NZ766879A - Method of treatment and compositions comprising a dual pi3k delta-gamma kinase inhibitor and a corticosteroid - Google Patents
Method of treatment and compositions comprising a dual pi3k delta-gamma kinase inhibitor and a corticosteroid Download PDFInfo
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Abstract
This present disclosure relates to a method of treating autoimmune, respiratory and/or inflammatory diseases or conditions, e.g., asthma, COPD, rheumatoid arthritis and idiopathic Pulmonary Fibrosis (IPF). The method comprises administering a dual PI3K delta and gamma inhibitor and a corticosteroid, wherein the corticosteroid is selected from dexamethasone, fluticasone, fluticasone propionate and mometasone furoate. The present invention also relates to pharmaceutical compositions containing a dual PI3K delta and gamma inhibitor and a corticosteroid.
Description
METHOD OF TREATMENT AND COMPOSITIONS COMPRISING A DUAL PI3K
DELTA-GAMMA KINASE INHIBITOR AND A CORTICOSTEROID
The t ation is a divisional application of New Zealand Application No.
729419, which is incorporated in its entirety herein by reference.
The present application claims the benefit of Indian Patent Application No.
HE/2014, filed September 03, 2014, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to a method of treating autoimmune, respiratory and/or
inflammatory es and conditions sing administering to a patient in need thereof a dual
PI3K delta/gamma inhibitor and at least one corticosteroid. In red ments, the method
relates to the treatment of psoriasis, rheumatoid arthritis, idiopathic pulmonary is (IPF),
asthma, chronic obstructive pulmonary disease (COPD), and any combination thereof.
BACKGROUND OF THE INVENTION
Autoimmune, atory and inflammatory diseases such as rheumatoid arthritis (RA),
idiopathic pulmonary fibrosis (IPF), psoriasis, systemic lupus erythematosus (SLE), COPD and
asthma are chronic and often progressive diseases associated with a dysregulated or an overactive
immune system, respectively. The causes and the drivers of these diseases remain ill defined. They
are typically characterized by complex cellular interactions between multiple inflammatory cells of
the innate and adaptive immune system. Accordingly, the heterogeneity and complexity of the
disease etiology of these conditions makes the search for new appropriate cellular targets
challenging, as it is unclear who in the cellular infiltrate is a primary player of the pathology versus
an ent” bystander. Therefore, targeting signalling les that are required for the activation
of multiple immune cells may be the more likely route to success in combating these chronic,
immune cell mediated diseases.
toid tis (RA) is a progressive, systemic autoimmune disease characterized by
chronic inflammation of multiple joints with associated systemic symptoms such as fatigue. This
mation causes joint pain, stiffness and swelling, resulting in loss of joint function due to
destruction of the bone and cartilage, often leading to progressive
disability. ts with RA also have an increased likelihood of developing other systemic
complications such as osteoporosis, anaemia, and others affecting the lungs and skin.
RA is one of the most common forms of autoimmune disease and affects over
21 million people worldwide. Rheumatoid arthritis has a worldwide distribution with an
estimated prevalence of 1 to 2%. Prevalence increases with age, approaching 5% in women
over the age of 55. The average annual incidence in the United States is about 70 per 100,000
annually. Both incidence and prevalence of toid arthritis are two to three times greater
in women than in men. Although rheumatoid arthritis may present at any age, ts most
commonly are first affected in the third to sixth decades. RA is known to impact quality of
life, causing not only physical problems but also significant negative impact on quality of
life. RA also impacts on the average life expectancy, shortening it by three to seven years.
After 10 years, less than 50% of patients with RA can work or function normally on a day-to-
day basis. RA is also been reported to lead to an economic burden on national economies due
to hospital admissions, health care costs and lost productivity. RA is the cause of over nine
million y care physician visits in the UK annually, representing £833 million in lost
tion. It is also estimated to have cost the UK economy £55 n in 2000. In the US,
experts have estimated that RA costs more to business and industry than any other disease,
with 500,000 hospitalizations per year and the burden of illness on the economy for arthritis
(as a whole) is estimated to be $128 billion.
There are a number of ents ble to manage RA. Some address the
signs and symptoms of RA, others aim to modify the course of the disease and positively
impact the systemic effects of RA, such as fatigue and anaemia.
The current treatments e, for example, use of:
o Biologics: These are genetically-engineered drugs that target specific cell surface
markers or messenger substances in the immune system called cytokines, which are
produced by cells in order to regulate other cells during an inflammatory response. An
example of a ic cytokine targeted by biologics is tumor necrosis factor alpha
(TNFoc).
0 Traditional disease-modifying anti-rheumatic drugs (DMARDs): These are non-
specific immunosuppressive drugs, which are ed to combat the signs and
symptoms of RA as well as slowing down progressive joint destruction. These
treatments are often used in ation with one another, or in combination with a
biologic agent, to improve patient response
WO 2016035032
0 Glucocorticoids (corticosteroids): These are anti-inflammatory drugs related to
cortisol - a steroid produced naturally in the body - that work by countering
ation. However, the side-effects of glucocorticoids, which include
hyperglycemia, osteoporosis, hypertension, weight gain, cataracts, sleep problems,
muscle loss, and tibility to infections, limits their use
0 Non-steroidal anti-inflammatory drugs (NSAIDs): These manage the signs and
symptoms of RA, such as reducing pain, swelling, and inflammation, but do not alter
the course of the disease or slow the progression ofj oint destruction
There are also a number of RA therapies targeting other components of the
immune system. These include biologic treatments targeting alternative cytokines such as
eukin-6 (IL-6) that help to reduce inflammation and the progression of RA in the joints
and throughout the body.
Asthma is the most common chronic disease among children and also affects
millions of adults. Some 235 million people worldwide suffer from this disease. The causes
of asthma are not well understood, but effective medicines are ble that can treat it, thus
largely avoiding the shed lives, lities and death it can bring. unately, for
many people with asthma, particularly the poor, these effective treatments are too costly or
not available at all.
Chronic obstructive pulmonary disease (COPD) is a highly prevalent
condition and a major cause of morbidity and mortality worldwide. As the disease progresses,
patients with COPD may become prone to nt exacerbations, resulting in patient
anxiety, ing health status, lung function decline, and increase in mortality rate. These
episodes of worsening respiratory function lead to increases in health care utilization, al
admissions and costs. Worse, frequent exacerbations are associated with a faster decline in
lung function, thereby shortening life expectancy.
According to the recommendations of Global Initiative for Chronic
Obstructive Lung Disease (GOLD), the first line therapy for COPD are long acting [3-
agonists, long acting muscarinic antagonists and inhalation osteroids. However, these
drugs reduce the symptoms and exacerbations associated with the disease rather than
targeting its molecular and ar basis. Accordingly, there is still a need for further
ement of COPD therapy.
Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid
kinases that phosphorylate the 3 position hydroxyl group of the inositol ring of
oinositide lipids (PIs) generating lipid second gers. While alpha and beta
ms are tous in their distribution, expression of delta and gamma is restricted to
circulating hematogenous cells and endothelial cells. Unlike PI3K-alpha or beta, mice lacking
expression of gamma or delta do not show any adverse ype indicating that targeting of
these specific isoforms would not result in overt toxicity.
Recently, targeted inhibitors of the phosphoinositidekinase (PI3K) y
have been suggested as immunomodulatory agents. This interest stems from the fact that the
PI3K pathway serves multiple functions in immune cell signalling, primarily through the
generation of phosphatidylinositol )—trisphosphate (PIP3), a membrane bound second
messenger. PIP3 recruits proteins to the cytoplasmic side of the lipid bilayer, including
protein kinases and GTPases, initiating a complex k of ream signalling
cascades important in the regulation of immune cell adhesion, migration, and cell—cell
communication.
The four class I PI3K isoforms differ significantly in their tissue distribution.
PI3KOL and PI3KB are ubiquitous and activated downstream of receptor tyrosine kinases
(RTK), whereas PI3K5 and PI3Ky are primarily limited to hematopoietic and endothelial
cells, and are activated downstream of RTKs, and G protein coupled receptors (GPCR),
respectively. Mouse genetic studies have revealed that PI3KOL and PI3KB are essential for
normal pment, whereas loss of PI3K5 and/or PI3Ky yields viable offspring with
selective immune deficits
The expression pattern and functions of PI3K5 and PI3Ky have generated
much interest in developing PI3K 6/7 inhibitors as agents for many diseases, including
rheumatoid tis, allergies, asthma, chronic obstructive pulmonary disease and multiple
sclerosis (Hirsch et al., Pharmacol. Ther.,118, 192—205 2008; Marone et al., Biochim.
Biophys. Acta., 1784, 159—185. 2008, Rommel et al., Nat. Rev. Immunol., 7, 191—201., 2007,
Ruckle et al., Nat. Rev. Drug Discov., 5, 903—9182006). Studies using both cologic
and genetic methods have shown these two isoforms often demonstrate synergistic
interactions with each other (Konrad ez‘ al., J. Biol. Chem, 283, 33296—33303, 2008,
Laffargue et al., Immunity, 16, 441—451, 2002).
In mast cells, for example, PI3K8 is essential for degranulation in response to
IgE cross-linking of Fc-receptors (Ali el al., J. l, 180, 544. 2008), but PI3Ky
plays an important role in amplifying the response (Laffargue et al., Immunity, 16, 441—451
2002). Similar effects have been seen in other cellular functions, including lymphocyte
WO 35032
homing and the neutrophil respiratory burst where PI3Ky plays a critical role and PI3K5
amplifies each process. The nonredundant but related roles of PI3K6 and PI3Ky have made it
lt to determine which of the two isoforms (alone or in combination) is best targeted in a
particular inflammatory disorder. Studies using mice that lack PI3K6 and/or PI3Ky or express
kinase-dead variants of PI3K6 and PISKy have been valuable tools in tanding their
roles. For e, PI3K6 knockout mice demonstrated diminished neutrophil chemotaxis,
diminished antibody production (both T cell dependent and independent) (Jou et al, Mol.
Cell. Biol., 22, 8580—8591. 2002), and lower numbers of mature B cells (Clayton el al., J.
Exp. Med, 196, 753—763. 2002, Jou et al, Mol. Cell. Biol., 22, 8580—8591. 2002) and a
decrease in their proliferation in response to anti-IgM (Jou ei al, Mol. Cell Biol, 22, 8580—
8591. 2002). This ype was replicated in the PI3K6 -dead variant and with PI3K8
selective inhibitors along with decreased numbers of and proliferation of mast cells, and an
attenuated allergic response. The PI3Ky knockout contained higher numbers of, but less
responsive, neutrophils, lower s of and less responsive macrophages and dendritic
cells displayed decreased mast cell degranulation ((Laffargue ei al, Immunity, 16, 441—451
2002), a higher ratio of CD4+ to CD8+ T cells), increased thymocyte apoptosis, diminished
ion of CXCR3 on activated T cells and decreased cardiac contractility. This latter
effect on cardiac tissue was a concern for chronic dosing of patients with PI3Ky inhibitors.
However, this concern was largely mitigated when the PI3Ky kinase-dead variant (which
better mimics inhibition of the kinase rather than loss of the n) showed similar immune
cell phenotypes, but importantly had no cardiac defects. The cardiac effect was later shown to
be due to scaffolding effects rather than the catalytic activity of PI3Ky. The dual PI3K5
/PI3Ky knockout was viable but exhibited s s in T cell development and
thymocyte survival. The PI3Ky knockout/ PI3K8 kinase-dead combination produced a similar
phenotype suggesting that at least within the immune system, the role of PI3K6 is likely only
a catalytic one. Interpretation of studies using knockout and kinase—dead mice can be
challenging because these models provide only a steady-state picture of the immune system,
lack temporal and dose control, and do not permit a full understanding of how a dynamic
immune response will react to reversible inhibition. Selective inhibitors with varying profiles
(PI3K6, PI3Ky, and PI3K S/y) are necessary for studies of leukocyte signalling in order to
assess the ve contributions of each PI3K to immune cell activation. (see Olusegon et al,
Chemistry & Biology, 1,123-134 including the cited nces therein).
2015/056720
Dual inhibition of PI3K 6/3! is strongly implicated as an intervention strategy
in allergic and non-allergic inflammation of the airways and other autoimmune diseases.
Scientific evidence for PI3K-6 and y gamma ement in various cellular processes
ying asthma and COPD stems from inhibitor studies and argeting approaches.
Also, ance to conventional therapies such as corticosteroids in several COPD patients
has been attributed to an up-regulation of the PI3K S/y y. Disruption of PI3K 5/7
signalling therefore provides a novel strategy aimed at counteracting the immuno-
inflammatory response. Due to the pivotal role played by PI3K 6 and y in mediating
inflammatory cell functionality such as leukocyte migration and activation, and mast cell
degranulation, blocking these isoforms may also be an effective strategy for the treatment of
rheumatoid arthritis as well. Given the established criticality of these isoforms in immune
surveillance, inhibitors specifically ing the delta and gamma isoforms would be
expected to attenuate the ssion of immune se encountered in airway
inflammation and rheumatoid arthritis. Given the established criticality of these isoforms in
immune surveillance, inhibitors cally targeting the 6 and y isoforms would be expected
to attenuate the progression of immune response tered in airway ation and
rheumatoid arthritis (William et al., Chemistry & Biology, 17: 123—134, 2010; and Thompson,
et al., Chemistry & Biology, 17 :101-102, 2010)Reviews and studies regarding PI3K and
d protein kinase pathways have been given by Pixu Liu et. al. (Nature Reviews Drug
Discovery, 2009, 8, 627-644), Nathan T. et. al., Mol Cancer Ther., 2009;8 (1) Jan, 2009),
Romina Marone et al., Biochimica et Biophysica Acta., 1784 (2008) 159-185) and B.
Markman et al., Annals of Oncology, Advance Access published August 2009). Similarly
reviews and studies regarding role of PI3K 8 and V have been given by William et al.,
Chemistry & Biology, 17:123-134, 2010 and Timothy et al., JMea’. Chem, Web Publication
August, 27, 2012. All of these literature disclosures are incorporated herein as reference in
their entirety for all purposes.
Recent developed compounds, such as [PI-145 and CAL130 have been
reported as dual inhibitors of Pi3K 6/y. IPI-145 is under clinical investigation for cancer as
well as for asthma. There are currently no reports of CAL-130 being investigated for any
clinical purpose.
Additional reference is made herein to International Patent Application Nos.
2010/002804, filed November 3, 2010, and , filed May 4, 2012,
US. Patent Application Nos. 12/938,609, filed November 3, 2010, and 13/464,587 filed May
4, 2012 as well to the compounds as disclosed in International Publication Nos. WO
2009/088986, , and , each of which is
incorporated herein by reference in its entirety for all es.
Corticosteroids are potent anti-inflammatory agents, able to decrease the
number, activity and movement of inflammatory cells. Corticosteroids are ly used to
treat a wide range of c and acute inflammatory conditions including asthma, chronic
obstructive pulmonary disease (COPD), allergic rhinitis, rheumatoid tis, inflammatory
bowel disease and autoimmune diseases, Corticosteroids mediate their effects through the
glucocorticoid receptor (GR). The binding of corticosteroids to GR induces its nuclear
translocation which, in turn, affects a number of downstream pathways via DNA-binding-
dependent (e.g. transactivation) and -independent (e. g. transeXpression) mechanisms.
Corticosteroids for treating chronic atory conditions in the lung (such
as asthma and COPD) are currently administered h inhalation. One of the advantages
of employing d corticosteroids (ICS) is the possibility of delivering the drug directly to
the site of action, thereby limiting systemic side-effects, and resulting in a more rapid al
response and higher therapeutic ratio.
Although ICS treatment can afford important benefits, especially in asthma, it
is important to minimize ICS ic exposure, which leads to the occurrence and severity
of unwanted side s that may be associated with chronic administration. Moreover, the
limited duration of action of ICS currently available in the clinical practice contributes to
suboptimal management of the disease. While inhaler logy is an important point to
target the lung, the modulation of the substituents on the corticosteroids molecular scaffold is
important for the optimization of pharmacokinetic and pharmacodynamic properties in order
to decrease oral bioavailability, confine pharmacological activity only in the lung (prodrugs
and soft drugs) and se systemic clearance. Moreover, long lasting ICS activity in the
lung is highly desirable as once daily administration of ICS would allow the reduction of the
frequency of administration and, thus, substantially improve patient compliance and, as a
result, e management and control. In sum, there is a pressing medical need for
developing ICS with improved pharmacokinetic and pharmacodynamic characteristics.
Glucocorticoids olidine derivatives are described, for example, in WO
2006/005611, GB 1,578,446 and in ”Synthesis and topical anti-inflammatory ty of some
steroidal l70t-d] isoxazolidines”, M.J. Green et al., J. Med. Chem, 25, 1492-1495, 1982,
each of which is incorporated herein by reference in their entireties. Additional
glucocorticoid isoxazolidine derivatives are also described in WO 2011/029547 and WO
2012/123482.
Despite currently available intervention therapies, autoimmune disorders such as RA,
psoriasis and respiratory disorders such as asthma and COPD remains disease classes with a
significant unmet medical need.
Accordingly, it is an objective of the present ion to provide s and
pharmaceutical compositions for the treatment of respiratory and/or inflammatory diseases and
conditions having enhanced activity. The pharmaceutical compositions allow for treating
autoimmune, atory and inflammatory diseases and conditions with a smaller amount of active
nd(s) and/or allow for treating mune, respiratory and inflammatory diseases and
conditions in a more efficient way, thereby minimizing or obviating possibly existing adverse effects
generally linked to any kind of treatment with an active compound in high doses and/or for a longer
period of time.
As described herein, the objective may be ed by combining drugs ing two
diverse yet complimentary pathways, in order to be efficacious at lower doses compared to that of
either inhibitor alone. Thus, the t ion provides an effective approach of combining the
two different signalling pathways which hold significant therapeutic potential when combined
together. In particular the combination is therapeutically beneficial in lowering the required
therapeutically effective concentration of either or both the corticosteroid and the dual PI3K deltagamma
inhibitor.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition sing a PI3K delta and
gamma dual inhibitor and at least one corticosteroid, and to the use of such a pharmaceutical
composition for treating autoimmune, respiratory and inflammatory diseases and conditions.
[27a] According to a first , the t invention provides use of (i) a dual PI3K delta and
gamma inhibitor, and (ii) a corticosteroid in the manufacture of a medicament for treating an
autoimmune, atory and/or inflammatory disease or condition, wherein the dual PI3K delta and
gamma inhibitor and the osteroid are to be administered in a therapeutically effective amount,
wherein the corticosteroid is selected from dexamethasone, fluticasone, fluticasone propionate,
mometasone furoate, and pharmaceutically able salts thereof.
[27b] According to a second , the present invention provides a pharmaceutical composition
comprising (i) a dual PI3K delta and gamma inhibitor, (ii) a osteroid, and (iii) optionally, a
pharmaceutically acceptable carrier, glidant, diluent, or excipient,
8a (followed by page 9)
n the corticosteroid is selected from dexamethasone, fluticasone, fluticasone propionate,
and sone furoate, and pharmaceutically acceptable salts thereof.
[27c] ing to a third aspect, the present invention provides the use of a pharmaceutical
composition according to the invention in the manufacture of a medicament for the treatment of
autoimmune, respiratory and inflammatory diseases and conditions are selected from asthma, chronic
obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel e,
glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis,
vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis,
interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation
(organ, bone , stem cells and other cells and tissues) graft rejection, graft-versus-host disease,
lupus erythematosus, matory e, type I diabetes, pulmonary fibrosis, dermatomyositis,
Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis,
autoimmune hemolytic anemia, cystic fibrosis, thic pulmonary fibrosis (IPF), c relapsing
hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis, and combinations
thereof.
[27d] According to a fourth aspect, the present invention es a kit for treating an
autoimmune, atory or inflammatory disease or condition, the kit comprising:
(i) a dual PI3K delta and gamma inhibitor, and (ii) a corticosteroid, or a pharmaceutically
acceptable salt thereof, in a single pharmaceutical composition,
(ii) instructions for treating the autoimmune, respiratory or matory disease or condition
with the dual PI3K delta and gamma inhibitor and corticosteroid and
(iii) a container for g the ceutical composition or pharmaceutical compositions,
wherein the corticosteroid is selected from dexamethasone, fluticasone, fluticasone propionate,
and mometasone furoate, and pharmaceutically acceptable salts thereof.
Another embodiment is a pharmaceutical composition sing a PI3K delta and gamma
dual inhibitor and at least one corticosteroid.
Another embodiment is a method of treating a t suffering from an autoimmune,
respiratory and/or inflammatory disease or condition comprising administering to the patient a PI3K
delta and gamma dual inhibitor and at least one corticosteroid. In one preferred embodiment, the
PI3K delta and gamma dual inhibitor and at least one corticosteroid are administered together in a
single pharmaceutical composition. In one
preferred embodiment, the disease or condition is idiopathic pulmonary s (IPF),
, toid arthritis (RA) or COPD.
Yet another embodiment is the use of a combination of a PI3K delta and
gamma dual inhibitor and at least one corticosteroid for the treatment in a patient of an
autoimmune, respiratory and/or inflammatory disease or condition, such as for the treatment
of asthma, RA or COPD.
In a preferred ment, the PI3K delta and gamma dual inhibitor is a
compound of formula A (shown below) or a pharmaceutically acceptable salt thereof.
Formula A
Suitable corticosteroids include, but are not limited to thasone,
betamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, fluticasone,
triamcinolone, cortisone, naflocort, deflazacort, halopredone acetate, budesonide,
ethasone dipropionate, hydrocortisone, triamcinolone ide, fluocinolone
acetonide, fluocinonide, tolone pivalate, methylprednisolone aceponate,
dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate,
alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone
furoate, Iimexolone, prednisolone farnesylate, onide, deprodone propionate, fluticasone
propionate, halobetasol nate, loteprednol etabonate, betamethasone butyrate
propionate, flunisolide, prednisone, dexamethasone sodium phosphate, inolone,
betamethasone l7-Valerate, betamethasone, betamethasone dipropionate, hydrocortisone
acetate, hydrocortisone sodium ate, prednisolone sodium phosphate, hydrocortisone
probutate, and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the corticosteroids are selected from
dexamethasone, betamethasone, prednisolone, methyl prednisolone, prednisone,
hydrocortisone, fluticasone, triamcinolone, nide, cortisone, and any combination of
any of the foregoing.
One embodiment is a pharmaceutical composition sing a compound of
formula A or a pharmaceutically acceptable salt thereof, and a corticosteroid. In one
preferred embodiment, the pharmaceutical composition comprises a therapeutically effective
amount of a compound formula A or a pharmaceutically acceptable salt thereof, and a
therapeutically effective amount of a corticosteroid (for example, for treating , RA, or
COPD).
Another embodiment is a method of treating an autoimmune, respiratory
and/or inflammatory disease or condition, such as asthma, RA or COPD, comprising
administering to a patient in need thereof a compound of formula A:
Formula A
or a pharmaceutically acceptable salt thereof and a osteroid. In one preferred
embodiment, the compound of formula A or a pharmaceutically acceptable salt thereof and at
least one corticosteroid are administered together in a single pharmaceutical composition. In
one embodiment, the e or condition is . In another ment, the disease or
condition is RA. In yet another ment, the e or condition is COPD.
Yet another embodiment is a method of treating a patient suffering from an
autoimmune, respiratory and/or inflammatory disease or condition, such as asthma, RA, or
COPD, comprising administering to the patient a nd of formula A or a
pharmaceutically acceptable salt thereof, and a corticosteroid selected from thasone,
betamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, fluticasone,
triamcinolone, budesonide or cortisone, and any combination thereof. In one preferred
embodiment, the compound of formula A or a ceutically acceptable salt thereof and at
least one corticosteroid are administered together in a single pharmaceutical composition.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1A is a bar graph depicting the effect of compound A on the ICso of
dexamethasone (Dex) in TGF-Bl treated A549 cells according to the procedure in Example 1.
Figure 1B is a bar graph depicting the effect of compound A on the ICso of
dexamethasone (Dex) on 1L-8 concentrations in H202 treated U937 cells according to the
procedure in Example 2‘
Figure 2A is a bar graph depicting the effect of nd A on cigarette
smoke induced immune cell infiltration in BALF of Balb/c mice according to the procedure
in Example 3.
Figure 2B is a bar graph depicting the effect of compound A on cytokines in
BALF according to the procedure in Example 3.
Figure 3A is a bar graph depicting the effect of nd A and Fluticasone
on cigarette smoke induced macrophage infiltration in BALF of Balb/c mice according to the
procedure in e 4.
Figure 3B is a bar graph depicting the effect of combination of compound A
and Fluticasone on cigarette smoke induced macrophage infiltration in BALF of Balb/c mice
according to the ure in Example 4.
Figure 4 is a bar graph depicting the IL-8 concentration-dependent inhibitory
curve for neutrophils from healthy and COPD patients stimulated with CSE 5% in the
presence of Compound A (0.01 nM - 100 uM) or dexamethasone according to the procedure
in Example 6.
Figure 5 is a bar graph depicting inhibition of CSE-induced IL-8 release in
neutrophils from COPD patients by addition of a fixed tration of dexamethasone 1 nM
to concentrations of Compound A of O.lnM, lnM, and lOnM according to the procedure in
Example 6.
Figure 6 is a bar graph depicting relative MKPl mRNA expression ated
with CSE 5% alone or in the presence of 10 nM or 100 nM of Compound A according to the
procedure in Example 7.
Figure 7 is a bar graph depicting relative PI3Ky mRNA sion stimulated
with CSE 5% alone or in the presence of 10 nM or 100 nM of Compound A according to the
ure in Example 7.
Figure 8 is a bar graph depicting PIP3 tion in the ce of CSE 5%
alone, CSE5% and 10 nM of Compound A, or 10 nM of Compound A alone.
ED DESCRIPTION OF THE INVENTION
In one aspect, the method of combining a dual PI3K delta and gamma
inhibitor (such as a compound of formula A, or a pharmaceutically acceptable salt thereof)
with a corticosteroid, as described in any of the embodiments herein, exhibits an activity (i.e.,
a synergistic activity) which is significantly higher than the activity ed based on the
individual activities of each of the dual PI3K delta and gamma inhibitor or the corticosteroid
alone.
In another aspect, the method of combining a dual PI3K delta and gamma
inhibitor (such as a compound of formula A, or a pharmaceutically able salt thereof)
with a corticosteroid exhibits an ty even when the corticosteroid alone is insensitive as a
single agent.
Thus, the methods described herein allow for treating autoimmune, respiratory
and inflammatory diseases and conditions with a smaller amount of active compound(s)
and/or allow for treating autoimmune, respiratory and inflammatory diseases and conditions
for a longer period of time in a more efficient way.
Another embodiment is a pharmaceutical composition sing a dual PI3K
delta and gamma tor (such as a compound of formula A, or a pharmaceutically
acceptable salt thereof) with a corticosteroid, for use in the treatment of an autoimmune,
respiratory and/or inflammatory disease or condition.
Yet another embodiment is a method of treating an autoimmune, respiratory
and/or atory disease or condition comprising administering to a t in need
thereof a therapeutically effective amount of a pharmaceutical composition according to the
present ion.
Yet r embodiment is the use of a pharmaceutical composition according
to any of the embodiments described herein for making a medicament useful for treating an
mune, respiratory and/or inflammatory disease or condition.
In the pharmaceutical compositions described herein, the PI3K delta and
gamma dual inhibitor (such as a compound of formula A, or a pharmaceutically able
salt thereof) may be in a form selected from solvates, hydrates and/or salts with
pharmacologically acceptable acids or bases.
In the pharmaceutical compositions described herein, the corticosteroid may
be in a form selected from es, hydrates or salts with pharmacologically acceptable acids
or bases.
WO 35032
Yet another embodiment is a method of treating an immune system-related
disease (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g.,
asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel
disease, glomerulonephritis, nflammatory diseases, multiple sclerosis, uveitis and
disorders of the immune ), cancer or other erative disease, a hepatic disease or
disorder, or a renal disease or disorder. The method includes administering an effective
amount of one or more compositions of the present invention.
Examples of immune disorders which can be treated by the methods and
itions described herein e, but are not limited to, psoriasis, rheumatoid arthritis,
itis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory
muscle disease, allergic is, vaginitis, interstitial cystitis, scleroderma, orosis,
eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other
cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus,
atory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's
syndrome, ditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis,
autoimmune tic anemia, multiple sclerosis, cystic fibrosis, Idiopathic pulmonary
fibrosis (IPF), chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and
atopic dermatitis.
Pharmaceutically acceptable salts, as bed herein, include salts d
from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn, salts of organic bases
such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide,
dicyclohexylamine, min, benzylamine, trialkylamine, and thiamine, salts of chiral
bases such as alkylphenylamine, glycinol, and phenyl glycinol, salts of natural amino acids
such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine,
methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, and serine,
quaternary ammonium salts of the compounds of ion with alkyl halides, alkyl sulphates
such as MeI l iodide) and (Me)2SO4, salts of non-natural amino acids such as D-
isomers or substituted amino acids, salts of guanidine; and salts of substituted guanidine
n the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or
substituted ammonium salts and aluminum salts. Salts may include acid addition salts where
appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides,
acetates, tartrates, maleates, citrates, tes, succinates, palmoates, methanesulphonates,
benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
2015/056720
When ranges are used herein, all combinations and subcombinations of ranges
and specific embodiments therein are intended to be ed. The term "about" when
referring to a number or a numerical range means that the number or numerical range referred
to is an approximation within experimental variability (or within tical experimental
error), and thus the number or numerical range may vary from, for example, between 1% and
% of the stated number or numerical range. The term "comprising" (and related terms such
as "comprise" or ises" or "having" or "including") includes those embodiments, for
example, an embodiment of any composition of matter, composition, method, or process, or
the like, that "consist of’ or "consist essentially of’ the described features.
The following abbreviations and terms have the indicated meanings
throughout: P13 -K = Phosphoinositide 3-kinase; P1 = phosphatidylinositol.
Abbreviations used herein have their conventional meaning within the
chemical and biological arts, unless otherwise ted.
The term "effective amount" or "therapeutically effective amount" refers to
that amount of a compound described herein that is sufficient to effect the intended
application ing, but not limited to, disease treatment, as defined below. The
therapeutically effective amount may vary depending upon the ed application (in vitro
or in vivo), or the t and disease condition being treated, e.g., the weight and age of the
subject, the severity of the disease condition, the manner of administration and the like,
which can readily be determined by one of ry skill in the art. The term also applies to a
dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion
and/or cell migration. The specific dose will vary depending on the particular compounds
chosen, the dosing n to be ed, whether it is administered in combination with
other compounds, timing of administration, the tissue to which it is administered, and the
physical delivery system in which it is carried.
As used herein, the terms "treatment" and "treating" refer to an approach for
obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or
a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the
underlying disorder being d. Also, a therapeutic benefit is achieved with the eradication
or amelioration of one or more of the physiological symptoms associated with the underlying
disorder such that an improvement is observed in the patient, notwithstanding that the patient
may still be afflicted with the underlying er. For prophylactic , the compositions
may be administered to a patient at risk of developing a ular disease, or to a patient
2015/056720
reporting one or more of the physiological symptoms of a disease, even though a diagnosis of
this disease may not have been made.
A "therapeutic effect," as that term is used herein encompasses a therapeutic
benefit and/or a prophylactic benefit as described above. A prophylactic effect includes
delaying or eliminating the appearance of a disease or condition, delaying or eliminating the
onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of
a disease or condition, or any combination thereof.
The term "subject" or “patient” refers to an animal, such as a mammal, for
example a human. The methods described herein can be useful in both human therapeutics
and veterinary ations. In some embodiments, the patient is a mammal, and in some
embodiments, the patient is human. For veterinary purposes, the term ct” and “patient”
include, but are not limited to, farm animals including cows, sheep, pigs, , and goats;
companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals
including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens,
s, ducks, and geese.
The term "selective inhibition" or "selectively inhibit" as d to a
biologically active agent refers to the agent's ability to selectively reduce the target signaling
activity as ed to off—target signaling activity, via direct or indirect interaction with the
target.
As used herein, the term “dual PI3—kinase Delta (6) and Gamma (y) inhibitor"
generally refers to a compound that inhibits the activity of both the nase 6 and y
isozyme more effectively than other isozymes of the PI3K family. A PI3-kinase 6 and 7 dual
inhibitor compound is therefore more selective for PI3 -kinase 6 and 7 than conventional PI3K
inhibitors such as CAL-130, wortmannin and LY294002, which are lective PI3K
inhibitors." Examples of “dual PI3-kinase Delta (6) and Gamma (7) inhibitor" include, but
are not limited to, compounds such as IPI—l45, and the compounds disclosed in International
Patent Application Nos. , filed November 3, 2010, and
PCT/U82012/36594, filed May 4, 2012; US. Patent ation Nos. ,609, filed
November 3, 2010, and 13/464,587 filed May 4, 2012 and to compounds disclosed in
International Publication Nos. WO 88986, , and
, each of which is incorporated herein by reference in its entirety for all
purposes.
For instance, the Dual nase 6 and y selective inhibitor may refer to a
compound that exhibits a 50% inhibitory concentration (ICso) with respect to the delta and
gamma type I PI3-kinase that is at least 10—fold, at least 20-fold, at least 50-fold, or at least
lOO-fold lower than the inhibitor's ICso with respect to the other types of P13 kinases (i.e.,
alpha and beta).
Inhibition of PI3-kinase 5 and y may be of therapeutic benefit in ent of
various conditions, e.g., conditions characterized by an inflammatory response including but
not limited to autoimmune diseases, allergic diseases, and tic diseases. antly,
tion of PI3-kinase 6 and y function does not appear to affect biological functions such
as viability and fertility.
"Inflammatory response" as used herein is characterized by redness, heat,
swelling and pain (i.e., inflammation) and typically es tissue injury or destruction. An
inflammatory response is usually a localized, protective response elicited by injury or
destruction of tissues, which serves to destroy, dilute or wall off (sequester) both the injurious
agent and the injured tissue. Inflammatory ses are notably associated with the influx of
leukocytes and/or leukocyte (e.g., phil) chemotaxis. Inflammatory responses may result
from infection with enic sms and viruses, non-infectious means such as trauma
or reperfusion following myocardial infarction or , immune responses to foreign
antigens, and mune diseases. Inflammatory ses amenable to treatment with the
methods and compounds according to the invention encompass conditions associated with
reactions of the specific defence system as well as conditions associated with reactions of the
non-speciflc defence system.
The therapeutic methods of the invention include methods for the treatment of
conditions associated with inflammatory cell activation. "Inflammatory cell activation" refers
to the induction by a stimulus (including, but not limited to, cytokines, antigens or auto-
antibodies) of a proliferative cellular response, the production of soluble mediators (including
but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive amines), or
cell surface expression of new or increased numbers of mediators (including, but not limited
to, major histocompatibility antigens or cell adhesion molecules) in inflammatory cells
ding, but not limited to, monocytes, hages, T lymphocytes, B lymphocytes,
granulocytes (polymorphonuclear leukocytes including neutrophils, basophils, and
eosinophils) mast cells, dendritic cells, hans cells, and elial cells). It will be
appreciated by s skilled in the art that the activation of one or a combination of these
ypes in these cells can contribute to the initiation, perpetuation, or exacerbation of an
inflammatory condition.
"Autoimmune disease" as used herein refers to any group of disorders in
which tissue injury is associated with humoral or cell-mediated responses to the body's own
constituents.
"Transplant rejection" as used herein refers to an immune se directed
against grafted tissue (including organs or cells (e.g., bone marrow), characterized by a loss
of function of the grafted and surrounding s, pain, swelling, leukocytosis, and
thrombocytopenia).
"Allergic disease" as used herein refers to any symptoms, tissue , or
loss of tissue function ing from allergy.
"Arthritic e" as used herein refers to any disease that is characterized by
inflammatory lesions of the joints attributable to a variety of etiologies.
"Dermatitis" as used herein refers to any of a large family of diseases of the
skin that are characterized by inflammation of the skin attributable to a variety of gies.
One embodiment is a pharmaceutical composition comprising a dual PI3K
delta and gamma inhibitor (such as a nd of formula A, or a pharmaceutically
acceptable salt thereof) and at least one corticosteroid and optionally one or more
pharmaceutically acceptable carriers or excipients.
In one embodiment, the pharmaceutical composition es a
therapeutically ive amount of a dual PI3K delta and gamma inhibitor (such as a
compound of formula A, or a pharmaceutically able salt thereof) and at least one
corticosteroid, and optionally one or more pharmaceutically acceptable carriers or excipients..
The ceutical composition may include one or more additional active ingredients as
described .
The pharmaceutical carriers and/or excipients may be selected from diluents,
fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release
matrices, colorants, flavorings, buffers, stabilizers, solubilizers, and combinations thereof.
The pharmaceutical compositions of the present invention can be administered
alone or in combination with one or more other active agents. Where desired, the subject
compounds and other agent(s) may be mixed into a preparation or both components may be
formulated into separate preparations to use them in combination separately or at the same
time.
The dual PI3K delta and gamma inhibitor and the corticosteroid can be
stered together or in a sequential manner with one or more other active . Where
desired, the subject compounds and other agent(s) may be co-administered or both
components may be administered in a sequence to use them as a combination.
The compounds and pharmaceutical compositions of the present invention can
be administered by any route that enables ry of the compounds to the site of action,
such as orally, intranasally, topically (e.g., transdermally), intraduodenally, erally
(including enously, intraarterially, intramuscularally, intravascularally, intraperitoneally
or by injection or infusion), intradermally, by intramammary, intrathecally, intraocularly,
retrobulbarly, intrapulmonary (e.g., aerosolized drugs) or subcutaneously (including depot
stration for long term release e.g., ed-under the-splenic capsule, brain, or in the
cornea), sublingually, anally, rectally, vaginally, or by surgical implantation (e.g., embedded
under the c capsule, brain, or in the cornea).
The compositions can be administered in solid, semi-solid, liquid or gaseous
form, or may be in dried powder, such as lyophilized form. The pharmaceutical
compositions can be packaged in forms convenient for delivery, including, for example, solid
dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, suppositories,
s, pills, troches, and lozenges. The type of packaging will lly depend on the
desired route of administration. Implantable sustained release formulations are also
contemplated, as are transdermal formulations.
The dosing frequency of the compounds may vary. For e, a dual PI3K
delta and gamma tor may be administered at a frequency ranging from twice daily to
once every three weeks. The corticosteroid may be administered at a frequency ranging from
twice daily to once every three weeks.
The amount of the compound to be administered is dependent on the mammal
being treated, the severity of the disorder or condition, the rate of administration, the
disposition of the compound and the discretion of the prescribing physician. However, an
effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day,
preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this
would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day An effective
amount of a compound of the invention may be administered in either single or multiple
doses (e.g., twice or three times a day).
In one ment, the pharmaceutical compositions described herein
se from about 0.001 mg to about 1000 mg, such as from about 0.01 mg to about 500
mg or from about 0.010 mg to about 250 mg or from about 0.030 mg to about 125 mg of a
dual PI3K delta and gamma inhibitor (such as a compound of formula A, or a
pharmaceutically able salt thereof) and/or from about 0.001 mg to about 1000 mg, such
as from about 0.01 mg to about 500 mg or from about 0.010 mg to about 250 mg or from
about 0.010 mg to about 125 mg or from about 0.030 mg to about 50 mg of at least one
corticosteroid.
In one embodiment, the pharmaceutical compositions described herein
comprise the dual PI3K delta and gamma inhibitor and the corticosteroid in a ratio of
between about 100:1 and about 1:100 by weight, such as between about 50: 1 and about 1: 50
by weight or between about 1: 10 and about 10: l by weight, or between about 1: 5 and about
: 1 by weight.
The term "co-administration, administered in combination with," and their
grammatical equivalents, as used , encompasses administration of two or more agents
(such as the dual PI3K delta and gamma inhibitor and the corticosteroid) to an animal so that
both agents and/or their metabolites are present in the animal at the same time. Co-
administration includes simultaneous administration in separate compositions, administration
at different times in separate compositions, or administration in a composition in which both
agents are present.
The pharmaceutical compositions described herein may contain one or more
corticosteroids selected form dexamethasone, thasone, solone, methyl
prednisolone, prednisone, hydrocortisone, fluticasone, triamcinolone budesonide or
cortisone prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate,
budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide,
fluocinolone acetonide, fluocinonide, clocortolone pivalate, prednisolone aceponate,
thasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate,
alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone
furoate, lone, prednisolone farnesylate, ciclesonide, deprodone propionate, fluticasone
propionate, halobetasol nate, loteprednol etabonate, betamethasone te
propionate, flunisolide, prednisone, thasone sodium phosphate, triamcinolone,
betamethasone l7-valerate, betamethasone, betamethasone dipropionate, hydrocortisone
acetate, hydrocortisone sodium succinate, solone sodium phosphate and hydrocortisone
probutate, and any combination of any of the foregoing.
In certain embodiments, the corticosteroid is ed from dexamethasone,
betamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, fluticasone,
triamcinolone, nide or cortisone, and any combination thereof.
One particular embodiment of the present invention relates to pharmaceutical
compositions wherein the corticosteroid is fluticasone.
Another particular embodiment of the present invention relates to
pharmaceutical compositions wherein the corticosteroid is budesonide.
Yet another particular embodiment of the present invention relates to
pharmaceutical compositions wherein the corticosteroid is prednisolone.
Yet another particular embodiment of the present invention relates to
pharmaceutical compositions wherein the corticosteroid is dexamethasone.
A r embodiment of the present invention relates to a method of treating
an indication selected from respiratory diseases and conditions such as diseases of the
s and lungs which are accompanied by increased or altered production of mucus and/or
inflammatory and/or ctive diseases of the airways such as acute bronchitis, chronic
bronchitis, c ctive bronchitis (COPD), cough, pulmonary emphysema, allergic or
non—allergic is or tis, chronic sinusitis or rhinitis, nasal polyposis, chronic
rhinosinusitis, acute rhinosinusitis, , allergic bronchitis, alveolitis, Farmer's disease,
hyperreactive airways, bronchitis or pneumonitis caused by infection, eg. by bacteria or
viruses or helminthes or fungi or protozoons or other pathogens, pediatric asthma,
iectasis, pulmonary fibrosis, adult respiratory distress syndrome, bronchial and
pulmonary edema, bronchitis or pneumonitis or interstitial pneumonitis caused by different
origins, e.g. aspiration, inhalation of toxic gases, vapors, bronchitis or pneumonitis or
interstitial pneumonitis caused by heart failure, X-rays, radiation, chemotherapy, bronchitis or
pneumonitis or interstitial pneumonitis associated with enosis, eg. lupus
erythematodes, systemic scleroderrna, lung s, idiopathic ary lung fibrosis (IPF),
interstitial lung es or interstitial pneumonitis of different origin, including asbestosis,
silicosis, M. Boeck or sarcoidosis, granulomatosis, cystic fibrosis or mucoviscidosis, or a-l-
ypsin deficiency, or selected from inflammatory diseases and conditions such as
inflammatory diseases of the intestinal tract of various origins such as inflammatory
pseudopolyps, Crohn's disease, ulcerative s, inflammatory diseases of the joints, such as
WO 2016035032
rheumatoid arthritis, or allergic inflammatory diseases of the oro-nasopharynx, skin or the
eyes, such as atopic dermatitis, seasonal and perenial, chronic uritcaria, hives of n
cause and allergic conjunctivitis; and in particular selected from , allergic and non-
allergic rhinitis, COPD and atopic dermatitis, comprising administering a therapeutically
effective amount of a pharmaceutical composition according to the present invention to a
patient in need thereof.
A r embodiment of the present invention relates to the use of a
pharmaceutical composition according to the present invention for making a medicament for
treating respiratory and/or inflammatory es and conditions, particularly wherein the
respiratory and/or inflammatory diseases or ions are ed from asthma, allergic and
non-allergic rhinitis, COPD and atopic dermatitis.
A further embodiment of the present invention relates to a pharmaceutical
composition according to any embodiment , for use in the treatment of atory and
inflammatory diseases and ions, particularly wherein the respiratory and inflammatory
diseases or conditions are selected from asthma, allergic and non-allergic rhinitis, COPD and
atopic dermatitis.
The present invention is now further illustrated by means of the following,
non-limiting, examples.
Provided below are illustrative examples of the combination of a PI3K delta
and gamma dual inhibitor and a corticosteroid.
Example 1: TGF-Bl induced Corticosteroid Insensitivity in A549 Cells
Test Procedure
A549 cells were trypsinized and 2*104 cells per well were seeded in a 96-well
plate and incubated at 37° C and 5% C02.
Media was removed and 100 pl of serum free media with 0.1 uM of
Compound A was added and incubated for 30 min.
50 ul of 3X TGF-Bl in F12K with 0.5% BSA was added such that the final
concentration was 400 pM and incubated at 37° C and 5% CO2 for 4 h.
50 ul of 4X of desired trations of dexamethasone (Dex) was added and
incubated for 45 min at 37°C and 5% CO2.
50 pl of 5X concentration of TNF-d was added such that the final
tration was 1 ng/ml to induce IL-8 and incubated for 24 h.
atant was collected and IL-8 was estimated by ELISA.
Cytokine Assay
IL-8 strips were plated with fresh or thawed supernatants and incubated at
room temperature for 2 h or overnight at 4° C.
Contents were discarded and strips were washed with 200 pl of wash buffer
per well for 15 s for a total of 5 times.
Strips were blotted dry and 100 pl per well of IX detection antibody was
added and incubated at room temperature for 1 h,
Contents were discarded and strips were washed with 200 pl of wash buffer
per well for 15 s for a total of 5 times.
Strips were blotted dry and 100 pl per well of IX Avidin-HRP antibody was
added and incubated at room temperature for 30 mini
[1 l 1] Contents were discarded and the strips were washed with 200 p1 per well of
wash buffer for 15 s for a total of 5 times.
100 pl per well of TMB ate were added and incubated at room
temperature for 5-15 min.
Reaction was d by adding 50 pl per well of 2N H2SO4.
Absorbance was read on a plate reader at A450 nm and A570 nm.
% inhibition for Blank subtracted ance values were determined based
on the control wells. Data was d using GraphPad Prism (Version 5.02).
Results
The results are depicted in Figure 1A. Compound A (de A) decreased the
ICso of dexamethasone for IL-8 concentrations in TGF-Bl treated A549 cells indicating
significant potentiation of dexamethasone activity.
Example 2: H202 Induced Corticosteroid Insensitivity in U937 cells
Test Procedure
U937 cells were maintained in RPMI—l640 with 15 mM glutamine. 6* 106 cells
were taken in T-25 flask with 12 ml of fresh medium and treated with 1 pM of Compound A
and incubated at 370 C and 5% C02 for 30 min.
H202 was added at a final tration of 200 pM to the above cells and
incubated for 2 h.
Cells were pelleted and resuspended in serum free media and seeded on to a
96-well plate at O. 15*106 cells per well in 100 pl.
50 pl of 3X Dexamethasone at desired concentrations was added and
incubated for 45 min.
50 pl of 4X concentration of TNF-u was added such that the final
concentration was 10 ng/ml, to induce 1L-8 and incubated for 18 h.
Supernatant was collected and lL-8 was estimated by ELISA.
Cytokine Assay
IL-8 strips were plated with fresh or thawed atants and incubated at
room temperature for 2 h or overnight at 4°C.
Contents were discarded and strips were washed with 200 pl of wash buffer
per well for 15s for a total of 5 times.
Strips were blotted dry and 100 pl per well of IX ion antibody was
added and incubated at room temperature for 1 h.
Contents were discarded and strips were washed with 200 pl of wash buffer
per well for 15s for a total of 5 times.
Strips were blotted dry and 100 pl per well of IX Avidin—HRP antibody was
added and incubated at room temperature for 30 min.
Contents were discarded and the strips were washed with 200 pl per well of
wash buffer for 15 s for a total of 5 times.
100 pl per well of TMB substrate were added and ted at room
temperature for 5-15 min.
Reaction was stopped by adding 50 pl per well of 2N H2SO4.
Absorbance was read on a plate reader at A450 nm and A570 nm.
As depicted in Figure 1B, Compound A (de A) decreased the ICso of
thasone (Dex) on IL-8 concentrations in H202 treated U937 cells indicating
significant potentiation of dexamethasone activity.
Example 3: Chronic Cigarette Smoke Induced Cell Infiltration in Male Balb/c mice
Animals were acclimatized for seven days prior to the start of the experiment.
Animals were randomly distributed to various groups based on their body weights. Mice were
exposed to the mainstream smoke of 2 cigarettes from day l to day 11. Exposure to the
smoke of each cigarette lasted for 10 min (each cigarette was completely burned in the first
two minutes, followed by an air flow with animal ventilator) and were exposed for the next
min with fresh room air. After every second cigarette an additional break of 20 min with
exposure to fresh room air was conducted. Control animals were exposed to the room air
chamber. Test nd was administered by the intranasal route as suspension from day 12
to day 14 before 30 mins whole body smoke exposure. Mice were exposed to the ream
smoke of l cigarette from day 12 to day 14. On day 15, 24 hours after the last cigarette
smoke (CS) exposure animals were exsanguinated under hesia, and the trachea was
cannulated and the lungs were lavaged with 0.5 ml aliquots of heparinised PBS (1 unit/ml)
four times through tracheal cannula (total volume 2 ml). Bronchioalveolar (BAL) collected
was stored at 2-8 °C until assayed for total cell and differential leukocyte count. BAL fluid
was centrifuged (500><g for 10 min) and the resulting cell pellet was resuspended in 0.5 ml of
heparinised saline. The total number of white blood cells was determined in BAL fluid and
blood using a blood cell r and adjusted to l><lO6 cell/ml. Differential cell count was
calculated manually. Forty microliters of the cell suspension was fuged using cytospin 3
to prepare a cell smear. The cell smear was stained with a blood staining solution for
differentiation and microscopically observed by identifying each cell according to its
morphological characteristics. The number of each cell type among 300 white blood cells in
the cell smear was determined and expressed as a percentage, and the number of neutrophils
and macrophages in each BAL fluid were calculated. In addition BAL supernatant were
analysed for various cytokinines using ELISA assay.
The s are shown in Table l and Figures 2A and 2B.
All animals survived to the scheduled termination. Compound A showed
significant beneficial eutic effect in the established murine c COPD model as
determined by evaluation of cell count in BAL. Macrophage ation in BAL fluid with
treated animals differed significantly from disease controls with significant ions
(toward normal) of BAL cell count seen in mice treated with Compound A -3 mg/kg)
in a dose dependent manner. hage count was significantly reduced toward normal for
mice given 0.003-3 mg/kg Compound A. The t inhibitions of cytokines are given in
Table l.
WO 2016035032
Table 1
nes in BALF (% inhibition)
Dose (mg/kg) 0 003 0.03 0.3
IL-6 44% 99%
TNFot 40% 99%
IL-12/IL-23 0% 100%
IFNy 25% 90%
Example 4: al of Corticosteroid itivity in Chronic Cigarette Smoke
Induced Cell Infiltration in Male Balb/c Mice
Animals were acclimatized for seven days prior to the start of the experiment.
Animals were randomly distributed to various groups based on their body weights. Mice were
d to the mainstream smoke of 2 cigarettes from day 1 to day 11. Exposure to the
smoke of each cigarette lasted for 10 min (each cigarette was completely burned in the first
two minutes, followed by an air flow with animal ator) and were exposed for the next
min with fresh room air. After every second cigarette an additional break of 20 min with
exposure to fresh room air was conducted. Control animals were exposed to the room air
chamber. Corticosteroid, fluticasone was stered by intranasal route from day 6 to day
11 before 30 mins whole body smoke exposure. Mice were exposed to the mainstream smoke
of l cigarette from day 12 to day 14. Test compound was administered by the intranasal route
as suspension from day 12 to day 14 before 30 mins whole body smoke re. On day 15,
24 hours after the last cigarette smoke (CS) exposure animals were exsanguinated under
anaesthesia, and the a was cannulated and the lungs were lavaged with 0.5 ml aliquots
of heparinised PBS (1 unit/ml) four times through tracheal cannula (total volume 2 ml).
Bronchioalveolar (BAL) collected was stored at 2-8 °C until assayed for total cell and
differential leukocyte count. BAL fluid was centrifuged (500>< g for 10 min) and the ing
cell pellet was resuspended in 0.5 ml of heparinised saline. The total number of white blood
cells was determined in BAL fluid and blood using a blood cell counter and adjusted to 1X106
cell/ml. Differential cell count was calculated manually. Forty microliters of the cell
suspension was centrifuged using cytospin 3 to prepare a cell smear. The cell smear was
stained with a blood staining solution for differentiation and microscopically observed by
identifying each cell according to its morphological characteristics. The number of each cell
WO 2016035032
type among 300 white blood cells in the cell smear was determined and expressed as a
percentage, and the number of neutrophils and macrophages in each BAL fluid were
calculated. In on BAL supernatant were analysed for various cytokines using ELISA
assay.
In combination with sone (FLT), Compound A showed significant
beneficial therapeutic effect and reversal of corticosteroid insensitivity by showing a
synergistic effect on macrophage infiltration. The EDso of the combination was 0.021 mg/kg
in the established murine chronic COPD model as determined by evaluation of cell count in
BAL compared to an EDso of 0.093 mg/kg of Compound A alone. The results are also shown
in Figures 3A and 3B.
Example 5: General Description related to Patient Identification, Isolation of Neutrophils
and Preparation of tte Smoke Extract (CSE) for ro testing of Compound A
A. Patient Selection
Healthy subjects and COPD patients were included for leukocyte experiments.
Pulmonary function tests (forced spirometry) and arterial blood gas measurements were
performed during the days prior to sampling. According to their spirometry results and
smoking habits, patients were classified into two groups: A) Healthy subjects, patients with
normal lung function and who did not smoke, B) COPD, patients who had smoked more than
pack-years and with airflow obstruction evidenced by a forced expiratory volume in l s
(FEVl) of <80% predicted and an FEVl forced vital capacity (FVC) ratio of <70%.
Clinical characteristics of the patients are provided in Table 2.
Table 2: Clinical features. COPD: c obstructive pulmonary disease; FEVl: forced
expiratory volume in one second, FVC: forced vital capacity, Pack-yr = 1 year smoking 20
cigarettes-day. Data are mean :: SE.
Table 2
y COPD
n=7 =
e r 66.1i6 65.1:14
Sex,l\/I/F 6/2
Tobacco otion, oack- r 35,2:
FEVl, % ored
FVC, % ored
VC %
GOLD 1 mild atients, no.
2015/056720
-]—__—_
-I!-I_____
-—__—
Receivin- theoh ilines no ____
in- .“-
in- anticholiner-ics no “—
Peripheral neutrophils and monocytes as well as whole blood were obtained from
8 patients with COPD, defined according to GOLD guidelines and 7 healthy subjects.
Patients were aged 65.1 i14 years, FEVl 58.2 i 3 % ted. All ts were current
smokers. There were no exacerbations of the disease within 2 weeks prior to taking blood
samples.
7 age-matched non-smoking control subjects with normal lung function (age
66.1 i 6 years old, FEVl 98 i 3 % predicted) who did not have any respiratory disease, were
also ted as normal controls, respectively. Routine lung function tests were performed to
te forced vital capacity (FVC), forced expiratory volume in 1 s (FEVl) and FEVl/FVC
ratio using a Vitalograph® alpha III eter (Vitalograph, Maids Moreton, UK). This
project was approved by the local ethics committee of General University Hospital, Valencia,
Spain, and n informed consent was taken from each patient or volunteer before starting
blood sampling and lung function testing.
B. Isolation of Human Neutrophils
Neutrophils were isolated from peripheral venous blood by standard
laboratory procedures. In brief, peripheral venous blood was mixed with dextran 500 at 3%
(in 0.9% saline) in a proportion of 2:1. This mixture was incubated at room temperature for
min until erythrocytes were sedimented. The upper phase was lly collected and
added on Ficoll-Paque Histopaque 1077 (Amershan Pharrnacia Biotech, Barcelona, Espafia)
density gradient in a proportion of 3:1. The two phases generated were centrifuged at 150 g,
4°C for 30 min. Thus, the pellet obtained (which is consisted a mixture of neutrophils and low
proportion of residual erythrocytes and traces of eosinophils and basophils) was resuspended
in an erythrocyte lysis buffer (Biolegend, UK) for 5 min in ice. Cell suspension was washed
two times with phosphate buffer (PBS). The preparations were >97% pure in neutrophils as
assessed by Giemsa staining, and had a viability of >99%, measured by trypan blue
exclusion. Neither purity nor viability was affected in the study’s different experimental
conditions.
WO 2016035032 2015/056720
C. Preparation of Cigarette Smoke Extract solutions
CSE was prepared as follows: Briefly, the smoke of a research cigarette
(2R4F, Tobacco Health Research, University of Kentucky, KY, USA) was generated by a
respiratory pump (Apparatus Rodent ator 680; Harvard, Germany) through a puffing
mechanism related to the human smoking n (3 puff/min, 1 puff 35 ml, each puff of 2 s
on with 0.5 cm above the filter) and was bubbled into a flask containing 25 ml of pre-
warmed (37°C) Roswell Park Memorial Institute (RPMI)-164O culture medium. The CSE
on was sterilized by filtration through a 0.22-um cellulose acetate sterilizing system
(Corning, NY). The resultant CSE solution was considered to be 100% CSE and was used for
experiments within 30 min of preparation. CSE 10% corresponds approximately to the
re associated with smoking two packs per day. The quality of the prepared CSE
on was assessed based on the absorbance at 320 nm, which is the c absorption
wavelength of peroxynitrite. Stock solutions with an ance value of 3.0 i 0.1 were used.
To test for cytotoxicity from CSE, isolated neutrophils were treated with CSE concentrations
of up to 5% for 24. No significant difference in the lactate dehydrogenase supernatant level
(lactate dehydrogenase xicity assay; Cayman, Spain) was observed in comparison with
the control group (data not shown).
Example 6
Assay: Effect of Compound A, dexamethasone and combination thereof on secretion of
inflammatory marker IL-8 induced by CSE in peripheral blood neutrophils from healthy
non-smokers and COPD smoker patients.
Isolated human neutrophils from healthy volunteers and COPD patients were
incubated with Compound A (0.01nM-100uM) and thasone (0.1nM-1uM) or vehicle
for 30 s before incubation with or without CSE 5% for 6 hours in standard cell culture
conditions (37°C and 5% C02). Supernatants were collected to measure different
inflammatory markers.
IL-8 was measured by ELISA using a commercially available kit.
Experiments were done in triplicate in almost three patients per experimental
condition.
phils from healthy and COPD patients were stimulated with CSE 5% in
the presence of Compound A (0.01nM - 100uM) or dexamethasone (DEX; 0.1nM-1uM) for
WO 2016035032
6h and IL-8 supernatants were measured. Concentration-dependent inhibitory curves are
shown in Figure 4 and in Table 3.
Table 3. Inhibition of IL-8 release in isolated peripheral blood neutrophils from healthy
(N=3) and COPD patients (N=3). Inhibitory tration—dependent curves were generated
by incubation with Compound A (de A; 0.01nM-100uM) or Dexamethasone (DEX; 0.1nM-
luM) in response to cigarette smoke extract (CSE 5%). Values are mean i SEM of 3
independent experiments run in cate. ICso values for half—maximum inhibition were
calculated by nonlinear regression analysis. *p < 0.05 vs Healthy values.
Table 3
Stimulus HEALTHY COPD
CSE 5% Maximal -log ICso N Maximal -log ICso N
% Inhibition % Inhibition
deA 97.4:53 6.53:0.22 .24 7.32:0.21
DEX 83.9::10.7 0.1719,84::11.46* 7.87:0.78
The addition of a fixed concentration of dexamethasone 1 nM to increasing
concentrations of nd A of 0.1 nM, 1 nM, and 10 nM, showed increases in ting
CSE-induced IL-8 release in neutrophils from COPD patients (Figure 5).
Compound A concentration-dependently inhibited IL-8 secretion in
neutrophils from healthy and COPD patients with a maximal percent inhibition of 97.4 ::
.3% and 85.14 i 8.24% respectively. As a reference, the anti-inflammatory dexamethasone
showed a ble inhibitory profile on duced IL—8 release only in neutrophils from
Healthy patients with a maximal percent inhibition of 83.9 :: 10%. However in neutrophils
from COPD patients, dexamethasone was not able to significantly inhibit lL—8 release
showing a corticosteroid insensitive profile.
Example 7
Assay: Effect of Compound A on basal RNA expression of corticosteroid resistance
mediators and PI3K isoforms using eral blood neutrophils from healthy non-
smokers and COPD smoker patients
WO 5032
Measurement of basal RNA expression of corticosteroid resistant
mediators: Total RNA was isolated from peripheral human neutrophils from COPD patients
in basal ions and after experimental conditions. Cells were homogenized and RNA was
extracted using TriPure® Isolation t (Roche, Indianapolis, USA). The e
transcription was performed in 300ng of total RNA with TaqMan reverse transcription
reagents kit (Applied Biosystems, Perkin-Elmer Corporation, CA, USA). 1.5 ul of result
cDNA was amplified with specific predesigned primers (Applied Biosystems) for MIF (cat
no Hs00236988), MKP-l (cat no H500610256), PI3K-5 (cat n° 2399), PI3Ky (cat n°
Hs00277090) and GAPDH (cat no 4310884E) as endogenous control in a 7900HT Fast Real-
Time PCR System ed Biosystem) using Universal Master Mix (Applied Biosystems).
Relative quantification of these different transcripts was determined with the Z'AACt method
and normalized to control groups.
mRNA expression of the MIF, MKP-l, PI3K-5 and PI3Ky genes was measured
in basal conditions and at the end of the experiments.
Experiments were done in triplicate in at least three patients per experimental
condition.
Results: The expression of MIF was not significantly affected by CSE or
Compound A exposure. In contrast, CSE decreased the expression of MKPl to
approximately 04-fold of control. nd A increased the expression of MKPl near to
control levels which correlates well with the tory effect of Compound A on E-S
release. See Figure 6. While PI3K6 was not affected by CSE treatment, administration of
Compound A caused a significant reduction in CSE induced PI3Ky expression (Figure 7).
Example 8
Assay: Effect of Compound A, Dexamethasone and combination thereof on basal
expression of PI3K ms using peripheral blood neutrophils from healthy non-smokers
and COPD smoker patients.
Measurement of Pi3K isoforms: To measure PI3K activity, phils
from COPD patients were isolated and incubated with Compound A at 10nM for 1h. Then
cells were stimulated with CSE 5% for 30 min. After cell ation, neutrophils were
centrifuged and total protein was extracted from neutrophils. Total protein amount was
measured using The Bio-Rad assay (Bio-Rad Laboratories Ltd., Herts, UK) to ensure equal
. PI3K activity was ed using the PI3-Kinase Activity ELISA: Pico (cat. n° k-
1000s, Echelon ence, Salt Lake City, USA) according to the cturer’s protocol.
In brief, PI3-K reactions were run with the Class I PI3-K physiological substrate PI(4,5)P2
(PIP2). The enzyme reactions, PIP3 standards and controls were then mixed and incubated
with PIP3 binding protein that is highly specific and sensitive to PIP3. This e was then
transferred to a PIP3-coated microplate for competitive binding. Afterwards, a peroxidase-
linked secondary detector and colorimetric detection was used to detect the amount of PIP3
produced by PI3 -K h comparing the enzyme reactions with a PIP3 standard curve.
Experiments were done in triplicate in at least three patients per mental
condition.
Results: In neutrophils from COPD patients, CSE 5% increased the PI3K
activity measured as PIP3 production. The addition of Compound A at lOnM completely
suppressed the PI3K activity (Figure 8)‘
Although the invention herein has been described with reference to particular
embodiments, it is to be tood that these embodiments are merely illustrative of the
principles and applications of the present invention. It is therefore to be understood that
numerous modifications may be made to the illustrative ments and that other
arrangements may be devised without ing from the spirit and scope of the present
invention as described above. It is intended that the appended claims define the scope of the
invention and that methods and structures within the scope of these claims and their
equivalents be covered thereby.
All publications, patents and patent applications cited in this application are
herein incorporated by reference to the same extent as if each dual publication, patent
or patent application was specifically and individually indicated to be incorporated herein by
reference.
Claims (24)
1. Use of (i) a dual PI3K delta and gamma inhibitor, and (ii) a osteroid in the manufacture of a ment for treating an autoimmune, respiratory and/or inflammatory disease or condition, wherein the dual PI3K delta and gamma inhibitor and the corticosteroid are to be administered in a therapeutically effective amount, wherein the corticosteroid is selected from thasone, fluticasone, fluticasone propionate, mometasone furoate, and pharmaceutically acceptable salts thereof.
2. The use according to claim 1, wherein the corticosteroid is selected from the group consisting of dexamethasone, sone furoate, and fluticasone propionate and pharmaceutically acceptable salts thereof.
3. The use according to claims 1 or claim 2, wherein the corticosteroid is selected from the group consisting of thasone, mometasone furoate, and fluticasone, and pharmaceutically acceptable salts f.
4. The use according to any one of claims 1-3, wherein the corticosteroid is selected from dexamethasone, fluticasone, and pharmaceutically acceptable salts f.
5. The use according to any one of claims 1-4, wherein the therapeutically effective amount of (i) the dual PI3K delta and gamma tor, and the therapeutically effective amount of (ii) the corticosteroid are to be administered simultaneously as a combined formulation.
6. The use according to any one of claims 1-5, wherein the therapeutically effective amount of (i) the dual PI3K delta and gamma inhibitor, and the therapeutically effective amount of (ii) the corticosteroid are to be administered tially.
7. The use according to claim 6, wherein the therapeutically effective amount of the corticosteroid is to be administered before the therapeutically effective amount of the dual PI3K delta and gamma inhibitor.
8. The use according to any one of claims 1-7, wherein the therapeutically effective amount of the dual PI3K delta and gamma inhibitor is to be administered twice daily to once every three weeks, and the therapeutically effective amount of the osteroid is to be administered twice daily to once every three weeks.
9. The use ing to any one of claims 1-8, wherein the autoimmune, respiratory and/or inflammatory disease or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuro inflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, osteoarthritis, inflammatory muscle e, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, , allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory e, type I diabetes, pulmonary is, dermatomyositis, Sjogren's syndrome, thyroiditis, enia gravis, autoimmune hemolytic anemia, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, atopic dermatitis, and combinations thereof.
10. The use according to any one of claims 1-9, wherein the autoimmune, atory and/or inflammatory disease or condition is selected from the group ting of , allergic rhinitis, non-allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis (IPF) and atopic dermatitis.
11. The use according to any one of claims 1-10, wherein the dual PI3K delta and gamma inhibitor and the corticosteroid are each to be administered in an amount ranging from about 0.01 mg to about 1000 mg.
12. The use of any one of claims 1-11, wherein the dual PI3K delta and gamma inhibitor and the osteroid are to be administered at a ratio of about 1:100 to about 100:1 by .
13. A pharmaceutical composition comprising (i) a dual PI3K delta and gamma inhibitor, (ii) a corticosteroid, and (iii) optionally, a pharmaceutically acceptable carrier, glidant, diluent, or excipient, wherein the corticosteroid is selected from dexamethasone, fluticasone, fluticasone nate, and mometasone furoate, and pharmaceutically acceptable salts thereof.
14. The ceutical composition ing to claim 13, wherein the corticosteroid is selected from the group consisting of dexamethasone, mometasone furoate, and fluticasone propionate, and pharmaceutically acceptable salts thereof.
15. The pharmaceutical ition according to claim 13 or claim 14, wherein the corticosteroid is selected from the group consisting of dexamethasone, mometasone furoate, and fluticasone, and pharmaceutically acceptable salts thereof.
16. The pharmaceutical composition according to any one of claims 13-15, wherein the corticosteroid is selected from dexamethasone, fluticasone, and pharmaceutically acceptable salts thereof.
17. The pharmaceutical composition of any one of claims 13-16, wherein the composition comprises about 0.01 mg to about 1000 mg of the dual PI3K delta and gamma inhibitor and about 0.01 mg to about 1000 mg of the corticosteroid.
18. The pharmaceutical composition according to any one of claims 13-17, for use in a method of treating an autoimmune, respiratory and/or matory disease or condition selected from the group consisting of asthma, chronic obstructive ary disease, rheumatoid arthritis, matory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, rthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, derma, osteoporosis, eczema, allogeneic or neic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I es, ary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, Idiopathic pulmonary is (IPF), chronic relapsing hepatitis, primary biliary cirrhosis, allergic ctivitis and atopic dermatitis, and combinations f.
19. The use of a pharmaceutical composition according to any one of claims 13-18 in the cture of a medicament for the treatment of autoimmune, respiratory and inflammatory diseases and conditions are ed from asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, itis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, , neic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, Idiopathic pulmonary fibrosis (IPF), chronic relapsing hepatitis, primary biliary sis, allergic conjunctivitis and atopic itis, and combinations thereof.
20. A kit for treating an autoimmune, atory or inflammatory disease or condition, the kit comprising: (i) a dual PI3K delta and gamma inhibitor, and (ii) a corticosteroid, or a pharmaceutically acceptable salt f, in a single pharmaceutical composition, (ii) instructions for treating the autoimmune, respiratory or inflammatory disease or condition with the dual PI3K delta and gamma inhibitor and corticosteroid and (iii) a container for placing the ceutical composition or pharmaceutical compositions, wherein the corticosteroid is selected from thasone, fluticasone, fluticasone propionate, and mometasone furoate, and pharmaceutically acceptable salts thereof.
21. The kit of claim 20, wherein the dual PI3K Delta and Gamma inhibitor and Corticosteroid are for the treatment of an autoimmune, respiratory or inflammatory disease or condition selected from asthma, chronic obstructive pulmonary disease, rheumatoid tis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic lantation (organ, bone marrow, stem cells and other cells and s) graft rejection, versus-host disease, lupus erythematosus, inflammatory disease, type I es, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and mune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, Idiopathic pulmonary fibrosis (IPF), chronic relapsing hepatitis, primary biliary sis, allergic conjunctivitis and atopic dermatitis.
22. The kit of claim 20 or claim 21, wherein the corticosteroid is selected from the group ting of dexamethasone, mometasone furoate, and fluticasone propionate, and pharmaceutically acceptable salts thereof.
23. The kit of any one of claims 20-22, wherein the corticosteroid is selected from the group consisting of dexamethasone, mometasone furoate, and fluticasone, and pharmaceutically acceptable salts thereof.
24. The kit of any one of claims 20-23, wherein the corticosteroid is selected from thasone and fluticasone, and pharmaceutically acceptable salts thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN4287/CHE/2014 | 2014-09-03 | ||
IN4287CH2014 | 2014-09-03 | ||
NZ729419A NZ729419B2 (en) | 2014-09-03 | 2015-09-03 | Method of treatment and compositions comprising a dual pi3k delta-gamma kinase inhibitor and a corticosteroid |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ766879A true NZ766879A (en) | 2021-08-27 |
NZ766879B2 NZ766879B2 (en) | 2021-11-30 |
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