U.S. patent application number 17/065316 was filed with the patent office on 2021-02-04 for methods of treating myeloproliferative disorders.
The applicant listed for this patent is Constellation Pharmaceuticals, Inc.. Invention is credited to Michael Cooper, Adrian Senderowicz.
Application Number | 20210030763 17/065316 |
Document ID | / |
Family ID | 1000005190063 |
Filed Date | 2021-02-04 |
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United States Patent
Application |
20210030763 |
Kind Code |
A1 |
Senderowicz; Adrian ; et
al. |
February 4, 2021 |
METHODS OF TREATING MYELOPROLIFERATIVE DISORDERS
Abstract
The present disclosure relates to the use of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, and pharmaceutically acceptable salts thereof, for
treating myelofibrosis.
Inventors: |
Senderowicz; Adrian;
(Somerville, MA) ; Cooper; Michael; (Cambridge,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Constellation Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
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|
Family ID: |
1000005190063 |
Appl. No.: |
17/065316 |
Filed: |
October 7, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2019/063515 |
Nov 27, 2019 |
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17065316 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/55 20130101;
A61P 35/00 20180101 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 27, 2018 |
US |
PCT/US2018/062534 |
Nov 5, 2019 |
US |
PCT/US2019/059784 |
Claims
1. A method of treating myelofibrosis in a subject comprising
administering to the subject a therapeutically effective amount of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the subject has previously
undergone treatment with a janus kinase (JAK) inhibitor.
3. The method of claim 1, wherein the subject is
progressed/relapsed to a JAK inhibitor.
4. The method of claim 1, wherein the subject is
refractory/resistant to a JAK inhibitor.
5. The method of claim 1, wherein the subject is intolerant to a
JAK inhibitor.
6. The method of claim 1, wherein the subject has previously
undergone treatment with ruxolitinib.
7. The method of claim 1, wherein the subject is a janus kinase
(JAK) inhibitor naive subject.
8. The method of claim 1, further comprising administering to the
subject a therapeutically effective amount of a janus kinase (JAK)
inhibitor.
9. The method of claim 8, wherein the subject is a janus kinase
(JAK) inhibitor naive subject prior to treatment.
10. The method of claim 8, wherein the JAK inhibitor is
ruxolitinib.
11. The method of claim 1, wherein the subject is cytopenic.
12. The method of claim 1, wherein the subject is anemic.
13. The method of claim 1, wherein the subject has a hemoglobin
count of less than 10 g/dL.
14. The method of claim 1, wherein the subject is
thrombocytopenic.
15. The method of claim 1, wherein the subject's platelet count is
less than 120,000 platelets/.mu.L.
16. The method of claim 1, wherein the subject is
thrombocytemic.
17. The method of claim 1, wherein the subject's platelet count is
more than 400,000 platelets/.mu.L.
18. The method of claim 1, wherein the subject's platelet count is
more than 500,000 platelets/.mu.L.
19. The method of claim 1, wherein the subject is neutropenic.
20. The method of claim 1, wherein the subject's absolute
neutrophil count is less than 1000 neutrophils/.mu.L of blood.
21. The method of claim 1, wherein the subject has an enlarged
spleen or liver.
22. The method of claim 1, wherein the subject is suffering from
abdominal discomfort, dyspnea on exertion, early satiety, fatigue,
headaches, night sweats, dizziness, insomnia, pruritus, or bone
pain.
23. The method of claim 1, wherein the subject is transfusion
dependent.
24. The method of claim 1, wherein the subject is administered from
100 mg/day to 300 mg/day of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo [c]isoxazolo
[4,5-e]azepin-4-yl)acetamide.
25-27. (canceled)
28. The method of claim 1, wherein the subject is administered
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide once per day.
29. The method of claim 1, wherein the subject is administered a
pharmaceutically acceptable salt of
6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetam-
ide.
30. The method of claim 1, wherein the subject is administered
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide.
31. The method of claim 1, wherein the subject's platelet count is
more than 450,000 platelets/.mu.L.
32. The method of claim 1, wherein the subject's platelet count is
more than 600,000 platelets/.mu.L.
33. The method of claim 1, wherein the subject is administered from
50 mg/day to 500 mg/day
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide or a pharmaceutically acceptable salt thereof.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of International
Application No. PCT/US2019/063515, filed Nov. 27, 2019, which
claims priority to International Application No. PCT/US2018/062534,
filed Nov. 27, 2018 and International Application No.
PCT/US2019/059784, filed Nov. 5, 2019, the entire contents of each
of which are incorporated herein by reference.
BACKGROUND
[0002] Myeloproliferative disorders are diseases of the bone marrow
and blood. Myelofibrosis, for example, is a clonal
myeloproliferative disease that is characterized by exaggerated
abnormalities in megakaryocytes. The abnormal megakaryocytes are
attributed primarily to dysregulation of the JAK/STAT pathway,
although there is dysregulation in a number of other pathways as
well. Due to the multiple pathways affected and the array of
downstream effects, myelofibrosis is a complex, heterogeneous
disease with many inter-related features. The abnormal
megakaryocytes release excess platelets and cytokines, both
pro-inflammatory and pro-fibrotic (transforming growth factor beta
[TGF- ]), into the bone marrow. The pro-inflammatory cytokines lead
to debilitating constitutional symptoms and exacerbate the
deposition of collagen signaled by pro-fibrotic pathways. Bone
marrow fibrosis is the hallmark of myelofibrosis, although
diagnosis is not necessarily dependent on it. The bone marrow
fibrosis is the key feature that causes the morbidity and mortality
associated with the disease. The bone marrow fibrosis and
inflammatory state of myelofibrosis often lead to cytopenias,
extramedullary hematopoiesis (EMH), organomegaly such as
splenomegaly and hepatomegaly and a myriad of constitutional
symptoms.
[0003] Myelofibrosis is a serious disease in that it is both
life-threatening and greatly diminishes the quality of life of the
patient before it affects survival. The two most common causes of
death are conversion to acute myeloid leukemia (AML) and
progression of the disease. The treatment paradigm is dictated by
the number of risk factors present, which then correlate with
different survival rates. While allogeneic hematopoietic stem cell
transplantation (HCT) can be curative, it is associated with its
own morbidity and mortality, which limit its use to those eligible
patients whose prognosis is worse (<5 years) than the risk of
moving forward with the transplant. The remaining treatments are
more palliative in nature, either due to their mechanism of action
(e.g., treatments specifically focused on the anemia that is
frequently associated with myelofibrosis) or due to the restricted
effects that the treatment can elicit (e.g., the standard of care
ruxolitinib).
[0004] Ruxolitinib, a JAK1/2 inhibitor, is approved for the
treatment of myelofibrosis. JAK is a key regulator in
hematopoiesis, immune regulation, growth and embryogenesis (Stahl
M, Zeidan A M (2017). Management of Myelofibrosis: JAK Inhibition
and Beyond. Expert Rev Hematol; 17(5): 459-477). Dysregulated JAK
signaling can lead to increased thrombopoietin signaling, which is
believed to be one of the causes of increased megakaryocyte
production and platelets in myelofibrosis. Further, JAK signaling
is implicated in the release of pro-inflammatory cytokines and
growth factors that cause constitutional symptoms and splenomegaly:
JAK-1 plays a role in the signaling of pro-inflammatory cytokines
(e.g., IL-1, IL-16, TNF-.alpha.), the cause of systemic symptoms in
myelofibrosis and JAK-2 impacts growth factors and other cytokines
(e.g., IL-3, IL-5) that are believed to promote splenomegaly in
myelofibrosis. Through this mechanism of action, ruxolitinib has
demonstrated an ability to reduce the spleen volumes and symptoms
of myelofibrosis patients, thereby improving their quality of life.
Unfortunately, however, there are a number of limitations with the
current use of ruxolitinib.
[0005] Ruxolitinib is considered a palliative treatment due to its
lack of disease-modifying effects. It does not affect the mutant
allele burden or bone marrow fibrosis (Novel Therapies for
Myelofibrosis, 2017, Curr Hematol Malig Rep; 12(6): 611-624). In
addition, constitutional symptoms will revert back after a week off
of ruxolitinib treatment (see Tefferi A (2017); Management of
Primary Myelofibrosis; UpToDate; 1-23). Next, anemia negatively
impacts patient quality of life, has the highest power of
predicting shortened survival, and limits access to optimal
standard of care. Ruxolitinib is not a viable treatment option for
some anemic patients because ruxolitinib is known to decrease red
blood cell production and hemoglobin levels. Anemic patients, for
example, are either not treated at all with ruxolitinib, given a
lower dose of ruxolitinib leading to inadequate response, or give a
full dose ruxolitinib, which typically leads to need for red blood
cell (RBC) transfusions. See e.g., Haematologica. 2016 December;
101(12): e482-e484. Patients who have become dependent on RBC
transfusions suffer from an even worse quality of life and
prognosis.
[0006] Another unmet medical need is the lack of alternative
therapies for treating myelofibrosis. This means that i) those who
do not achieve an adequate response to ruxolitinib; ii) those who
are intolerant to ruxolitinib; and iii) those who progress despite
treatment with ruxolitinib have little or no alternative treatment
options. Furthermore, approximately 75% of patients who do
initially respond to ruxolitinib end up discontinuing treatment due
to disease progression or toxicity.
SUMMARY
[0007] It has now been found that
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, an inhibitor of the Bromodomain and Extra-Terminal
(BET) family and referenced herein as Compound 1, is effective in
treating myelofibrosis and has numerous advantages over the current
standard of care, i.e., ruxolitinib.
[0008] Unlike ruxolitinib, treating myelofibrosic subjects with
Compound 1 increased hemoglobin levels. This is particularly
important for subjects who are also anemic. For example, patients
247 and 248 in the Exemplification section below experienced an
increase in hemoglobin levels from about 8 g/dL to near normal at
about 11.5 g/dL. See e.g., FIG. 5. In addition, platelet counts
were normalized from about 8 g/dl to about 10.9 g/dl. See e.g.,
FIG. 5.
[0009] Other results showed that uncontrolled thrombocytosis could
be alleviated (i.e., platelets were normalized) in a subject that
was refractory to all standard of care, including the JAK inhibitor
ruxolitinib, following treatment with Compound 1. See e.g., FIG. 6
and the Exemplification section below. An improvement in headaches
was also found.
[0010] Further results showed transfusion dependence could be
reversed following treatment with Compound 1. For example, the
subject who was transfusion dependent while taking the JAK
inhibitor ruxolitinib became transfusion independent after
undergoing treatment with Compound 1, and remained transfusion
independent for more than 24 weeks. See e.g., FIG. 5. Similar
results were seen using a combination of both ruxolitinib and
Compound 1. See e.g., Patients 245 and 246 in the Exemplification
section below and FIG. 6, as well as the expanded data provided
e.g., in FIG. 8, FIG. 10A, and FIG. 10B.
[0011] As an additional advantage, Compound 1 significantly
decreased spleen size, even in subjects who were resistant to
ruxolitinib. For example, prior to administration of Compound 1,
Patient 245 as described below became resistant to ruxolitinib with
her spleen increasing 25% in size (spleen volume was 12 cm by
palpation). However, after 4 weeks of therapy with Compound 1 and
ruxolitinib, her spleen size was reduced to 5 cm. See also FIG. 8,
FIG. 9 FIG. 10A, and FIG. 12A which shows the spleen reduction from
a Phase 2 human trial with Compound 1 and ruxolitinib.
[0012] Provided herein therefore are methods of using Compound 1,
or a pharmaceutically acceptable salt thereof, alone or in
combination with a JAK inhibitor such as ruxolitinib, to treat
myelofibrosis.
[0013] In certain aspects, also provided herein are methods of
using Compound 1, or a pharmaceutically acceptable salt thereof,
alone or in combination with a JAK inhibitor such as ruxolitinib,
to treat myelofibrosis in subjects with anemia.
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1 shows the effects of Compound 1 on IL6 and IL10 mRNA
transcript levels.
[0015] FIG. 2 depicts histograms of Compound 1 effect on
megakaryocyte differentiation.
[0016] FIG. 3 represents the histograms and quantitation of effects
on mature megakaryocyte marker CD42b after Treatment with Compound
1 and ruxolitinib for 10 days in stem-cell derived megakaryocyte
cultures from healthy donor 2 where the grey histrogram is DMSO
treated sample, blue histogram is Compound 1 treated sample, and
CD42b high calculations refer to the Compound 1-treated
samples.
[0017] FIG. 4 shows the repression of BET-target genes IL8 and CCR1
in circulating blood 2 hours post-dose as a function of the plasma
concentration of Compound 1.
[0018] FIG. 5 shows the changes in hemoglobin levels and
transfusion requirements in a combination arm of Compound 1 and
ruxolitinib.
[0019] FIG. 6 shows the change in platelet and hemoglobin levels in
patient 247 of the monotherapy arm.
[0020] FIG. 7 shows the study design for a Phase 2 trial with
Compound 1 and Compound 1 with ruxolitinib in patients with
myelofibrosis.
[0021] FIG. 8 shows the spleen reduction volume improvement from a
Phase 2 human trial using Compound 1 monotherapy or as an add-on to
ruxolitinib in myelofibrosis patients (panel A) as well as the
total symptom score (TSS) improvement from a Phase 2 human trial
using Compound 1 monotherapy or as an add-on to ruxolitinib in
myelofibrosis patients (panel B).
[0022] FIG. 9 shows the spleen reduction volume and total symptom
score (TSS) improvement from a Phase 2 human trial using Compound 1
and ruxolitinib in JAK inhibitor treatment naive myelofibrosis
patients.
[0023] FIG. 10A illustrates the percent spleen reduction volume at
24 weeks after treatment with Compound 1 as an add-on to
ruxolitinib (Arm 2) in patients with refractory or intolerant
myelofibrosis subjects who were transfusion dependent at the start
of therapy.
[0024] FIG. 10B illustrates the percent total symptom score
improvement after treatment with Compound 1 as an add-on to
ruxolitinib (Arm 2) in patients with refractory or intolerant
myelofibrosis subjects who were transfusion dependent at the start
of therapy.
[0025] FIG. 10C illustrates the Patient Global Impression of Change
after treatment with Compound 1 as an add-on to ruxolitinib (Arm 2)
in patients with refractory or intolerant myelofibrosis subjects
who were transfusion dependent at the start of therapy.
[0026] FIG. 11A illustrates the absolute hemoglobin and transfusion
requirement for patient 11-246 following treatment with Compound 1
as an add-on to ruxolitinib (Arm 2).
[0027] FIG. 11B illustrates the absolute hemoglobin and transfusion
requirement for patient 19-277 following treatment with Compound 1
as an add-on to ruxolitinib (Arm 2).
[0028] FIG. 11C illustrates the absolute hemoglobin and transfusion
requirement for patient 11-252 following treatment with Compound 1
as an add-on to ruxolitinib (Arm 2).
[0029] FIG. 11D illustrates the absolute hemoglobin and transfusion
requirement for patient 12-294 following treatment with Compound 1
as an add-on to ruxolitinib (Arm 2).
[0030] FIG. 12A illustrates the percent spleen reduction volume at
24 weeks after treatment with Compound 1 as an add-on to
ruxolitinib (Arm 2) in patients with refractory or intolerant
myelofibrosis who were non-transfusion dependent at the start of
therapy.
[0031] FIG. 12B illustrates the percent total symptom score
improvement after treatment with Compound 1 as an add-on to
ruxolitinib (Arm 2) in patients with refractory or intolerant
myelofibrosis who were non-transfusion dependent at the start of
therapy.
[0032] FIG. 12C illustrates the Patient Global Impression of Change
after treatment with Compound 1 as an add-on to ruxolitinib (Arm 2)
in patients with refractory or intolerant myelofibrosis who were
non-transfusion dependent at the start of therapy.
[0033] FIG. 13A illustrates the percent spleen reduction volume at
24 weeks after treatment with Compound 1 monotherapy (Arm 1) in
patients with refractory or intolerant myelofibrosis who were
transfusion (Cohort 1A) or non-transfusion dependent (Cohort 1B) at
the start of therapy.
[0034] FIG. 13B illustrates the percent total symptom score
improvement after treatment with Compound 1 monotherapy (Arm 1) in
patients with refractory or intolerant myelofibrosis who were
transfusion (Cohort 1A) or non-transfusion dependent (Cohort 1B) at
the start of therapy.
[0035] FIG. 13C illustrates the Patient Global Impression of Change
after treatment with Compound 1 monotherapy (Arm 1) in patients
with refractory or intolerant myelofibrosis who were transfusion
(Cohort 1A) or non-transfusion dependent (Cohort 1B) at the start
of therapy.
[0036] FIG. 14 shows the improvement in bone marrow fibrosis from
Arms 1 and 2 of the phase 2 clinical trial using Compound 1
monotherapy or as an add-on to ruxolitinib in patients with
refractory or intolerant myelofibrosis who were transfusion or
non-transfusion dependent at the start of therapy.
[0037] FIG. 15A illustrates the reduction of CRP in patients with
refractory or intolerant myelofibrosis who were transfusion or
non-transfusion dependent at the start of therapy and were treated
with Compound 1 alone, i.e., monotherapy.
[0038] FIG. 15B illustrates the reduction of IL-8 in patients with
refractory or intolerant myelofibrosis who were transfusion or
non-transfusion dependent at the start of therapy and were treated
with Compound 1 alone, i.e., monotherapy.
[0039] FIG. 15C illustrates the reduction of IL-18 in patients with
refractory or intolerant myelofibrosis who were transfusion or
non-transfusion dependent at the start of therapy and were treated
with Compound 1 alone, i.e., monotherapy.
[0040] FIG. 15D illustrates the reduction of CRP in patients with
refractory or intolerant myelofibrosis who were transfusion or
non-transfusion dependent at the start of therapy and were treated
with Compound 1 as an add-on to ruxolitinib.
[0041] FIG. 15E illustrates the reduction of IL-8 in patients with
refractory or intolerant myelofibrosis who were transfusion or
non-transfusion dependent at the start of therapy and were treated
with Compound 1 as an add-on to ruxolitinib.
[0042] FIG. 15F illustrates the reduction of IL-18 in patients with
refractory or intolerant myelofibrosis who were transfusion or
non-transfusion dependent at the start of therapy and were treated
with Compound 1 as an add-on to ruxolitinib.
[0043] FIG. 16 illustrates the percent spleen reduction volume at
12 weeks after treatment with Compound 1 in JAK inhibitor naive
(Arm 3) patients with myelofibrosis.
[0044] FIG. 17 illustrates the percent total symptom score
improvement after treatment with Compound 1 in JAK inhibitor naive
(Arm 3) patients with myelofibrosis.
[0045] FIG. 18 illustrates the Patient Global Impression of Change
after treatment with Compound 1 in JAK inhibitor naive (Arm 3)
patients with myelofibrosis.
DETAILED DESCRIPTION
[0046]
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azep-
in-4-yl)acetamide is exemplified as Compound 144 in U.S. Pat. No.
8,796,261, the entire contents of which are incorporated herein by
reference.
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide is used interchangeably herein with Compound 1 and/or
CPI-0610, and is represented by the following structural
formula:
##STR00001##
Crystalline forms of Compound 1 are disclosed in U.S. Pat. No.
9,969,747, the entire contents of which are incorporated by
reference herein.
[0047] Compound 1 is a potent and selective small molecule designed
to promote anti-tumor activity by selectively inhibiting the
function of BET protein. See e.g., J. Med. Chem., 2016; February
25; 59(4): 1330-9. Compound 1 is being investigated for its
profound effects in treating hematological malignancies including
progressive lymphoma. See e.g., U.S. Clinical Trials NCT02157636
and NCT01949883. It has now been found, however, that Compound 1 is
also effective in treating myelofibrosis. To this end, for example,
Compound 1 increased hemoglobin levels, normalized platelet counts,
and reduced spleen size. Subjects who were previously transfusion
dependent became transfusion independent after treatment.
[0048] Therefore, in a first embodiment, provided herein is a
method of treating myelofibrosis in a subject comprising
administering to the subject a therapeutically effective amount of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof. Also
provided is the use of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for treating myelofibrosis in a
subject. Further provided is
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof, for
treating myelofibrosis in a subject.
[0049] The terms "subject" and "patient" may be used
interchangeably, and mean a mammal in need of treatment, e.g.,
companion animals (e.g., dogs, cats, and the like), farm animals
(e.g., cows, pigs, horses, sheep, goats and the like) and
laboratory animals (e.g., rats, mice, guinea pigs and the like).
Typically, the subject is a human in need of treatment.
[0050] The terms "treatment," "treat," and "treating" refer to
reversing, alleviating, reducing the likelihood of developing, or
inhibiting the progress of myelofibrosis, or one or more symptoms
thereof, as described herein. In some embodiments, treatment may be
administered after one or more symptoms have developed, i.e.,
therapeutic treatment. In other embodiments, treatment may be
administered in the absence of symptoms. For example, treatment may
be administered to a susceptible individual prior to the onset of
symptoms (e.g., in light of a history of symptoms and/or in light
of genetic or other susceptibility factors), i.e., prophylactic
treatment. Treatment may also be continued after symptoms have
resolved, for example to prevent or delay their recurrence.
Symptoms specific to myelofibrosis include, but are not limited to,
abdominal discomfort, dyspnea on exertion, early satiety, fatigue,
headaches, night sweats, dizziness, fever, chills, insomnia,
pruritus, or bone pain.
[0051] As detailed in the Exemplification section below, Compound 1
was effective in subjects who have undergone treatment for
myelofibrosis with JAK inhibitors such as ruxolitinib. Therefore,
in a second embodiment, provided herein is a method of treating
myelofibrosis in a subject comprising administering to the subject
a therapeutically effective amount of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]-
azepin-4-yl)acetamide, or a pharmaceutically acceptable salt
thereof, wherein the subject has previously undergone treatment
with a janus kinase (JAK) inhibitor (e.g., ruxolitinib). Also
provided is the use of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for treating myelofibrosis in a subject
who has previously undergone treatment with janus kinase (JAK)
inhibitor (e.g., ruxolitinib). Further provided is
24(4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl-
)acetamide, or a pharmaceutically acceptable salt thereof, for
treating myelofibrosis in a subject who has previously undergone
treatment with a janus kinase (JAK) inhibitor (e.g.,
ruxolitinib).
[0052] As detailed in the Exemplification section below, Compound 1
was effective in subjects who have myelofibrosis, but are JAK
inhibitors naive subjects. Therefore, in a third embodiment,
provided herein is a method of treating myelofibrosis in a subject
comprising administering to the subject a therapeutically effective
amount of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof, wherein
the subject is janus kinase (JAK) inhibitor naive subject. Also
provided is the use of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for treating myelofibrosis in a subject
who is a janus kinase (JAK) inhibitor naive subject. Further
provided is
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide, or a pharmaceutically acceptable salt thereof, for
treating myelofibrosis in a subject who is a janus kinase (JAK)
inhibitor naive subject.
[0053] In a fourth embodiment, the subjects described in the first
and second embodiments are characterized as progressed/relapsed to
a JAK inhibitor. In a fifth embodiment, the subjects described in
the first and second embodiments are characterized is
refractory/resistant to a JAK inhibitor. Alternatively, as part of
a fifth embodiment, the subjects described in the first and second
embodiments are characterized as intolerant to a JAK inhibitor.
[0054] A subject who is characterized as progressed/relapsed is one
who at one time responded to treatment with a JAK inhibitor (e.g.,
ruxolitinib), but who no longer responds. A subject who is
characterized as refractory/resistant is one who is unresponsive or
demonstrates worsening of disease while on treatment with a JAK
inhibitor (e.g., ruxolitinib). In one aspect, evidence of
refractoriness/resistance (including loss of response) includes no
spleen size reduction or symptom improvement after 6 months of
therapy, disease progression, or intolerance to ruxolitinib (i.e.,
platelet count <50.times.10.sup.9/L and/or ANC
.ltoreq.0.5.times.10.sup.9/L despite recommended dose adjustments
and interruptions per approved ruxolitinib label; bleeding; or
other severe [i.e. .gtoreq.Grade 3 non-hematological]
toxicity).
[0055] A subject who is characterized as intolerant is one who
cannot tolerate the side effects from treatment with a JAK
inhibitor (e.g., ruxolitinib) and thus has to be removed from
treatment of said JAK inhibitor.
[0056] An illegible patient is defined as those patients for whom a
JAK inhibitor is indicated (e.g., ruxolitinib), but the healthcare
provider is reluctant to initiate treatment with the JAK inhibitor
due to prior history of severe infections such as tuberculosis,
PML, or skin malignancies that are known to be associated or
exacerbated by the JAK inhibitor (see e.g., the approved package
insert for ruxolitinib).
[0057] Compound 1 was also shown to be effective as a combination
treatment with the JAK inhibitor ruxolitinib. Therefore, in a sixth
embodiment, provided herein is a method of treating myelofibrosis
in a subject comprising administering to the subject a
therapeutically effective amount of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide and a therapeutically effective amount of a janus
kinase (JAK) inhibitor (e.g., ruxolitinib), or a pharmaceutically
acceptable salt of any of the foregoing. Also provided is the use
of
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide and a janus kinase (JAK) inhibitor (e.g., ruxolitinib),
or a pharmaceutically acceptable salt of any of the foregoing, in
the manufacture of a medicament for treating myelofibrosis in a
subject. Further provided is
2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-y-
l)acetamide and a janus kinase (JAK) inhibitor (e.g., ruxolitinib),
or a pharmaceutically acceptable salt of any of the foregoing, for
treating myelofibrosis in a subject. Alternatively, as part of a
sixth embodiment, the subject to be treated is a janus kinase (JAK)
inhibitor naive subject prior to treatment.
[0058] As used herein, ruxolitinib refers to the JAK inhibitor
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile phosphate having the following formula.
##STR00002##
[0059] The term "effective amount" or "therapeutically effective
amount" are used interchangeably and include an amount of a
compound described herein that will elicit a desired medical
response in a subject having myelofibrosis, e.g., reducing the
symptoms of and/or slowing the progression of the disease.
[0060] In a seventh embodiment, the subject treated by the methods
described herein (e.g., as in any one of the first through sixth
embodiments) is cytopenic. Cytopenic refers to subjects in which
the production of one or more blood cell types ceases or is greatly
reduced. Types of cytopenia include e.g., anemia (a deficiency of
red blood cells), leukopenia or neutropenia (a deficiency of white
blood cells), thrombocytopenia (a deficiency in the platelets), and
pancytopenia (a deficiency in all three of red blood cells, white
blood cells, and platelet counts).
[0061] In an eighth embodiment, the subject treated by the methods
described herein (e.g., as in any one of the first through seventh
embodiments) is anemic. A subject of the present disclosure (e.g.,
as in any one of the first through seventh embodiments) is said to
be anemic if their hemoglobin value is less than 13.5 g/dL of blood
for a male subject or less than 12.0 g/dL of blood for a female
subject. In some aspects, a subject (e.g., as in any one of the
first through seventh embodiments) is defined herein as being
anemic if their hemoglobin value is less than 10.0 g/dL. Subjects
treatable by the present methods (e.g., as in any one of the first
through seventh embodiments) therefore include those having
hemoglobin values less than 13.0 g/dL, less than 12.5 g/dL, less
than 12.0 g/dL, less than 11.5 g/dL, less than 11.0 g/dL, less than
10.5 g/dL, less than 10.0 g/dL, less than 9.5 g/dL, less than 9.0
g/dL, or less than 8.5 g/dL for male subjects and less than 11.5
g/dL, less than 11.0 g/dL, less than 10.5 g/dL, less than 10.0
g/dL, less than 9.5 g/dL, less than 9.0 g/dL, or less than 8.5 g/dL
for female subjects. In others aspects, a subject (e.g., as in any
one of the first through seventh embodiments) is defined herein as
being anemic if their hemoglobin value ranges from 7.5 g/dL of
blood to 13.5 g/dL of blood for a male subject or from 7.5 g/dL of
blood to 12.0 g/dL of blood for a female subject. In others
aspects, a subject (e.g., as in any one of the first through
seventh embodiments) is defined herein as being anemic if their
hemoglobin value ranges from 7.5 g/dL of blood to 10.5 g/dL of
blood for a male subject or from 7.5 g/dL of blood to 10.5 g/dL of
blood for a female subject. In others aspects, a subject (e.g., as
in any one of the first through seventh embodiments) is defined
herein as being anemic if their hemoglobin value ranges from 7.5
g/dL of blood to 10.0 g/dL of blood for a male subject or from 7.5
g/dL of blood to 10.0 g/dL of blood for a female subject. In others
aspects, a subject (e.g., as in any one of the first through
seventh embodiments) is defined herein as being anemic if their
hemoglobin value ranges from 7.7 g/dL of blood to 10.7 g/dL of
blood for a male subject or from 7.7 g/dL of blood to 10.5 g/dL of
blood for a female subject. In others aspects, a subject (e.g., as
in any one of the first through seventh embodiments) is defined
herein as being anemic if their hemoglobin value ranges from 7.7
g/dL of blood to 10.0 g/dL of blood for a male subject or from 7.7
g/dL of blood to 10.0 g/dL of blood for a female subject.
[0062] In a ninth embodiment, subjects treated by the methods
described herein (e.g., as in any one of the first through eighth
embodiments) are thrombocytopenic. A subject of the present
disclosure (e.g., as in any one of the first through eighth
embodiments) is said to be thrombocytopenic if their platelet count
is less than 150,000 platelets/4, of blood. Subjects treatable by
the present methods (e.g., as in any one of the first through
eighth embodiments) therefore include those having platelet levels
less than 140,000 platelets/.mu.L, less than 130,000
platelets/.mu.L, less than 120,000 platelets/.mu.L, less than
110,000 platelets/.mu.L, less than 100,000 platelets/.mu.L, less
than 90,000 platelets/.mu.L, less than 80,000 platelets/.mu.L, less
than 70,000 platelets/.mu.L, less than 60,000 platelets/.mu.L or
less than 50,000 platelets/.mu.L, alone or in combination with one
or more of the hemoglobin values described above.
[0063] In a tenth embodiment, subjects treated by the methods
described herein (e.g., as in any one of the first through eighth
embodiments) are thrombocytemic. A subject of the present
disclosure treated by the methods described herein (e.g., as in any
one of the first through eighth embodiments) is said to be
thrombocytemic if their platelet count is more than 450,000
platelets/.mu.L of blood. Subjects treatable by the present methods
(e.g., as in any one of the first through eighth embodiments)
therefore include those having platelet levels more than 450,000
platelets/.mu.L, more than 500,000 platelets/.mu.L, more than
550,000 platelets/.mu.L, or more than 600,000 platelets/.mu.L,
alone or in combination with one or more of the hemoglobin values
described above. Alternatively, as part of a tenth embodiment, a
subject of the present disclosure treated by the methods described
herein (e.g., as in any one of the first through eighth
embodiments) is said to be thrombocytemic if their platelet count
is more than 400,000 platelets/.mu.L of blood. Subjects treatable
by the present methods (e.g., as in any one of the first through
eighth embodiments) therefore include those having platelet levels
more than 400,000 platelets/.mu.L.
[0064] In an eleventh embodiment, the subject treated by the
methods described herein (e.g., as in any one of the first through
tenth embodiments) is leukopenic. A subject (e.g., as in any one of
the first through tenth embodiments) is said to be leukopenic if
their white blood cell (WBC) count is less than 4,000 WBCs/.mu.L of
blood. In certain aspects, subjects treatable by the present
methods (e.g., as in any one of the first through tenth
embodiments) include those having WBC counts of less than 3,500
WBCs/.mu.L, 3,200 WBCs/.mu.L, 3,000 WBCs/.mu.L, or 2,500
WBCs/.mu.L, alone or in combination with one or more of the
hemoglobin and/or platelet values described above.
[0065] In a twelfth embodiment, the subject treated by the methods
described herein is (e.g., as in any one of the first through
eleventh embodiments) neutropenic. In one aspect, a subject of the
present disclosure (e.g., as in any one of the first through
eleventh embodiments) is said to be neutropenic if their neutrophil
count is less than 1500 neutrophils/.mu.L of blood. In certain
aspects, subjects treatable by the present methods (e.g., as in any
one of the first through eleventh embodiments) include those having
neutrophil counts of less than 1250 neutrophils/.mu.L, 1000
neutrophils/.mu.L, 750 neutrophils/.mu.L, or 500 neutrophils/.mu.L,
alone or in combination with one or more of the hemoglobin,
platelet, and/or WBC values described above.
[0066] Myelofibrosis is often associated with an enlarging of the
spleen. Enlarging of the spleen can result in a feeling of
fullness, indigestion, and a loss of appetite. In a thirteenth
embodiment, subjects treatable by the present methods (e.g., as in
any one of the first through twelfth embodiments) include those
having an enlarged spleen or liver.
[0067] In a fourteenth embodiment, subjects treatable by the
present methods (e.g., as in any one of the first through
thirteenth embodiments) may also be experiencing one or more
additional symptoms. These symptoms include, but are not limited
to, abdominal discomfort, dyspnea on exertion, early satiety,
fatigue, headaches, night sweats, dizziness, insomnia, pruritus, or
bone pain.
[0068] In a fifteenth embodiment, subjects treated by the present
methods (e.g., as in any one of the first through fourteenth
embodiments) are transfusion dependent prior to treatment with
Compound 1. In some aspects, "transfusion dependent" means that a
subject requires red blood cell (RBC) transfusions in order to
maintain an acceptable level of hemoglobin. An acceptable level of
hemoglobin is determined by those skill in the art and can range
from e.g., from 13.5 to 17.5 g/dL of blood for men and from 12.0 to
15.5 g/dL of blood in women. It will be understood that subjects
undergoing treatment with Tux may have lower hemoglobin levels than
those described above and still be deemed an "acceptable" level in
order for treatment to continue.
[0069] In a sixteenth embodiment, subjects treated by the present
methods (e.g., as in any one of the first through fifteenth
embodiments) experience a reduction in spleen size. In one aspect,
the reduction comprises a 10% or more (e.g., a 15% or more, a 20%
or more, a 25% or more, a 30% or more, a 35% or more, a 40% or
more, a 45% or more, a 50% or more, a 55% or more, a 60% or more,
or a 65% or more reduction in spleen volume from baseline. In
another aspect, the reduction comprises from a 10% to a 65%
reduction in spleen volume from baseline.
[0070] In a seventeenth embodiment, subjects treated by the present
methods (e.g., as in any one of the first through sixteenth
embodiments) experience a reduction in headaches.
[0071] In an eighteenth embodiment, subjects treated by the present
methods (e.g., as in any one of the first through seventeenth
embodiments) have a reduction in the number of blood
transfusion.
[0072] In a nineteenth embodiment, subjects treated by the present
methods (e.g., as in any one of the first through eighteenth
embodiments) experience a normalization of platelets.
[0073] In a twentieth embodiment, subjects treated by the present
methods (e.g., as in any one of the first through nineteenth
embodiments) experience an increase in hemoglobin values.
[0074] In a twenty-first embodiment, subjects treated by the
present methods (e.g., as in any one of the first through twentieth
embodiments) experience an improvement in bone marrow fibrosis as
determined e.g., by the bone marrow fibrosis grading scale (see
Thiele J et al., Haematologica, 2005, 90, 1128). In one aspect, an
improvement is defined as at least one grade improvement in the
bone marrow fibrosis/reticulin grading compared to baseline.
[0075] In a twenty-second embodiment, subjects treated by the
present methods (e.g., as in any one of the first through
twenty-second embodiments) experience a reduction in
pro-inflammatory cytokines such as e.g., CRP, IL-8, and/or
IL-18.
[0076] The compounds of the methods described herein can be
formulated as pharmaceutical compositions and administered to a
subject, such as a human, in a variety of forms adapted to the
chosen route of administration. Typical routes of administering
such pharmaceutical compositions include, without limitation, oral,
topical, buccal, transdermal, inhalation, parenteral, sublingual,
rectal, vaginal, and intranasal. The term parenteral as used herein
includes subcutaneous injections, intravenous, intramuscular,
intrathecal, intrasternal injection or infusion techniques. Methods
of formulating pharmaceutical compositions are well known in the
art, for example, as disclosed in "Remington: The Science and
Practice of Pharmacy," University of the Sciences in Philadelphia,
ed., 21st edition, 2005, Lippincott, Williams & Wilkins,
Philadelphia, Pa.
[0077] Pharmaceutical compositions of the invention can be prepared
by combining a compound of the methods described herein with an
appropriate pharmaceutically acceptable carrier, diluent or
excipient, and may be formulated into preparations in solid,
semi-solid, liquid or gaseous forms, such as tablets, capsules,
powders, granules, ointments, solutions, suppositories, injections,
inhalants, gels, microspheres, and aerosols. Thus, the present
compounds of the methods described herein may be systemically
administered, e.g., orally, in combination with a pharmaceutically
acceptable excipient such as an inert diluent or an assimilable
edible carrier. They may be enclosed in hard or soft shell gelatin
capsules, may be compressed into tablets or may be incorporated
directly with the food of the patient's diet. For oral therapeutic
administration, the active compound may be combined with one or
more excipients and used in the form of ingestible tablets, buccal
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like.
[0078] A specific dosage and treatment regimen for any particular
patient 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 a compound described herein in the composition will
also depend upon the particular compound in the composition. In one
aspect, however, when used as a monotherapy (i.e., without a JAK
inhibitor such as ruxolitinib) Compound 1, or a pharmaceutically
acceptable salt thereof, may be formulated at a dose of from 50 mg
to 500 mg for e.g., administration once, twice, or three times
daily. For example, in monotherapies, Compound 1 may be
administered at a dosage of from 50 mg to 300 mg/day, from 75 mg to
300 mg/day, from 100 mg to 300 mg/day, from 150 mg to 250 mg/day,
or at 150 mg/day, 175 mg/day, 200 mg/day, 225 mg/day, or 250
mg/day. In other aspects, when used in combination with a JAK
inhibitor such as ruxolitinib, Compound 1, or a pharmaceutically
acceptable salt thereof, may be formulated at a dose of from 50 mg
to 500 mg for e.g., administration once, twice, or three times
daily. For example, in combination therapies, Compound 1 may be
administered at a dosage of from 50 mg to 300 mg/day, from 75 mg to
300 mg/day, from 100 mg to 300 mg/day, from 100 mg to 200 mg/day,
or at 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day, or 200
mg/day.
Exemplification
[0079] Compound 1 can be obtained following the procedures
described in U.S. Pat. No. 8,796,261 and WO 2015/195862, both of
which are incorporated herein by reference.
Inhibitory Effect on Cytokine Release In Vitro
[0080] Compound 1 was assessed for its ability to suppress the
expression of NF-.kappa.B target genes in two experiments. In one
experiment, THP-1 acute leukemia cell lines were exposed to
lipopolysaccharide treatment and then Compound 1 for 16 hours. IL6
release from the THP-1 acute leukemia cells was inhibited, with an
IC.sub.50 of 0.069 .mu.M. In the other experiment, the ability of
Compound 1 to suppress both IL6 and IL10 expression in TMD8
ABC-DLBCL cells was investigated (data on file). TMD8 cells were
incubated with DMSO or 1.6 .mu.M Compound 1 for 6 or 24 hours. RNA
was then extracted from the cells and quantified using qRT-PCR. As
shown in FIG. 1, Compound 1 substantially suppressed mRNA
transcription of both IL6 and IL10 after 6 and 24 hours of
treatment.
Effect of Compound 1 as a Single Agent on Megakaryocyte
Differentiation
[0081] The effects of Compound 1 on megakaryocyte differentiation
and proliferation were evaluated using CD34+ cells isolated from
healthy donor bone marrow (data on file). The CD34+ cells were
grown in megakaryocyte differentiation serum-free stem cell
differentiation base medium with a megakaryocyte-driving cytokine
cocktail for 14 days with DMSO or Compound 1 at concentrations
ranging from 3 nM to 500 nM. The cells were then stained for CD34
(progenitor marker), CD45 (leukocyte marker) and CD41a (mature
megakaryocyte marker) and assessed by FACS for viability and marker
expression. CD41a expression and cell size were used as markers of
megakaryocyte differentiation. Compound 1 reduced the number of
cells with high CD41a expression in a concentration-dependent
manner. The shift from high to low CD41a expression began at
approximately 50 nM, with pronounced effects observed at 200 to 500
nM, as shown in FIG. 2. The loss of CD41a-high-expressing cells
suggests impaired megakaryocyte differentiation and loss of mature
megakaryocytes.
Effects of Compound 1 Alone and in Combination with Ruxolitinib on
Megakaryocyte Differentiation and Proliferation
[0082] In a similar experiment, CD34+ cells that were isolated from
the bone marrow of two healthy donors were incubated for 10 days in
megakaryocyte differentiation media with DMSO; Compound 1 alone, at
a concentration of 30 to 500 nM; ruxolitinib alone at concentration
of 8 to 1000 nM; or Compound 1 in combination with ruxolitinib at
the same concentrations they were tested alone (data on file). The
cells were then harvested for FACS analysis with live/dead stain
and gating with CD34 (progenitor marker) and CD41a and CD42b
(mature megakaryocyte markers). While Compound 1 showed limited
effects on overall viability (percent of live cells by live/dead
stain), it demonstrated potent effects on overall cell
proliferation (total live count) and megakaryocyte differentiation
(percent of cells double positive for CD41a and CD42b), which led
to an overall loss of live mature megakaryocytes (mean EC.sub.50 of
28 nM; Table 1).
[0083] In contrast to Compound 1, ruxolitinib exerted effects on
megakaryocyte differentiation at a similar concentration that
killed the progenitor cells (mean EC.sub.50 values of 526 and 644
nM, respectively; Table 1), suggesting the inhibitory effects of
ruxolitinib on megakaryocytes are based on its cytotoxicity. When
serial dilutions of Compound 1 were combined with serial dilutions
of ruxolitinib, an additive inhibitory effect was observed on
megakaryotcyte differentiation (FIG. 3). A similar additive effect
was seen on overall cell proliferation where the mean EC.sub.50 for
Compound 1 decreased from 38 to 17 nM (extrapolated), below the
lowest dose tested in the presence of 250 nM ruxolitinib,
indicating that concentrations of Compound 1 and ruxolitinib near
their IC.sub.50 values for megakaryocyte differentiation and
proliferation were effective at reducing the quantity of the other
agent needed to elicit the same effect.
TABLE-US-00001 TABLE 3 Compound 1 EC50 values following 10 days of
treatment of CD34+ cells Compound 1 EC.sub.50 (nM) Ruxolitinib
EC.sub.50 (nM) Parameter Donor 1 Donor 2 Mean Donor 1 Donor 2 Mean
Viability 300 >500 400 676 611 644 Total live count 43 32 38 288
259 274 Megakaryocyte 60 131 96 517 535 526 differentiation
Megakaryocyte 26 29 28 312 258 285 live count
Reduction in Cytokine Levels in Peripheral Blood
[0084] A panel of selected BET target genes (CCR1, CCR2, IL8, FN1,
CSF1R and THBS1) was evaluated in peripheral blood samples from
patients participating in the Compound 1 Phase 1 clinical studies,
in order to determine the relationship between systemic exposure of
Compound 1 and suppression of these BET inhibitor-sensitive genes.
Gene expression analysis, along with the Compound 1 plasma
concentration versus time data, shows that there is a time- and
concentration-dependent relationship. Consistent with non-clinical
data, Compound 1-induced changes in expression were most
consistently observed for IL8 and CCR1 at 2 hours post treatment,
indicating the rapid effects of BET inhibition on transcription.
Examples of the exposure-response relationships for CCR1 and IL8
are presented in FIG. 4. The data shown includes samples taken from
patients with lymphoma who were treated with Compound 1 in Study
0610-01. Gene expression values were normalized to those measured
at a single time point pre-treatment (100%). This data demonstrated
the rapid on-target effects of BET inhibition on key
pro-inflammatory genes and supports the use of this clinical
biomarker assay.
Initial Human Clinical Data Set
Clinical Signs Overview of Activity in Patients with
Myelofibrosis
[0085] Four patients with myelofibrosis were enrolled in a human
trial that demonstrated clinical benefit which extended at least 6
months. Two myelofibrosis patients to enroll (Patients 245 and 246)
received Compound 1 in combination with ruxolitinib and received 18
treatment cycles (11 months of treatment). The other two patients
to enroll (Patients 247 and 248) received 10 cycles of Compound 1
as monotherapy (6 months of treatment). All four patients
experienced a reduction in their constitutional symptoms along with
a decrease in spleen volume and an increase in hemoglobin. One of
the patients who was transfusion dependent at study entry became
transfusion independent (defined as >12 weeks without the need
for a red blood cell (RBC) transfusion. Indeed, 7 months had
elapsed since their last transfusion.
[0086] All four patients experienced an increase in their
hemoglobin levels with multiple treatment cycles with Compound 1.
In addition, one of the patients who entered the study with
uncontrolled thrombocytosis (baseline platelets were
895.times.10.sup.9/L) experienced a normalization of their platelet
counts within the first month of monotherapy treatment with
Compound 1. The patient's platelet counts remained normal for more
than 20 weeks. This patient's thrombocytosis was also accompanied
by severe headaches requiring multiple hospital admission.
Following treatment with Compound 1, however, the patient's
headaches were resolved. Brief narratives for all four patients
treated for at least 6 months are presented below.
Combination Therapy Arm
[0087] Patient 245, a 66 year-old female was diagnosed with
myelofibrosis in May 2014, remained treatment naive until January
2016 when she initiated treatment with ruxolitinib 15 mg twice
daily (BID). Panobinostat was added in February 2016 and
discontinued in March 2017, due to the development of anemia. From
March 2017, while on ruxolitinib alone, the patient became
resistant to ruxolitinib, with her spleen increasing 25% in
size.
[0088] At entry into the study with Compound 1, her spleen volume
by MRI was 1404 cc and was 12 cm by palpation. The patient
presented with early satiety, night sweats, and dyspnea at the
start of the study. Within 4 months of treatment with Compound 1,
125 mg QD and ruxolitinib 15 mg BID, the patient had resolution of
early satiety; her spleen was 5 cm by palpation and her liver was
no longer palpable. The lowest spleen volume by MRI was 1144 cc, a
19% reduction, at the 6-month MM. The dose of ruxolitinib was
reduced on Cycle 10 to 7.5 mg BID to address decreasing platelet
count. Her platelets counts gradually improved following the dose
reduction of ruxolitinib and remained below the protocol-specified
criteria of 100.times.10.sup.9/L for two treatment cycles to permit
a dose increase in Compound 1.
[0089] Patient 246 is a 53 year-old female who was diagnosed with
myelofibrosis in 2009. During 2002 and 2006, the patient cycled
between epoetin alfa, lenalidomide and thalidomide then received
lenalidomide for 7 years until 2013. She required RBC transfusions
during 2013 and initiated interferon in 2014, which allowed her to
become transfusion independent. Interferon was discontinued almost
a year later due to fatigue. The patient remained transfusion
independent and without further treatment until late 2016 when they
once again became transfusion dependent. Ruxolitinib 5 mg BID was
started in January 2017. Ruxolitinib was increased to 10 mg BID in
April 2017, but the patient remained transfusion dependent and
symptomatic. She was considered ruxolitinib resistant due an
increasing spleen size and exacerbated symptoms (extreme fatigue,
shortness of breath, distress on exertion, occasional nausea and
night sweats) while on ruxolitinib therapy.
[0090] When Patient 246 initiated combination treatment with
Compound 1 125 mg QD and ruxolitinib 10 mg BID her spleen volume
was 607 cc by MRI and 2 cm by palpation and she required regular
transfusions (2 units of RBC every 3-4 weeks). The dose of Compound
1 was titrated up to 175 mg QD after five treatment cycles and
within 7 months of combination therapy, the patient had become
transfusion independent (defined as >12 weeks without a
transfusion and hemoglobin >8 g/dL; see FIG. 5), which has been
maintained for >30 weeks (most recent hemoglobin measurement was
10.9 g/dL). She has also experienced a clinically meaningful
improvement in her associated constitutional symptoms (fatigue and
dyspnea) and has had an incremental decrease in spleen volume,
achieving a 37% reduction in spleen volume by Cycle 12 (380
cc).
Monotherapy Arm
[0091] Patient 247 is a 46 year-old female who was diagnosed with
myelofibrosis in April 2014. In 2009, it was suspected that the
patient had essential thrombocytosis (ET) for which she received
hydroxyurea treatment from April 2009 to December 2017. The patient
also received one month of epoetin alpha in 2015, three months of
imetelstat in 2016 and four months of pembrolizumab in 2017.
Ruxolitinib was administered from October 2015 to May 2016.
Ruxolitinib was discontinued due to worsening symptomatic
splenomegaly, anemia, leukocytosis, and thrombocytosis.
[0092] Upon entry into the study with Compound 1, Patient 247 had a
spleen volume of 858 cc by Mill and 5 cm by palpation and a host of
constitutional symptoms, including: abdominal discomfort, dyspnea
on exertion, early satiety, fatigue, headaches, night sweats,
dizziness, insomnia, pruritus, and bone pain. The patient also
presented with uncontrolled thrombocytosis at study entry (platelet
count of 895.times.10.sup.9/L at baseline) despite hydroxyurea. In
addition, the patient had experienced persistent and debilitating
headaches that required multiple hospital admissions for pain
control. Their platelets were normalized after receiving their
first two weeks of Compound 1 monotherapy (183.times.10.sup.9/L)
and have remained within the normal range for the remainder of the
time they have been on study (see FIG. 6). Within 2 months on
Compound 1 monotherapy, the patient's severe headaches had
resolved; their night sweats were less frequent; and a 37%
reduction in symptoms was assessed by the Myeloproliferative
Neoplasm Symptom (MNS) score. Their ECOG performance score
decreased from 2 to 1 after two treatment cycles with CPI-0610 and
a 25% decrease in spleen volume (640 cc) was assessed by MRI after
8 treatment cycles, the most recent measurement.
[0093] Patient 248, a 76 year-old male who was diagnosed with
myelofibrosis in September 2011 was treated with fresolemunib
(December 2011 to October 2012) and itacitinib (December 2012 to
July 2014). Ruxolitinib 5 mg BID was initiated in January 2015 and
increased to 15 mg BID in December 2015. Ruxolitinib was
discontinued in September 2016 because the patient was experiencing
generally worsening fatigue, anemia and thrombocytopenia.
Subsequent to ruxolitinib treatment, the patient received
imetalstat from June 2016 through March 2017, followed by
pembrolizumab from June to October 2017.
[0094] Upon entry into the study with Compound 1, the patient had a
spleen volume of 1148 cc by MRI and 5 cm by palpation. Their
constitutional symptoms at study entry included fatigue, early
satiety, and difficulty concentrating. The patient did not tolerate
the 225 mg QD starting dose of Compound 1 (he experienced nausea,
diarrhea, malaise and dizziness), requiring dose interruption after
the first 5 doses of Cycle 1. The patient was reinitiated with a
reduced Compound 1 dose of 175 mg at the beginning of Cycle 2,
which has been tolerated for the remaining time on study (>6
months). While the patient's spleen has shown minimal change
through palpation a spleen volume reduction of 11% (1023 cc) was
measured by MRI after 3 months on treatment with Compound 1. Their
MNS score improved 19% after 2 months on the 175 mg QD dose and
after 6 months of Compound 1 treatment his bone marrow fibrosis
grade decreased from MF-2 at baseline to MF-1 based on a local
pathologist's assessment.
Human Phase 2 Clinical Data Set
[0095] A Phase 2 study of Compound 1 in subjects with myelofibrosis
(MF) was conducted. Three treatment arms were studied:
[0096] Arm 1=monotherapy with Compound 1 in patients (pts) who are
no longer on Rux and are with refractory, intolerant, or
ineligible. In this arm patients were further stratified based on
transfusion dependence status [transfusion dependent (TD), defined
as an average of .gtoreq.2 units per month over 12 wks, or non-TD
cohorts]. Primary endpoint: spleen volume response (SVR) for non-TD
cohorts or TD to transfusion independence (TI, no transfusion for
consecutive 12 wks) conversion for TD cohorts; secondary endpoints:
change in total symptom score (TSS) per MFSAF v4.0, patient global
impression of change (PGIC), safety and PK; additional endpoints:
changes in proinflammatory Ck levels, BM morphology and mutant
allele burden.
[0097] Arm 2=combination add-on treatment of Compound 1 in patients
(pts) who are already being administered Rux. In this arm patients
were further stratified based on transfusion dependence status
[transfusion dependent (TD), defined as an average of .gtoreq.2
units per month over 12 wks, or non-TD cohorts]. The starting dose
of Compound 1 was 125 mg daily on days 1-14 of a 21-day cycle in
both arms. Primary endpoint: spleen volume response (SVR) for
non-TD cohorts or TD to transfusion independence (TI, no
transfusion for consecutive 12 wks) conversion for TD cohorts;
secondary endpoints: change in total symptom score (TSS) per MFSAF
v4.0, patient global impression of change (PGIC), safety and PK;
additional endpoints: changes in proinflammatory Ck levels, BM
morphology and mutant allele burden.
[0098] Arm 3--combination treatment with Compound 1 and Rux in
patients (pts) who have not previously been administered a JAK
inhibitor, i.e., JAK inhibitor treatment naive. In this arm, key
eligibility criteria of included JAKi naive myelofibrosis (MF)
patients (pts) with Dynamic International Prognostic Scoring
(DIPSS) score int-1 or higher, ECOG performance status .ltoreq.2,
platelet counts (PLT) .gtoreq.100.times.109/L, peripheral blood
blast count <10%, anemia (hemoglobin <10 g/dL), .gtoreq.5 cm
palpable spleen, .gtoreq.2 symptoms measurable (score .gtoreq.3) or
a total symptom score (c using the MFSAF v4.0. Primary endpoint:
spleen volume response (SVR); key secondary endpoints: change in
TSS, safety and PK; additional endpoints: changes in
proinflammatory cytokine (Ck) levels, BM morphology and mutant
allele burden.
[0099] The starting dose of Compound 1 was 125 mg given orally,
once daily for 2 weeks on/1 week off in a 21-day dosing cycle. Two
separate time points for data analysis occurred for at least Arms 1
and 2 and are discussed below: one at approximately 12 weeks of
treatment (first assessment of spleen volume by Mill or CT and
every 12 weeks thereafter) and another at approximately 24 weeks of
treatment (first assessment of bone marrow biopsy and every 24
weeks thereafter). Patients were added to the study following the
first time point. An overview of the study profile is shown in FIG.
7.
[0100] Time Point 1:
Arm 1 and Arm 2--Compound 1 as Monotherapy or Add-on to Ruxolitinib
in Patients with Refractory or Intolerant Advanced
Myelofibrosis
[0101] Demographics and results are as follows: At baseline, median
age: 69 years (41-88), gender: 28 (58%) male, ECOG .ltoreq.1: 45
(94%) patients, primary MF: 33 (69%) patients, DIPSS score high: 10
(21%) patients, median platelet: 199.times.109/L (77-895), 34 (71%)
patients with Hgb <10 g/dL, median spleen volume: 2183 cc
(123-3909), median TSS: 17.6 (1.4-56), 46 (96%) patients had
.gtoreq.1 JAK2/MPL/CALR mutations, and 34 (71%) patients had HMR
(high molecular risk) mutations. 33 (69%) patients on treatment for
.gtoreq.12 wks, 4 on treatment for >18 months.
[0102] Spleen volume reduction observed in 29 of 31 (94%) patients
(median best change: -17% [range: -50.7, 10.2]) (FIG. 8, panel A).
TSS improvement was reported in 26 of 28 (93%) patients (median
best change: -46.4% [range: -95.3%, 27%]), 11 (39%) patients with
.gtoreq.50% TSS improvement (FIG. 8, panel B). PGIC improvement
score in 28 of 33 (85%) patients; 21 (64%) reported much or very
much improved scores. Increase in hemoglobin by 1.5 mg/dL
post-baseline observed with both Compound 1 monotherapy (4 of 8,
50%) and Compound 1 with ruxolitinib (4 of 25, 16%)). Improvement
in BM fibrosis and/or reticulin by .gtoreq.1 Gr reported in 7 of 12
(58%) evaluable patients with baseline and 1 post-baseline biopsy
and as early as 6-months of Compound 1 treatment. 4 TD patients in
Arm 2 treated with Compound 1 with ruxolitinib converted to TI-2 of
whom are TI for >36 wks, no longer anemic, and showed spleen
volume reduction, improvement in symptom and BM fibrosis; 12
additional patients are being monitored for potential TI
conversion. 41 patients remain active on treatment and 7 patients
discontinued, including 1 patient, initially transplant ineligible,
underwent stem cell transplantation after 6 cycles of Compound 1
with ruxolitinib treatment. Most common (.gtoreq.20%)
treatment-emergent adverse events (TEAE) of any Gr include
diarrhea, nausea, cough and upper respiratory tract infection. Most
common (.gtoreq.5%) .gtoreq.3 Gr TEAE include anemia (8.3%) and
thrombocytopenia (8.3%, asymptomatic, non-cumulative and generally
reversible).
[0103] This data indicates that Compound 1 alone or "add-on" to
ruxolitinib is generally well-tolerated and provides clinical
benefits in MF patients with inadequate responses or who are
refractory to ruxolitinib. Improvement in BM fibrosis and anemia
responses indicate the potential for meaningful disease
modification.
Arm 3--Compound 1 and Ruxolitinib in JAK Inhibitor Treatment Naive
Myelofibrosis Patients
[0104] Demographics and results are as follows: Baseline median
age: 71 years (52-76), gender: 8 male (72.7%), ECOG .ltoreq.1: 10
(90.9%) patients, primary MF: 8 (72.7%) patients, DIPSS score:
int-1/int-2/high: 2/7/2 patients, median platelet: 368.times.109/L
(112-951), 9 (81.8%) patients with hemoglobin <10 g/dL, median
spleen volume: 1379 cc (580-2807), median TSS: 11.8 (4.1-17),
driver mutations: 11 (100%) with .gtoreq.1 JAK2/MPL/CALR mutations,
HMR (high molecular risk) mutations: 6 (56%) patients, and
.gtoreq.3 mutations: 4 (36%) patients. All 4 (100%) patients on
treatment for .gtoreq.12 weeks achieved .gtoreq.35% spleen volume
reduction (median: -52.4%, [range -68.7%, -42.7%]) and all 4
patients (100%) achieved .gtoreq.50% improvement in TSS (median
best change: -79.35% [range -90.2%, -70.1%]). See FIG. 9, where *
is data post cut off-date. A reduction of proinflammatory Ck,
including IL-18 and CRP, was also observed. Safety data from the
first 6 patients who received treatment for at least 1 cycle were
reviewed: no DLTs or grade .gtoreq.3 thrombocytopenia was observed.
The most common treatment-emergent adverse events (TEAE) observed
in .gtoreq.2 patients include anemia (1 grade 3), fatigue (all
.ltoreq.grade 2), and non-cumulative reversible thrombocytopenia
(all .ltoreq.grade 2).
[0105] Overall, the combination of Compound 1 and ruxolitinib was
generally well-tolerated demonstrating that the safety of this
combination is acceptable in JAKi naive MF patients with anemia.
Early clinical activity was observed with the combination: all 4
evaluable patients achieved both .gtoreq.35% SVR and .gtoreq.50%
improvement in TSS as early as 3 months after treatment. Available
data in JAKi naive anemic MF patients, a population with poor
prognosis, along-with additional information on reduction in
pro-inflammatory Ck and BM fibrosis improvement in Compound 1
treated patients in ruxolitinib refractory MF, collectively
indicate that addition of Compound 1 to ruxolitinib could have
disease-modifying effects in JAKi naive MF patients.
[0106] An expanded patient population (n=15) for Arm 3 were treated
for at least 12 weeks. About 80% of patients achieved .gtoreq.35%
SVR with an average of about -49.7%. See FIG. 16. Hgb was less than
10 g/dL and DIPSS score was int-2 or higher. In addition, about 71%
of patients had a TSS of .gtoreq.10 (see FIG. 17) and about 80% of
patients had an overall improvement in PGIC (see FIG. 18).
[0107] Time Point 2
[0108] Patients were added to the study following the first data
cut and treatment was continued for approximately 25.9 weeks
(median, range: 0.4, 116.6). A summary of the results from the
trial are provided below.
[0109] FIGS. 10A-C illustrates the 24 week results from treatment
with Compound 1 as an add-on to ruxolitinib (Arm 2) in patient's
with refractory or intolerant myelofibrosis subjects who were
transfusion dependent at the start of therapy. At 24 weeks, about
35% of patients converted from transfusion dependent to transfusion
independent as represented by the upward arrows (FIG. 10A). The
average spleen volume reduction was about -24.9%. About 76.5% of
patients had improvement in disease symptoms per total symptom
score (TSS) about 75% of patients had improved Patient Global
Impression of Change (PGIC). See FIGS. 10B and 10C. Further, about
63% of patients showed improvement in bone marrow fibrosis (data
not shown).
[0110] FIGS. 11A-D shows the absolute hemoglobin values and
transfusion requirements for representative patients from Arm 2.
The average time of conversion from transfusion dependent (TD) to
transfusion independent (TI) was about 14 weeks. The average
transfusion free time post-conversion was about 14 weeks with a
maximum of 85 weeks. About 41% of patients had greater than or
equal to a 50% reduction in transfusion intensity.
[0111] FIGS. 12A-C illustrates the 24 week results from treatment
with Compound 1 as an add-on to ruxolitinib (Arm 2) in patients
with refractory or intolerant myelofibrosis subjects who were
non-transfusion dependent at the start of therapy. At 24 weeks, the
average spleen volume reduction was about -10.9% (FIG. 12A). About
38% of patients had improvement in disease symptoms per total
symptom score (TSS) about 69% of patients had improved Patient
Global Impression of Change (PGIC). See FIGS. 12B and 12C. Further,
about 25% of patients showed improvement in bone marrow fibrosis
(data not shown).
[0112] FIGS. 13A-C illustrates the 24 week results from treatment
with Compound 1 monotherapy (Arm 1) in patients with refractory or
intolerant myelofibrosis subjects who were transfusion (Cohort 1A)
or non-transfusion dependent (Cohort 1B) at the start of therapy.
At 24 weeks, the average spleen volume reduction was about -3.2%
for TD patients and about -26% for non-TD patients (FIG. 13A).
About 60% of non-TD patients had improvement in disease symptoms
per total symptom score (TSS) about 50% of TD and 100% of non-TD
patients had improved Patient Global Impression of Change (PGIC).
See FIGS. 13B and 13C. Further, about 25% of TD patients showed
improvement in bone marrow fibrosis (data not shown).
[0113] The improvement in bone marrow fibrosis from Arms 1 and 2
were also evaluated. See FIG. 14. It was found that about 38% of
subjects had bone marrow fibrosis improvement with about 32% having
improvement as early as 6-months. Additionally, the best
improvement in bone marrow fibrosis was seen in Cohort 2B (See FIG.
7) at 63% of patients having improvement, i.e., those patients who
were transfusion dependent at the start of therapy and were given
Compound 1 as an add-on to ruxolitinib.
[0114] Pro-inflammatory cytokine levels showed a trend toward
normalization within 14 days for both monotherapy and combination
therapy arms. See FIGS. 15A-F.
[0115] While have described a number of embodiments of this, it is
apparent that our basic examples may be altered to provide other
embodiments that utilize the compounds and methods of this
disclosure. Therefore, it will be appreciated that the scope of
this disclosure is to be defined by the appended claims rather than
by the specific embodiments that have been represented by way of
example.
[0116] The contents of all references (including literature
references, issued patents, published patent applications, and
co-pending patent applications) cited throughout this application
are hereby expressly incorporated herein in their entireties by
reference. Unless otherwise defined, all technical and scientific
terms used herein are accorded the meaning commonly known to one
with ordinary skill in the art.
* * * * *