkylalkyl group is C742 heterocycloalkylalkyl, and, for example, the alkyl moiety of
the heterocycloalkylalkyl group is C1_2 and the heterocycloalkyl moiety is C640.
The term “isotopologue,” as used , refers to an isotopically enriched
fumarate.
The term “isotopically ed,” as used herein, refers to an atom having an
isotopic composition other than the natural isotopic ition of that atom. In one
embodiment, an “isotopically enriched” filmarate contains at least one atom having an isotopic
composition other than the natural isotopic composition of that atom.
The term “isotopic ition,” as used herein, refers to the amount of each
isotope present for a given atom.
The term “pharmaceutically acceptable salt,” as used herein, refers to a salt
prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid
and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts
of the filmarates provided herein e, but are not limited to, ic salts made from
aluminum, calcium, m, magnesium, potassium, sodium and zinc or organic salts made from
lysine, N,N’-dibenzylethylenediamine, procaine, choline, diethanolamine,
ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids
include, but are not limited to, nic and organic acids such as acetic, alginic, anthranilic,
benzenesulfonic, benzoic, rsulfonic, citric, ethenesulfonic, formic, fumaric, furoic,
galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phenylacetic, phosphoric, propionic, salicylic, stearic, ic, sulfanilic, sulfuric, tartaric acid,
and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic,
phosphoric, sulfilric, and methanesulfonic acids. Others are well known in the art, see for
example, Remington’s Pharmaceutical Sciences, 18th eds., Mack hing, Easton PA (1990)
or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA
(1 995).
The term oisomer” as used herein refers to one stereoisomer of a fumarate
that is substantially free of other isomers of that fumarate. For example, a “stereomerically
pure” filmarate haVing one chiral center will be substantially free of the opposite enantiomer of
the fiamarate. A “stereomerically pure” fumarate haVing two chiral centers will be substantially
free of the other diastereomers of the fiamarate. A typical “stereomerically pure” fumarate
comprises greater than about 80% by weight of one isomer of the fumarate and less than
about 20% by weight of other stereoisomers of the fumarate, greater than about 90% by weight
of one stereoisomer of the fumarate and less than about 10% by weight of the other
stereoisomers of the fumarate, greater than about 95% by weight of one stereoisomer of the
fumarate and less than about 5% by weight of the other stereoisomers of the filmarate, or r
than about 97% by weight of one stereoisomer of the fumarate and less than about 3% by weight
of the other stereoisomers of the fumarate. The filmarate can have chiral centers and can occur
as racemates, indiVidual enantiomers or diastereomers, and mixtures thereof All such isomeric
forms are ed within the embodiments disclosed , including mixtures thereof. The use
of stereomerically pure forms of such fiamarates, as well as the use of mixtures of those forms,
are encompassed by the embodiments disclosed herein. For e, mixtures comprising equal
or unequal amounts of the enantiomers of a particular fumarate may be used in methods and
compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved
using standard ques such as chiral columns or chiral resolving agents. See, e. g., Jacques, J.,
et al., Enantiomers, Racemates and tions (Wiley Interscience, New York, 1981); Wilen, S.
H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon nds
(McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and l
Resolutions p. 268 (EL. Eliel, Ed., Univ. e Dame Press, Notre Dame, IN, 1972).
The term “substituted,” as used herein, refers to a group in which one or more
hydrogen atoms are independently replaced with the same or different substituent group(s). In
certain embodiments, each substituent group is independently halogen, -OH, -CN, -CF3, =0, -
N02, benzyl, -C(O)NH2, -R", -OR", -C(O)R", -COOR", -S(O)2R"or -NR2" wherein each R" is
independently hydrogen or C1_6 alkyl. In certain embodiments, each substituent group is
independently halogen, -OH, -CN, -CF3, -N02, benzyl, -R", -OR", or —NR2" wherein each R" is
independently hydrogen or C1_4 alkyl. In certain embodiments, each substituent group is
ndently halogen, -OH, -CN, -CF3, =0, -N02, benzyl, R2", -R", -OR", -C(O)R", -
COOR", or —NR2" wherein each R" is independently en or C1_4 alkyl. In certain
embodiments, each substituent group is ndently -OH, C1_4 alkyl, and —NH2.
The number of carbon atoms in a group is specified herein by the prefix “CHX”,
wherein x and xx are integers. For example, “C1_4 alkyl” is an alkyl group which has from 1 to 4
carbon atoms; “C1_6 alkyl” is an alkyl group having from 1 to 6 carbon atoms; and “C640 aryl” is
an aryl group which has from 6 to 10 carbon atoms.
4. BRIEF DESCRIPTION OF DRAWINGS
Figure 1 depicts mean ALCs (::SE) over time. ALC = absolute lymphocyte count;
SE = standard error; BL = baseline; LLN = lower limit of normal.
Figure 2 depicts mean ALCs over time in patients with ALCs less than SOO/mm3
persisting for greater than or equal to 6 months versus all other patients. Shaded area in top
panel is expanded in bottom panel. ALC = absolute lymphocyte count; SE = rd error.
aDMF is delayed-release DMF (also known as gastro-resistant DMF, and as TECFIDERA®).
bBaseline (Week 0) 11 includes all patients for whom a baseline ALC value was available. cMean
ALCs over time are ted out to approximately 5 years (week 240), as this is the minimum
follow-up for patients remaining on study in ENDORSE.
Figure 3 depicts that ALCs generally increased post-dosing in the 4 weeks
following discontinuation of treatment in 9 patients with ALCs less than 500 cells/uL for at least
6 months. ALC = absolute lymphocyte count; BID = twice daily; LLN = lower limit of normal;
TID = three timers daily. aDMF is delayed-release DMF (also known as gastro-resistant DMF,
and as TECFIDERA®).
Figures 4A-4B depict reduction in ARR at 2 years in DEFINE (Figure 4A) and
M (Figure 4B) in patients in the DMF BID group with lymphopenia (at least 1 ALC less
than LLN) or without penia (all ALCs greater than or equal to LLN) ed with all
patients in placebo group. ARR = annualized relapse rate; CI = confidence interval. aDMF is
delayed-release DMF (also known as gastro-resistant DMF, and as TECFIDERA®). bBased on
negative al regression, adjusted for study, baseline EDSS (52.0 vs >2.0), baseline age
(<40 vs 240), region, and number of relapses in the 1 year prior to study entry.
. DETAILED DESCRIPTION
The invention provides methods of treating a patient with MS, and improving
safety in ent with MS, based on the ition of PML as a complication of treatment
with the fumarates described herein in some patients. One fatal case of progressive multifocal
ncephalopathy (PML) occurred in a patient with MS who received TECFIDERA® for 4
years while ed in a clinical trial. The patient ing TECFIDERA® had not previously
been treated with immunosuppressive medications or natalizumab, which has a known
association with PML, and had no identified systemic l conditions resulting in
compromised immune system function. The patient was also not taking any immunosuppressive
or immunomodulatory medications itantly. During the clinical trial, the patient
experienced prolonged lymphopenia (lymphocyte counts predominantly less than 0.5x109/L for
3.5 years) while taking ERA®.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a fumarate to the patient, n the fumarate is a dialkyl
fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a monoalkyl filmarate,
a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing, or a
pharmaceutically able salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; and (b) monitoring the patient for a sign or
symptom suggestive ofPML in the patient.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a fumarate for a sign or symptom suggestive of PML in the patient, wherein the filmarate is
a dialkyl fumarate, a monoalkyl filmarate, a combination of a dialkyl filmarate and a monoalkyl
fumarate, a g of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
ing, or a combination of any of the foregoing.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a filmarate to the t, wherein the fumarate is a dialkyl
fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a monoalkyl te,
a prodrug of monoalkyl fumarate, a ated form of any of the ing, or a
ceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; and (b) informing the patient that PML has
occurred in a patient who received dimethyl fumarate.
ed herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a filmarate to the patient, wherein the fumarate is a l
fumarate, a monoalkyl te, a combination of a dialkyl te and a monoalkyl filmarate,
a prodrug of monoalkyl te, a deuterated form of any of the ing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; and (b) instructing the patient of the
importance of contacting the patient’s doctor if the patient develops any symptoms suggestive of
PML.
Provided herein is a method of ing safety in ent of a t with
multiple sis comprising informing a patient with multiple sclerosis who is being treated
with a fumarate that PML has occurred in a patient who received dimethyl filmarate, wherein the
fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
ing, or a combination of any of the foregoing.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising instructing a patient with multiple sclerosis who is being treated
with a fumarate of the importance of contacting the patient’s doctor if the patient ps any
symptoms suggestive of PML, wherein the fumarate is a dialkyl te, a monoalkyl filmarate,
a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate,
a deuterated form of any of the foregoing, or a ceutically acceptable salt, clathrate,
solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the
foregoing.
Provided herein is a method of treating a patient with multiple sclerosis
sing (a) administering a pharmaceutical ition comprising a fumarate to the patient;
wherein the te is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a
combination of any of the foregoing; with the proviso that a filmarate salt is not present in the
pharmaceutical composition; and (b) monitoring the patient for a sign or symptom suggestive of
PML in the patient.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate for a sign or symptom suggestive of
PML in the t; wherein the fumarate is a dialkyl fumarate, a kyl filmarate, a
combination of a dialkyl filmarate and a monoalkyl filmarate, a prodrug of monoalkyl filmarate,
a deuterated form of any of the foregoing, or a clathrate, solvate, tautomer, or stereoisomer of
any of the foregoing, or a ation of any of the foregoing; with the proviso that a fumarate
salt is not present in the pharmaceutical composition.
Provided herein is a method of treating a patient with le sclerosis
comprising (a) administering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a l
fumarate and a monoalkyl fumarate, a prodrug of kyl fumarate, a deuterated form of any
of the foregoing, or a ate, e, tautomer, or stereoisomer of any of the foregoing, or a
combination of any of the foregoing; with the proviso that a te salt is not present in the
pharmaceutical composition; and (b) informing the patient that PML has ed in a patient
who ed dimethyl fumarate.
2015/060850
Provided herein is a method of treating a t with multiple sclerosis
comprising (a) administering a pharmaceutical composition sing a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of kyl fumarate, a deuterated form of any
of the ing, or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a
combination of any of the foregoing; with the proviso that a filmarate salt is not present in the
pharmaceutical ition; and (b) instructing the patient of the importance of ting the
t’s doctor if the patient develops any symptoms suggestive of PML.
Provided herein is a method of improving safety in ent of a patient with
multiple sclerosis comprising informing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate that PML has occurred in a patient
who received dimethyl fumarate; wherein the fumarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the ing, or a clathrate, solvate, tautomer,
or isomer of any of the foregoing, or a combination of any of the foregoing; with the
proviso that a te salt is not t in the pharmaceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising instructing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate of the importance of ting the
patient’s doctor if the patient develops any symptoms suggestive of PML; wherein the filmarate
is a dialkyl filmarate, a monoalkyl filmarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a clathrate, solvate, tautomer, or isomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) stering a pharmaceutical composition comprising a fumarate to the t;
wherein the fumarate is a dialkyl fumarate, a kyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the ing, or a combination of any of the foregoing; with the proviso
that an ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; and (b)
monitoring the patient for a sign or symptom suggestive of PML in the patient.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with le sclerosis who is being treated
with a pharmaceutical composition comprising a te for a sign or symptom suggestive of
PML in the patient; wherein the fumarate is a dialkyl fumarate, a monoalkyl te, a
combination of a l filmarate and a monoalkyl filmarate, a prodrug of monoalkyl filmarate,
a ated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate,
solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the
foregoing; with the proviso that an ethyl hydrogen fumarate salt is not present in the
ceutical composition.
Provided herein is a method of treating a patient with multiple sis
comprising (a) administering a pharmaceutical composition sing a fumarate to the t;
wherein the te is a dialkyl fumarate, a monoalkyl te, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that an ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; and (b)
informing the patient that PML has occurred in a patient who received dimethyl fumarate.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition sing a fumarate to the patient;
wherein the fumarate is a l fumarate, a monoalkyl te, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, ate, solvate, er, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that an ethyl hydrogen fumarate salt is not t in the pharmaceutical composition; and (b)
instructing the patient of the importance of contacting the patient’s doctor if the patient develops
any symptoms suggestive of PML.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising informing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition sing a filmarate that PML has occurred in a patient
who received dimethyl fumarate; n the fumarate is a dialkyl fumarate, a monoalkyl
te, a combination of a dialkyl fumarate and a monoalkyl filmarate, a g of
monoalkyl fumarate, a ated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the o that an ethyl hydrogen fumarate salt is not t in the
ceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis sing instructing a patient with le sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate of the ance of contacting the
patient’s doctor if the patient develops any symptoms suggestive of PML; wherein the filmarate
is a dialkyl filmarate, a monoalkyl filmarate, a combination of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, ate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical composition.
Provided herein is a method of treating a t with multiple sclerosis
comprising (a) stering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, e, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the ing; with the proviso
that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical composition; and (b) monitoring the patient for a sign or symptom suggestive of
PML in the patient.
Provided herein is a method of improving safety in treatment of a t with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate for a sign or symptom suggestive of
PML in the patient; wherein the fumarate is a dialkyl fumarate, a monoalkyl filmarate, a
combination of a dialkyl filmarate and a monoalkyl filmarate, a prodrug of monoalkyl filmarate,
a deuterated form of any of the foregoing, or a ceutically acceptable salt, clathrate,
solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the
foregoing; with the proviso that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate
magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate copper salt are
not present in the pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) stering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a kyl fumarate, a prodrug of monoalkyl te, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen te calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not t in the
pharmaceutical composition; and (b) informing the patient that PML has occurred in a patient
who ed dimethyl te.
Provided herein is a method of ng a patient with le sclerosis
comprising (a) administering a pharmaceutical composition comprising filmarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the ing, or a ceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate ium salt, ethyl
hydrogen fumarate zinc salt, and ethyl en filmarate copper salt are not present in the
ceutical composition; and (b) instructing the t of the ance of contacting the
patient’s doctor if the patient develops any symptoms suggestive of PML.
] Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising informing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate that PML has occurred in a patient
who received yl fumarate; wherein the fumarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogen
te magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate copper
salt are not present in the pharmaceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sis comprising instructing a patient with le sclerosis who is being treated
with a pharmaceutical composition comprising a filmarate of the importance of contacting the
t’s doctor if the patient develops any symptoms tive of PML; wherein the filmarate
is a dialkyl filmarate, a monoalkyl filmarate, a ation of a dialkyl filmarate and a
monoalkyl fumarate, a prodrug of monoalkyl te, a deuterated form of any of the foregoing,
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that ethyl en
fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition.
Provided herein is a method of ng a patient with multiple sclerosis
sing (a) administering a pharmaceutical composition consisting essentially of yl
fumarate and/or monomethyl filmarate to the patient; and (b) monitoring the patient for a sign or
symptom suggestive ofPML in the patient.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition ting essentially of dimethyl fumarate and/or
monomethyl te for a sign or symptom suggestive ofPML in the patient.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition consisting essentially of dimethyl
fumarate and/or monomethyl filmarate to the patient; and (b) informing the patient that PML has
occurred in a t who received dimethyl fumarate.
ed herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition consisting essentially of dimethyl
fumarate and/or monomethyl fumarate to the patient; and (b) instructing the patient of the
importance of ting the patient’s doctor if the patient develops any ms suggestive of
PML.
Provided herein is a method of improving safety in treatment of a patient with
2015/060850
multiple sclerosis comprising informing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition consisting essentially of dimethyl fumarate and/or
monomethyl fumarate that PML has ed in a patient who received dimethyl fiamarate.
Provided herein is a method of improving safety in treatment of a patient with
multiple sis comprising instructing a patient with multiple sclerosis who is being treated
with a pharmaceutical composition consisting essentially of dimethyl fumarate and/or
monomethyl fumarate of the importance of contacting the patient’s doctor if the patient develops
any symptoms suggestive of PML.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a fumarate to the patient, wherein the fumarate is a dialkyl
fumarate, a monoalkyl fumarate, a combination of a l te and a monoalkyl te,
a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing, or a
ceutically able salt, ate, solvate, er, or stereoisomer of any of the
ing, or a combination of any of the ing; and (b) obtaining a complete blood count
including lymphocyte count after 6 months of repeated stering of said pharmaceutical
ition to said patient, and every 6 to 12 months thereafter.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical ition comprising a fumarate to the t;
wherein the fumarate is a dialkyl fumarate, a monoalkyl te, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a
combination of any of the foregoing; with the proviso that a filmarate salt is not present in the
pharmaceutical composition; and (b) obtaining a complete blood count including lymphocyte
count after 6 months of repeated administering of said pharmaceutical composition to said
patient, and every 6 to 12 months thereafter.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition comprising a filmarate to the patient;
n the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that an ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; and (b)
ing a complete blood count including lymphocyte count after 6 months of repeated
administering of said pharmaceutical ition to said patient, and every 6 to 12 months
thereafter.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical ition comprising a fumarate to the t;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of kyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically able salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen te calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical composition; and (b) obtaining a complete blood count including lymphocyte
count after 6 months of repeated administering of said pharmaceutical composition to said
patient, and every 6 to 12 months thereafter.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition consisting ially of dimethyl
fumarate and/or monomethyl fumarate to the patient; and (b) obtaining a complete blood count
including lymphocyte count after 6 months of repeated administering of said pharmaceutical
composition to said patient, and every 6 to 12 months thereafter.
] ed herein is a method of treating a patient with le sclerosis
sing (a) prior to initiating treatment of the patient with a pharmaceutical composition
comprising a fumarate: (i) performing a complete blood count including lymphocyte count; and
(ii) if the lymphocyte count is found to be below the normal range, ering alternative causes
of lymphopenia, and taking corrective measures as appropriate regarding said alternative causes;
and (b) administering said pharmaceutical composition to the patient, wherein the fumarate is a
dialkyl filmarate, a kyl fumarate, a ation of a dialkyl fumarate and a kyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) repeatedly administering a pharmaceutical composition comprising a fumarate to
the patient; wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a
l fumarate and a monoalkyl filmarate, a prodrug of monoalkyl fumarate, a ated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; and (b) ing
a complete blood count including lymphocyte count every 3 months after starting y of said
patient with said ceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl te, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, e, er, or
isomer of any of the foregoing, or a combination of any of the foregoing; and (b)
monitoring the patient y for signs or symptoms of appearance ofnew neurological
dysfunction if the patient experiences lymphopenia after administering of said pharmaceutical
composition.
ed herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with le sclerosis who is being treated
with a pharmaceutical composition comprising a fumarate, and who experiences lymphopenia,
for signs or symptoms of appearance ofnew neurological dysfunction; wherein the filmarate is a
dialkyl filmarate, a kyl fumarate, a combination of a dialkyl fumarate and a kyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically able salt, clathrate, e, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical
composition comprising a te; wherein the filmarate is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl te, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; said method comprising the following steps in the stated order: (a) stopping
2015/060850
administration of said multiple sclerosis disease-modifying y to said patient; (b)
considering the half-life and mode of action of said multiple sclerosis disease-modifying therapy
in order to avoid an additive immune effect whilst at the same time minimizing the risk of
disease reactivation; and (c) administering the pharmaceutical composition comprising the
filmarate to the patient.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) discontinuing
administration of interferon or glatiramer acetate to the patient; and (b) immediately after said
discontinuing, starting administering to the patient of a pharmaceutical composition comprising a
fumarate; wherein the te is a dialkyl filmarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a monoalkyl filmarate, a prodrug of kyl fumarate, a deuterated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, er, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) stering a pharmaceutical composition comprising a fumarate to the patient;
n the fumarate is a dialkyl te, a monoalkyl fumarate, a combination of a dialkyl
te and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
isomer of any of the foregoing, or a combination of any of the foregoing; and (b) prior to
the initial administering of the pharmaceutical composition comprising the filmarate to the
patient, and periodically during treatment of said patient with said pharmaceutical composition
comprising the fumarate, having a blood test done to count the number of white blood cells in the
t; and (c) considering ng said treatment with said pharmaceutical composition
comprising the fumarate if the number of white blood cells decreases during said ent.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) prior to initiating treatment of the patient with a pharmaceutical composition
comprising a te: (i) ming a complete blood count ing lymphocyte count; and
(ii) if the lymphocyte count is found to be below the normal range, considering alternative causes
of lymphopenia, and taking corrective measures as appropriate regarding said alternative causes;
and (b) administering said ceutical composition to the patient, wherein the fumarate is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
clathrate, solvate, er, or stereoisomer of any of the ing, or a combination of any of
the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition.
Provided herein is a method of ng a patient with multiple sclerosis
comprising (a) repeatedly administering a pharmaceutical composition comprising a te to
the patient; wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a kyl filmarate, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,
or a combination of any of the foregoing; with the proviso that a filmarate salt is not present in
the pharmaceutical composition; and (b) obtaining a te blood count including cyte
count every 3 months after starting therapy of said patient with said pharmaceutical composition.
Provided herein is a method of treating a t with multiple sclerosis
comprising (a) administering a pharmaceutical composition comprising a fumarate to the patient;
n the fumarate is a dialkyl fumarate, a monoalkyl te, a combination of a dialkyl
te and a monoalkyl fumarate, a prodrug of monoalkyl te, a deuterated form of any
of the foregoing, or a ate, solvate, tautomer, or stereoisomer of any of the ing, or a
combination of any of the foregoing; with the proviso that a filmarate salt is not present in the
pharmaceutical composition; and (b) monitoring the patient closely for signs or symptoms of
appearance ofnew ogical dysfunction if the patient experiences lymphopenia after
administering of said pharmaceutical composition.
Provided herein is a method of ing safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with multiple sis who is being treated
with a pharmaceutical composition comprising a fumarate, and who experiences penia,
for signs or symptoms of appearance ofnew neurological dysfunction; wherein the filmarate is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of
the foregoing; with the proviso that a fumarate salt is not present in the pharmaceutical
composition.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical
ition comprising a filmarate; wherein the te is a dialkyl fumarate, a monoalkyl
fumarate, a combination of a l fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a ate, solvate, tautomer,
or stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the
proviso that a filmarate salt is not present in the pharmaceutical composition; said method
comprising the following steps in the stated order: (a) stopping administration of said multiple
sclerosis e-modifying therapy to said patient; (b) considering the half-life and mode of
action of said le sclerosis e-modifying therapy in order to avoid an additive immune
effect whilst at the same time minimizing the risk of disease reactivation; and (c) administering
the pharmaceutical ition comprising the te to the patient.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) discontinuing
stration of interferon or glatiramer acetate to the patient; and (b) immediately after said
discontinuing, starting administering to the patient of a ceutical composition comprising a
fumarate; wherein the te is a dialkyl filmarate, a monoalkyl fumarate, a combination of a
l fumarate and a monoalkyl filmarate, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a clathrate, solvate, tautomer, or isomer of any of the foregoing,
or a combination of any of the foregoing; with the proviso that a filmarate salt is not present in
the pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical ition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a
combination of any of the foregoing; with the proviso that a filmarate salt is not present in the
pharmaceutical composition; and (b) prior to the l administering of the pharmaceutical
composition comprising the filmarate to the patient, and periodically during treatment of said
t with said pharmaceutical composition comprising the fumarate, having a blood test done
to count the number of white blood cells in the patient; and (c) considering stopping said
treatment with said pharmaceutical ition comprising the fumarate if the number of white
blood cells decreases during said treatment.
Provided herein is a A method of treating a patient with multiple sclerosis
comprising (a) prior to initiating treatment of the patient with a pharmaceutical composition
comprising a fumarate: (i) performing a complete blood count including lymphocyte count; and
(ii) if the lymphocyte count is found to be below the normal range, ering alternative causes
of lymphopenia, and taking corrective measures as appropriate regarding said alternative causes;
and (b) administering said pharmaceutical composition to the patient, n the fumarate is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl te and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a ated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the o that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) repeatedly administering a ceutical composition comprising a fumarate to
the patient; wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a monoalkyl filmarate, a prodrug of kyl fumarate, a deuterated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the ing; with the proviso
that an ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; and (b)
obtaining a complete blood count including lymphocyte count every 3 months after starting
therapy of said patient with said pharmaceutical composition.
Provided herein is a method of treating a patient with le sclerosis
comprising (a) administering a ceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a g of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, e, er, or
stereoisomer of any of the ing, or a combination of any of the foregoing; with the proviso
that an ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; and (b)
monitoring the patient closely for signs or symptoms of appearance ofnew neurological
dysfunction if the patient experiences lymphopenia after administering of said pharmaceutical
composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sis comprising monitoring a t with multiple sclerosis who is being d
with a pharmaceutical composition comprising a fumarate, and who experiences lymphopenia,
for signs or symptoms of appearance ofnew neurological dysfunction; n the filmarate is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, e, tautomer, or stereoisomer of any of the
ing, or a combination of any of the foregoing; with the proviso that an ethyl hydrogen
fumarate salt is not present in the pharmaceutical ition.
Provided herein is a method of treating multiple sis in a patient who is being
treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical
composition comprising a filmarate; wherein the filmarate is a dialkyl fumarate, a monoalkyl
fumarate, a ation of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a ation of any
of the foregoing; with the o that an ethyl hydrogen fumarate salt is not present in the
pharmaceutical composition; said method comprising the following steps in the stated order: (a)
stopping administration of said multiple sclerosis disease-modifying therapy to said patient; (b)
considering the half-life and mode of action of said multiple sclerosis disease-modifying therapy
in order to avoid an additive immune effect whilst at the same time minimizing the risk of
disease reactivation; and (c) administering the pharmaceutical composition comprising the
filmarate to the patient.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer acetate, said method comprising (a) discontinuing
administration of interferon or glatiramer acetate to the t; and (b) immediately after said
discontinuing, starting administering to the patient of a pharmaceutical composition sing a
fumarate; wherein the fumarate is a dialkyl filmarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a monoalkyl te, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that an ethyl hydrogen fumarate salt is not present in the pharmaceutical composition.
Provided herein is a A method of treating a patient with multiple sclerosis
sing (a) administering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of kyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that an ethyl en fumarate salt is not present in the ceutical composition; and (b)
prior to the initial administering of the pharmaceutical composition comprising the fumarate to
the patient, and periodically during treatment of said patient with said pharmaceutical
composition comprising the filmarate, having a blood test done to count the number of white
blood cells in the patient; and (c) considering stopping said treatment with said pharmaceutical
composition comprising the fumarate if the number of white blood cells decreases during said
treatment.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) prior to ting treatment of the patient with a pharmaceutical composition
comprising a fumarate: (i) performing a te blood count including cyte count; and
(ii) if the lymphocyte count is found to be below the normal range, considering alternative causes
of penia, and taking corrective measures as riate regarding said alternative ;
and (b) administering said pharmaceutical composition to the patient, wherein the fumarate is a
dialkyl filmarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl
te, a prodrug of monoalkyl filmarate, a deuterated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a ation of any of the foregoing; with the proviso that ethyl hydrogen
fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) edly administering a ceutical composition comprising a te to
the patient; wherein the fumarate is a l fumarate, a kyl fumarate, a combination of a
dialkyl fumarate and a kyl filmarate, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical composition; and (b) obtaining a te blood count including lymphocyte
count every 3 months after starting therapy of said patient with said pharmaceutical ition.
Provided herein is a method of treating a patient with multiple sis
comprising (a) administering a pharmaceutical composition comprising a fumarate to the patient;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically able salt, ate, solvate, tautomer, or
isomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl en filmarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical composition; and (b) monitoring the patient closely for signs or symptoms of
appearance ofnew neurological ction if the patient experiences lymphopenia after
stering of said pharmaceutical composition.
Provided herein is a method of ing safety in treatment of a t with
multiple sclerosis comprising monitoring a patient with multiple sclerosis who is being treated
with a pharmaceutical composition comprising a fumarate, and who experiences lymphopenia,
for signs or symptoms of appearance ofnew neurological dysfunction; wherein the filmarate is a
dialkyl te, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl
fumarate, a prodrug of monoalkyl filmarate, a ated form of any of the foregoing, or a
pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the
foregoing, or a combination of any of the foregoing; with the proviso that ethyl hydrogen
fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc
salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition.
Provided herein is a method of treating multiple sis in a patient who is being
treated with a multiple sclerosis e-modifying therapy other than a pharmaceutical
composition comprising a filmarate; wherein the filmarate is a dialkyl te, a monoalkyl
fumarate, a combination of a dialkyl fumarate and a monoalkyl filmarate, a prodrug of
kyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable
salt, ate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any
of the foregoing; with the proviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogen
fumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate copper
salt are not present in the pharmaceutical composition; said method sing the following
steps in the stated order: (a) stopping administration of said multiple sclerosis disease-modifying
therapy to said patient; (b) considering the half-life and mode of action of said multiple sclerosis
disease-modifying therapy in order to avoid an additive immune effect whilst at the same time
zing the risk of disease reactivation; and (c) stering the pharmaceutical
composition comprising the filmarate to the patient.
] Provided herein is a method of treating multiple sclerosis in a patient who is being
d with interferon or glatiramer acetate, said method comprising (a) discontinuing
administration of interferon or glatiramer acetate to the patient; and (b) immediately after said
discontinuing, starting administering to the patient of a pharmaceutical ition comprising a
fumarate; wherein the fumarate is a dialkyl filmarate, a monoalkyl fumarate, a combination of a
dialkyl fumarate and a kyl filmarate, a prodrug of monoalkyl fumarate, a deuterated form
of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen filmarate m salt, ethyl en fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical composition.
] Provided herein is a method of ng a t with multiple sclerosis
comprising (a) administering a ceutical composition comprising a fumarate to the patient;
wherein the fumarate is a l fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso
that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not t in the
pharmaceutical composition; and (b) prior to the initial administering of the pharmaceutical
composition comprising the filmarate to the patient, and periodically during treatment of said
patient with said ceutical composition comprising the fumarate, having a blood test done
to count the number of white blood cells in the t; and (c) considering stopping said
treatment with said pharmaceutical composition comprising the fumarate if the number of white
blood cells decreases during said treatment.
Provided herein is a method of treating a patient with multiple sclerosis
sing (a) prior to ting treatment of the patient with a pharmaceutical composition
consisting essentially of dimethyl fumarate and/or monomethyl fumarate: (i) performing a
complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to
be below the normal range, considering alternative causes of lymphopenia, and taking corrective
measures as appropriate regarding said alternative ; and (b) administering said
pharmaceutical composition to the patient.
Provided herein is a method of treating a patient with multiple sclerosis
sing (a) repeatedly stering a pharmaceutical composition consisting essentially of
dimethyl fumarate and/or thyl fumarate to the patient; and (b) ing a complete
blood count including lymphocyte count every 3 months after starting therapy of said t
with said ceutical composition.
Provided herein is a method of treating a patient with multiple sclerosis
comprising (a) administering a pharmaceutical composition consisting essentially of dimethyl
te and/or monomethyl fumarate to the t; and (b) monitoring the patient closely for
signs or symptoms of appearance ofnew neurological dysfilnction if the patient experiences
lymphopenia after administering of said pharmaceutical composition.
Provided herein is a method of improving safety in treatment of a patient with
multiple sclerosis comprising monitoring a patient with le sis who is being treated
with a pharmaceutical composition consisting essentially of dimethyl fumarate and/or
monomethyl fumarate, and who experiences lymphopenia, for signs or symptoms of appearance
ofnew neurological dysfiJnction.
ed herein is a method of treating multiple sclerosis in a patient who is being
treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical
composition consisting essentially of dimethyl fumarate and/or monomethyl filmarate; said
method comprising the following steps in the stated order: (a) stopping stration of said
multiple sclerosis disease-modifying therapy to said patient; (b) considering the half-life and
mode of action of said multiple sclerosis e-modifying therapy in order to avoid an additive
immune effect whilst at the same time minimizing the risk of disease reactivation; and (c)
WO 81355
administering the ceutical composition consisting essentially of dimethyl te and/or
monomethyl fumarate.
Provided herein is a method of treating multiple sclerosis in a patient who is being
treated with interferon or glatiramer e, said method comprising (a) discontinuing
administration of interferon or glatiramer acetate to the patient; and (b) immediately after said
discontinuing, starting administering a pharmaceutical ition consisting essentially of
dimethyl fumarate and/or monomethyl fumarate to the patient.
Provided herein is a method of treating a patient with le sclerosis
comprising (a) administering a pharmaceutical composition consisting ially of dimethyl
fumarate and/or monomethyl filmarate to the t; and (b) prior to the initial administering of
said pharmaceutical composition to the patient, and periodically during treatment of said patient
with said pharmaceutical composition, having a blood test done to count the number of white
blood cells in the patient; and (c) considering stopping said treatment with said pharmaceutical
composition if the number of white blood cells decreases during said treatment.
All of the various aspects, embodiments, and options disclosed herein can be
combined in any and all ions. The compositions and methods provided are exemplary and
are not intended to limit the scope of the claimed embodiments.
.1 Active Agents for Use in the Methods Provided Herein
The active agents (i.e., drugs) for use in the methods and compositions of the
invention are tes. Such a fumarate can be a dialkyl fumarate (e.g., dimethyl fumarate), a
monoalkyl filmarate (e.g., monomethyl fumarate), a combination of dialkyl and kyl
tes (e.g., dimethyl fumarate and monomethyl filmarate), a prodrug of monoalkyl (e. g.,
thyl) fumarate, a deuterated form of any of the foregoing, or a pharmaceutically
acceptable salt, ate, solvate, tautomer, or isomer of any of the foregoing, or a
combination of any of the foregoing. In one embodiment, the fumarate used in the methods,
compositions and products described in this specification is dimethyl fumarate. In a ic
embodiment, the filmarate is (i) a monoalkyl fumarate or prodrug thereof, or (ii) a dialkyl
fumarate. In one embodiment, the monoalkylfumarate is monomethyl fumarate (“MMF”). In
another embodiment, the dialkyl filmarate is dimethyl fumarate (“DMF”).
.1.1 Mono- and Dialkyl tes
In particular, provided herein are mono- and dialkyl fumarates or
pharmaceutically acceptable salts, clathrates, solvates, or stereoisomers thereof for use in the
methods provided herein.
In one embodiment, the fumarate is a monoalkyl filmarate of Formula I:
R1\OJ‘W/ OH
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
wherein
R1 is C1_6 alkyl.
In certain embodiments of a compound of Formula (I), R1 is methyl (monomethyl
fumarate, “MMF”).
In one embodiment, the compounds of Formula I may be prepared using methods
known to those skilled in the art, for example, as sed in US. Patent No. 4,959,3 89.
In another embodiment, the filmarate is a dialkyl fumarate of Formula II:
R\OWO\
(11)
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
wherein
each R2 is ndently C1_6 alkyl.
In certain embodiments of a compound of Formula (II), each R2 is methyl
(dimethyl filmarate, . In a specific embodiment, the agent is administered as a
pharmaceutical composition, n the ceutical composition is TECFIDERA®. In
another specific embodiment, the agent is as a pharmaceutical composition, n the
ceutical composition is FUMADERM®. FUMADERM® comprises of the following
active ingredients: yl filmarate, calcium salt of ethyl hydrogen te, magnesium salt
of ethyl hydrogen fumarate, and zinc salt of ethyl hydrogen fumarate.
In one embodiment, the compounds of Formula (II) may be prepared using
methods known to those skilled in the art, for example, as disclosed in US. Patent No. 4,959,3 89.
In one embodiment, the fumarate is dimethyl fumarate and/or monomethyl
fumarate.
In one ment, the te is dimethyl fumarate
.1.2 Prodrugs of Monoalkyl Fumarates
Further provided herein are gs of monoalkyl fumarates or pharmaceutically
acceptable salts, clathrates, solvates, or stereoisomers thereof for use in the methods provided
herein.
In particular, the prodrugs of monoalkyl fiamarates are the prodrugs disclosed in
W02013/l 19677, such as the compounds of Formula (111):
R3“M#w’/ o R7
0 R4 IRS R6
(111)
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer
thereof,
R3 is c1.6 alkyl;
R4 and R5 are each ndently en, C1_6 alkyl, or substituted C1_6 alkyl;
R6 and R7 are each independently hydrogen, C1_6 alkyl, substituted C1_6 alkyl, C1_6
heteroalkyl, substituted C1_6 heteroalkyl, C442 cycloalkylalkyl, substituted C442
cycloalkylalkyl, C742 arylalkyl, or substituted C742 arylalkyl; or R6 and R7
together with the en to which they are ed form a ring chosen from C 5-
heteroaryl, substituted C540 heteroaryl, C540 heterocycloalkyl, and substituted
€5-10 heterocycloalkyl; and
wherein each substituent is ndently halogen, -OH, -CN, -CF3, =0, -N02,
benzyl, -C(O)NR82, -R8, -OR8, -C(O)R8, -COOR8, or -NR82 wherein each R8 is
independently hydrogen or C1_4 alkyl.
In n embodiments of a compound of Formula (III), when R3 is ethyl; then R6
and R7 are each independently hydrogen, C1_6 alkyl, or tuted C1_6 alkyl.
In certain embodiments of a compound of Formula (111), each substituent group is
independently halogen, -OH, -CN, -CF3, -R8, -OR8, or -NR82 wherein each R8 is independently
hydrogen or C1_4 alkyl. In certain embodiments, each substituent group is independently —OH or
-COOH.
In certain embodiments of a compound of Formula (III), each tuent group is
independently =0, C1_4 alkyl, or —COOR8, wherein R8 is hydrogen or C1_4 alkyl.
In certain embodiments of a compound of Formula (III), R3 is .
In n embodiments of a compound of Formula (111), R3 is ethyl.
In certain embodiments of a compound of Formula (III), R3 is C3_6 alkyl.
In certain embodiments of a compound of Formula (III), R3 is methyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
In certain embodiments of a compound of Formula (III), R3 is methyl, ethyl, n-
propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or utyl.
In certain embodiments of a compound of Formula (III), each of R4 and R5 is
hydrogen.
In certain embodiments of a compound of Formula (III), one of R4 and R5 is
en and the other of R4 and R5 is C1_4 alkyl.
] In certain embodiments of a compound of a (III), one of R4 and R5 is
hydrogen and the other of R4 and R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl
, or tert-butyl.
In certain embodiments of a compound of Formula (III), one of R4 and R5 is
hydrogen and the other of R4 and R5 is .
In certain embodiments of a compound of Formula (III), R6 and R7 are each
independently hydrogen or C1_6 alkyl.
In certain embodiments of a compound of a (III), R6 and R7 are each
independently en or C1_4 alkyl.
In certain embodiments of a nd of Formula (III), R6 and R7 are each
independently hydrogen, methyl, or ethyl.
In certain embodiments of a compound of Formula (III), R6 and R7 are each
hydrogen; in certain embodiments, R6 and R7 are each methyl; and in certain embodiments, R6
and R7 are each ethyl.
] In certain embodiments of a compound of a (III), R6 is hydrogen; and R7 is
c1.4 alkyl, substituted c1.4 alkyl n each substituent independently is =0, -OR8, -COOR8,
or -NR82, and wherein each R8 is independently hydrogen or C1_4 alkyl.
In certain embodiments of a compound of Formula (III), R6 is hydrogen; and R7 is
C1_4 alkyl, benzyl, 2-methoxyethyl, carboxymethyl, carboxypropyl, l,3,4-thiadiazolyl, y,
-COOCH3, 2-oxo-l,3-oxazolidinyl, 2-(methylethoxy)ethyl, 2-ethoxyethyl, (tert-
butyloxycarbonyl)methyl, (ethoxycarbonyl)methyl, (methylethyl)oxycarbonylmethyl, or
carbonylmethyl.
In certain embodiments of a compound of Formula (III), R6 and R7 together with
the nitrogen to which they are attached form a ring chosen from a C 5-6 heterocycloalkyl,
tuted C5_6 heterocycloalkyl, C5_6 heteroaryl, and substituted C5_6 heteroaryl ring. In certain
ments of a nd of Formula (III), R6 and R7 together with the nitrogen to which
they are attached form a ring chosen from a C5 heterocycloalkyl, substituted C5 heterocycloalkyl,
C5 heteroaryl, and substituted C5 heteroaryl ring. In certain embodiments of a compound of
a (III), R6 and R7 together with the nitrogen to which they are attached form a ring chosen
from a C6 heterocycloalkyl, substituted C6 heterocycloalkyl, C6 heteroaryl, and substituted C6
heteroaryl ring. In n embodiments of a compound of Formula (III), R6 and R7 together with
the nitrogen to which they are attached form a ring chosen from piperazine, 1,3-oxazolidinyl,
pyrrolidine, and morpholine ring.
In n embodiments of a compound of Formula (III), R6 and R7 together with
the nitrogen to which they are attached form a C5-10 heterocycloalkyl ring.
In certain embodiments of a compound of Formula (III), one of R4 and R5 is
hydrogen and the other of R4 and R5 is C1_6 alkyl; R6 is hydrogen; R7 is hydrogen, C1_6 alkyl, or
In certain embodiments of a compound of Formula (III), R3 is methyl; one of R4
and R5 is hydrogen and the other of R4 and R5 is C1_6 alkyl; R6 is en; and R7 is hydrogen,
C1_6 alkyl, or benzyl.
In certain embodiments of a compound of Formula (III), one of R4 and R5 is
hydrogen and the other of R4 and R5 is hydrogen or C1_6 alkyl; and each of R6 and R7 is C1_6 alkyl.
] In certain embodiments of a compound of Formula (III), R3 is methyl; one of R4
and R5 is hydrogen and the other of R4 and R5 is hydrogen or C1_6 alkyl; and each of R6 and R7 is
C1_6 alkyl. In certain embodiments of a compound of Formula (III), R5 is methyl; each of R4 and
2015/060850
R5 is hydrogen; and each of R6 and R7 is C1_6 alkyl.
] In certain embodiments of a compound of Formula (III), R3 is methyl; one of R4
and R5 is hydrogen and the other of R4 and R5 is hydrogen or C1_4 alkyl; R6 is hydrogen; and R7 is
c1.4 alkyl or substituted c1.4 alkyl wherein the substituent group is =0, -OR8, -COOR8, or -NR82,
n each R8 is independently hydrogen or C1_4 alkyl. In n embodiments of a compound
of Formula (III), R3 is methyl; one of R4 and R5 is hydrogen and the other of R4 and R5 is methyl;
R6 is hydrogen; and R7 is C1_4 alkyl or substituted C1_4 alkyl wherein the substituent group is =0,
-OR8, -COOR8, or -NR82, wherein each R8 is independently hydrogen or C1_4 alkyl. In certain
embodiments of a compound of Formula (III), R3 is methyl; each of R4 and R5 is en; R6 is
hydrogen; and R7 is C1_4 alkyl or substituted C1_4 alkyl wherein the substituent group is =0, -
OR“, -COOR11, or -NR112, wherein each R11 is independently hydrogen or C1_4 alkyl.
In certain embodiments of a compound of Formula (III), R6 and R7 together with
the nitrogen to which they are attached form a C5-10 heterocycloalkyl ring.
In certain embodiments of a compound of Formula (III), R3 is methyl; one of R4
and R5 is hydrogen and the other of R4 and R5 is hydrogen or C1_6 alkyl; and R6 and R7 er
with the nitrogen to which they are attached form a ring chosen from C5_6 heterocycloalkyl,
substituted C5_6 heterocycloalkyl, C5_6 heteroaryl, and substituted C5_6 heteroaryl ring. In n
embodiments of a compound of Formula (III), R3 is methyl; one of R4 and R5 is hydrogen and
the other of R4 and R5 is methyl; R6 and R7 together with the nitrogen to which they are attached
form a ring chosen from a C5_6 heterocycloalkyl, tuted C5_6 heterocycloalkyl, C5_6
heteroaryl, and substituted C5_6 aryl ring. In certain embodiments of a compound of
Formula (III), R3 is methyl; each of R4 and R5 is hydrogen; and R6 and R7 er with the
nitrogen to which they are attached form a ring chosen from C5_6 heterocycloalkyl, substituted
C5_6 heterocycloalkyl, C5_6 heteroaryl, and substituted C5_6 heteroaryl ring.
In certain embodiments of a compound of Formula (III), one of R4 and R5 is
hydrogen and the other of R4 and R5 is hydrogen or C1_6 alkyl; and R6 and R7 together with the
en to which they are attached form a ring chosen from line, piperazine, and N-
substituted piperazine.
In certain embodiments of a compound of Formula (III), R3 is ; one of R4
and R5 is hydrogen and the other of R4 and R5 is hydrogen or C1_6 alkyl; and R6 and R7 together
with the nitrogen to which they are attached form a ring chosen from morpholine, piperazine,
and N—substituted piperazine.
In certain ments of a nd of Formula (III), R3 is not methyl.
In certain embodiments of a compound of Formula (III), R4 is hydrogen, and in
certain ments, R5 is hydrogen.
In certain embodiments of a compound of Formula (III), R6 and R7 are
independently hydrogen, C1_6 alkyl, substituted C1_6 alkyl, €6-10 aryl, substituted €6-10 aryl, C442
cycloalkylalkyl, substituted C442 cycloalkylalkyl, C742 arylalkyl, substituted C742 arylalkyl, C1_6
heteroalkyl, substituted C1_6 heteroalkyl, €6-10 heteroaryl, substituted €6-10 heteroaryl, €4-12
heterocycloalkylalkyl, substituted C442 heterocycloalkylalkyl, C742 arylalkyl, substituted
C742 heteroarylalkyl; or R6 and R7 er with the nitrogen to which they are attached form a
ring chosen from a C540 heteroaryl, substituted C540 heteroaryl, C540 heterocycloalkyl, and
substituted C5-10 cycloalkyl.
In certain embodiments of a compound of Formula (III), the compound is:
(N,N—diethylcarbamoyl)methyl (2E)butene- l ,4-dioate;
methyl[N-benzylcarbamoyl]methyl(2E)butene- l ,4-dioate;
methyl holinyloxoethyl(2E)butene-l ,4-dioate;
ylcarbamoyl)methyl methyl(2E)butene- l ,4-dioate;
[N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)butene- l ,4-dioate;
2- {2-[(2E)(methoxycarbonyl)propenoyloxy]acetylamino} acetic acid;
4- {2-[(2E)(methoxycarbonyl)propenoyloxy]acetylamino}butanoic acid;
methyl(N—(l ,3 ,4-thiadiazolyl)carbamoyl)methyl(2E)but-2ene- l ,4-dioate;
(N,N—dimethylcarbamoyl)methyl methyl(2E)butene- l ate;
(N-methoxy-N—methylcarbamoyl)methyl methyl(2E)butene- l ,4-dioate;
bis-(2-methoxyethylamino)carbamoyl]methyl methyl(2E)butene- l ,4-dioate;
[N-(methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2ene- l ,4-dioate;
4- {2-[(2E)(methoxycarbonyl)propenoyloxy]acetylamino}butanoic acid, sodium salt;
methyl 2-oxopiperazinylethyl(2E)butene-l ,4-dioate;
methyl 2-oxo(2-oxo(l ,3-oxazolidinyl)ethyl(2E)but-2ene- l ,4-dioate;
{N—[2-(dimethylamino)ethyl]carbamoyl}methyl methyl(2E)but-2ene- l ,4 dioate;
methyl 2-(4-methylpiperazinyl)oxoethyl(2E)but—2-ene- l ,4-dioate;
methyl {N—[(propylamino)carbonyl]carbamoyl}methyl(2E)but-2ene- l ,4-dioate;
WO 81355
2-(4-acetylpiperazinyl)oxoethyl methyl(2E)but-2ene- l ,4-dioate;
{N,N—bis[2-(methylethoxy)ethyl]carbamoyl}methyl (2E)butene- l ,4-dioate;
methyl 2-(4-benzylpiperazinyl)oxoethyl(2E)butene-l ,4-dioate;
is(2-ethoxyethyl)carbamoyl]methyl methyl(2E)butene- l ,4-dioate;
2- {(ZS) [(tert-butyl)oxycarbonyl]pyrrolidinyl} oxoethyl methyl(2E)but—2ene-l ,4-dioate;
l- {2- {(2E)—3 -(methoxycarbonyl)propenoyloxy]acetyl} (2S)pyrrolidinecarboxylic acid;
(N- { [(tert-butyl)oxycarbonyl]methyl} -N-methylcarbamoyl)methyl methyl(2E)but-2enel ,4-
dioate; {N—(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl methyl(2E)butene- l ,4-
methyl l-methylmorpholinyloxoethyl(2E)butene- l ,4-dioate;
[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)butene-l ate;
(N,N—dimethylcarbamoyl)ethyl methyl(2E)butene- l ,4-dioate;
2- {2-[(2E)(methoxy carbonyl)propenoyloxyl]-N-methylacetylamino} acetic acid;
(N- { -butyl)oxycarbonyl]methyl} carbamoyl)methyl methyl(2E)butene-l ,4-dioate;
(2E)but-methyl-N— { [(methylethyl)oxycarbonyl]methyl} carbamoyl)methyl(2E)butene- l ,4-
dioate; {N—[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl methyl(2E)butene- l ,4-
dioate;
{N—[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl} ethyl methyl(2E)butene- l ,4-dioate;
{N—[(ethoxycarbonyl)methyl]-N-methylcarbamoyl} ethyl methyl(2E)butene- l ,4-dioate;
(l S)— l -methylmorpholinyloxo ethyl (2E)butene-l ,4-dioate;
(l S)- l -[N,N—bis(2-methoxyethyl)carbamoyl] ethyl methyl(2E)butene- l ,4-dioate;
(1R)(N,N—diethylcarbamoyl)ethyl methyl(2E)butene- l ,4-dioate; or
(1 S)— l -(N,N—diethylcarbamoyl)ethyl methyl(2E)butene-l ,4-dioate; or a pharmaceutically
acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof.
In certain embodiments of a compound of Formula (111), the compound is:
O O O O
\OJWOQLN/\ \OJWO\JLM
o n o
\OMwkN/W \OJWoQL
o k/o. H
WO 81355
O O
\OJWOQL
\OJWO
O O
° J13“ °
\0%O 7< \M0a1
[ii/Er W4;O L/ o /
g O
O O
0 o
\ MOQL
O O\/ \OJWO\HkN
o [ii/\fl/ O
; a
o o
o o
\ Mofk /\/O\/ MO%
0 /
O L/OV ;\o O T/j
o o o o
\OJWOdLTWOH \OJWOQLNWO\EO O ; O O 3
O \jL
o WCY;
\OMOiN/YOV \OMOWJkN/YOV
o o
\OJWOII,HkN/TDO/0\ \:JJWOWJkNAog
. k
0 O
\OMOMIHKVAO
K ; or a pharmaceutically acceptable salt, ate, solvate,
tautomer, or stereoisomer thereof
In certain embodiments of a nd of Formula (111), the compound is:
(N,N—diethylcarbamoyl)methyl methyl(2E)butene- l ,4-dioate;
methyl[N-benzylcarbamoyl]methyl(2E)butene-l ,4-dioate; methyl 2-morpholinyl
oxoethyl(2E)butene-l ,4-dioate;
(N-butylcarbamoyl)methyl methyl(2E)butene- l ,4-dioate;
[N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)butene- l ,4-dioate;
2- E)(methoxycarbonyl)propenoyloxy]acetylamino} acetic acid;
{2-[(2E)—3-(methoxycarbonyl)propenoyloxy]acetylamino}butanoic acid;
methyl(N-(l ,3 ,4-thiadiazolyl)carbamoyl)methyl(2E)but-2ene- l ,4-dioate;
(N,N—dimethylcarbamoyl)methyl methyl(2E)butene- l ,4-dioate;
(N-methoxy-N—methylcarbamoyl)methyl methyl(2E)butene- l ,4-dioate;
-methoxyethylamino)carbamoyl]methyl methyl(2E)butene- l ,4-dioate;
[N-(methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2ene- l ,4-dioate;
methyl 2-oxopiperazinylethyl(2E)butene-l ,4-dioate;
methyl 2-oxo(2-oxo(l ,3-oxazolidinyl)ethyl(2E)but-2ene- l ,4-dioate;
{N—[2-(dimethylamino)ethyl]carbamoyl}methyl methyl(2E)but-2ene- l ,4-dioate;
(N-[(methoxycarbonyl)ethyl]carbamoyl)methyl methyl(2E)butene-l ,4-dioate; or
2- {2-[(2E)(methoxycarbonyl)propenoyloxy]acetylamino}propanoic acid; or a
pharmaceutically acceptable salt, ate, solvate, er, or stereoisomer thereof.
In certain embodiments of a compound of Formula (111), the compound is:
O O O O
LN/\ \OiWOdLm
o n o
O O O O
\OJW S’\\ ”W \OJWOQLMAN/
O O ; O
O O O O
\OJW0%N/ \OMOQL o N/
O | _ O |
WWW;or a pharmaceutically acceptable salt, clathrate, e,
tautomer, or stereoisomer thereof.
In certain embodiments of a nd of Formula (III), the compound is:
O O
\OJWoQkN/\
K ; or a clathrate or solvate f. In a particular embodiment,
O O
\OModLN/\
0 K
may be administered as a cocrystal in the s provided
herein. In certain embodiments, the cocrystals are cocrystals with urea, fumaric acid, succinic
acid, maleic acid, malic acid, or citric acid or those disclosed in US patent application
publication number US 2014-0179778 Al.
In certain embodiments of a compound of Formula (III), the compound is:
O \oW/ Odin
0; or a clathrate or solvate thereof.
In certain ments of a compound of Formula (III), the compound is:
\ ; or a clathrate or solvate thereof.
] In certain embodiments of a nd of a (III), the compound is:
o o
\OMOQLT/0
; or a clathrate or solvate thereof.
The compounds recited in paragraphs ] and [00263] are named using
Chemistry 4-D Draw Pro, Version 7.01c (ChemInnovation Software, Inc., San Diego, California).
In one embodiment, the compounds of Formula (III) may be prepared using
methods known to those skilled in the art, for example, as disclosed in US. Patent No. 8,148,414
In one embodiment, the prodrugs of monoalkyl filmarates are the prodrugs
disclosed in W02013/119677, such as the compounds of Formula (IV):
RKOWOYOTRQ
0 R10 R11 0
(1V)
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer
thereof, wherein
R9 is C1_6 alkyl;
R10 and R11 are each independently hydrogen, C1_6 alkyl, or substituted C1_6 alkyl; and
R12 is c1_6 alkyl, substituted c1_6 alkyl, c1_6 alkenyl, tuted c1_6 l, c1_6
heteroalkyl, substituted C1_6 heteroalkyl, C3_g cycloalkyl, substituted C3_g
cycloalkyl, C6_g aryl, substituted C6_g aryl, or
-OR13 wherein R13 is C1_6 alkyl, substituted C1_6 alkyl, C340 cycloalkyl, substituted
€3-10 cycloalkyl, €6-10 aryl, or substituted €6-10 aryl;
wherein each substituent is independently halogen, -OH, -CN, -CF3, =0, -N02,
benzyl, -C(O)NR142, -R14, -OR14, 14, -COOR14, or -NR142 wherein each R14
is ndently hydrogen or C1_4 alkyl.
In certain embodiments of a compound of Formula (IV), each substituent is
independently halogen, -OH, -CN, -CF3, -R14, -OR14, or —NR142 n each R14 is
independently hydrogen or C1_4 alkyl.
In certain embodiments of a compound of Formula (IV), each substituent is
ndently =0, C1_4 alkyl, and -COOR14 wherein R14 is hydrogen or C1_4 alkyl.
In n embodiments of a compound of Formula (IV), R9 is C1_6 alkyl; in
certain embodiments, R9 is C1_3 alkyl; and in certain embodiments, R9 is methyl or ethyl.
] In certain embodiments of a compound of Formula (IV), R9 is methyl.
In certain embodiments of a compound of Formula (IV), R9 is ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
In certain embodiments of a nd of Formula (IV), R9 is methyl, ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
In certain embodiments of a compound of Formula (IV), one of R10 and R11 is
hydrogen and the other of R10 and R11 is C1_6 alkyl. In certain ments of a compound of
Formula (IV), one of R10 and R11 is hydrogen and the other of R10 and R11 is C1_4 alkyl.
] In certain embodiments of a nd of Formula (IV), one of R10 and R11 is
hydrogen and the other of R10 and R11 is methyl, ethyl, n-propyl, or isopropyl. In certain
embodiments of a compound of Formula (IV), each of R10 and R11 is hydrogen.
In certain embodiments of a compound of Formula (IV), R12 is C1_6 alkyl; one of
R10 and R11 is hydrogen and the other of R10 and R11 is C1_6 alkyl; and R9 is C1_6 alkyl.
In certain embodiments of a compound of Formula (IV), R12 is -OR13.
In certain ments of a compound of Formula (IV), R13 is C1_4 alkyl,
cyclohexyl, or phenyl.
In certain embodiments of a compound of a (IV), R12 is , ethyl, n-
propyl, or isopropyl; one of R10 and R11 is hydrogen and the other of R10 and R11 is methyl, ethyl,
n-propyl, or isopropyl.
In certain embodiments of a compound of Formula (IV), R12 is substituted C1_2
alkyl, wherein each substituent is independently -COOH, -NHC(O)CH2NH2, or -NH2.
In certain embodiments of a compound of Formula (IV), R12 is ethoxy,
methylethoxy, isopropyl, phenyl, cyclohexyl, cyclohexyloxy, -CH(NH2)CH2COOH, -
CH2CH(NH2)COOH,
C(O)CH2NH2)—CH2COOH, or -CH2CH(NHC(O)CH2NH2)—COOH.
In certain embodiments of a compound of Formula (IV), R9 is methyl or ethyl;
one of R10 and R11 is hydrogen and the other of R10 and R11 is hydrogen, , ethyl, n-propyl,
or isopropyl; and R12 is C1_3 alkyl, substituted C1_2 alkyl wherein each substituent group is -
COOH, -NHC(O)CH2NH2, -NH2, or —0R13 wherein R13 is c1_3 alkyl, cyclohexyl, phenyl, or
cyclohexyl.
In certain embodiments of a compound of Formula (IV), the compound is:
ethoxycarbonyloxyethyl methyl(2E)butene-l ,4-dioate;
methyl(methylethoxycarbonyloxy)ethyl(2E)butene- l ,4-dioate; or
(cyclohexyloxycarbonyloxy)ethyl methyl(2E)butene-l,4-dioate; or a clathrate, solvate, or
stereoisomer thereof.
] In certain embodiments of a compound of Formula (IV), the compound is:
O O O O
o l o / NO OJLOA / NOkOJLOk
O ; O :or
O A o O
0 ; or a clathrate, solvate, or stereoisomer thereof.
In certain embodiments of a compound of Formula (IV), the compound is:
methyl(2-methylpropanoyloxy)ethyl(2E)butene- l ,4-dioate;
methyl carbonyloxyethyl(2E)butene-l ,4-dioate;
cyclohexylcarbonyloxybutyl (2E)butene-l ,4-dioate;
[(2E)(methoxycarbonyl)propenoyloxy]ethyl methyl(2E)butene-l ,4-dioate; or
methyl 2-methyl- l -phenylcarbonyloxypropyl(2E)butene-l ate; or a clathrate, solvate, or
stereoisomer thereof.
In certain ments of a compound of a (IV), the compound is:
WO 81355
NWN**o
whoNWT
r a clathrate, solvate, or stereoisomer thereof
In n ments of a compound of Formula (IV), the compound is:
ethoxycarbonyloxyethyl methyl(2E)butene-l ,4-dioate;
methyl(methylethoxycarbonyloxy)ethyl(2E)butene- l ,4-dioate;
methyl(2-methylpropanoyloxy)ethyl(2E)butene-l ,4-dioate;
methyl phenylcarbonyloxyethyl(2E)butene-l ,4-dioate;
cyclohexylcarbonyloxybutyl methyl(2E)butene- l ,4-dioate;
[(2E)(methoxycarbonyl)propenoyloxy]ethyl methyl(2E)butene-l ,4-dioate;
(cyclohexyloxycarbonyloxy)ethyl methyl(2E)butene-l ,4-dioate;
methyl 2-methyl-l-phenylcarbonyloxypropyl(2E)butene-l,4-dioate; or a clathrate, solvate, or
stereoisomer thereof.
In certain embodiments of a compound of Formula (IV), the compound is:
3 -( { [(2E)-3 -(methoxycarbonyl)propenoyloxy]methyl} oxycarbonyl)(3 S)aminopropanoic
acid, 2,2,2-trifluoroacetic acid;
3 -( { [(2E)-3 -(methoxycarbonyl)propenoyloxy]methyl} oxycarbonyl)(2S)aminopropanoic
acid, 2,2,2-trifluoroacetic acid;
3 -( { [(2E)-3 -(methoxycarbonyl)propenoyloxy]methyl} oxycarbonyl)(3 S)—3 -(2-
aminoacetylamino)propanoic acid, 2,2,2-trifluoroacetic acid; or
3- {[(2E)—3-(methoxycarbonyl)prop-2enoyloxy]ethoxycarbonyloxy} (2S)aminopropanoic acid,
de; or a clathrate, solvate, or stereoisomer thereof.
In certain embodiments of a compound of Formula (IV), the compound is:
WO 81355
o o o
o k o / No OJLOA / NokoJLok
O ; O
O O
O k /0 A
/ \
\ O O
o o
O ; ,
/ON0
O OJKO /ONOJ\OJWO\; 0 0
0w o
/ NO010 /ONO GAO O
O ; or OJK©; or a clathrate,
solvate, or stereoisomer thereof.
In certain embodiments of a compound of Formula (IV), the compound is:
O O O
O NHZ
; or a ceutically acceptable salt, clathrate,
solvate, or stereoisomer thereof.
In certain embodiments of a compound of Formula (IV), the compound is:
O O O
O OH F / NOAOJW FYkO.
o NH3+ o F
O OH O
+ O-
H N\)J\3 O O \
N \/ NO/ F>‘)kF
H F
O O ' or
O O O
O NH3+C"
; or a clathrate, solvate, or stereoisomer f.
The compounds recited in paragraphs [00287], [00289], [00291], and [00292] are
named using Chemistry 4-D Draw Pro, Version 7.01c (ChemInnovation Software, Inc., San
Diego, California).
In one embodiment, the compounds of Formula (IV) may be prepared using
methods known to those skilled in the art, for example, as disclosed in US. Patent No. 8,148,414
In one embodiment, the prodrugs of monoalkyl fiJmarates are the prodrugs
disclosed in US. Patent Application ation No. 2014/0057918, such as the compounds of
Formula (V):
o (\o
W \H’ \Jo N
or a pharmaceutically acceptable salt, clathrate, or solvate thereof, wherein
R15 is C1_6 alkyl; and
m is an integer from 2 to 6.
In certain embodiments of a compound of a (V), R15 is methyl.
In certain embodiments of a compound of Formula (V), R15 is ethyl.
In certain embodiments of a compound of Formula (V), R15 is C3_6 alkyl.
In certain embodiments of a compound of Formula (V), R15 is methyl, n-propyl,
isopropyl, n-butyl, tyl, isobutyl, or tert-butyl.
In certain embodiments of a compound of Formula (V), R15 is methyl, ethyl, n-
propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
] In certain embodiments of a compound of Formula (V), the compound is:
methyl (2-morpholinoethyl)fumarate;
methyl (3-morpholinopropyl)fumarate;
methyl (4-morpholinobutyl)fumarate;
methyl (5-morpholinopentyl)fi1marate; or
methyl (6-morpholinohexyl)fi1marate;
or a pharmaceutically acceptable salt, ate, or solvate f.
In certain ments of a compound of Formula (V), the compound is:
\OWOWO;\OWOWN\)o (\o
\OJWONNfi \OMOVWOo
o k/o; 0 m
\WOW
; or a pharmaceutically able salt, clathrate,
or solvate f.
The compounds recited in paragraph [00304] are named using Chemistry 4-D
Draw Pro, Version 7.0lc (ChemInnovation Software, Inc., San Diego, California).
In one ment, the compounds of Formula (V) may be prepared using
methods known to those skilled in the art, for example, as disclosed in US. Patent Application
Publication No. 2014/0057918.
In one embodiment, the prodrugs of monoalkyl fiamarates are the prodrugs
disclosed in W02013/l 19677, such as the compounds of Formula (VI):
[ mR17
/Si R18
[(I:Ff
(V1)
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof, wherein:
R16 is C140 alkyl, C544 aryl, yl, -O-C1_10 alkyl, or -O-C5_14 aryl;
each of R17, R18, and R19 independently is C140 alkyl, C544 aryl, hydroxyl, 10
alkyl, —O-C5_14 aryl, or
EILQWO\R20
wherein R20 is C1_6 alkyl; each of which can be optionally substituted; and
each of n, p, and q independently is 0-4;
provided that at least one of R17, R18, and R19 is
%O\R20
In certain embodiments of a compound of Formula (VI), R20 is ally
substituted C1_6 alkyl. In certain embodiments of a compound of Formula (VI), R20 is optionally
substituted methyl, ethyl, or isopropyl. In certain embodiments of a compound of Formula (VI),
R20 is methyl.
In certain embodiments of a compound of Formula (VI), R16 is €1-10 alkyl. In
certain embodiments of a compound of a (VI), R16 is optionally substituted C1_6 alkyl. In
certain embodiments of a compound of Formula (VI), R16 is optionally substituted methyl, ethyl,
or isopropyl. In n embodiments of a compound of Formula (VI), R16 is optionally
substituted C5-15 aryl. In certain embodiments of a compound of Formula (VI), R16 is optionally
substituted C5-C10 aryl.
] In one embodiment, the prodrugs of monoalkyl filmarates are the gs
disclosed in W02013/l 19677, such as the compounds of Formula (VI’):
[ rrnR
/Si R18
R16 [01“:
(VI’)
or a pharmaceutically acceptable salt, ate, solvate, or stereoisomer thereof,
wherein
R16 is C140 alkyl, C640 aryl, hydroxyl, -O-C1_10 alkyl, or -O-C6_10 aryl;
each of R17, R18, and R19 independently is C140 alkyl, C640 aryl, hydroxyl, -O-C1_10
alkyl, -O-C6_10 aryl, or
EILOWO\R20
n R20 is C1_6 alkyl; each of which can be optionally substituted; and
each of n, p, and q ndently is 0-4;
provided that at least one of R17, R18, and R19 is
%0\R20
In certain embodiments of a compound of Formula (VI’), R20 is methyl.
In certain embodiments of a compound of Formula (VI) or Formula (VI’), the
compound is: (dimethylsilanediyl)dimethyl difumarate; methyl ethoxysilyl)methyl)
fumarate; methyl ((trihydroxysilyl)methyl) fumarate; or trimethyl (methylsilanetriyl) trifumarate;
or a pharmaceutically acceptable salt thereof.
In certain embodiments of a compound of Formula (VI) or a (VI’), the
compound is:
o O\
—Si 0
/ \o o o
0M\MeO HO
/ 0 \ O \ O
\ WiAJV/Wr \
M («Adv/fire
OMe OH
o ; o ; 0 ;or
0 ; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compounds of Formula (VI) and a (VI’) may be
prepared using s known to those skilled in the art, for example, as disclosed in
W02013/l 19677.
In one embodiment, the prodrugs of monoalkyl fiamarates are the prodrugs
disclosed in W02013/l 19677, such as the compounds of a (VII):
o—R21
O /
O O
RZZ—S‘I / O
R; \o ‘R21
(VII)
or a pharmaceutically acceptable salt, ate, solvate, or stereoisomer f,
wherein:
wherein R21 is C1_6 alkyl; and
each of R22 and R23 independently is C140 alkyl or C544 aryl;
each of which can be optionally substituted.
] In certain embodiments of a compound of Formula (VII), R21 is optionally
substituted C1_6 alkyl. In certain embodiments of a compound of Formula (VII), R21 is optionally
substituted methyl, ethyl, or isopropyl. In certain ments of a compound of Formula (VII),
R21 is methyl.
In certain embodiments of a compound of Formula (VII), each of R22 and R23
independently is optionally substituted C140 alkyl. In certain embodiments of a compound of
Formula (VII), each of R22 and R23 independently is ally substituted C1_6 alkyl. In certain
embodiments of a compound of Formula (VII), each of R22 and R23 independently is optionally
substituted methyl, ethyl, or isopropyl. In certain embodiments of a compound of Formula (VII),
2015/060850
each of R22 and R23 independently is optionally substituted C544 aryl. In certain embodiments of
a compound of Formula (VII), each of R22 and R23 independently is optionally substituted C540
aryl.
In one embodiment, the prodrugs of monoalkyl fiamarates are the prodrugs
disclosed in W02013/l 19677, such as the compounds of Formula (VII’):
o—R21
O /
O O
RZZ—S‘I / O
R; \o ‘R21
(VIP)
or a ceutically acceptable salt, ate, solvate, or stereoisomer f,
wherein
R21 is C1_6 alkyl; and
each of R22 and R23 independently is C140 alkyl or C640 aryl.
In one ment, the compounds of Formula (VII) and Formula (VII’) may be
prepared using methods known to those skilled in the art, for example, as disclosed in
W02013/l 19677.
In one embodiment, the gs of monoalkyl filmarates are the prodrugs
disclosed in W02013/l 19677, such as the compounds of Formula (VIII):
R25_S:i/HS\O)WO\R24R26
R27 0
(VIII)
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
wherein:
R24 is C1_6 alkyl;
each of R25, R26, and R27 independently is hydroxyl, C140 alkyl, C544 aryl, -O-C1_10
alkyl, or —O-C5_14 aryl;
each of which can be optionally substituted; and
sislor2.
In certain embodiments of a compound of Formula (VIII), R24 is optionally
substituted C1-C6 alkyl. In n embodiments of a compound of Formula (VIII), R24 is
optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of a compound of
Formula (VIII), R24 is methyl.
In certain embodiments of a compound of Formula (VIII), each of R25, R26, and
R27 is hydroxyl. In certain embodiments of a compound of Formula (VIII), each of R25, R26, and
R27 ndently is optionally substituted C140 alkyl. In certain ments of a compound of
Formula (VIII), each of R25, R26, and R27 independently is optionally substituted C1_6 alkyl. In
certain embodiments of a compound of Formula (VIII), each of R25, R26, and R27 independently
is optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of a compound of
a (VIII), each of R25, R26, and R27 independently is ally substituted C544 aryl. In
certain embodiments of a compound of a (VIII), each of R25, R26, and R27 independently
is optionally substituted C 5-10 aryl.
In one embodiment, the prodrugs of kyl filmarates are the gs
disclosed in W02013/l 19677, such as the compounds of Formula (VIII’):
R25_S:i/{"L\O)WO\R24R26
R27 0
(VIII’)
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
wherein:
R24 is c1.6 alkyl;
each of R25, R26, and R27 independently is hydroxyl, C140 alkyl, C640 aryl, -O-C1_10
alkyl, or —O-C6_10 aryl; and
sis l or 2.
In one embodiment, the nds of a (VIII) and Formula (VIII’) may
be prepared using s known to those skilled in the art, for example, as disclosed in
W02013/l 19677.
In one embodiment, the prodrugs of monoalkyl fiJmarates are the prodrugs
disclosed in W02013/l 19677, such as the compounds of Formula (IX):
WO 81355
(1X)
or a pharmaceutically able salt, clathrate, solvate, or stereoisomer thereof,
wherein
each of R28 independently is C1_6 alkyl; and
R29 is €1-10 alkyl;
each of which can be optionally substituted.
In certain embodiments of a compound of Formula (IX), each of R28
independently is optionally substituted C1_6 alkyl. In certain embodiments of a nd of
Formula (IX), each of R28 independently is optionally substituted methyl, ethyl, or pyl. In
certain embodiments of a compound of Formula (IX), each of R28 is methyl.
In certain embodiments of a compound of Formula (IX), R29 is optionally
substituted C1_6 alkyl. In n embodiments of a compound of Formula (IX), R29 is optionally
substituted methyl, ethyl, or isopropyl.
In one embodiment, the prodrugs of monoalkyl fiamarates are the prodrugs
disclosed in W02013/l 19677, such as the compounds of Formula (IX’):
o—R28
(IX’)
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
wherein
R28 is C1_6 alkyl; and
R29 is C140 alkyl.
] In one embodiment, the compounds of Formula (IX) and Formula (IX’) may be
prepared using methods known to those skilled in the art, for example, as disclosed in
W02013/l 19677.
In one embodiment, the prodrugs of monoalkyl fiamarates are the prodrugs
disclosed in US. Patent No. 8,669,281 B1, such as the compounds of Formula (X):
R\w/La\O)WO\R3031
R32 o
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer
thereof, wherein
R30 is unsubstituted C1_6 alkyl;
La is tuted or tituted C1_6 alkyl linker, substituted or unsubstituted C340
carbocycle, substituted or unsubstituted €6-10 aryl, substituted or unsubstituted
heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms
ed from N, O, and S, or tuted or tituted heteroaryl comprising
one or two 5- or 6-member rings and l-4 heteroatoms selected from N, O, and S;
R31 and R32 are each, independently, hydrogen, substituted or unsubstituted C1_6 alkyl,
substituted or unsubstituted C2_6 alkenyl, tuted or unsubstituted C2_6 alkynyl,
substituted or unsubstituted C640 aryl, substituted or unsubstituted C340
carbocycle, substituted or tituted heterocycle comprising one or two 5- or
6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or
unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4
heteroatoms selected from N, O, and S;
or alternatively, R31 and R32, together with the nitrogen atom to which they are
ed, form a substituted or unsubstituted aryl comprising one or two 5-
or 6-member rings and 1-4 heteroatoms selected from N, O, and S or a substituted
or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4
heteroatoms selected from N, O, and S.
In certain ments of a compound of Formula (X), R30 is methyl. In certain
embodiments of a compound of Formula (X), R30 is ethyl.
] In certain embodiments of a compound of Formula (X), La is substituted or
unsubstituted C1_6 alkyl linker. In certain embodiments of a compound of Formula (X), La is
substituted or unsubstituted C1_3 alkyl . In certain embodiments of a compound of Formula
(X), La is substituted or unsubstituted C2 alkyl linker. In certain embodiments of a compound of
Formula (X), La is a methyl substituted or unsubstituted C2 alkyl linker. In certain embodiments
of a compound of Formula (X), La is a hyl substituted or unsubstituted C2 alkyl linker. In
certain embodiments of a compound of Formula (X), La is a methyl or di-methyl substituted C2
alkyl linker. In certain embodiments of a compound of Formula (X), La is unsubstituted C2 alkyl
linker.
In certain embodiments of a compound of Formula (X), R31 is tuted or
unsubstituted C1_6 alkyl. In n embodiments of a compound of Formula (X), R31 is
unsubstituted C1_6 alkyl. In certain embodiments of a compound of a (X), R31 is
unsubstituted C1_3 alkyl. In certain embodiments of a compound of Formula (X), R31 is
unsubstituted C1_2 alkyl.
In certain embodiments of a compound of Formula (X), R31 is C(O)ORa-
substituted C1_6 alkyl, wherein Ra is hydrogen or unsubstituted C1_6 alkyl. In certain
embodiments of a compound of Formula (X), R31 is S(O)(O)Rb-substituted C1_6 alkyl, wherein
Rb is unsubstituted C1_6 alkyl.
In n embodiments of a compound of Formula (X), R32 is hydrogen. In
certain embodiments of a compound of Formula (X), R32 is substituted or unsubstituted C1_6
alkyl. In certain ments of a compound of Formula (X), R32 is unsubstituted C1_6 alkyl.
] In certain embodiments of a compound of Formula (X), R31 and R32, together with
the nitrogen atom to which they are ed, form a substituted or tituted heteroaryl
comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or a
substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4
heteroatoms selected from N, O, and S.
In certain ments of a nd of a (X), R31 and R32, together with
the nitrogen atom to which they are attached, form a substituted or tituted heterocycle
comprising one or two 5- or er rings and 1-4 heteroatoms selected from N, O, and S.
In certain embodiments of a compound of Formula (X), R31 and R32, together with
the nitrogen atom to which they are attached, form a substituted or unsubstituted idinyl,
imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofilranyl,
piperidinyl, piperazinyl, or linyl ring.
In certain embodiments of a compound of a (X), R31 and R32, together with
the nitrogen atom to which they are ed, form a substituted or unsubstituted dinyl ring.
In certain embodiments of a nd of Formula (X), R31 and R32, together with
the nitrogen atom to which they are attached, form an unsubstituted piperidinyl ring.
In certain embodiments of a compound of Formula (X), R31 and R32, together with
the nitrogen atom to which they are attached, form a halogen tuted piperidinyl ring. In
certain embodiments of a compound of Formula (X), R31 and R32, together with the nitrogen
atom to which they are attached, form a 4-halogen substituted piperidinyl ring.
In certain embodiments of a compound of Formula (X), R31 and R32, together with
the nitrogen atom to which they are ed, form an unsubstituted morpholinyl ring.
In n embodiments of a compound of a (X), R31 and R32, together with
the nitrogen atom to which they are attached, form an unsubstituted pyrrolidinyl ring.
In certain embodiments of a compound of Formula (X), R31 and R32, together with
the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl
comprising one or two 5 or 6-member rings and 1-4 heteroatoms selected from N, O, and S.
In certain embodiments of a compound of Formula (X), R31 is substituted or
unsubstituted €6-10 aryl. In certain embodiments of a compound of Formula (X), R31 is
unsubstituted C6-C10 aryl. In certain embodiments of a compound of Formula (X), R31 is
unsubstituted phenyl. In certain embodiments of a compound of Formula (X), R31 is
unsubstituted benzyl.
In one embodiment, the compounds of Formula (X) may be prepared using
methods known to those skilled in the art, for example, as disclosed in US. Patent No. 8,669,281
B l .
In one embodiment, the prodrugs of monoalkyl filmarates are the prodrugs
disclosed in US. Patent No. 8,669,281 B1, such as the nds of Formula (X’):
\\/ a"oL / o
\R33
0 o
(X’)
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or isomer
thereof, wherein
R33 is unsubstituted C1_6 alkyl;
La, is substituted or unsubstituted C1_6 alkyl linker, substituted or unsubstituted €3-10
carbocycle, substituted or unsubstituted €6-10 aryl, substituted or unsubstituted
heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms
selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising
one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
R34 is hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or tituted
C2_6 l, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted
€6-10 aryl, substituted or unsubstituted €3-10 carbocycle, substituted or
unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4
heteroatoms ed from N, O, and S, or tuted or unsubstituted heteroaryl
comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N,
O, and S.
In certain embodiments of a compound of Formula (X’), R33 is . In certain
embodiments of a compound of Formula (X’), R33 is ethyl.
In certain embodiments of a compound of Formula (X’), La, is substituted or
unsubstituted C1_6 alkyl linker. In certain embodiments of a compound of Formula (X’), La, is
substituted or unsubstituted C1_3 alkyl linker.
] In certain embodiments of a compound of Formula (X’), La, is substituted or
unsubstituted C2 alkyl linker. In certain embodiments of a compound of Formula (X’), La, is
methyl substituted or unsubstituted C2 alkyl . In certain embodiments of a compound of
Formula (X’), La, is di-methyl tuted or unsubstituted C2 alkyl linker. In certain
2015/060850
embodiments of a nd of Formula (X’), La, is methyl or di-methyl substituted C2 alkyl
linker. In certain embodiments of a compound of Formula (X’), La, is unsubstituted C2 alkyl
linker.
In certain embodiments of a compound of a (X’), R34 is substituted or
unsubstituted C1_6 alkyl. In certain embodiments of a compound of Formula (X’), R34 is
unsubstituted C1_6 alkyl. In n embodiments of a nd of Formula (X’), R34 is methyl.
In certain embodiments of a compound of Formula (X’), R34 is unsubstituted C1_3 alkyl. In
certain embodiments of a compound of Formula (X’), R34 is unsubstituted C1_2 alkyl.
In certain embodiments of a compound of Formula (X’), R34 is C(O)ORa’-
tuted C1_6 alkyl, wherein Ra, is H or unsubstituted C1_6 alkyl. In certain embodiments of a
compound of Formula (X’), R34 is S(O)(O)Rb’-substituted C1_6 alkyl, wherein Rb is unsubstituted
C1_6 alkyl.
In one embodiment, the compounds of Formula (X’) may be prepared using
methods known to those skilled in the art, for example, as disclosed in US. Patent No. 8,669,281
B l .
In one embodiment, the prodrugs of monoalkyl tes are the prodrugs
disclosed in US. Patent No. 8,669,281 B1, such as the compounds of Formula (X’ ’):
\ +’La"\ / O\
,N O R35
R37 \
A' 0
or a clathrate, solvate, tautomer, or stereoisomer thereof, wherein
A7 is a ceutically acceptable anion;
R35 is unsubstituted C1_6 alkyl;
Law is substituted or unsubstituted C1_6 alkyl linker, substituted or unsubstituted €3-10
carbocycle, substituted or unsubstituted €6-10 aryl, substituted or tituted
heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms
selected from N, O, and S, or substituted or unsubstituted heteroaryl sing
one or two 5- or er rings and 1-4 heteroatoms selected from N, O, and S;
R36 and R37 are each, independently, hydrogen, substituted or unsubstituted C1_6 alkyl,
substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2-C6
alkynyl, substituted or tituted €6-10 aryl, substituted or unsubstituted C340
carbocycle, tuted or tituted heterocycle comprising one or two 5- or
6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or
unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4
heteroatoms selected from N, O, and S;
or alternatively, R36 and R37, together with the nitrogen atom to which they are
attached, form a substituted or unsubstituted heteroaryl comprising one or two 5-
or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or a
substituted or unsubstituted heterocycle comprising one or two 5- or 6-member
rings and 1-4 heteroatoms selected from N, O, and S; and
R38 is substituted or unsubstituted C1_6 alkyl.
In certain embodiments of a compound of Formula (X’ ’), R35 is methyl. In
certain embodiments of a compound of Formula (X”), R35 is ethyl.
In certain embodiments of a compound of Formula (X’ ’), Law is substituted or
unsubstituted C1_6 alkyl linker. In certain ments of a compound of Formula (X’ ’), Law is
substituted or unsubstituted C1_3 alkyl linker.
In certain embodiments of a compound of Formula (X’ ’), Law is substituted or
unsubstituted C2 alkyl linker. In certain embodiments of a compound of Formula ( ’ ’), Law is
methyl substituted or unsubstituted C2 alkyl linker. In certain embodiments of a compound of
Formula (X”), Law is di-methyl substituted or unsubstituted C2 alkyl linker. In certain
ments of a compound of Formula (X’ ’), Law is methyl or di-methyl substituted C2 alkyl
linker. In certain embodiments of a compound of Formula (X’ ’), Law is unsubstituted C2 alkyl
linker.
In n ments of a compound of Formula (X’ ’), R36 is substituted or
unsubstituted C1_6 alkyl. In certain embodiments of a nd of a (X’ ’), R36 is
unsubstituted C1_6 alkyl. In certain embodiments of a compound of Formula (X’ ’), R36 is
unsubstituted C1_3 alkyl. In certain embodiments of a compound of Formula (X’ ’), R36 is
unsubstituted C1_2 alkyl.
] In certain embodiments of a compound of Formula (X’ ’), R36 is aw-
tuted C1_6 alkyl, n Ra” is hydrogen or unsubstituted C1_6 alkyl. In certain
embodiments of a compound of Formula ( ”), R36 is S(O)(O)wa-substituted C1_6 alkyl, wherein
Rb” is unsubstituted C1_6 alkyl.
In certain embodiments of a compound of Formula (X’ ’), R36 and R37, together
with the nitrogen atom to which they are ed, form a substituted or unsubstituted heteroaryl
comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or a
substituted or unsubstituted heterocycle comprising one or two 5- or er rings and 1-4
heteroatoms selected from N, O, and S.
In certain embodiments of a compound of Formula (X’ ’), R36 and R37, er
with the nitrogen atom to which they are attached, form a substituted or unsubstituted
heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O,
and S.
] In certain ments of a compound of Formula (X’ ’), R36 and R37, together
with the nitrogen atom to which they are ed, form a substituted or unsubstituted
pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring.
In certain embodiments of a compound of Formula (X’ ’), R36 and R37, together
with the nitrogen atom to which they are attached, form a substituted or tituted piperidinyl
ring. In certain ments of a compound of Formula (X’ ’), R36 and R37, together with the
nitrogen atom to which they are attached, form an unsubstituted piperidinyl ring. In certain
embodiments of a nd of Formula (X’ ’), R36 and R37, together with the nitrogen atom to
which they are attached, form a halogen substituted piperidinyl ring. In certain embodiments of
a compound of Formula (X’ ’), R36 and R37, er with the nitrogen atom to which they are
attached, form a 4-halogen substituted piperidinyl ring.
In certain embodiments of a compound of Formula (X’ ’), R36 and R37, together
with the nitrogen atom to which they are attached, form an unsubstituted morpholinyl ring.
] In certain embodiments of a compound of Formula (X’ ’), R36 and R37, together
with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidinyl ring.
] In certain embodiments of a compound of Formula (X’ ’), R36 and R37, together
with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl
comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S.
] In n embodiments of a compound of Formula (X’ ’), R36 is substituted or
unsubstituted €6-10 aryl. In certain embodiments of a compound of Formula ( ”), R36 is
unsubstituted €6-10 aryl. In certain embodiments of a compound of Formula ( ”), R36 is
unsubstituted phenyl. In certain embodiments of a compound of Formula (X”), R36 is
unsubstituted benzyl.
In certain embodiments of a compound of Formula (X’ ’), R37 is hydrogen.
In certain embodiments of a nd of Formula (X’ ’), R37 is substituted or
unsubstituted C1_6 alkyl. In n embodiments of a compound of Formula (X”), R37 is
unsubstituted C1_6 alkyl.
In certain embodiments of a compound of Formula (X’ ’), R38 is unsubstituted C1_6
alkyl. In certain embodiments of a compound of Formula (X’ ’), R38 is unsubstituted C1_3 alkyl. In
certain embodiments of a compound of Formula (X”), R38 is methyl.
In one embodiment, the compounds of a (X’ ’) may be prepared using
s known to those skilled in the art, for example, as disclosed in US. Patent No. 8,669,281
B l .
] In one embodiment, the prodrugs of monoalkyl fiamarates are the gs
disclosed in US. Patent No. 8,669,281 B1, such as the compounds of Formula (XI):
R40 R43 R42 0
R41’N%o| / O‘Rse
R45 R44 0
(X1)
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer
thereof, wherein
R39 is unsubstituted C1_6 alkyl;
R40 and R41 are each, independently, hydrogen, substituted or tituted C1_6 alkyl,
substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl,
substituted or unsubstituted C640 aryl, tuted or unsubstituted C340
ycle, substituted or unsubstituted heterocycle comprising one or two 5- or
6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or
unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4
heteroatoms selected from N, O, and S;
R42, R43 , R44, and R45 are each, independently, hydrogen, substituted or unsubstituted
2015/060850
C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted
C2_6 alkynyl or C(O)ORb; and Rb is H or substituted or unsubstituted C1-C6 alkyl.
In certain ments of a compound of Formula (XI), R39 is . In certain
embodiments of a compound of Formula (XI), R39 is ethyl.
In certain embodiments of a compound of Formula (XI), R40 is substituted or
unsubstituted C1_6 alkyl. In certain embodiments of a compound of a (XI), R40 is
unsubstituted C1_6 alkyl. In certain embodiments of a compound of Formula (XI), R40 is
unsubstituted C1_3 alkyl. In certain embodiments of a compound of Formula (XI), R40 is
tituted C1_2 alkyl.
In certain embodiments of a compound of Formula (XI), R40 is C(O)ORb-
substituted C1_6 alkyl, wherein Rb is hydrogen or unsubstituted C1_6 alkyl. In certain
embodiments of a compound of Formula (XI), R40 is S(O)(O)Rb-substituted C1_6 alkyl, wherein
Rb is unsubstituted C1_6 alkyl.
In certain embodiments of a compound of Formula (XI), R40 is tuted or
unsubstituted €6-10 aryl. In certain ments of a compound of Formula (XI), R40 is
unsubstituted €6-10 aryl. In certain embodiments of a compound of a (XI), R40 is
unsubstituted phenyl. In certain embodiments of a compound of Formula (XI), R40 is
unsubstituted benzyl.
In certain embodiments of a compound of Formula (XI), R41 is en.
In certain embodiments of a compound of Formula (XI), R41 is tuted or
unsubstituted C1_6 alkyl. In certain embodiments of a compound of Formula (XI), R41 is
unsubstituted C1_6 alkyl.
In certain ments of a compound of Formula (XI), R42, R43, R44, and R45 are
each hydrogen.
] In n embodiments of a compound of Formula (XI), R42 is substituted or
unsubstituted C1_6 alkyl and R43, R44, and R45 are each hydrogen. In certain embodiments of a
compound of Formula (XI), R42 is unsubstituted C1_6 alkyl and R43 , R44, and R45 are each
hydrogen.
In certain embodiments of a compound of Formula (XI), R44 is substituted or
unsubstituted C1_6 alkyl and R42, R43, and R45 are each hydrogen. In certain embodiments of a
compound of Formula (XI), R44 is unsubstituted C1_6 alkyl and R42, R43, and R45 are each
hydrogen.
In certain embodiments of a compound of Formula (XI), R42 and R44 are each,
independently, substituted or unsubstituted C1_6 alkyl and R43 and R45 are each hydrogen. In
certain embodiments of a compound of Formula (XI), R42 and R44 are each, independently,
unsubstituted C1_6 alkyl and R43 and R45 are each hydrogen.
In certain embodiments of a compound of Formula (XI), R42 and R43 are each,
independently, tuted or unsubstituted C1_6 alkyl and R44 and R45 are each en. In
certain embodiments of a compound of a (XI), R42 and R43 are each, independently,
unsubstituted C1_6 alkyl and R44 and R45 are each en.
In certain embodiments of a compound of Formula (XI), R44 and R45 are each,
independently, substituted or unsubstituted C1_6 alkyl and R42 and R43 are each hydrogen. In
certain embodiments of a compound of Formula (XI), R44 and R45 are each, independently,
unsubstituted C1_6 alkyl and R42 and R43 are each hydrogen.
In one ment, the compounds of Formula (XI) may be prepared using
methods known to those skilled in the art, for example, as sed in US. Patent No. 8,669,281
B l .
In one embodiment, the gs of monoalkyl fiJmarates are the prodrugs
disclosed in US. Patent No. 8,669,281 B1, such as the compounds of Formula (XII):
l’ \ R48 R47 0
\‘~-_,4N%OJWO\R46
R50 R49 0
(XII)
or a ceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer
thereof, wherein
R46 is unsubstituted C1_6 alkyl;
(R51>V
\ N.5;: IM—m
NIX- “II (R5I)V\
is 29 IE F‘i,or "0/ X
9 9
X is N, O, S, or S02;
Z is C orN;
tis 0, l, 2, or 3;
yislor2;
wis 0, 1,2, or 3;
Vis 0, l, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R47, R48, R49, and R50 are each, independently, hydrogen, substituted or unsubstituted
C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted
C2_6 alkynyl or C(O)OR52; and
R52 is hydrogen or substituted or unsubstituted C1_6 alkyl; and
each R51 is, independently, hydrogen, halogen, substituted or unsubstituted C1_6 alkyl,
substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl,
substituted or unsubstituted C340 ycle, tuted or unsubstituted
heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms
selected from N, O, and S, or substituted or unsubstituted heteroaryl sing
one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
or, alternatively, two R51's attached to the same carbon atom, together with the carbon
atom to which they are attached, form a carbonyl, substituted or unsubstituted C3-
carbocycle, substituted or unsubstituted cycle comprising one or two 5-
or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted
or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4
heteroatoms selected from N, O, and S;
or, alternatively, two R51's attached to different atoms, together with the atoms to
which they are attached, form a substituted or unsubstituted C3-C10 carbocycle,
tuted or tituted heterocycle comprising one or two 5- or 6-member
rings and 1-4 heteroatoms ed from N, O, and S, or substituted or
unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4
heteroatoms selected from N, O, and S.
In certain embodiments of a compound of Formula (XII), R46 is methyl. In
certain embodiments of a compound of a (XII), R46 is ethyl.
] In certain embodiments of a nd of Formula (XII),
'.-~‘
: I [EWUVN
\ N~5;;
is Hi
In certain embodiments of a compound of Formula (XII),
2015/060850
(R51)V
, x
I“ N‘
“ f: is
] In certain embodiments of a compound of Formula (XII),
. _ ~ (R51 )v
’ ‘
I’ x
\“JNi’i is Zafii
In certain embodiments of a compound of Formula (XII),
I"-~‘
' “ I
t. (RM
In n embodiments of a compound of Formula (XII), R47 is substituted or
unsubstituted C1_6 alkyl and R48, R49, and R50 are each hydrogen. In certain embodiments of a
compound of Formula (XII), R47 is tituted C1_6 alkyl and R48, R49, and R50 are each
hydrogen.
In certain embodiments of a compound of Formula (XII), R49 is substituted or
unsubstituted C1_6 alkyl and R47, R48, and R50 are each hydrogen. In certain embodiments of a
compound of Formula (XII), R49 is unsubstituted C1_6 alkyl and R47, R48, and R50 are each
hydrogen.
] In n embodiments of a compound of Formula (XII), R47 and R49 are each,
independently, substituted or unsubstituted C1_6 alkyl and R48 and R49 are each hydrogen. In
certain ments of a compound of Formula (XII), R47 and R49 are each, ndently,
unsubstituted C1_6 alkyl and R48 and R50 are each hydrogen.
In certain embodiments of a compound of Formula (XII), R47 and R48 are each,
independently, substituted or unsubstituted C1_6 alkyl and R49 and R50 are each hydrogen. In
certain embodiments of a compound of Formula (XII), R47 and R48 are each, independently,
unsubstituted C1_6 alkyl and R49 and R50 are each hydrogen.
In certain embodiments of a compound of Formula (XII), R49 and R50 are each,
independently, substituted or unsubstituted C1_6 alkyl and R47 and R48 are each hydrogen. In
certain embodiments of a compound of Formula (XII), R49 and R50 are each, independently,
unsubstituted C1_6 alkyl and R47 and R48 are each hydrogen.
In one embodiment, the compounds of Formula (XII) may be prepared using
methods known to those skilled in the art, for e, as disclosed in US. Patent No. 8,669,281
In n embodiments of a compound of Formula (X), (X’), ( ”), (X1), or (XII),
the compound is:
HOOC
HOOCVNWOWO\ \/s<\/N\/\0)WO\/\o I o
O O
/NY\OWO\>ANJ\/\OJWO\O O
UWMW\JMM
©NWOW:\ WWO\
O\\//0
/Nro0M0\ /S\/\OM‘/O\
0/\\fi/8ONWOWK WWO\
I O
N\AOJW NwowMO\
0 o (Do/W0 o
N\/\OWO\ K/NwOWo:
9 9
WO 81355 2015/060850
(0ob O O O
NW0W0\ NW0W0\
o o
, 9
| O W O
/N\/\O / 0\ \/N\/\O / O\
O ,OI' O
In certain embodiments of a compound of (XII), the compound is
O 0
In one embodiment, the prodrugs of monoalkyl filmarates are the prodrugs
disclosed in W02014/096425, such as the compounds of Formula (XIII):
o (\A
\OJWO\L/N\)
(XIII)
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
L is is an diyl group with l to 6 carbon atoms;
A is so, soz, or NR53, and
R53 is C1_6 alkyl or C3_6 cycloalkyl.
In certain embodiments of a compound of Formula (XIII), L is an alkanediyl
group with 2, 3 or 4 carbon or with 2 or 4 carbon atoms, or with 2 carbons atoms. In
certain embodiments of a compound of Formula (XIII), L is —CH2CH2-. In certain embodiments
of a compound of Formula (XIII), A is SO or SOZ. In certain embodiments of a compound of
Formula (XIII), R53 is methyl, ethyl, propyl, pyl, butyl, isobutyl, tert-butyl, pentyl, sec-
pentyl, or hexyl. In certain embodiments of a compound of Formula (XIII), R53 is cyclopropyl,
utyl, cyclopentyl and cyclohexyl. In certain embodiments of a compound of Formula
(XIII), R53 is C1_4 alkyl, C3 or C4 or C5 cycloalkyl. In certain embodiments of a compound of
2015/060850
Formula (XIII), R53 is methyl or isopropyl.
] In one embodiment, the compounds of Formula (XIII) may be prepared using
methods known to those skilled in the art, for example, as disclosed in W02014/096425.
In one embodiment, the prodrugs of monoalkyl filmarates are the prodrugs
disclosed in W02014/096425, such as the compounds of Formula (XIV):
\ok/Y’I O
NNONO/
% o
(XIV)
or a clathrate, or solvate thereof.
In one embodiment, the compounds of Formula (XIV) may be prepared using
s known to those skilled in the art, for example, as disclosed in W02014/096425.
In one embodiment, the prodrugs of kyl fiamarates are the prodrugs
disclosed in W02014/096425, such as the compounds of a (XV):
O O\
O O O O
(XV)
or a clathrate, or solvate thereof.
] In one embodiment, the compounds of Formula (XV) may be prepared using
methods known to those skilled in the art, for example, as disclosed in W02014/096425.
In one embodiment, the prodrugs of monoalkyl tes are the prodrugs
disclosed in W02014/096425, such as the compounds of Formula (XVI):
o 0\\ /OR56
/o \
O /P\
c do OR57
0 R54 R55
(XVI)
or a clathrate, solvate, or stereoisomer thereof, wherein
R54 and R55 are each, independently, hydrogen, C1_6 alkyl, or C3_6 cycloalkyl;
R56 and R57 are each, independently, hydrogen or C1_6 alkyl; and
c and d are each, independently, an integer from 0 to 3.
In certain embodiments of a compound of Formula (XVI), R54 and R55 are each,
independently, hydrogen, methyl, or ethyl. In certain embodiments of a compound of Formula
(XVI), R54 and R55 are each, independently, hydrogen or methyl. In certain embodiments of a
compound of Formula (XVI), R54 and R55 are both hydrogen; or R54 is hydrogen and R55 is
. In certain embodiments of a nd of Formula (XVI), c and d each are,
independently, 0 or 1. In certain embodiments of a compound of Formula (XVI), c and d are
both 0. In certain embodiments of a compound of Formula (XVI), R56 and R57 are each,
independently, C1_5 alkyl or C1_4 alkyl. In certain embodiments of a compound of Formula (XVI),
R56 and R57 are tert-butyl. In certain embodiments of a compound of Formula (XVI), R56 and
R57 are identical.
In one embodiment, the compounds of Formula (XVI) may be prepared using
methods known to those d in the art, for e, as disclosed in W02014/096425.
In one embodiment, the prodrugs of kyl filmarates are the prodrugs
disclosed in W02014/096425, such as the nds of a (XVII):
0 R58 R59 R60
/ o o R61
\O N/
f g I
o o R62
(XVII)
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer
thereof, wherein
R58, R59, R61, and R62 are each, ndently, hydrogen, C1_6 alkyl, or C3_6 cycloalkyl;
R60 is hydrogen, C3_6 lkyl or C1_6 alkyl, wherein the C1_6 alkyl is optionally
substituted with or or more of amino, NH-C(NH)NH2, carboxamide, carboxylic
acid, hydroxy, imidazole, , mercapto, methylthio, phenyl, hydroxyphenyl,
and wherein one of R61 and R62 together with R60 optionally belong to a 5 or 6-
membered heteroaliphatic ring; and
f and g are each, independently, an integer from 0 to 3, with the proviso that both f
and g are not 0.
In certain embodiments of a compound of Formula (XVII), R61 and R62 are each,
independently, hydrogen or C1_2 alkyl. In certain embodiments of a compound of Formula
(XVII), R61 and R62 are hydrogen. In n embodiments of a compound of Formula (XVII),
R61 is hydrogen and R62 is methyl. In certain embodiments of a compound of Formula , at
least one of f and g is 0. In n embodiments of a compound of Formula , g is 0.
In certain embodiments of a compound of Formula (XVII), R60 is a substituted C1-
6 alkyl, wherein the substituent is one or more of the following: n, nitro, nitrile, urea,
phenyl, aldehyde, sulfate, amino, NH-C(NH)NH2, carboxamide, carboxylic acid, hydroxy,
imidazole, indole, mercapto, methylthio, phenyl, and hydroxyphenyl. In particular embodiments
the substituents are one or more of the following: amino, NH-C(NH)NH2, carboxamide,
carboxylic acid, hydroxy, imidazole, indole, mercapto, methylthio, phenyl, and hydroxyphenyl.
In certain embodiments of a nd of Formula , R60 is -CH2-C6H5. In certain
embodiments of a compound of Formula (XVII), the compound is a compound of a
XVII’:
(XVII’)
In one embodiment, the compounds of Formula (XVII) or ) may be
prepared using methods known to those skilled in the art, for example, as disclosed in
W02014/096425.
In one ment, the prodrugs of monoalkyl filmarates are the prodrugs
disclosed in W02014/096425, such as the compounds of Formula (XVIII):
WO 81355
(XVIII)
or a ceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
wherein
R63 is hydrogen, C1_6 alkyl, C3_6 cycloalkyl, C2_6 alkenyl, halogen, cyano, hydroxy,
amino, carboxy, mercapto, 5 or 6-membered aryl or hetero aryl optionally
substituted With one of or more of methyl, tert—butyl, hydroxy, methoxy, halogen,
nitro, nitrile, amine, and carboxamide.
In certain embodiments of a compound of Formula (XVIII), R63 is en, C1_2
alkyl, halogen, cyano, amino, or hydroxy. In certain ments of a compound of Formula
(XVIII), R63 is hydrogen, hydroxyl, or methyl. In certain embodiments of a compound of
Formula (XVIII), R63 is methyl.
In one embodiment, the compounds of Formula (XVIII) may be prepared using
s known to those skilled in the art, for example, as disclosed in W02014/096425.
In certain embodiments of a compound of Formula (XIII), (XVI), , or
(XVIII), the compound is:
fi \OJWOWNO
\Owowo
O NH2 O
01' O
’ -
.1.3 Deuterated Fumarates
In one embodiment, the fumarates are isotopically enriched with deuterium (2H).
In a particular embodiment, a deuterated fiJmarate is a nd disclosed in US.
patent application publication number US 2014-0179779 Al, such as a compound of Formula
(XIX):
(XIX)
or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer
thereof, wherein
R64 and R67 are each independently hydrogen, deuterium, deuterated methyl,
deuterated ethyl, C1_6 alkyl, phenyl, 3-7 membered saturated or lly
unsaturated monocyclic carbocyclic ring, 3-7 membered ted or partially
unsaturated monocyclic heterocyclic ring haVing 1-3 atoms ndently
selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring
haVing 1-3 heteroatoms independently ed from nitrogen, oxygen, and sulfur;
R65 and R66 are each independently hydrogen or ium, provided that the
compound of Formula (XIX) contains at least one deuterium atom and that R64
and R67 are not hydrogen or deuterium at the same time.
In particular, fumarate Isotopologues are the compounds disclosed in US patent
application publication number US 2014-0179779 Al, such as the compounds of Formula
(XIX’):
2015/060850
(XIX’)
or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof,
wherein
R64 and R67 are each independently hydrogen, deuterium, deuterated methyl,
deuterated ethyl, or C1_6 aliphatic, and
R65 and R66 are each independently hydrogen or deuterium, provided that the
compound of formula (XIX’) contains at least one deuterium atom and that R64
and R67 are not hydrogen or deuterium at the same time.
] In certain embodiments of a compound of Formula (XIX) or Formula (XIX’), R64
is hydrogen or —CH3. In certain embodiments of a compound of Formula (XIX) or Formula
, R64 is —CD3. In certain embodiments of a compound of Formula (XIX) or Formula
(XIX’), R64 is —CD2CD3.
In certain embodiments of a compound of Formula (XIX) or Formula (XIX’), R67
is —CH2D, —CHD2, or —CD3. In certain embodiments of a compound of a (XIX) or
Formula (XIX’), R67 is H, -CH3, —CH2D, —CHD2, or —CD3.
In certain embodiments of a compound of Formula (XIX) or Formula (XIX’), R64
is hydrogen or —CH3 and R67 is —CH2D, —CHD2, or —CD3.
] In n embodiments of a nd of a (XIX) or Formula (XIX’), R64
is —CD3 and R67 is —CH2D, —CHD2, or —CD3.
In certain embodiments of a compound of Formula (XIX) or a (XIX’), at
least one of R65 and R66 is deuterium. In certain embodiments of a compound of Formula (XIX)
or Formula (XIX’), both of R65 and R66 are deuterium.
In certain embodiments of a compound of Formula (XIX) or Formula (XIX’), at
least one of R65 and R66 is deuterium and R67 is hydrogen, —CH3, —CH2D, —CHD2, or —CD3. In
certain embodiments of a compound of Formula (XIX) or a (XIX’), both of R65 and R66
are deuterium and R67 is hydrogen, —CH3, —CH2D, —CHD2, or —CD3.
In certain embodiments of a compound of Formula (XIX) or Formula (XIX’), R64
is —CD2CD3 and R67 is H, -CH3, —CH2D, —CHD2, or —CD3
WO 81355
In certain embodiments of a compound of Formula (XIX) or Formula (XIX’), the
compound is (2H6)dimethyl fumaric acid ester, ethyl fumaric acid ester, (2H3)dimethyl
fumaric acid ester, dimethyl filmaric(2,3-2H2) acid ester, methyl filmaric(2,3-2H2) acid ester,
ethyl filmaric(2,3-2H2) acid ester, ethyl fumaric(2,3-2H2) acid ester, (2H6)dimethyl
fumaric(2,3-2H2) acid ester, methyl (2-morpholino-2—oxoethyl) fumaric(2,3-2H2) acid ester,
methyl (4-morpholino-l-butyl) filmaric(2,3-2H2) acid ester, 2-(benzoyloxy)ethyl methyl
fumaric(2,3-2H2) acid ester, 2-(benzoyloxy)ethyl (2H3)methyl fumaric acid ester, (S)—2-((2-
aminophenylpropanoyl)oxy)ethyl methyl fumaric(2,3-2H2) acid ester, or (S)((2-amino
phenylpropanoyl)oxy)ethyl (2H3)methyl fumaric acid ester; or a pharmaceutically acceptable salt,
clathrate, solvate, or stereoisomer thereof.
] In certain embodiments of a compound of Formula (XIX) or Formula (XIX’), the
compound is:
o H
D3COWOCD3 DaCOJH/H(OH meow/ / OCH3
H H o -
; or a pharmaceutically acceptable salt, clathrate,
solvate, or stereoisomer thereof.
In one embodiment, the compounds of Formula (XIX) and (XIX’) may be
prepared using methods known to those skilled in the art, for example, as disclosed in US patent
application publication number US 2014-0179779 Al.
Deuterated fumarates are useful as active agents for the methods provided herein,
e. g., treating multiple sis.
In one ment, when a particular position in a fumarate is designated as
having deuterium, it is understood that the abundance of deuterium at that position is
substantially r than the natural nce of deuterium, which is 0.015%. A position
designated as having deuterium typically has a minimum ium enrichment factor of at least
3340 (50.1% deuterium incorporation) at each atom designated as deuterium in said compound.
In other embodiments, a fumarate provided herein has an isotopic enrichment
factor for each ated deuterium atom of at least 3500 (52.5% deuterium incorporation at
each designated deuterium atom), at least 4000 (60% ium incorporation), at least 4500
(67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium
incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium
oration), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium
incorporation), or at least 6633.3 (99.5% deuterium incorporation).
.1.4 Salts
In particular aspects, included within the scope of the fumarates described herein
are the non-toxic pharmaceutically acceptable salts of the fiamarates described hereinabove
(wherein the filmarate is a dialkyl te, a monoalkyl filmarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a clathrate, solvate, er, or stereoisomer of any of the foregoing, or a
combination of any of the foregoing). Acid addition salts are formed by mixing a solution of a
te with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloride,
romide, hydroiodide, nitrate, e, bisulfate, phosphate, acid phosphate, isonicotinate,
acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, gluconate, glucaronate, saccharate, formate, benzoate, ate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. Acceptable base salts
include aluminum, calcium, lithium, ium, potassium, sodium, zinc, and diethanolamine
salts.
.2 Pharmaceutical Compositions
In one embodiment, the fumarate for use in the methods of the invention is
contained in a pharmaceutical composition comprising a therapeutically effective amount of the
fumarate and a pharmaceutically acceptable carrier, z'.e., a pharmaceutically acceptable excipient.
In a specific embodiment, the pharmaceutical composition comprises a fumarate;
wherein the fumarate is a dialkyl fumarate, a monoalkyl te, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a clathrate, e, tautomer, or isomer of any of the foregoing, or a
combination of any of the foregoing; with the proviso that a filmarate salt is not present in the
pharmaceutical composition.
In a specific embodiment, the ceutical composition comprises a fumarate;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, er, or
stereoisomer of any of the ing, or a combination of any of the ing; with the proviso
that an ethyl en fumarate salt is not present in the pharmaceutical composition.
In a specific embodiment, the pharmaceutical composition comprises a fumarate;
wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl
fumarate and a kyl fumarate, a prodrug of monoalkyl fumarate, a ated form of any
of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or
stereoisomer of any of the foregoing, or a combination of any of the ing; with the proviso
that ethyl hydrogen filmarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl
hydrogen fumarate zinc salt, and ethyl hydrogen filmarate copper salt are not present in the
pharmaceutical ition.
In a specific ment, the pharmaceutical composition consists essentially of
DMF and/or monomethyl fumarate.
In a ic embodiment, the pharmaceutical ition comprises DMF. In a
specific embodiment, the pharmaceutical ition consists essentially of DMF. In a specific
embodiment, the pharmaceutical composition comprises DMF, with the o that ethyl
hydrogen filmarate calcium salt, ethyl hydrogen filmarate magnesium salt, ethyl hydrogen
fumarate zinc salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical
composition. In a specific embodiment, the pharmaceutical composition comprises DMF and/or
monomethyl fumarate, with the proviso that ethyl hydrogen fumarate calcium salt, ethyl
hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen
te copper salt are not present in the pharmaceutical composition. In a specific
ment, the pharmaceutical composition comprises DMF, with the proviso that no
additional te other than DMF or monomethyl fumarate is present.
In a specific embodiment, the pharmaceutical ition can be an oral dosage
form, e. g., a solid oral dosage form. In a specific embodiment, the pharmaceutical composition
is a tablet, capsule, or capsule containing microtablets. Optionally, the tablet or ablets are
enterically coated. In a specific embodiment, the pharmaceutical composition is in the form of
enterically coated tablets or microtablets (optionally contained in a capsule), which, once the
enteric coating is dissolved in the gastro-intestinal tract, act as immediate release dosage forms.
In another specific embodiment, the pharmaceutical composition is a controlled,
or sustained, release composition, optionally enterically coated.
The pharmaceutical preparations described herein are manufactured in a manner
which is itself known, for example, by means of conventional , granulating, dragee-
making, dissolving, or lyophilizing ses. Thus, pharmaceutical preparations for oral use
may be obtained by ing the fumarates with solid excipients, optionally grinding the
resulting e and processing the mixture of granules, after adding suitable auxiliaries, if
desired or necessary, to obtain tablets or dragee cores.
] In general, when the drug load (or weight t of an active ingredient) of a
solid oral dosage form (e.g., a tablet or a microtablet) is significantly sed, the weight
percent of the excipient(s) must decrease (especially if the size of the solid oral dosage form
remains the same). The solid oral dosage form often s unstable due to the se in the
amount of excipient(s), e.g., binders, that filnction to hold all the components together in a
cohesive mix. It is unexpected that increasing the amount ofDMF (e.g., from 120 mg to 240 mg)
and decreasing the amount of binder, while keeping the size of the solid oral dosage form (e.g.,
capsule size) to be the same, the strength or integrity of solid dosage form does not suffer.
Suitable excipients are, in particular, fillers such as saccharides, for example
lactose or sucrose, mannitol or ol, cellulose preparations and/or m phosphates, for
example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch
paste, using, for example, maize starch, wheat starch, rice starch, potato starch, n,
tragacanth, methyl ose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,
and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-
mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or
alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating
agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium
stearate or calcium te, and/or polyethylene glycol. Dragee cores are ed with suitable
coatings which, if desired, are resistant to c juices. For this purpose, concentrated
saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl
pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic
solvents or solvent es. In order to produce coatings ant to gastric juices, solutions of
suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-
cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee
coatings, for e, for identification or in order to terize combinations of active
compound doses.
In one embodiment, the pharmaceutical preparations described herein comprise a
capsule containing the agent or pharmaceutical composition described herein in the form of an
enteric-coated microtablet. The coating of the microtablet may be composed of different layers.
The first layer may be a methyacrylic acid - methyl methacrylate copolymer/isopropyl solution
which isolates the tablet cores from potential hydrolysis from the next applied water suspensions.
The enteric coating of the tablet may then be conferred by an aqueous methacrylic acid - ethyl
acrylate copolymer suspension.
In another embodiment, is provided a composition comprising a te,such as
dimethyl te, and one or more excipients, wherein a total amount of the fumarate in the
composition ranges, for example, from about 43% w/w to about 95% w/w, based on the total
weight of the ition, excluding the weight of any g.
The total amount of the fumarate, such as dimethyl filmarate, in the composition
described herein can range, for example, from about 43% w/w to about 95% w/w, from about 50%
w/w to about 95% w/w, from about 50% w/w to about 85% w/w, from about 55% w/w to about
80% w/w, from about 60% w/w to about 75% w/w, from about 60% w/w to about 70% w/w, or
from about 65% w/w to about 70% w/w, based on the total weight of the composition, excluding
the weight of any coating.
] The composition described herein can comprise the fumarate, such as yl
fumarate, for example, in about 43% w/w, about 45% w/w, about 50% w/w, about 55% w/w,
about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 90%
w/w, or about 95% w/w, based on the weight of the composition, excluding the weight of any
coating. For example, the composition can contain about 65% to about 95% w/w (e. g., 65% w/w)
of DMF.
Some or all of the fumarate, such as dimethyl te, in the composition can
have a particle size of 250 microns or less. For example, and t being limiting, at least
80%, at least 90%, at least 95%, at least 97%, or at least 99% of the fumarate, such as dimethyl
fumarate, in the composition can have a particle size of 250 microns or less. Particle size can be
measured, for example, by sieve analysis, air elutriation analysis, photoanalysis, electrical
counting methods, electroresistance counting methods, sedimentation techniques, laser
diffraction methods, acoustic spectroscopy, or ultrasound attenuation spectroscopy. In one
embodiment, the particle size is measured using laser ction methods.
The composition described herein can comprise a total amount of ent(s), for
example, in an amount of about 5 .0 % w/w to about 57% w/w, based on the total weight of the
composition, excluding the weight of any coating.
The composition bed herein can comprise a total amount of excipient(s) in
an amount ranging, for example, from about 5% w/w to about 57% w/w, from about 15% w/w to
about 57% w/w, from about 20% w/w to about 57% w/w, from about 25% w/w to about 57%
w/w, from about 30% w/w to about 57% w/w, from about 35% w/w to about 57% w/w, from
about 40% to about 57% w/w, from about 45% w/w to about 57% w/w, from about 50% w/w to
about 57% w/w, from about 55% w/w to about 57% w/w, from about 5% w/w to about 55% w/w,
from about 5% w/w to about 50% w/w, from about 5% w/w to about 45% w/w, from about 5%
w/w to about 40% w/w, from about 5% w/w to about 35% w/w, from about 5% w/w to about 30%
w/w, from about 5% w/w to about 25% w/w, from about 5% w/w to about 20% w/w, from about
% w/w to about 15% w/w, from about 15% w/w to about 55% w/w, from about 20% w/w to
WO 81355
about 50% w/w, from about 25% w/w to about 45% w/w, from about 30% w/w to about 40%
w/w, from about 35% to about 40% w/w, based on the total weight of the composition, ing
the weight of any coating.
The excipient(s) can be, for example, one or more selected from the group
consisting of a filler (or a binder), a glidant, a disintegrant, a lubricant, or any combination
thereof.
The number of excipients that can be included in a composition is not limited.
Examples of fillers or binders include, but are not limited to, um alginate,
calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible
sugar, confectioner’s sugar, dextrates, n, dextrose, erythritol, ethylcellulose, fructose,
glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose,
mannitol, ium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium
chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylates, simethicone,
sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-
cyclodextrin, talc, tragacanth, trehalsoe, polysorbate 80, and xylitol. In one ment, the
filler is microcrystalline cellulose. The microcrystalline ose can be, for example,
PROSOLV SMCC® 50, PROSOLV SMCC® 90, PROSOLV SMCC® HD90, PROSOLV
SMCC® 90 LM, and any combination thereof.
Examples of disintegrants include, but are not limited to, hydroxypropyl starch,
alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium,
ed cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, vidone,
docusate sodium, guar gum, hydroxypropyl cellulose, low substituted hydroxypropyl ose,
magnesium aluminum silicate, cellulose, microcrystalline cellulose, polacrilin potassium,
povidone, sodium alginate, sodium starch glycolate, starch, and pregelatinized starch. In one
embodiment, the disintegrant is croscarmellose sodium.
] Examples of glidants include, but are not limited to, calcium phosphate, calcium
silicate, powdered cellulose, magnesium silicate, ium trisilicate, silicon dioxide, talcum
and colloidal silica, and colloidal silica anhydrous. In one embodiment, the glidant is colloidal
silica anhydrous, talc, or a combination thereof.
Examples of lubricants include, but are not limited to, canola oil, hydroxyethyl
cellulose, lauric acid, leucine, l oil, poloxamers, polyVinyl alcohol, talc, oxtyldodecanol,
sodium hyaluronate, sterilizable maize starch, triethanolamine, calcium stearate, magnesium
stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor
oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, medium-chain
triglycerides, mineral oil, myristic acid, ic acid, poloxamer, polyethylene glycol, potassium
benzoate, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, talc, and zinc
te. In one embodiment, the lubricant is magnesium stearate.
The composition bed herein can comprise a total amount of filler(s) in an
amount ranging from about 3.5% w/w to about 55% w/w of the composition, based on the total
weight of the composition, excluding the weight of any g.
] The filler(s) can be comprised in the composition described herein, for example,
in a total amount, for e, ranging from about 5% w/w to about 55% w/w, from about 10%
w/w to about 55% w/w, from about 15% w/w to about 55% w/w, from about 20% w/w to about
55% w/w, from about 25% w/w to about 55% w/w, from about 30% w/w to about 55% w/w,
from about 35% w/w to about 55% w/w, from about 40% w/w to about 55% w/w, from about 3.5%
w/w to about 55% w/w, from about 3.5% to about 50%, from about 3.5% w/w to about 40% w/w,
from about 3.5% w/w to about 30% w/w, from about 3.5% w/w to about 25% w/w, from about
3.5% w/w to about 20% w/w, from about 3.5% w/w to about 15% w/w, from about 15% w/w to
about 40% w/w, from about 20% w/w to about 35% w/w, or from about 25% w/w to about 30%
w/w, based on the total weight of the composition, excluding the weight of any coating.
The filler(s) can be comprised in the composition, for example, in a total amount
of about 5% w/w, about 7% w/w, about 10% w/w, about 12% w/w, about 14% w/w, about 16%
w/w, about 18% w/w, about 20% w/w, about 22% w/w, about 24% w/w, about 26% w/w, about
28% w/w, about 30% w/w, about 32% w/w, about 34% w/w, about 36% w/w, about 38% w/w,
about 40% w/w, about 42% w/w, about 44% w/w, about 46% w/w, about 48% w/w, about 50%
w/w, about 52% w/w, about 54% w/w, or about 55% w/w, based on the total weight of the
composition, excluding the weight of any coating.
The composition described herein can se a total amount of disintegrant(s),
for example, in an amount ranging from about 0.2 % w/w to about 20% w/w, based on the total
weight of the composition, excluding the weight of any coating.
The disintegrant(s) can be contained in the ition, for example, in a total
amount ranging from about 0.2% w/w to about 19% w/w, about 0.2% w/w to about 15% w/w,
about 0.2% w/w to about 12% w/w, about 0.2% w/w to about 6% w/w, about 0.2% w/w to about
% w/w, about 0.2% w/w to about 4% w/w, about 0.2% w/w to about 3% w/w, about 0.2% w/w
to about 2% w/w, about 0.2% w/w to about 20% w/w, about 3% w/w to about 20% w/w, about 4%
w/w to about 20% w/w, about 5% w/w to about 20% w/w, about 6% w/w to about 20% w/w,
about 7% w/w to about 20% w/w, about 8% w/w to about 20% w/w, about 9% w/w to about 20%
w/w, about 2% w/w to about 20% w/w, or about 3% w/w to about 20% w/w, based on the weight
of the composition, excluding the weight of any coating.
The disintegrant(s) can be contained in the composition, for example, in a total
amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%
w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 12% w/w, about 14%
w/w, about 16% w/w, about 18% w/w, or about 19% w/w, based on the total weight of the
composition, ing the weight of any coating.
The glidant(s) can be contained in the composition, for example, in a total amount
ranging from about 0.1% w/w to about 9.0% w/w, based on the total weight of the composition,
excluding the weight of any coating.
The t(s) can be contained in the composition, for example, in a total amount
ranging from about 0.1% w/w to about 9.0% w/w, from about 0.1% w/w to about 8% w/w, from
about 0.1% w/w to about 6% w/w, from about 0.1% w/w to about 4% w/w, from about 0.1%
w/w to about 2.8% w/w, from about 0.1% w/w to about 2.6% w/w, from about 0.1% w/w to
about 2.4% w/w, from about 0.1% w/w to about 2.2% w/w, from about 0.1% w/w to about 2.0%
w/w, from about 0.1% w/w to about 1.8% w/w, from about 0.1% w/w to about 1.6% w/w, from
about 0.1% to about 1.4% w/w, from about 0.1% w/w to about 1.2% w/w, from about 0.1% w/w
to about 1.0% w/w, from about 0.1% w/w to about 0.8% w/w, from about 0.1% w/w to about
0.4% w/w, from about 0.2% w/w to about 3.0% w/w, from about 0.4% w/w to about 3.0% w/w,
from about 0.6% w/w to about 3.0% w/w, from about 0.8% w/w to about 3.0% w/w, from about
1.0% w/w to about 3.0% w/w, from about 1.2% w/w to about 9.0% w/w, from about 1.4% w/w
to about 9.0% w/w, from about 1.6% w/w to about 9.0%, from about 1.8% w/w to about 9.0%
w/w, from about 2.0% w/w to about 9.0% w/w, from about 2.2% w/w to about 9.0% w/w, from
about 2.4% w/w to about 9.0% w/w, from about 2.6% w/w to about 9.0% w/w, from about 2.8%
w/w to about 9.0% w/w, from about 3.0% w/w to about 9.0% w/w, from about 4.0% w/w to
about 9.0% w/w, from about 5.0% w/w to about 9.0% w/w, from about 6.0% w/w to about 9.0%
w/w, from about 7.0% w/w to about 9.0% w/w, from about 8.0% w/w to about 9.0% w/w, from
about 0.5% w/w to about 2.5% w/w, or from about 1.0% w/w to about 2.0% w/w, based on the
total weight of the composition, excluding the weight of any coating.
The glidant(s) can be contained in the composition, for example, in a total amount
of about 0.1 % w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about
0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1.0 % w/w, about 1.2%
w/w, about 1.4% w/w, about 1.6% w/w, about 1.8% w/w, about 2.0% w/w, about 2.2% w/w,
about 2.4% w/w, about 2.6% w/w, about 2.8% w/w, about 3% w/w, about 4% w/w, about 5%
w/w, about 6% w/w, about 7% w/w, about 8% w/w, or about 9% w/w, based on the total weight
of the ition, excluding the weight of any coating.
The lubricant(s) can be contained in the composition, for example, in a total
amount ranging from about 0.1% w/w to about 3.0% w/w, based on the total weight of the
composition, excluding the weight of any coating.
The lubricant(s) can be contained in the composition, for example, in a total
amount ranging from about 0.1% w/w to about 2% w/w, about 0.1% w/w to about 1% w/w,
from about 0.1% w/w to about 0.7% w/w, from about 0.1% w/w to about 0.6% w/w, from about
0.1% w/w to about 0.5% w/w, from about 0.1% w/w to about 0.4% w/w, from about 0.1% w/w
to about 0.3% w/w, from about 0.1% w/w to about 0.2% w/w, from about 0.2% w/w to about 3.0%
w/w, from about 0.3% w/w to about 3.0% w/w, from about 0.4% w/w to about 3.0% w/w, from
about 0.5% w/w to about 3.0% w/w, from about 0.6% w/w to about 3.0% w/w, from about 0.7%
w/w to about 3.0% w/w, from about 0.8% w/w to about 3.0% w/w, from about 0.9% w/w to
about 3.0% w/w, from about 1% w/w to about 3.0% w/w, from about 2% w/w to about 3% w/w,
from about 0.2% w/w to about 0.7% w/w, from about 0.3% w/w to about 0.6% w/w, or from
about 0.4% w/w to about 0.5% w/w, based on the total weight of the composition, excluding the
weight of any coating.
] The lubricant(s) can be ned in the composition, for example, in a total
amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w,
about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1.0% w/w, about
2.0% w/w, or about 3.0% w/w, based on the total weight of ition, excluding the weight of
any coating.
In some embodiments, for example, the composition described herein comprises
one or more fillers in a total amount ranging from about 3.5% w/w to about 55% w/w, one or
more disintegrants in a total amount ranging from about 0.2 % w/w to about 20% w/w, one or
more glidants in a total amount ranging from about 0.1% w/w to about 9.0% w/w, and one or
more ants in a total amount ranging from about 0.1% w/w to about 3.0% w/w.
In some ments, for example, the composition described herein ses a
filler, a disintegrant, a glidant, and a lubricant. In some embodiments, the filler is
microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is colloidal
silica anhydrous, and the lubricant is magnesium stearate. In other embodiments, the filler is
microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is a combination
of colloidal silica anhydrous and talc, and the lubricant is magnesium te.
The ingredients in the ition described herein can be, for example,
homogeneous or heterogeneously mixed. The composition ingredients can be, for e,
mixed by any known method including shaking, stirring, mixing with forced air, mixing in a
spinning container, and the like. The ition ingredients can be, for e, mixed all at
once, or with progressive addition of one or more ingredients. The composition ingredients can
be mixed in any order, for example, individually, in groups, or as a blend of all of the ingredients.
For example, the glidant(s) can be mixed with the DMF and/or disintegrant(s) prior to mixing
with any or all of the filler(s) and/or lubricants. The blend can also be prepared by mixing DMF,
egrant(s) (e. g., croscarmellose sodium) and a n of binder (e.g., microcrystalline
cellulose) before then passing through a screen or sieve. The remaining binder can be mixed
with lubricant(s) (e.g., magnesium stearate) before passing through a screen or sieve. These two
mixtures can then be combined and mixed before adding glidant(s) (e.g., silica colloidal
anhydrous). The glidant(s) can also be added to one or both of the aforementioned mixtures
before they are combined and mixed to produce the final blend.
The composition described herein can have a flowability index, for example,
ranging from about 8 mm to about 24 mm. For e, the flowability index can range from
about 12 mm to about 22 mm, from about 12 mm to about 20 mm, from about 12 mm to about
18 mm, from about 12 mm to about 16 mm, from about 12 mm to about 14 mm, from about 14
mm to about 24 mm, from about 16 mm to about 24 mm, from about 18 mm to about 24 mm,
from about 20 mm to about 24 mm, from about 22 mm to about 24 mm, from about 14 mm to
about 22 mm, or from about 16 mm to about 20 mm.
The flowabilty index can be, for e, less than 18 mm (e. g., about 8 mm,
about 12 mm, about 14 mm, about 16 mm) with an amount of t(s) ranging from about 0.1%
w/w to about 2.0% w/w (e.g., 1.0% w/w).
The flowability index can be measured, for example, on a FLODEX device
(manufactured by Hanson Research). The following protocol, for example, can be employed: A
powder sample (e.g., 50 g) is loaded into the cylinder on the FLODEX device such that the
powder is within about 1 cm from the top of the cylinder. A m of 30 s is allowed
to pass before testing commences. Starting with a 16 mm flow disk, the e lever is slowly
turned until the closure drops open without vibration. The test is positive when the open hole at
the bottom is visible when looking down from the top. If a positive result is obtained, the test is
repeated with smaller and smaller disk holes until the test is negative. For negative results, the
size of the flow disk hole is sed until the test is positive. The flowability index is the
diameter of the smallest hole through which the sample will pass for three successive tests.
The composition can have, for example, a compressibility index ranging from
about 15% to about 28%. The compressibility index can range, for example, from 17% to about
28%, from about 19% to about 28%, from about 21% to about 28%, from about 23% to about
28%, from about 25% to about 28%, from about 15% to about 26%, from about 15% to about
24%, from about 15% to about 22%, from about 15% to about 20%, from about 15% to about
18%, from about 17% to about 26%, from about 19% to about 24%, or from about 20% to about
22%.
The composition can have a compressibility index, for example, of about 16%,
about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%,
about 25%, about 26%, or about 27%.
The compressibility index can be defined, for e, by the formula: (((VO-
Vf)/V0) x 100%) where V0 is unsettled apparent volume of the particle and Vf is the final tapped
volume of the powder. The compressibility index can be determined, for example, as follows:
powder is placed in a container and the powder’s unsettled apparent volume (V0) is noted. Next,
the powder is tapped until no fiarther volume changes occur. At this point, the final tapped
volume of the powder is measured (Vf). The compressibility index is then calculated by using
the formula above.
In some ments, the composition can be in the form of a powder (not
compressed) or a compact (compressed). The shape of the compact is not limited and can be, for
example, cubic, spherical, or cylindrical (e.g., disc-shaped).
The compact can be, for example, in the form of tablets, caplets, or microtablets.
The compact can be prepared by any means known in the art. For e, if the compact is in
the form of microtablets, the ablets can be made by compressing the composition
described above using any known method, such as using a rotary tablet press equipped with a
multi-tip tooling and having concave tips.
] Multi-tip tableting tools, for example, can be used. For example, a multi-tip tool
having from about 16 tips to about 40 tips using, for e, about 2 mm er tips. In this
ion, applied compressing force can be expressed as an average kN/tip. For example, an
applied compressing force of 2 kN used with a 16 multi-tip tool yields an d compressing
force of about 0.125 kN/tip. rly, an applied compressing force of about 15 kN used with a
16 multi-tip tool yields an applied compressing force of about 0.94 kN per tip.
The microtablets can have a mean diameter (excluding any coatings), for example,
ranging from about 1 mm to about 3 mm. For e, the microtablets can have a mean
diameter ranging from about 1 mm to about 2.5 mm. The microtablets can have a mean diameter
of about 1.0 mm, about 2.0 mm, or about 3.0 mm.
Compact tensile strength can be determined by any means known in the art. For
example, the ing protocol could be ed. First, compact(s) are compressed to about
360 mg weight using an instrumented rotary tablet press equipped to measure compression force
with round flat tooling of approximately 10 mm diameter. Next, e the diametrial crushing
strengthusing a suitable tablet hardness tester and then calculate tensile strength by the procedure
reported by Newton (Newton, J. M., Journal ofPharmacy and Pharmacology, 26: 215-216
(1974)). See also Pandeya and Puri, KONA Powder and Particle Journal, 30: 211-220 (2013),
Jarosz and Parrott, J. Pharm. Sci. 72(5):530-535 (1983), and ck, Intl. J. Pharm. 436214-
232 (2012).
The composition described herein, in the form of a compact, can have a tensile
strength equal to or greater than 1.5 MPa at an applied or compaction pressure of about 100 MPa.
For example, the tensile strength can range from about 2.0 to about 5.0 MPa (e. g., from about 2.5
to about 4.5 MPa, from about 3.0 to about 4.5 MPa or from about 3.5 to about 4.5 MPa) at an
applied or compaction pressure of about 100 MPa. For example, the tensile strength can be
about 4.0 MPa at an applied or compaction pressure of about 100 MPa.
] The compact in the form of one or more microtablets produced using 16 multi-tip
tooling can have a hardness or breaking strength or crushing strength ranging from about 8 N to
about 35 N When the microtablet is formed by a compression force ranging from 2 kN to about
kN and the microtablet has a 2 mm er, a thickness of 2 mm, and a 1.8 mm radius of the
convex surface. In one embodiment, microtablets each having a 2 mm diameter, a thickness of 2
mm, and a 1.8 mm radius of the convex e have a hardness ranging from about 17 N to
about 24 N for a compression force of about 4 kN to about 7 kN. The hardness can be, for
example, of from about 23 N to about 27 N (e.g., about 24 N, about 25 N, or about 26 N) for a
compression force of about 10 kN to about 15 kN. Hardness or breaking strength or crushing
strength can be determined for e, using an Erweka tester or a Schleuniger tester as
described in Lachman, L. et al., The Theory & Practice ofIndustz'ral Pharmacology (3rd ed.
1986), p. 298.
In some embodiments, the composition can be optionally coated or partially
coated by one or more coatings. The coating(s) can be pH independent or pH dependent. The
coating(s) can be, for example, enteric coatings, seal coatings, or combinations of enteric
coatings and seal coatings.
The seal coating can n, for example, one or more plasticizers, one or more
copolymers, one or more polymers, or combinations thereof.
The plasticizer can be, for example, one or more of acetyltributyl citrate,
acetyltriethyl citrate, benzyl benzoate, cellulose acetate phthalate, chlorbutanol, dextrin, dibutyl
phthalate, l secacate, diethyl phthalate, dimethyl ate, glycerin, glycerin monostearate,
hypromellose phthalate, mannitol, mineral oil an lanolin alcohols, palmitic acid, polyethylene
glycol, polyvinyl acetate phthalate, propylene glycol, olidone, sorbitol, stearic acid,
triacetin, tributyl citrate, triethanolamine, and triethyl e.
The copolymer can be, for example, a rylic acid-methacrylate copolymer
or a methacrylic acid-ethylacrylate copolymer.
Additionally, the seal g can contain one or more polymers, for example,
cellulose tives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
and methylcellulose, polyvinylpyrrolidone, a nylpyrrolidone/vinyl acetate copolymer,
ethyl cellulose, and ethyl ose aqueous dispersions (AQUACOAT®, SURELEASE®),
EUDRAGIT® RL 30 D, OPADRY®, EUDRAGIT® S, EUDRAGIT® L, and the like.
If present in the seal coating, the total amount of one or more copolymer(s) and/or
one or more polymer(s) in the seal coating can range, for e, from a positive amount
greater than 0% w/w to about 100% w/w, based on the weight of the seal coating. The amount
of one or more copolymer(s) and/or one or more r(s) in the seal coating can range, for
example, from about 10% w/w to about 100% w/w, from about 20% w/w to about 100% w/w,
from about 30% w/w to about 100% w/w, from about 40% w/w to about 100% w/w, from about
50% w/w to about 100% w/w, from about 60% w/w to about 100% w/w, from about 70% w/w to
about 100% w/w, from about 80% w/w to about 100% w/w, or from about 90% w/w to about
100% w/w, based on the weight of the seal coating.
The amount of one or more copolymer(s) and/or one or more polymer(s) in the
seal coating can be, for example, about 10% w/w, about 20% w/w, about 30% w/w, about 35%
w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about
65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w,
or about 95% w/w, based on the weight of the seal coating.
If present in the seal coating, the mean amount of plasticizer in the seal coating
can range, for example, from a positive amount greater than 0 % w/w to about 70 % w/w, based
on the weight of the seal coating.
The enteric coating can n, for example, one or more plasticizers, one or
more fillers, one or more lubricants, one or more mers, one or more polymers, and any
combinations thereof.
The plasticizer(s) in the enteric coat can be the same or different than any
plasticizer(s) in a seal coat, if present, and can be one of more of the cizers listed above.
The filler(s) in the enteric coat can be the same or different than any filler(s) in the
ition. Additionally, the filler(s) in the enteric coat can be the same or different than any
filler(s) in a seal coat, if present, and can be one or more of the fillers listed above.
The lubricant(s) in the enteric coat can be the same or different than any
lubricant(s) in the composition. Additionally, the lubricant(s) in the enteric coat can be the same
or different than the copolymer(s) in a seal coat, if present, and can be one or more of the
lubricants listed above. In one ment, the lubricant is talcum that is optionally micronized.
The copolymer(s) in the enteric coat can be the same or different than the
copolymer(s) in a seal coat, if present, and can be one or more of the copolymer(s) listed above.
In one embodiment, the enteric coat contains one or more of a methyl acrylate-methyl methacrylate-
methacrylic acid copolymer (EUDRAGIT® FS 30 D), a methacrylic acid-methyl methacrylate
copolymer and a rylic acid-ethyl acetate copolymer.
The enteric polymers used in the composition described herein can be modified
by mixing or layering with other known coating products that are not pH sensitive. es of
such coating products include ethyl cellulose, hydroxylpropyl ose, l methacrylic acid
esters with a small portion of trimethylammonioethyl methacrylate chloride, sold currently under
the trade names EUDRAGIT® RS and EUDRAGIT® RL; a neutral ester dispersion without any
functional groups, sold under the trade names EUDRAGIT® NE 30 D; and other pH
independent g products.
The total amount of the copolymer(s) and/or polymer(s) in the enteric coating can
range, for example, from about 25% w/w to about 100% w/w, based on the weight of the enteric
coating.
If present in an enteric coating, the total amount of lubricant(s) in the enteric
coating can range, for example, from a positive amount greater than 0% w/w to about 58 % w/w,
based on the weight of the enteric coating.
If t in an enteric coating, the total amount of filler(s) in the enteric coating
can range, for example, from a positive amount greater than 0% w/w to about 5.0% w/w, based
on the weight of the enteric coating.
Solvents for ng the g materials, can be, but are not limited to, water,
acetone, hexane, ethanol, methanol, propanol, isopropanol, butanol, anol, sec-butanol, tert-
butanol, dichlormethane, trichloromethane, chloroform, and the like.
Coatings can be applied by any known means, ing spraying. In some
embodiments, the compositions are coated or partially coated with one or more seal coatings, for
example one, two, three or more seal coatings. In some embodiments, the compositions are
coated or partially coated with one or more enteric coatings, for example one, two, three or more
c gs. In some embodiments, the compositions are coated with one or more seal
coatings and one or more enteric coatings. In some ments, the compositions are coated
with one seal coating and one enteric coating.
In a specific embodiment, the pharmaceutical composition is a tablet, for example,
the tablet set forth in Table 2 and further coated with a seal g solution and an enteric
g solution according to Formula A as set forth in Table 3 (See Example 1, Section 6.1
infra).
In a specific embodiment, the pharmaceutical composition is a tablet, for example,
the tablet set forth in Table 2 and further coated with a seal coating solution and an enteric
coating solution according to Formula B as set forth in Table 3 (See e 1, n 6.1
infra).
In a specific embodiment, the pharmaceutical composition is the same as in
TECFIDERA®. In another specific embodiment, the pharmaceutical composition is the same as
in FUMADERM®. In another specific embodiment, the pharmaceutical composition contains
different filmarates from those filmarates in FUMADERM®.
In one embodiment, the pharmaceutical composition is in the form of a tablet or a
capsule. In one embodiment, the pharmaceutical composition is in the form of an enterically
coated tablet. In one embodiment, the pharmaceutical composition is in the form of an
enterically coated microtablets.
.3 Dosing Regimens
] This sure es dosing regimens for administering the fumarate as
described herein. The fumarates and pharmaceutical compositions bed herein may be
administered by any means that achieve their intended purpose. For example, administration
may be by parenteral, aneous, uscular, intraperitoneal, ermal, buccal,
intrathecal, intracranial, intranasal, or topical routes. In one embodiment, the administering is
done orally. The dosage stered will be dependent upon the age, health, and weight of the
recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the
effect d.
The amount of filmarate that can be combined with the r materials to
produce a single dosage form will vary depending upon the host treated, and the particular mode
of administration. It should be understood, however, that a specific dosage and treatment
regimen for any particular subject will depend upon a variety of factors, including the activity of
the specific compound employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the judgment of the treating physician
and the severity of the particular disease being treated. The amount of filmarate can also depend
upon the therapeutic or prophylactic agent, if any, with which the agent is co-administered.
A composition comprising a total amount of dimethyl filmarate (DMF) ranging
from about 43% w/w to about 95% w/w (e.g., from about 50% w/w to about 80% w/w or from
about 60% w/w to about 70% w/w) and one or more excipients formulated in such a manner that
about 160 mg of DMF to about 500 mg of DMF (e.g., about 240 mg to about 480 mg DMF) can
be included in a single dosage form that can be administered, for e, once per day (QD),
twice per day (BID), or thrice per day (TID). For example, a capsule (e.g., size 0) can contain
about 240 mg of DMF. As r example, a capsule can contain about 480 mg of DMF.
When the filmarate is administered to a human, the compound may quickly
metabolize to MMF. The pharmacokinetics properties (e.g., Cmax and AUC) can be therefore
measured based on the concentration ofMMF in the plasma after administration. The
pharmacokinetics properties can be determined after single dosing or at steady state. In some
ments, subjects orally administered a dosage form described above containing a fumarate
or a pharmaceutically able salt, ate, solvate, tautomer, or stereoisomer thereof exhibit
a time to maximum plasma MMF concentration (Tmax) of, for example, from about 1.5 hours to
about 3.5 hours, from about 1.75 hours to about 3.25 hours, or from about 2 hours to about 2.5
hours.
In some embodiments, subjects orally administered a dosage form described
above containing a te exhibit a mean MMF plasma area under the curve 0-12 12) of
about 2.36 h.mg/L to about 5.50 h.mg/L, from about 2.75 h.mg/L to about 5.10 h.mg/L, or from
about 3.14 h.mg/L to about 4.91 h.mg/L. In one ment, subjects exhibit a mean AUC0_12
of about 3.93 h.mg/L.
In some embodiments, subjects orally administered a dosage form described
above containing a fumarate exhibit a mean MMF plasma area under the curve 0-inf1nity (AUC0_
infinity) of about 2.4 h.mg/L to about 5.6 h.mg/L, from about 2.75 h.mg/L to about 5.10 , or
from about 3.14 h.mg/L to about 4.91 h.mg/L. In one embodiment, subjects exhibit a mean
AUCO_infinity of about 3.93 h.mg/L.
In some embodiments, subjects orally administered a dosage form described
above containing a fumarate twice daily t a mean MMF plasma overall area under the
curve of about 4.81 h.mg/mL to about 11.2 h.mg/mL, or from about 6.40 h.mg/L to about 10.1
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h.mg/L. In one embodiment, subjects exhibit a mean AUCoverau of about 8.02 h.mg/L when
orally administered the dosage forms twice daily.
In some embodiments, subjects orally administered a dosage form bed
above containing a fumarate exhibit a mean MMF plasma concentration (Cmax) of from about
1.45 mg/L to about 3.39 mg/L, from about 1.69 mg/L to about 3.15 mg/L, or from about 1.93
mg/L to about 3.03 mg/L. In one embodiment, subjects exhibit a mean Cmax of about 2.42 mg/L.
In one embodiment, subjects orally administered a dosage form described above
containing a fumarate exhibit a mean Cmax of about 1.02 mg/L to about 2.41 mg/L, or about 1.37
mg/L to about 2.15 mg/L. In one embodiment, subjects exhibit a mean Cmax of about 1.72 mg/L
when orally administered the dosage forms twice daily.
Additionally, subjects orally administered a dosage form described above
containing a fumarate can exhibit one or more of the following pharmacokinetic parameters: (a)
a mean plasma MMF Tmax of from about 1.5 hours to about 3.5 hours; (b) a mean plasma MMF
Cmax ranging from about 1.03 mg/L to about 3.4 mg/L; (c) a mean plasma MMF AUCoverall
ranging from about 4.81 h.mg/L to about 11.2 h.mg/L; (d) a mean plasma MMF AUC0_12 ranging
from about 2.4 h.mg/L to about 5.5 ; and (e) a mean AUCO_infinity ranging from about 2.4
h.mg/L to about 5.6 h.mg/L.
In some ments, the compounds and pharmaceutical itions
described herein can be administered in an amount ranging from about 1 mg/kg to about 50
mg/kg (e. g., from about 2.5 mg/kg to about 20 mg/kg or from about 2.5 mg/kg to about 15
mg/kg). The amount of the compounds and pharmaceutical compositions described herein
administered will also vary, as recognized by those skilled in the art, dependent on route of
administration, excipient usage, and the possibility of co-usage with other therapeutic treatments
including use of other therapeutic agents.
For example, the compounds and pharmaceutical compositions described herein
can be stered to a t, for example orally, in an amount of from about 0.1 g to about 1
g per day, or for e, in an amount of from about 100 mg to about 800 mg per day.
The amount of compounds and pharmaceutical compositions described herein
may be administered once a day or in te administrations of 2, 3, 4, 5 or 6 equal doses per
day.
In addition to administering the agent as a raw chemical, the agents described
herein may be administered as part of a pharmaceutical preparation containing suitable
pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate
processing of the agents into preparations which may be used ceutically. For example,
the preparations, ularly those preparations which may be administered orally, such as
tablets, dragees, and capsules, and also preparations which may be administered rectally, such as
itories, as well as suitable solutions for administration by injection or orally, n from
about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of fumarate(s), together with
the excipient.
In one ment, the composition is in the form of a dosage form, such that
one composition provides the total DMF dose. In other embodiments, the dosage form ns
multiple compositions to provide the total DMF dose. For example, a dosage form may contain
le ts, such as microtablets, to provide the desired total DMF dose.
If the dosage form contains multiple compacts, such as multiple microtablets, to
provide the required total DMF dose, the compacts in the dosage form can differ from one
another. For example, the dosage form can contain two or more different microtablet types (e. g.,
the capsule can contain one group of microtablets coated with only an enteric coating and a
second group of microtablets coated with only a seal coating, or one group coated with an enteric
coating with a lower pH release and the other coated with an c g with a higher pH
release).
In some embodiments, the ition is placed in a capsule. In other
embodiments, the composition, in the form of microtablets, is placed in a capsule. The capsule
can contain, for example, from about 30 microtablets to about 60 microtablets, from about 35
microtablets to about 55 microtablets, from about 30 to about 50 microtabletes or from about 40
microtablets to about 50 microtablets (e.g., about 44, about 45, about 46, about 47, or about 48
microtablets).
The dosage form can be administered, for example, once, twice, thrice, four time,
five times, or six times per day. One or more dosage form can be administered, for example, for
one, two, three, four, five, six, or seven days. One or more dosage forms can be administered,
for example, for one, two, three, or four weeks. One or more dosage forms can be administered,
for example, for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve months or
longer. One or more dosage forms can be stered until the subject in need thereof does not
require treatment, prophylaxis, or amelioration of any disease or condition such as, for example,
multiple sis.
In some embodiments, a method described herein comprises orally administering
a dosage form that provides a total amount of about 60 mg to about 1000 mg of dimethyl
fumarate daily. The dosage form can, for e, contain a total amount ofDMF effective for
treatment, prophylaxis, or amelioration of multiple sclerosis in a subject. The daily effective
amount can range, but is not d to, a total amount of about 60 mg to about 800 mg DMF,
about 60 mg to about 720 mg DMF, 60 mg to about 500 mg DMF, about 60 mg to about 480 mg
DMF, about 60 mg to about 420 mg DMF, about 60 mg to about 360 mg DMF, about 60 mg to
about 240 mg DMF, about 60 mg to about 220 mg DMF, about 60 mg to about 200 mg DMF,
about 60 mg to about 180 mg DMF, about 60 mg to about 160 mg DMF, about 60 mg to about
140 mg DMF, about 60 mg to about 120 mg DMF, about 60 mg to about 100 mg DMF, about 60
mg to about 80 mg DMF, about 80 mg to about 480 mg DMF, about 100 mg to about 480 mg
DMF, about 120 mg to about 480 mg DMF, about 140 mg to about 480 mg DMF, about 160 mg
to about 480 mg DMF, about 180 mg to about 480 mg DMF, about 200 mg to about 480 mg
DMF, about 220 mg to about 480 mg DMF, about 240 mg to about 480 mg DMF, about 300 mg
to about 480 mg DMF, about 360 mg to about 480 mg DMF, about 400 mg to about 480 mg
DMF, about 450 mg to about 500 mg DMF, about 480 mg to about 500 mg DMF, about 80 to
about 400 mg DMF, about 100 to about 300 mg DMF, about 120 to about 180 mg DMF, or
about 140 mg to about 160 mg DMF.
The dosage form can contain, but is not limited to, a total amount of DMF of
about 60 mg DMF, about 80 mg DMF, about 100 mg DMF, about 120 mg DMF, about 140 mg
DMF, about 160 mg DMF, about 180 mg DMF, about 200 mg DMF, about 220 mg DMF, about
240 mg DMF, about 260 mg DMF, about 280 mg DMF, about 300 mg DMF, about 320 mg
DMF, about 340 mg DMF, about 360 mg DMF, about 380 mg DMF, about 400 mg DMF, about
420 mg DMF, about 450 mg DMF, about 480 mg DMF, about 500 mg DMF, about 520 mg
DMF, about 540 mg DMF, about 560 mg DMF, about 580 mg DMF, about 600 mg DMF, about
620 mg DMF, about 640 mg DMF, about 660 mg DMF, about 680 mg DMF, about 700 mg
DMF, about 720 mg DMF, about 740 mg DMF, about 760 mg DMF, about 780 mg DMF or
about 800 mg DMF.
In some embodiments, DMF is the only active ingredient in the pharmaceutical
composition. In one embodiment, the pharmaceutical composition consists essentially of DMF.
For the treatment of multiple sclerosis (e.g., relapsing forms of multiple sclerosis
such as RR—MS), the dosage form administered to the t can be a capsule with microtablets
containing DMF as the only active ingredient or microtablets consisting essentially of DMF,
wherein the ive amount is about 480 mg DMF per day, and the subjects can receive the
effective amount, z'.e., 240 mg DMF BID, in the form of two capsules a day, to be taken orally.
For the treatment of le sclerosis (e. g., relapsing forms of le sclerosis such as RR-
MS), the dosage form administered to the subject can be a capsule with microtablets containing
DMF as the only active ingredient or microtablets consisting essentially of DMF, wherein the
effective amount is about 720 mg DMF per day, and the subjects can receive the effective
amount, z'.e., 240 mg DMF TID, in the form of three capsules a day, to be taken orally. In one
embodiment, the therapeutically effective amount is 240 mg twice daily.
] In a specific embodiment of the methods bed herein, the fumarate is DMF
and the dose of DMF is 120 mg DMF BID stered orally for the first 7 days. In certain
embodiments, the dose is sed to the maintenance dose of 240 mg DMF BID (z'.e., 480 mg
DMF per day) administered orally. In another embodiment, the dose is increased to 240 mg
DMF TID (2'.e., 720 mg DMF per day) administered orally. In one embodiment, the
administering is of 120 mg twice daily for 7 days, followed by 240 mg twice daily as a
maintenance dose.
In a specific embodiment, the filmarate is DMF, and the dose ofDMF is 120 mg
DMF BID administered orally for at least 7 days, followed by a maintenance dose of 240 mg
DMF BID administered orally.
] In a specific embodiment, the fiamarate is DMF, and the dose ofDMF is 240 mg
DMF BID administered orally.
DMF is known to cause flushing and gastrointestinal (GI) side s in certain
subjects. While the side effects generally subside soon after subjects start on the treatment, in a
specific embodiment, the ng dose is 120 mg DMF BID orally for the first 7 days. The dose
can be increased to 240 mg DMF BID (i.e., 480 mg DMF per day). In other embodiments, the
dose can be increased to 240 mg DMF TID (i.e., 720 mg DMF per day). In certain ments,
the filmarate is administered with food. In other embodiments, the fumarate is administered
without food. For those subjects who experience G1 or flushing side effects, administering a
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fumarate, for example, DMF, with food improves tolerability. In one embodiment,
stering a fumarate, such as DMF, with food s the incidence of flushing.
In a specific embodiment, a NSAID (e. g., aspirin) is administered concurrently,
before, and/or after administration of the fumarate (e.g., DMF). In a healthy volunteer study,
administration of 325 mg non-enteric coated aspirin 30 minutes prior to DMF dosing is found to
reduce the occurrence and severity of flushing in the participating subjects. Some subjects who
experience flushing with gastrointestinal side s may reduce the dose to 120 mg DMF BID
arily. Within a month, the effective dose of 240 mg DMF BID or 240 mg DMF TID
should be resumed.
In one embodiment, subjects administered a dosage form described above may
take one or more non-steroidal anti-inflammatory drugs (e.g., aspirin) before (for example, 10
minutes to an hour, e.g., 30 minutes before) taking the dosage form described above. In one
embodiment, the subject administered the dosage form takes the one or more non-steroidal anti-
inflammatory drugs (e. g., aspirin) to reduce g. In another embodiment, the one or more
non-steroidal nflammatory drugs is selected from a group consisting of aspirin, ibuprofen,
en, ketoprofen, xib, and combinations thereof The one or more non-steroidal anti-
inflammatory drugs can be administered in an amount of about 50 mg to about 500 mg before
taking the dosage form described above. In one embodiment, a subject takes 325 mg aspirin
before taking each dosage form described above.
In some embodiments, subjects orally administered one or more non-steroidal
anti-inflammatory drugs (e.g., aspirin) before taking the dosage form described above exhibit the
same pharmacokinetic properties (e. g., Cmax and AUC) as subjects orally administered the dosage
form described above t administering one or more non-steroidal anti-inflammatory drugs
(e.g., aspirin).
In one embodiment, subjects with le sclerosis are administered a capsule
containing 240 mg DMF, twice daily for a total daily dose of 480 mg, wherein the capsule
contains multiple microtablets comprising about 43% w/w to about 95% w/w (e.g., from about
50% to about 80% w/w) DMF, by weight of the microtablets without any coatings. In another
embodiment, subjects having multiple sclerosis are administered a capsule containing 240 mg
DMF, thrice daily for a total daily dose of 720 mg, wherein the capsule contains multiple
microtablets comprising about 43% w/w to about 95% w/w (e. g., from about 50% to about 80%
w/w) DMF, by weight of the microtablets t any coatings. In one embodiment, the
microtablets are first coated with a seal coat and then coated with an c coat. In one
embodiment, the subjects stered the capsular dosage form exhibit one or more of the
pharmacokinetic parameters described above.
.4 Progressive Multifocal Leukoencephalopathy [PML]
Progressive ocal leukoencephalopathy (PML) is an opportunistic brain
infection caused by the JC virus (JCV). PML occurs ily in immunocompromised
individuals and in patients receiving certain immunomodulatory therapies, including natalizumab.
PML is hypothesized to be the result of a complex ction between host and viral factors,
leading to reactivation and mutation of latent archetype JCV to a neurotrophic form which can
infect oligodendrocytes in the central nervous system.
In a specific embodiment, the invention provides for monitoring patients and
withholding treatment with a filmarate described herein, such as dimethyl fumarate (e.g.,
TECFIDERA®), at the first sign or symptom suggestive of PML, and optionally performing an
appropriate diagnostic evaluation.
.4.1 Monitoring a sign or symptom suggestive of PML
In specific embodiments, the invention provides for monitoring a MS patient that
is being treated with a fumarate for the first sign or symptom suggestive of PML. l
symptoms associated with PML are diverse and progress over days to weeks. Sign or symptoms
suggestive of PML include, but are not limited to the following typical symptoms: progressive
weakness on one side of the body, clumsiness of limbs, bance of vision, and changes in
thinking, memory, and orientation leading to confilsion and personality s. Mental
function, speech, and movement may also be affected. Additional symptoms may include ataxia,
loss of cognitive function, visual loss, changes in balance and coordination, and loss of sensation.
The progression of deficits usually leads to death or severe disability over weeks or months.
] Unlike le sclerosis, in PML involvement of the spinal cord or optic nerves
rarely occurs. d, about one-third of patients have visual field loss or cortical blindness,
while another third will show altered mentation or or changes (Dworkin et al., Curr. Clin.
Top. Infect. Dis., 2002, -195). Also unlike le sclerosis, hemiparesis is a common
symptom. These symptoms are typically sub-acute at onset, and slowly progress. Often, ts
and their families are the first to notice the onset of PML through s in the ability to
perform routine activities of daily liVing, even before changes on neurological examination (see
WC 2007/100770 at paragraph [094]).
In certain ments, a patient with multiple sclerosis who is being treated
with a fumarate is monitored for a sign or m suggestive of PML in the patient.
In certain embodiments, the treatment with the fumarate is withheld from the
patient at the first sign or symptom suggestive of PML in the patient.
] In one embodiment, the methods provided herein further comprise performing a
diagnostic evaluation for PML in the t at the first sign or symptom suggestive of PML in
the patient.
.4.2 Performing diagnostic evaluation for PML
In specific embodiments, the invention provides performing a stic
evaluation for PML in the patient at the first sign or symptom tive of PML in the patient.
The diagnostic evaluation can be by any method known in the art, including but not limited to
magnetic resonance g (MRI), detection of JC Viral DNA in the cerebrospinal fluid (CSF),
ion of consistent white matter lesions by MRI, assessing the progressive course of disease,
or a combination of any of the foregoing.
In a specific embodiment, PML is diagnosed based on a combination of (1)
detection of JC Viral DNA in CSF; (2) consistent white matter lesions shown by MRI, and
optionally (3) progressive course of the disease.
As described in WC 2007/100770, the pathology ofPML is distinctive, involving
foci of demyelination of varying size from nt lesions to areas of several centimeters.
Lesions generally appear in the cerebral hemispheres, less often in the cerebellum and brain stem
and rarely in the spinal cord, although they can appear elsewhere. The oligodendrocytes in the
peripheral zone surrounding an area of demyelination appear grossly abnormal. The nuclei of
these abnormal oligodendrocytes contain many IC Virions.
] Certain clinical features of PML help distinguish it from the demyelination
associated with multiple sis.
.4.2.1. Magnetic Resonance Imaging [MRI]
Magnetic Resonance Imaging (MRI) can be used to se PML. As shown in
Table 1, there are features of PML lesions that help differentiate them from other etiologies (Post
et al., Am. J. Neuroradiol., 1999, 20(10):1896-1906; Yousry et al., N. Engl. J. Med., 2006,
354(9):924-933; Berger et al., Ann. Neural., 1998, 44(3):341-349; Hoffrnann et al., J. Neural.
Neurosurg. Psychiatry, 2003, 74(8): 1 142-1 144; Langer-Gould et al., N Engl. J. Med., 2005,
353(4):375-381).
In a specific embodiment, the diagnostic evaluation for PML in a patient involves
detection of consistent white matter lesions by MRI.
Table 1. ential Dia nosis of multi le sclerosis and PML as taken from WO
2007/100770 at pp 29-301
le Sclerosis PML
Location ofnew Mostly focal, may affect entire e, mainly sub-cortical, rarely
lesions brain and spinal cord, in white and periventricular, almost exclusively
possibly gray matter; in white matter, although occasional
extension to gray matter seen;
ior fossa lesions rarely seen
Posterior fossa frequently involved
(cerebellum)
Borders Sharp edges, shapes mostly round Ill-defined edges, infiltrating,
or finger-like (especially irregular in shape, confined to white
periventricular), nt with matter, g gray matter, pushing
other single lesions, U-fibers may against , U-f1bers destroyed
be involved
Mode of extension Focal, enlarging of lesions within Diffuse, asymmetrical, extending
days/weeks, later decreasing in size homogeneously, no confluence with
within months other lesions, defined to white
matter tracks, sparing cortex,
continuous progression
Mass effect Acute lesions may show some mass No mass effect even in large s
effect (but process is slightly pushing
against cortex)
T2-weighted Acute lesions: ntense center, Diffuse hyperintense, slightly
sequence isointense ring, discrete increased intensity of newly
hyperintensity outside ring involved areas compared to old
structure; areas, little lar signal intensity
of lesions
Sub-acute/chronic lesions:
hyperintense no ring structure
T 1 -weighted Acute lesions: densely hypointense Slightly hypointense from the onset,
sequence (large lesion) or isointense (small signal intensity decreasing over
lesion), increasing signal intensity time and along the affected area, no
over time in 80% decreasing signal reversion of signal intensity
ity (axonal loss) in about 20%
Flair sequence Hyperintense, sharply delineated Hyperintensity more obvious, true
ion of abnormality more
clearly visible than in T2-weighted
images
Enhancement Acute lesions: dense homogeneous Usually no enhancement even in
enhancement, sharp edges large lesions, in HIV+ patients some
eral enhancement possible,
Sub-acute lesions: ring- especially under y
enhancement
Chronic lesions: no ement
Atrophy Focal atrophy possible due to focal No focal atrophy since extending
White matter degeneration, no pathological process is slightly
progression pushing against cortex (extension of
tissue)
.4.2.2. Histological and gical Examination
In a specific embodiment, the diagnostic evaluation comprises a test for the
presence of JC viral DNA in the CSF of the patient. PCR analysis of the ospinal fluid
(CSF) for JC viral DNA is a highly sensitive and specific test for the diagnosis of PML. The
city of this test approaches 100%, with a sensitivity ranging from 60% to 90% (Henson et
al., Neurology, 1991, :1967-1971; Gibson et al., J. Med. Virol., 1993, 39(4):278-281;
Weber et al., AIDS, 1994, 8(1):49-57; Weber et al., J. . Dis., 1994, 169(5):1138-1141;
Vago et al., J. Acquir. Imm. Def1c. Syndr. Hum. Retrovirol., 1996, 12(2):139-146). In cases with
a high clinical suspicion of PML and negative CSF results, repeat testing often leads to detection
of JC viral DNA. Thus, PCR is of the CSF for JC viral DNA is a useful method for
diagnosing PML.
In one embodiment, the diagnostic evaluation r comprises a test for the
presence in the patient of antibodies to JCV. In one aspect, the diagnostic evaluation for PML in
2015/060850
the patient es evaluating the level of anti-JCV antibody in a biological sample from the
patient. In general, antibodies to JCV in the blood of ts treated with a fumarate may be
indicative of risk of future PML, but are not themselves diagnostic of PML.
In one aspect, the diagnostic evaluation for PML in the patient involves
evaluating a patient’s risk of developing PML by a method comprising a test for the presence in
the patient of antibodies to JCV. In one aspect, the diagnostic evaluation for PML in the patient
es evaluating a patient’s risk of developing PML by a method comprising a test evaluating
the level of anti-JCV antibody in a biological sample from the patient.
A wide variety of serological tests are available to detect JCV, e. g.,
complementfixation (CFT), haemagglutination-inhibition (HA1), -linked immunoassay
(EIA), radioimmunoassay (RIA), particle agglutination, immunofluorescence (IF), single radial
hemolysis, and Western blot. The sensitivity and specificity varies y between different
techniques. Most techniques will detect all classes of antibody, whereas some assays e. g., RIA,
EIA, and IF can be designed to detect one specific class, for example, IgM, IgG, or IgA.
In n embodiments, the patient is tested for JCV in the patient’s urine, blood,
and/or cerebrospinal fluid (CSF). In a specific embodiment, the testing ses ly
removing samples of the patient's blood, measuring the amount of IgG antibodies to JCV in the
samples, and comparing the amount of the antibodies in the samples over time. In other specific
embodiments, the testing includes measuring the amount of IgM antibodies to JCV in the
samples, and comparing the amount of IgM and IgG antibodies in the samples.
In certain embodiments, the testing detects seroconversion and/or an increasing
titer of JCV in the patient’s urine and/or blood, and fiarther includes removing a sample of the
t’s cerebrospinal fluid when the comparison of the serial urine and/or blood samples detect
seroconversion and/or an increasing titer of JCV; and g the cerebrospinal fluid for the
presence of JCV antibodies.
In one embodiment, the diagnostic evaluation comprises testing for clinical and/or
ogic symptoms of PML. In certain embodiments, the testing for clinical symptoms
comprises g for new or worsening neurological symptoms. In specific embodiments, the
neurological symptoms comprise one or more of central blindness, mental confilsion, personality
change, and dyskinesia. In other embodiments, the testing for ogic symptoms ofPML
comprises ming a Gd-enhanced magnetic resonance imaging scan.
In one embodiment, testing tests for JCV in the patient's urine, blood, and/or
cerebrospinal fluid. In a specific embodiment, the monitoring comprises serially removing
samples of the patient’s blood, measuring the amount of IgG antibodies to JCV in the samples,
and comparing the amount of the antibodies in the samples over time. In some embodiments, the
testing further comprises measuring the amount ofIgM antibodies to JCV in the samples, and
comparing the amount of the IgM and IgG antibodies in the samples. In one ment, the
monitoring s seroconversion and/or an increasing titer of JCV in the patient’s urine and/or
blood by removing a sample of the patient’s ospinal fluid when the comparison of the
serial urine and/or blood samples detect seroconversion and/or an sing titer of JCV; and
testing the cerebrospinal fluid for the presence of JCV.
In one , the diagnostic evaluation for PML in the patient involves
evaluating a patient’s risk of developing PML by a method comprising determining a JCV
antibody titer in a biological sample from the patient, wherein the patient has a negative prior
immunosuppressant exposure classification; wherein if the titer is determined to be above a pre-
determined level, e.g., above an index level of 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, the
patient is determined to be at a higher risk of developing PML, and wherein if the titer is
determined to be at or below a pre-determined level, e.g., at or below an index level of 1.5, 1.4,
1.3, 1.2, 1.1, 1.0, 0.9, 0.8, or 0.7, the patient is ined to be at a lower risk of developing
PML.
] In one aspect, the diagnostic evaluation for PML in the patient involves
evaluating a patient’s risk of developing PML by a method comprising ining a JCV
antibody titer in two or more biological samples obtained from the patient over a period of time
(e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or more
months); wherein if the titer is determined to be above zero, but at or below a termined
level, e.g., at or below an index level of 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, or 0.7, in the two or
more samples, the patient is determined to be at a lower risk of developing PML, and wherein if
the titer is determined to be above a pre-determined level, e.g., above an index level of 0.7, 0.8,
0.9. 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, in the two or more samples, the patient is determined to be at a
higher risk of developing PML.
In one aspect, the stic evaluation for PML in the t involves
determining a patient’s risk of ping PML by a method comprising evaluating the level of
anti-JCV antibody in a biological . The method comprises one or more or all of the
following steps (see WC 2012/166971):
(a) forming a first reaction mixture comprising a first aliquot of sample and a substrate on
which is disposed HPVLP (Highly d Virus-Like Particle consisting predominantly of the
JCV major capsid protein VPl);
(b) detecting the level of anti-JCV antibody bound to said substrate on which is disposed
HPVLP, e.g., by detecting a labeled detection reagent, e.g., an enzyme labeled anti-IgG antibody,
bound to anti-JCV antibody bound to said substrate; thereby evaluating the level of anti-JCV
antibody in a sample (the method can comprise classifying, or assigning, to the sample, a value
tive of the level of anti-JCV antibody, which can be used in embodiments, to ine
whether to proceed to an onal step of the method, e.g., step (c) below); and
(c) forming a second reaction mixture containing a second t of sample and
solution-phase HPVLP, and detecting the level of unbound anti-JCV antibody in said second
reaction mixture, such as by detecting anti-JCV antibody capable of binding with a substrate on
which is disposed HPVLP (the method can comprise classifying, or assigning, to the sample, a
value indicative of the degree to which incubation with the soluble-phase HPVLP reduces the
level of unbound anti-JCV antibody in the second reaction mixture, which value can be referred
to as inhibition, % tion, or the like), thereby evaluating the level of CV antibody in
the .
In an embodiment, the method further comprises (see WC 2012/166971): (d)
forming a third reaction mixture containing a third aliquot under conditions where anti-JCV
antibodies in the sample are not bound by HPVLP or other antigen, and detecting the level of
anti-JCV dy in the third reaction mixture, such as by detecting anti-JCV dy capable
of binding with a substrate on which is disposed HPVLP. The inhibition or % inhibition can be
ated as a function of the degree that incubation with soluble-phase HPVLP (step (c))
reduces the amount of unbound anti-JCV antibody, as compared to the result in step (d).
In one aspect, the diagnostic evaluation for PML in the patient involves a method
of evaluating a patient’s risk of developing PML, the method comprising:
determining a JC Virus (JCV) antibody titer expressed as nOD, index or other unit, or other
teristics such as affinity or avidity expressed as percent inhibition in the anti-JCV
antibody confirmation assay in a biological sample from the patient, and comparing the titer
or/and percent inhibition, or function of both values, to a pre-determined level.
In one embodiment, a method of ting a patient’s risk of developing PML
further includes testing the serum or plasma of the sample for both IgG and IgM antibodies to
JCV and initiating treatment with a filmarate if the serum or plasma is negative for both IgG and
IgM antibodies to JCV.
.4.3 Treating PML
The cellular receptor for JCV has been reported to be the serotonin 5-HT2A
receptor (Elphick et al., Science, 2004, 306(5700):1380-1383). It has also been suggested that
the 5HT2 antagonist mirtazapine may be useful in the prophylaxis or treatment of PML (Verma
et al., J Infect Dis., 2007, 196(5):709-711).
cyloxypropyl-Cidofovir (CMXOOl) has also been studied as a treatment
option for JCV (Gosert et al., Antimicrob. Agents her., 2011, 2129-2136) e
of its ability to suppress JVC by ting viral DNA replication.
Mefloquine has been reported to block JCV replication without significant
toxicity, and at concentrations achievable in the central s system. Although cases of
successful PML treatment with mefloquine in HIV and non-HIV infected patients have been
reported (e.g., Young et al., Ann. Acad. Med. Singap., 2012, 41(12):620-624), unsuccessful
cases of mefloquine use for treatment of PML have also been reported (Clifford et al., J.
Neurovirol., 2013, 19:351-358; Tyler et al., J. Neurovirol., 2013, 19(4):311-313).
In accordance with the methods provided herein, when the diagnostic tion
for PML indicates PML in the patient or an elevated risk of the patient for developing PML, a
method of the invention can further comprise administering a therapeutic to the patient for the
treatment or prevention of PML. Such therapeutic can be any therapeutic known in the art.
Currently, there is no established drug treatment for PML. However, various tions have
been tested, including acyclovir, idoxuridine, vidarabine, amantadine, adenine arabinoside,
cytosine arabinoside (cytarabine, also known as ARA-C), cidofovir, interferon a, interleukin-2
(IL-2), zidovudine, camptothecin, topotecan, mefloquine, and mirtazapine nik, Curr. Opt.
., 2004, 17(3):365-370; n et al., Curr. Clin. Top. Infect. Dis., 2002, 22:181-195;
Seth et al., J. Neurovirol., 2003, 9(2):236-246; Collazos, CNS Drugs, 2003, 17(12):869-887;
Mamidi et al., J. Neurovirol., 2002, 8(3): 7; Przepiorka et al., Bone Marrow Transplant,
1997, 20(11):983-987; Redington et al., Arch. Neural., 2002, 59(5):712-718; Padgett et al., Prog.
Clin. Biol. Res., 1983, 105:107-117). Thus, in a specific embodiment, such a eutic can be
HAART, acyclovir, idoxuridine, vidarabine, amantadine, adenine arabinoside, ne
arabinoside (cytarabine, also known as ARA-C), cidofovir, interferon a, interleukin-2 (IL-2),
zidovudine, camptothecin, topotecan, chlorpromazine, clozapine. zisprasidone, risperidone,
olanzapine, hexadecyloxypropyl-Cidofovir (CMX001), mefloquine, or mirtazapine.
In one embodiment, the methods provided herein e, when a stic
evaluation indicates the presence of PML, providing at least one treatment of PML selected from
intravenous immunoglobulin therapy, plasmapheresis, and antiviral therapy. In certain
embodiments, the antiviral therapy comprises the administration of at least one therapeutically
ive dose of an ral agent selected from cytosine arabinoside (cytarabine), cidofovir,
and a serotonin antagonist.
] Provided herein is a method of using a fumarate described herein to treat a patient
with multiple sclerosis by removing a sample of blood from the patient; testing the serum or
plasma of the sample for the ce of IgG antibodies to JCV; initiating treatment of the
patient with the filmarate in the event the sample is negative for IgG antibodies to JCV;
monitoring the patient for signs or symptoms of ssive multifocal leukoencephalopathy;
and discontinuing the administration of the fumarate in the presence of signs or ms of
PML.
] In one aspect, an entity, e.g., a healthcare provider, acquires information resulting
from an anti-JCV antibody assay described herein, and responsive to the information,
administers a ent described herein to the patient.
In another aspect, a JCV assay described herein is performed on a patient, and
then the patient is d based on the results of the assay. Thus, for example, if the assay is
negative for JCV, treatment with a fumarate continues or is initiated, or re-initiated (if filmarate
has been withheld at the first sign or symptom of PML)
.5 Complete Blood Count
In specific embodiments, the invention provides for obtaining a complete blood
count (CBC) including lymphocyte count after 6 months of ed administering of a
pharmaceutical composition described herein (e.g., TECFIDERA®) to a MS patient, and every 6
to 12 months thereafter. In one ment, the administering of the ceutical
composition (e.g., TECFIDERA®) is interrupted when the patient has a lymphocyte count less
than 0.5 x 109/L persisting for more than six months. In a specific embodiment, the invention
es for measuring of lymphocyte count in the patient until lymphopenia is resolved in the
patient.
A CBC, also known as a complete blood cell count, full blood count (FBC), or
full blood exam (FBE), is a blood test. A CBC provides information about the three general
types of cells circulating in the bloodstream: white blood cells (leukocytes), red blood cells
(erythrocytes), and platelets (thrombocytes). A CBC measures red blood cells, white blood cells,
hemoglobin, hematocrit, and platelets. Evaluation of white blood cells in a CBC panel may
include a white blood cell count, which is the total number of white blood cells in a person's
sample of blood, and may also include white blood cell differential, which identifies and counts
the various types of white blood cells such as lymphocytes, monocytes, neutrophils, eosinophils,
and basophils. tion of red blood cells in a CBC panel may include a total red blood cell
count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin
(MCH), mean corpuscular obin concentration (MCHC), red blood cell distribution width
(RDW), and reticulocyte count. Platelet evaluation in a CBC test may include platelet count,
mean platelet volume (MPV), and platelet distribution width (PDW). Abnormally high or low
counts of a particular type of cell in the bloodstream may indicate the presence of an underlying
l condition.
A CBC can be conducted by using methods well known in the art, which may
comprise collecting the blood sample through venipuncture, drawing the blood into a test tube
containing an anticoagulant, and counting the blood cells using manual techniques or an
ted analyzer (see, e.g., Buttarello and Plebani, Am. J. Clin. Pathol., 2008, :lO4-
1 16).
In controlled and uncontrolled clinical trials of TECFIDERA®, 2% of patients
experienced lymphocyte counts less than 0.5 x 109/L for at least six months. In these patients,
the majority of lymphocyte counts remained less than 0.5x109/L with continued therapy.
.6 t Populations
As used , the terms “patient” and “subject” can be used interchangeably.
The fumarate as described herein is administered to a subject in need thereof, a subject having
MS. In a specific embodiment, said subject has been diagnosed as having MS by a medical
practitioner.
In some embodiments, the form of the multiple sclerosis is relapsing remitting,
secondary progressive, primary progressive, or chronic progressive multiple sclerosis. In one
embodiment, the t with multiple sclerosis is a patient with a relapsing form of MS. In a
specific embodiment, the patient has relapse-remitting MS (RR-MS). In another specific
embodiment, the patient has ary-progressive MS (SP-MS). In yet another specific
embodiment, the patient has ssive-relapsing MS (PR-MS).
] In one embodiment, the patient is not pregnant. In another embodiment, the
patient is not a nursing mother.
In one embodiment, the patient has no hypersensitivity to a fumarate, such as
dimethyl fumarate, administered in the methods described herein. In a further embodiment, the
patient has no hypersensitivity to the te, such as dimethyl te, or does not know
about his hypersensitivity to the fumarate.
In one embodiment, the patient is not treated aneously with both one or
more fumarates (e.g., dimethyl fumarate) and any suppressive or antineoplastic
medication. In n embodiments, the patient is not treated simultaneously with a fumarate
(e. g., dimethyl fumarate) and any immunosuppressive or immunomodulatory medications or
zumab. In certain embodiments, the patient is not treated simultaneously with a fumarate
described herein (e.g., dimethyl fumarate) and any medications carrying a known risk of causing
progressive multifocal leukoencephalopathy (PML).
] In one embodiment, the patient has never been treated with a fumarate, e.g.,
dimethyl fumarate, prior to cement of therapy in accordance with the methods disclosed
herein. In another embodiment, the patient has not been treated with a fumarate, e.g., dimethyl
fumarate, l, 2, 3, 4, 6, 8, 10, or 12 months or 1, 2, 3, 5, 10, 20, 30, 40, or 50 years, prior to
commencement of therapy in accordance with the methods disclosed herein.
In one embodiment, the patient has never been d with any
immunosuppressive or antineoplastic medication prior to commencement of therapy in
accordance with the methods disclosed . In a further embodiment, the patient has not been
d with any immunosuppressive or antineoplastic medication 1, 2, 3, 4, 6, 8, 10, or 12
months or 1, 2, 3, 5, 10, 20, 30, 40, 50 years, prior to commencement of therapy in accordance
with the methods disclosed herein. In another embodiment, the patient has never been d
with any immunosuppressive or modulatory medications or natalizumab prior to
commencement of therapy in accordance with the methods disclosed herein. In yet another
embodiment, the patient has not been treated with any immunosuppressive or
immunomodulatory medications or natalizumab 1, 2, 3, 4, 6, 8, 10, or 12 months or 1, 2, 3, 5, 10,
, 30, 40, or 50 years, prior to commencement of therapy in accordance with the methods
disclosed . In another embodiment, the patient has never been treated with any
medications carrying a known risk of causing PML prior to commencement of therapy in
ance with the methods disclosed herein. In yet another embodiment, the patient has not
been treated with any medications carrying a know risk of causing PML 1, 2, 3, 4, 6, 8, 10, or 12
months or 1, 2, 3, 5, 10, 20, 30, 40, or 50 years, prior to cement of therapy in accordance
with the s disclosed herein.
In one embodiment, the immunosuppressive or antineoplastic medication is
selected from one or more of: chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide,
dacarbazine, procarbazine, temozolomide, hexamethylmelamine, bicine, daunarubicine,
idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine,
cytarabine, busulfan, amonifide, S-fluorouracil, topotecan, mustargen, bleomycin, lomustine,
semustine, cin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate,
trimetrexate, raltitrexid, flurorodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-
thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D,
vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, edroxyprogesterone, megestrol,
raloxifene, letrozole, anastrzole, flutamide, bicalutamide, ic acids, arsenic trioxide,
rituximab, CAMP ATH-l, rg, enolic acid, tacrolimus, glucocorticoids,
sulfasalazine, glatiramer, fumarate, laquinimod, FTY -720, interferon tau, umab,
infliximab, ILlO, anti-IL2 receptor antibody, anti-IL-12 antibody, L6 receptor antibody,
CDP-571, umab, entaneracept, mide, anti-interferon gamma antibody, abatacept,
fludarabine, cyclophosphamide, oprine, cyclosporine, intravenous immunoglobulin, 5-
ASA (mesalamine), and a B-interferon.
In one embodiment, the immunosuppressive or immunomodulatory medication is
selected from one or more of: calcinerurin inhibitors, corticosteroids, cytostatics, nitrosoureas,
n synthesis inhibitors, dactinomycin, anthracyclines, mithramycin, polyclonal ntibodies
such as atgum and thymoglobulin, monoclonal antibodies such as muromonab-CD3, and
basiliximab, ciclosporin, sirolimus, rapamycin, y—interferon, opioids, TNF binding proteins,
TNF-0L binding proteins, etanercept, mycophenolate, fingolimode, and myriocin.
In one embodiment, the patient being treated in accordance with the methods
described herein has no identified systemic medical condition resulting in a compromised
immune system fianction.
In one embodiment, the patient has been free of an immunosuppressant or
modulatory therapy for the patient’s lifetime, or since diagnosis with MS, for example a
relapsing form of MS.
6. EXAMPLES
6.1 Example 1: Compositions of Dimethyl te
] A pharmaceutical composition comprising dimethyl fumarate was prepared as 2
millimeter enteric coated microtablets in a size 0 hard gelatin capsule. Each capsule contained
either 120 mg dimethyl fumarate or 240 mg dimethyl te.
6.1.1 Uncoated core microtablet formulations
Dimethyl filmarate (DMF), croscarmellose sodium, talc, and colloidal silica
anhydrous were mixed together to form a blend ing to the amounts as bed in Table 2.
The blend was then passed through a screen (e.g., screen with 800 micron aperture) and
microcrystalline cellulose (PROSOLV SMCC® HD90) was added to the blend and mixed.
Magnesium stearate was added to the blend and the blend was remixed. The resulting blend was
then compressed on a le rotary tablet press equipped with 16 multi-tip tooling having 2 mm
round concave tips.
Table 2 below provides the weight tages of ingredients t in two types
of microtablets, 120 mg DMF and 240 mg DMF, respectively, made using the method described
above. Microtablets were coated as described in Section 6.1.2 and then loaded into capsules. A
size 0 capsule containing microtablets made with blend A contains about 120 mg of DMF,
whereas the same size capsule ning ablets made with blend B contains about 240 mg
of DMF.
Table 2
Blend A Blend B, % w/w
Ingredients Composition, % Per ablet Composition, % Per microtablet
w/w content (mg) w/w content (mg)
DMF 42 3.1 65 5.2
sod1um
Prosolv
SMCC®
HD90
Avicel PH200 3.2
Magnesium
0.12
Stearate
Talc 0.49
Silica colloidal
0.86 0.067 0.6 0.048
anh drous
Total 100 100 8
6.1.2 Microtablet coating formulations
The ablets were coated with two coatings; a seal g, followed by an
enteric coating, using the seal coating formulation and enteric coating formulation of Formula A
and Formula B as described in Table 3. The seal coating formulation was a t-based
formulation which used isopropyl l as a solvent, and the enteric coating formulation was
based on methyl acrylic acid copolymer dispersion and provided effective enteric protection.
The enteric coating formulation contained methacrylic acid copolymer dispersion and tale in
addition to an antifoaming agent (simethicone). The coated microtablets were then loaded into
size 0 hard gelatin capsules.
Table 3
Coating Formula A, Coating Formula B,
Ingredients
% w/w 0/ w/w0
Seal Coating Formulation
rylic acid
copolymer, 5 1 .7
Type A2
Triethyl citrate 1.3
lsopropyl alcohol1 47.1
Enteric Coating Formulation
rylic acid
copolymer 36.9 44.3
dis oersion2
Triethyl citrate 2.6
Talc, micronized 5.5
Simethicone
(3O % emulsion) '
Purified water 1 47.3
1Ingredients are removed during the process
2Methacrylic acid copolymer Type A and methacrylic acid copolymer dispersion are anionic
copolymers comprising methacrylic acid and methacrylate and are the primary nces in various
EUDRAGIT® formulations, which mediate pH-dependent e of compounds.
6.2 Example 2: Formation of es Containing Microtablets
Dimethyl filmarate, croscarmellose sodium, talcum and colloidal n
anhydrous are mixed together to form a blend according to the amounts described in Table 4
below. The blend is passed through a screen. A suitable grade of microcrystalline ose, for
example, PROSOLV SMCC® 90 or PROSOLV SMCC® HD90 is added to the blend and mixed.
Magnesium stearate is added to the blend and the blend is remixed.
] The blend is then compressed on a suitable rotary tablet press equipped with
multi-tip tooling (e.g., a 16 multi-tip tooling) having 2 mm round concave tips. The resulting 2
mm sized microtablets are coated with a solution of methacrylic ethyl methacrylate
copolymer and triethyl citrate in isopropanol (see amounts in Table 4 below). The coated
microtablets are then coated with a second layer of coating consisting of methacrylic acid-
ethylacrylate copolymer, polysorbate 80, sodium lauryl sulfate, yl citrate, simethicone, and
talcum micronized suspended in water (see amounts in Table 4 below).
The desired amount of coated microtablets are encapsulated in a two piece hard
n capsule using a capsule machine. For example, coated microtablets are encapsulated in a
capsule such that the amount of dimethyl filmarate is about 240 mg per capsule.
In Table 4 below, % w/w is based on the total weight of the coated microtablet
(e.g., in this table, % w/w includes the weight contributions of the coatings).
Table 4
In ' ts Net ca n sule content, % w/w of the ca n sule com I onents
ExampleNo. l 7 8 9 10
”methyl
43.01 72.30 58.40 54.08 83.60 73.90 39.50 65.00 33.90 42.00
fumarate
meflose 1.26 0.33 3.72 4.17 0.46 0.89 4.43 4.00 4.24 3.00
sod1um
Mlcmcrysmflme
41.82 15.91 17.31 23.57 7.00 9.42 31.31 13.66 37.18 35.79
Cellulose
1.05 0.25 0.69 0.41 0.26 0.63
Stearate
51110300110931
0.22 0.78 0.97 0.43 0.29 0.40 0.73 0-68
anh drous
Methacrylic
acid methyl
acrylate
co ool mer
Methacrylic
acid ethyl
6.23 4.98 9.93 7.72 9.04 9.98
acrylate . . . .
co ool mer
1.61 1.74 2.33 2.12 0.97 1.67
Talc 2.56 2.81 4.32 3.90 2.65 3.06 8.32 5.30 9.46 4.12
———---IMI
SOdlumLauryl
0.06 0.06 0.08 0.07 0.05 0.06 0.08 0.06 0.06 0.08
sulfate
6.3 Example 3: Formation of Microtablets
Dimethyl filmarate, croscarmellose sodium, talcum and dal silicon
anhydrous were mixed together to form blends l, 2, 4, 5, and 6 according to the amounts
described in Table 5 below. Each blend was passed through a screen. rystalline cellulose
(PROSOLV SMCC® HD90) was added to the blends ing to the amounts in Table 5 and
mixed. Magnesium stearate was then added to each blend and the blend was d. Each
blend was then compressed on a suitable rotary tablet press equipped with 16 multi-tip tooling
having 2 mm round concave tips.
Blends 3, 7, 8, and 9 can be made using the same method as described above.
Table 5
Ingredient Percent w/w Composition of the Core Microtablet
WO 81355
Blend Blend Blend Blend Blend Blend Blend Blend Blend
1 2 3 4 5 6 7
Dimethylfumarate 42.0 42.0 -m 65.0 70.0 85.0 95.0
Croscarmellose sodium
Microcrystalline
Cellulose
Magnesium Stearate 1-7
anh drous
Talc 6. -- 2.0 -- -- -- 1.0 -- --
total 100 100 100 100 100 100 100 100 100
6.4 Exam le 4: Com acts Containin 42% w/w 60% w/w and 70% w/w
Dimeth ate and Control Com acts
Dimethyl fumarate, croscarmellose sodium, and silica colloidal anhydrous were
blended together to form a blend. The blend was passed through a screen. A suitable grade of
microcrystalline cellulose was added to the screened blend and the blend was mixed. A suitable
grade of microcrystalline cellulose, is, for e PROSOLV SMCC® 90, having an average
particle size by laser diffraction of about 60 um and a bulk density ranging from about 0.38 to
about 0.50 g/cm3 . Magnesium stearate was added to the mixed blend and remixing was effected.
The respective blended materials were compressed on a le rotary press (e.g.,
a rotary tablet press) to form compacts (10 mm cylindrical compacts).
Table 6 provides percentages for representative compacts made by this process.
Table 6
Ingredients 70%
Dimethyl fumarate 70
Croscarmellose sodium 5.0
Microcrystalline ose 23
Magnesium Stearate 1.7
Silica colloidal anhydrous 0.9
6.5 Exam le 5: Com ositions Containin 65% w/w 95% w/w and 99.5% w/w
Dimethyl Fumarate
] Four DMF-containing blends were prepared according to the method as described
in Example 4 above with the amounts as described in Table 7 below.
Table 7
Ingredients Composition, % by weight
Blend 93 Blend 97 Blend 104 Blend 108
Dimethyl fumarate
Prosolv SMCC 90
Croscarmellose
Sodium
Silica colloidal,
anhydrous
Magnesium
stearate
Particle size of
dimethyl fumarate
Flodex(mm)
Bulk density(g/ml)
Tapped
density(g/ml)
Compressibility, %
6.6 e 6: cting the Patient
] By way of example, but not tion, instructions in a TECFIDERA® label can
be as follows:
WARNINGS AND PRECAUTIONS
Progressive Multifocal Leukoencep_halop_athy
Monitor patients and withhold ERA® at the first sign or symptom
suggestive of PML and perform an appropriate diagnostic evaluation. Typical symptoms
associated with PML are diverse, progress over days to weeks, and include progressive weakness
on one side of the body or clumsiness of limbs, disturbance of , and changes in thinking,
memory, and orientation g to confusion and personality changes. The progression of
deficits usually leads to death or severe disability over weeks or months.
PATIENT COUNSELLING INFORMATION
Progressive Multifocal Leukoencep_halop_athy
Inform ts that progressive multifocal leukoencephalopathy (PML) has
occurred in a patient who received TECFIDERA®. Instruct the patient of the importance of
contacting their doctor if they develop any symptoms suggestive of PML. Instruct the patient that
l symptoms associated with PML are diverse, progress over days to weeks, and include
progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and
changes in thinking, memory, and orientation leading to confusion and personality s.
Instruct the patient that the progression of deficits usually leads to death or severe disability over
weeks or months.
Instruct patients to continue to look for new signs and symptoms suggestive of
PML for approximately 6 months following discontinuation of TECFIDERA® [see WARNINGS
AND PRECAUTIONS].
6.7 Example 7: Instructing the Patient — Lymphopenia and Lymphocyte Counts
] By way of example, but not limitation, instructions in a TECFIDERA® label can
be as follows:
WARNINGS AND PRECAUTIONS
Lymphopenia
Before initiating treatment with TECFIDERA®, a CBC including lymphocyte
count should be obtained. A CBC including lymphocyte count should also be obtained after 6
months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider
interruption of TECFIDERA® in patients with lymphocyte counts less than 0.5 x 109/L persisting
for more than six months. Given the potential for delay in cyte recovery after
tinuation of TECFIDERA®, consider ing lymphocyte counts until lymphopenia is
resolved. Withholding treatment should be considered in patients with s ions until
the infection(s) is ed. Decisions about whether or not to restart TECFIDERA® should be
individualized based on clinical circumstances.
PATIENT COUNSELLING INFORMATION
Lymphocfle Counts
Inform ts that TECFIDERA® may decrease cyte counts. A blood
test should be obtained before they start therapy. Blood tests are also ended after 6
months of treatment, every 6 to 12 months thereafter, and as clinically indicated.
6.8 Example 8: Characterization of absolute lymphocyte count profiles in MS
patients treated with delayed-release dimethyl fumarate: considerations for
patient management
Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF,
and as TECFIDERA®) demonstrated robust efficacy on clinical and neuroradiological es
and an acceptable safety profile in relapsing-remitting multiple sclerosis (RRMS) in al
trials including a Phase 2b study, the Phase 3 DEFINE and CONFIRM studies, and the
ENDORSE extension studyl'6
In clinical trials, DMF was associated with flushing and gastrointestinal events as
well as decreased white blood cell (WBC) and absolute lymphocyte counts (ALCs).7
ALC profiles were characterized in eated MS patients in this study.
ts at r risk for developing severe ged lymphopenia were fied. The study
also evaluated DMF efficacy in patients with and without lymphopenia.
OBJECTIVE
The ive of the analysis was to provide practical considerations for
ment ofDMF (as TECFIDERA®)-treated MS patients by characterizing ALC s
and examining efficacy in patients with and without lymphopenia enrolled in clinical trials
(Phase 2b, DEFINE, CONFIRM, and ENDORSE).
METHODS
Study Design
The Phase 2b study, DEFINE, and CONFIRM were multicenter, randomized,
double-blind, placebo-controlled, parallel-group clinical trials ofDMF as monotherapy for
RRMS.
] The Phase 2b study was 12 months in duration, including a 6-m0nth placebo-
controlled part (Part 1) and a 6-m0nth uncontrolled safety extension part (Part 2). During Part 1,
patients were randomized equally to DMF 120 mg once daily (QD), 120 mg three times daily
(TID), 240 mg TID, or placebo.
DEFINE and CONFIRM were 2 years in duration. ts were ized
equally to DMF 240 mg twice daily (BID), 240 mg TID, or matching placebo.
CONFIRM also included glatiramer acetate (GA) as a reference comparator arm.
ENDORSE is a multicenter, parallel-group, dose-blinded extension of
DEFINE/CONFIRM with up to 8 additional years of follow-up.
Patients who ed 240 mg DMF BID or TID for up to 2 years in the parent
studies remained on the same DMF dosage in ENDORSE.
Patients who received placebo (DEFINE and CONFIRM) or GA (CONFIRM) in
the parent studies were randomized y to 240 mg DMF BID or TID.
Key Inclusion and Exclusion Criteria
] Key inclusion and exclusion criteria for the Phase 2b study, DEFINE, and
CONFIRM are summarized in Table 8.
Table 8. Key inclusion and exclusion criteria
Key inclusion criteria
Ae 18—55 ears
Dia_nosis of RRMS oer ld criteria
EDSS score ofO 5 0
Key exclus10n crlterla
Pro _ress1ve forms of MS or other si; 1f1cant illness
Relapse within 50 days prior to randomization
Corticosteroids within 30 days (Phase 2b) or 50 days (DEFINE, CONFIRM) prior to
randomization
Pre-specif1ed abnormal laboratory parameters including WBC <3.5 x 109/L or eosinophils
>0.7 x 103/uL or >0.7 GI/L
Prior ent with otent immunosu ressant aents or orocedures
Prior treatment with MS therapies within predefined washout periods, ing interferon
beta, within 3 months prior to randomization; GA, within 3 months prior to randomization
(Phase 2b, ) or at any time (CONFIRM); or natalizumab, within 6 months prior to
randomization
Abbreviations: EDSS, Expanded Disability Status Scale; GA, amer acetate; WBC,
white blood cell.
Hematology
] In the Phase 2b study, blood was collected every 4 weeks.
In DEFINE and CONFIRM, blood was collected every 4 weeks for the first 3
months and every 12 weeks thereafter, and within 1 month after study withdrawal or study
completion if not continuing in the extension study.
In ENDORSE, blood was collected at baseline and every 12 weeks thereafter
Hematology included hemoglobin, hematocrit, red blood cell count, WBC count
(with differential), and platelet count.
ALCs were graded per Common ology Criteria for Adverse Events
(CTCAE; Table 9).9
Table 9. CTCAE V4.0 grading for ALCs
CTC rade 0 CTC rade 1 CTC rade 2 CTC rade 3 CTC rade 4
<LLN— <0.8— <0.5—
>LLNa 20.8 x 10% 20.5 x 10% 20.2 x 10% <02 x 10%
ALC = absolute lymphocyte count; CTCAE = Common Terminology Criteria for Adverse
Events
aLower limit of normal (LLN) = 0.91 x 109/L
Statistical Analysis
Data from DEFINE and CONFIRM after subjects switched to alternative MS
ent were excluded.
Data from the 6-month uncontrolled safety extension of the Phase 2b study were
included.
A data cut-off date was used.
RESULTS
Patients
] The safety tion comprised 2513 MS patients, including 1136 treated with
DMF 240 mg BID, 1249 d with DMF 240 mg TID, and 128 treated with lower doses of
DMF (Table 10). Mean (SD) time on study treatment amounted to 3.1 (2.2) years (Table 10).
A total of 2470 patients had any post-baseline ALC.
Table 10. Time on study treatment
Total DMFa’b
(n=2513)
Time on study treatment, mean (SD) yearsc 3.1 (2.2)
Total number of cumulative oatient- ears of eXoosure to stud treatment 7249.96
Patients on stud treatment for at least, 11 %
3 months 2218 88
6 months 2099 84
1 year 1869 (74)
2 ears 1602 64
3 years 1377 (55)
4 ears 1001 40
ears 740 29
6 ears 270 ll
7 ears 34 l
SD=standard deviation
aDMF, delayed-release DMF (also known as gastro-resistant DMF, and as TECFIDERA®)
des DMF 240 mg BID, DMF 240 mg TID, and lower doses ofDMF (120 mg QD or
TID)
0Each year sed 48 weeks.
Mean WBC and ALCs over time with continuing DMF treatment
Mean baseline ALCs were similar across the groups treated with DMF 240 mg
BID, DMF 240 mg TID, or lower doses ofDMF (Figure 1).
Mean ALCs decreased by approximately 30% during the first year of treatment,
then plateaued, ing above the lower limit of normal (LLN; 9lO/mm3) throughout the
observation period (Figure 1).
Incidence of CTC grade 0—4 lymphopenia
For the majority of patients, ALCs were within normal limits at all time points
(CTC grade 0).
The incidence of worst post-baseline CTC grades 0, l, 2, and 3 or 4 is shown in
Table ll.
Table 11. Incidence of CTC grades for worst post-baseline ALCs
Total DMFa’b
n (%) (n=2513)
CTC grade 0 1533161]
CTC grade 1 236 (9)
CTC grade 2 528 [21]
CTC grade 3 or 4C 173 [7]
No post-baseline ALC 43 (2)
CTC = Common Terminology Criteria
aDMF, delayed-release DMF (also known as gastro-resistant DMF, and as ERA®)
bIncludes DMF 240 mg BID, DMF 240 mg TID, and lower doses ofDMF (120 mg QD or
TID)
02 patients (<l%) had CTC grade 4
ALC Profiles
ALCs remained greater than or equal to LLN in 84% of ts during the first 6
months and in 76% of patients during the first year; of these patients, 0.1% and 0%, respectively,
developed ALCs less than 500/mm3 persisting for greater than or equal to 6 months at any time
(Table 12).
Among patients treated for greater than or equal to 6 months (N=2,099), 2.2%
(n=47) experienced ALCs less than 500/mm3 persisting for greater than or equal to 6 months,
ALCs generally remained less than 500/mm3 with continued therapy.
Table 12. Proportion of patients who subsequently developed ALCs <500/mm3 persisting 26
months at any time (up to 7 years after initiating treatment) ing to ALCs within the
first 6 months or first 1 year ofDMF treatment
n/N (%)
All ALCs >LLNb 3/2083 (0.1) 0/1876 (0)
All ALCs >800/mm3 9/2219 (0.4) 0/2050 (0)
AtleastlALC<500/mm310/24(42)31/6161)
ALC = absolute lymphocyte count
bLower limit of normal (LLN) = 0.91 x 109/L
Time course ofmean ALC s in patients with ALCs <500/mm3 persisting 26 months
Mean ALCs in the subgroup of patients with ALCs less than 500/mm3 persisting
for greater than or equal to 6 months showed a faster decline compared with mean counts in the
subgroup of patients without less than 500/mm3 persisting for greater than or equal to 6 months
(Figure 2).
Recovery ofALCs post-discontinuation of DMF treatment
Among the 47 patients with ALCs less than 500 cells/uL for at least 6 months, 9
patients discontinued or completed the study. Of the 9 patients, 8 had ALCs measured at least 1
month after their final dose. All 9 patients showed ses in ALCs ing their final dose
ofDMF (Figure 3). The remaining 38 ts remained on ent at the time of this analysis;
however, a protocol amendment for E went into effect six months later and stipulated
that study treatment must be temporarily withheld ifALC is less than 500/mm3 for more than 6
months. While dosing is withheld, patients will be followed every 4 weeks until the ALC is
greater than or equal to LLN or for 24 weeks after the last dose (whichever is sooner). IfALC
remains to be less than 500/mm3 for 24 weeks after the last dose, then study treatment must be
ently discontinued.
Efficacy in patients with lymphopenia 1<LLN2 versus patients without lymphopenia
Reduction in annualized relapse rate (ARR) at 2 years in patients treated with
DMF 240 mg BID versus placebo was not substantially different in patients with lymphopenia
(at least 1 ALC less than LLN) versus patients without lymphopenia (all ALCs greater than LLN)
in DEFINE and CONFIRM (Figures 4A-4B). In DEFINE (Figure 4A), the rate ratio (95% CI)
for adjusted ARR for DMF versus o was 0.424 (0.294, 0.611) and 0.509 (0.381, 0.681) in
patients with and without treatment-associated penia, respectively. In CONFIRM (Figure
4B), the rate ratio (95% CI) for adjusted ARR for DMF versus placebo was 0.525 (0.365, 0.756)
and 0.599 (0.429, 0.835) in patients with and without treatment-associated lymphopenia,
respectively.
Baseline teristics including EDSS score, age, region, and number of
relapses in the 1 year prior to study entry were similar across the placebo and DMF groups in
patients with or without lymphopenia.
General Safety
As identified in this m analysis of the Phase 2b, DEFINE, CONFIRM, and
ENDORSE clinical studies, lymphopenia in DMF-treated patients was not associated with an
overall increased risk of ions or serious infections, including opportunistic infections
(Table 13). uent to the data cut-off for this interim report, a case of PML in a patient
treated with DMF 240 mg TID was reported in the setting of severe, prolonged lymphopenia
(approximately less than 0.5x109/L of 3.5 years duration).
Table 13. Incidence of s infections by worst post-baseline CTC grade
Total DMFa’b
n=2513
s infections,c n (%)
CTC rade 0
CTC grade 1
CTC r2ade-
CTC grade 3 or 4
ALC, absolute lymphocyte count; CTC, Common Terminology Criteria.
aDMF, delayed-release DMF (also known as -resistant DMF, and as TECFIDERA®)
bIncludes DMF 240 mg BID, DMF 240 mg TID, and lower doses ofDMF (120 mg QD or
TID)
0For each CTC grade, numbers in parentheses are percentages based on the number with an
infection out of the number with worst post-baseline count in that grade as shown in Table 11.
CONCLUSIONS
ALC profiles are well characterized and stable over time. Mean ALCs sed
by approximately 30% in DMF-treated patients during the first year of treatment, then plateaued,
remaining above LLN throughout the observation .
ALCs remained greater than or equal to LLN in 84% of patients during the first 6
months and in 76% of patients during the first year; of these ts, 0. l% and 0%, respectively,
developed ALCs less than 500/mm3 persisting for r than or equal to 6 months at any time.
Among patients treated for at least 6 months, a small proportion (2.2%)
experienced ALCs less than 500/mm3 persisting for greater than or equal to 6 months and this
finding was an early predictor for those patients at greater risk for subsequently developing
severe, prolonged lymphopenia.
Aside from a single case of PML in the setting of severe, prolonged lymphopenia,
there is no overall increased risk for serious ions, including other opportunistic infections.
Before initiating treatment with DMF, a recent CBC including lymphocytes (ie,
within 6 months) should be available. A CBC including lymphocytes is also recommended after
6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated.7 As indicated
in the product labelling, consider interruption ofDMF in patients with ALCs less than 0.5 x
109/L persisting for more than 6 months. Following uption of DMF, ALCs should be
followed until lymphopenia is ed. 7.
] Although the data are limited, there is evidence ofALC ement following
discontinuation ofDMF treatment.
Therapeutic y ofDMF both in patients with lymphopenia and in patients
without lymphopenia suggests that lymphopenia is not a primary mechanism of action of DMF.
Efficacy in patients with and without lymphopenia suggests that lymphopenia is not a primary
ism of action of DMF.
The overall benefit-risk ofDMF remains favorable. Together with clinical and
neuroradiologic efficacy, these data continue to t DMF as a valuable long-term ent
option for patients with RRMS.
REFERENCES FOR EXAMPLE 8
l. Kappos L, Gold R, Miller DH, et al. Lancet 2008;372:1463-1472.
2. Gold R, Kappos L, Arnold DL, et al. NEnglJMed 2012;367:1098-1107.
3. Fox RJ, Miller DH, Phillips JT, et al. NEngl JMed 2012;367:1087-1097.
4. Gold R, ps JT, Bar-Or A, et al. Five-year follow-up of delayed-release yl
fumarate in RRMS: integrated clinical efficacy data from the DEFINE, M,
and ENDORSE studies. Poster presented at: Joint ECTRIMS-ACTRIMS Meeting;
September 10-13, 2014; Boston MA. P110.
. Arnold DL, Fox RJ, Havrdova E, et al. Five-year follow-up of delayed-release
dimethyl fumarate in ing-remitting multiple sclerosis: MRI outcomes from
DEFINE, CONFIRM, and ENDORSE. Poster presented at: Joint ECTRIMS-
ACTRIMS Meeting; ber 10-13, 2014; Boston MA. P059.
6. Pozzilli C, Phillips JT, Fox RJ, et al. erm follow-up of the safety of delayed-
release dimethyl filmarate in RRMS: m results from the ENDORSE extension
study. Poster presented at: Joint ECTRIMS-ACTRIMS Meeting; September 10-13,
2014; Boston MA. P066.
7. TECFIDERATM (dimethyl fumarate) [prescribing information]. Biogen Idec.
Cambridge, MA. Rev 12/2014.
8. Polman CH, ld SC, Edan G, et al. Ann Neur012005;58:840-846.
9. National Cancer Institute. Common Terminology Criteria for Adverse Events V4.0,
NCI, NIH, DHHS. May 29, 2009. NIH publication # 09-7473.
6.9 e 9: Instructing the Patient — Summary of Product Characteristics
By way of example, but not limitation, instructions for TECFIDERA® use in a
Summary of Product Characteristics can be as follows:
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Blood/laboratory tests
Changes in renal and hepatic laboratory tests have been seen in al trials in
subjects treated with TECFIDERA®. The clinical ations of these changes are unknown.
ments of renal fianction (e.g. creatinine, blood urea nitrogen and urinalysis) and hepatic
function (e.g. ALT and AST) are recommended prior to treatment initiation, after 3 and 6 months
of treatment, every 6 to 12 months thereafter and as clinically indicated.
TECFIDERA® may decrease lymphocyte counts. TECFIDERA® has not been
2015/060850
studied in patients with pre-existing low lymphocyte counts and caution should be exercised
when treating these patients. Prior to initiating treatment with TECFIDERA®, a current
complete blood count, including lymphocytes, must be performed. If lymphocyte count is found
to be below the normal range, alternative causes of lymphopenia should be considered and
corrective measures taken as appropriate. After starting therapy, complete blood counts,
including lymphocytes, must be performed every 3 months. Treatment should be discontinued if
lymphocyte count <0.7x109/L is confirmed on repeat testing (at 3 months). cyte counts
should be followed until recovery.
Progressive Multifocal Leukoencephalopathy [PML]
PML cases have occurred with TECFIDERA® in the setting of severe and
prolonged lymphopenia. PML is an opportunistic infection caused by John-Cunningham virus
(JCV), which may be fatal or result in severe disability. PML is likely caused by a combination
of factors. Risk factors include an altered or weakened immune system and potentially r
genetic or environmental risk factors.
Patients with lymphocyte counts <0.5x109/L were observed in <1% of patients
treated with placebo and 6% of patients d with TECFIDERA®. In clinical s (both
controlled and uncontrolled), 2% of patients experienced lymphocyte counts <0.5 x 109/L for at
least six months. In these patients, the majority of lymphocyte counts remained <0.5 x 109/L
with continued therapy.
If therapy is continued in ce of severe prolonged lymphopenia, the risk of
an opportunistic infection, ing PML cannot be ruled out. Therefore patients who
experience lymphopenia should be red closely for signs and symptoms of appearance of
new neurological dysfunction (e.g. motor dysfunction, cognitive or psychiatric symptoms). In
case PML is suspected, treatment with TECFIDERA® should be withheld immediately and
further evaluations performed.
Prior ent with immunosuppressive or immunomodulating therapies
No controlled clinical studies have been med ting the efficacy and
safety of TECFIDERA® when switching patients from other disease modifying therapies to
TECFIDERA®. The contribution of prior immunosuppressive y to the pment of
PML in TECFIDERA® treated patients is unknown. When switching patients from another
disease modifying therapy to TECFIDERA®, the half-life and mode of action of the other
therapy must be considered in order to avoid an additive immune effect whilst at the same time
minimising the risk of disease reactivation. A complete blood count, including lymphocytes,
must be med prior to initiating TECFIDERA® and rly during ent (see
blood/laboratory tests above).
TECFIDERA® can generally be started immediately after discontinuation of
interferon or glatiramer acetate.
In accordance with good clinical practice an MRI should be considered when
switching between disease modifying therapies.
Severe renal and hepatic impairment
TECFIDERA® has not been studied in patients with severe renal or severe hepatic
impairment and caution should, ore, be used in these patients.
Severe active gastrointestinal disease
TECFIDERA® has not been studied in patients with severe active gastrointestinal
disease and caution should, therefore, be used in these patients.
Flushing
In clinical trials, 34% of TECFIDERA® treated patients experienced flushing. In
the majority of patients who experienced flushing, it was mild or moderate in severity.
In clinical trials, 3 ts out of a total of 2,560 patients treated with
TECFIDERA® experienced serious flushing symptoms that were probable ensitivity or
anaphylactoid reactions. These events were not life-threatening, but led to hospitalisation.
Prescribers and ts should be alert to this possibility in the event of severe flushing
reactions..
Infections
In phase III placebo-controlled studies, the incidence of infections (60% vs 58%)
and serious infections (2% vs 2%) was similar in ts treated with TECFIDERA® or o,
respectively. There was no increased incidence of serious infections observed in patients with
lymphocyte counts 09/L or <0.5x109/L. During treatment with TECFIDERA® in the MS
placebo controlled trials, mean lymphocyte counts decreased by approximately 30% from
baseline at one year and then plateaued. Mean lymphocyte counts remained within normal .
Patients with lymphocyte counts <0.5x109/L were observed in <1% of patients treated with
o and 6% of patients d with TECFIDERA®. In clinical s (both controlled and
uncontrolled), 2% of patients experienced lymphocyte counts <0.5 x 109/L for at least six .
In these patients, the majority of lymphocyte counts remained <0.5 X 109/L with continued
therapy.
If therapy is continued in presence of severe prolonged lymphopenia, the risk of
an opportunistic infection, including Progressive ocal Leukoencephalopathy (PML) cannot
be ruled out (please refer to subsection PML above for r details).
If a patient develops a serious infection, suspending treatment with
TECFIDERA® should be considered and the benefits and risks should be reassessed prior to re-
initiation of y. Patients receiving TECFIDERA® should be cted to report symptoms
of infections to a ian. Patients with serious infections should not start treatment with
TECFIDERA® until the infection(s) is resolved.
6.10 Example 10: Instructing the Patient — Package Leaflet
By way of example, but not limitation, instructions for TECFIDERA® use in a
Package Leaflet can be as follows:
WARNINGS AND PRECAUTIONS
TECFIDERA® may affect your white blood cell , your kidneys and liver.
Before you start TECFIDERA®, your doctor will do a blood test to count the number of your
white blood cells and will check that your kidneys and liver are working ly. Your doctor
will test these periodically during treatment. If your number of white blood cells decreases
during treatment, your doctor may consider stopping your treatment.
7. INCORPORATION BY REFERENCE
Various references such as patents, patent applications, and publications are cited
herein, the disclosures ofwhich are hereby incorporated by reference herein in their entireties.
Claims (24)
1. The use of a pharmaceutical composition comprising monomethyl fumarate, dimethyl fumarate or a combination thereof; with the provisos (i) that a te salt is not present in the pharmaceutical composition and (ii) that no te other than dimethyl fumarate or monomethyl fumarate is present in the pharmaceutical composition; in the manufacture of a medicament for treating a patient with multiple sis, wherein the t has a lymphocyte count less than 0.5 x 109/L, the treating comprising the steps of: (a) administration of said ceutical composition; (b) obtaining a complete blood count including cyte count after 6 months of repeated administration of said pharmaceutical composition to said patient, and every 6 to 12 months thereafter; and (c) interrupting administration of said pharmaceutical composition to said patient when the patient has a cyte count less than 0.5 x 109/L persisting for more than six months.
2. The use of claim 1, wherein the fumarate is a combination of dimethyl fumarate and monomethyl fumarate.
3. The use of claim 1, wherein the fumarate is dimethyl fumarate.
4. The use according to any one of claims 1 to 3, wherein the administration is done orally.
5. The use according to claim 1, wherein the administration is of 240 mg fumarate twice daily orally.
6. The use of claim 1, wherein the administration is of 120 mg fumarate twice daily orally for 7 days, followed by 240 mg fumarate twice daily orally as a maintenance dose.
7. The use of any one of claims 1 to 6, wherein the stration is of not greater than 720 mg daily total fumarates.
8. The use of any one of claims 1 to 6, wherein the administration is of not greater than 480 mg daily total fumarates.
9. The use of any one of claims 1 to 8, wherein the treating further comprises monitoring the t for a sign or symptom suggestive of progressive multifocal leukoencephalopathy (PML) in the patient.
10. The use of claim 9, wherein the sign or symptom suggestive of PML is selected from the group consisting of progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to ion and ality changes.
11. The use of claim 9 or 10, wherein the patient exhibits a sign or symptom tive of PML, and the treating further comprises withholding the pharmaceutical composition and performing an appropriate diagnostic evaluation for PML.
12. The use of claim 11, wherein the said treating further comprises informing the t that PML has occurred in a MS patient who received fumarate.
13. Use of a pharmaceutical composition comprising dimethyl fumarate, with the proviso that a fumarate salt is not present in the ceutical composition, in the manufacture of a medicament for treating a patient with le sclerosis (“MS”), wherein the patient has a lymphocyte count less than 0.5 x 109/L and wherein the treating comprises the steps of: (a) administration of said pharmaceutical composition to the patient; (b) obtaining a complete blood count including lymphocyte count after 6 months of repeated administering of said pharmaceutical composition to said t, and every 6 to 12 months thereafter; and (c) interrupting administration of the fumarate therapy to said patient when the patient has a lymphocyte count less than 0.5 x 109/L that persists for more than six months.
14. The use of claim 13, wherein the administration of the pharmaceutical composition is done orally.
15. The use of claim 13, wherein the administration is of 240 mg dimethyl fumarate twice daily .
16. The use claim 13, wherein the administration is of 120 mg dimethyl fumarate administered twice daily orally for 7 days, followed by 240 mg dimethyl fumarate administered twice daily orally as a maintenance dose.
17. The use of any one of claims 13 to 16, wherein the administration is of not greater than 720 mg daily total dimethyl fumarate.
18. The use of any one of claims 13 to 16, n the administration is of not greater than 480 mg daily total dimethyl fumarate.
19. The use of any one of claims 13 to 18, wherein the treating further comprises a step of: monitoring the patients for a sign or symptom suggestive of progressive multifocal leukoencephalopathy (PML) in the t.
20. The use of claim 19, wherein the sign or symptom of PML is ed from the group consisting of progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in ng, , and orientation leading to confusion and personality changes.
21. The use of claim 19 or 20, wherein the patient exhibits a sign or symptom suggestive of PML, and the treating further comprises withholding the pharmaceutical composition and performing an riate diagnostic evaluation for PML.
22. The use of claim 21, wherein the treating further comprising step of: informing the patient that PML has occurred in a MS t who received dimethyl fumarate.
23. The use of claim 1, substantially as herein described or exemplified.
24. The use of claim 13, ntially as herein described or exemplified.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462080783P | 2014-11-17 | 2014-11-17 | |
US62/080,783 | 2014-11-17 | ||
US201562140255P | 2015-03-30 | 2015-03-30 | |
US62/140,255 | 2015-03-30 | ||
US201562232963P | 2015-09-25 | 2015-09-25 | |
US62/232,963 | 2015-09-25 | ||
PCT/US2015/060850 WO2016081355A1 (en) | 2014-11-17 | 2015-11-16 | Methods of treating multiple sclerosis |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ731528A NZ731528A (en) | 2021-11-26 |
NZ731528B2 true NZ731528B2 (en) | 2022-03-01 |
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