Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a
clinical-stage biopharmaceutical company using its expertise in
epigenetics to discover and develop novel therapeutics, today
presented results from the Phase 1b portion of the ProSTAR clinical
trial of CPI-1205 at the American Association for Cancer Research
(AACR) annual meeting in Atlanta. Poster CT094/18, ProSTAR: A phase
1b/2 study of CPI-1205, a small molecule inhibitor of EZH2,
combined with enzalutamide (E) or abiraterone/prednisone (A/P) in
patients with metastatic castration-resistant prostate cancer
(mCRPC), was presented at the poster session starting at 1:00 PM
EDT today. The Company will present two other posters highlighting
its preclinical pipeline later in the AACR meeting.
“We are pleased to report the ProSTAR Phase 1b results,” said
Adrian Senderowicz, Chief Medical Officer. “These results show
clinical activity in subsets of a heterogeneous population of
advanced mCRPC patients in combination with either abiraterone or
enzalutamide. Activity was particularly noteworthy in patients
taking CPI-1205 in combination with abiraterone, an agent where
responses in second-line patients have historically been poor, and
in AR-V7-negative patients. Based on the entirety of the results,
we initiated the Phase 2 portion of the trial in late 2018 to
better define the patient populations most likely to benefit from
CPI-1205. We look forward to reporting initial Phase 2 data in the
second half of 2019.”
The poster presentation included the following highlights from
the Phase 1b portion of ProSTAR, using a February 6, 2019, data
cutoff:
Baseline Characteristics
- The Phase 1b portion of ProSTAR enrolled 36 patients: 20 in the
CPI-1205 + abiraterone arm and 16 in the CPI-1205 + enzalutamide
arm.
- Each arm studied two different dose regimens of CPI-1205 as
part of the combination: 800 mg three times daily or 400 mg twice
daily + cobicistat (to block CYP3A4).
- The Phase 1b portion of ProSTAR was conducted in a
heterogeneous patient population who had been treated with a
variety of treatment regimens, including chemotherapy. As such, a
significant proportion of patients had indicators of poor prognosis
at baseline. Of the 36 patients enrolled, 13 (36%) were positive
for Androgen Receptor Splice Variant 7, or AR-V7, isoforms
(proteins with similar structures); 20 (56%) had unfavorable
circulating tumor cell counts; 13 (36%) had previously received
chemotherapy; and 18 (50%) had abnormal levels of lactate
dehydrogenase (an enzyme in the blood that can indicate tissue
damage, cancer, or some noncancerous conditions) at
baseline.Because patients without AR-V7 isoforms have tended to
respond better to ARS inhibition than those with AR-V7 isoforms,
and given the hypothesis that ARS inhibition acts synergistically
with EZH2 inhibition, patients without AR-V7 isoforms may be more
likely to benefit from the potential synergistic effect of CPI-1205
with ARS inhibitor therapy.
Clinical Activity
- Clinical activity was observed in both the enzalutamide and
abiraterone arms, including ≥50% PSA reductions and an objective
response by RECIST 1.1 criteria.
- All PSA responses seen in the trial were ≥80%, deeper than the
≥50% reduction endpoint in the trial. All PSA responses were found
in AR-V7-negative patients. Two out of 18 patients in the
abiraterone arm achieved PSA reductions of more than 80%. Patients
being treated with abiraterone after enzalutamide historically have
been shown to achieve poor PSA responses and rapid time to disease
progression. PSA responses are summarized below:
|
≥80% PSA Reductions in AR-V7-Positive Patients |
≥80% PSA Reductions in AR-V7-Negative Patients |
CPI-1205 + abiraterone** |
0/8* (0%) |
2/10* (20%) |
CPI-1205 + enzalutamide** |
0/5 (0%) |
3/11 (27%) |
*2 patients
not evaluable for PSA response |
** Includes
patients treated with CPI-1205 800 mg three times daily and
CPI-1205 400mg twice daily + cobicistat |
- The majority of patients with measurable lesions achieved
durable disease control during the study, as follows:
|
Partial Response |
Stable Disease |
Disease Control Rate of Any Duration |
Disease Control Rate ≥3 Months |
CPI-1205 + abiraterone |
0/8 (0%) |
6/8 (75%) |
6/8 (75%) |
4/8 (50%) |
CPI-1205 + enzalutamide |
1/5 (20%) |
2/5 (40%) |
3/5 (60%) |
3/5 (60%) |
Several patients achieved disease control that exceeded or was
approaching six months at the data cutoff while continuing
therapy.
Safety
- CPI-1205 was generally well tolerated in combination with
enzalutamide or abiraterone. The most common treatment-related
adverse events (≥20%) were fatigue, diarrhea, and nausea, which
were usually mild to moderate in severity and manageable with
supportive care. In combination with enzalutamide,
treatment-related adverse events ≥ Grade 3 included fatigue,
nausea, and increased ALT (n=1; 6.3%, respectively). In combination
with abiraterone, treatment-related adverse events ≥ Grade 3
included fatigue and increased ALT (n=1; 5%, respectively). For
more details, please see the poster here.
Pharmacokinetics/Pharmacodynamics (PK/PD)
- Patients in two treatment arms were dosed with 800 mg of
CPI-1205 three times daily with enzalutamide or abiraterone.
Patients in the other two arms were dosed with 400 mg of CPI-1205
twice daily in combination with cobicistat, a CYP3A4 inhibitor, and
enzalutamide or abiraterone. While the Company observed in the
trial that cobicistat increased the exposure of CPI-1205, the
Company did not observe meaningful differences in pharmacodynamics
or efficacy compared to 800 mg of CPI-1205 three times daily
without cobicistat. Therefore the recommended Phase 2 dose of
CPI-1205 for ProSTAR Phase 2 was determined to be 800 mg three
times daily.
Phase 2
- The Phase 1b portion of ProSTAR was designed primarily to study
the safety, pharmacokinetics, pharmacodynamics, maximum tolerated
dose, and a recommended Phase 2 dose of CPI-1205 with abiraterone
and enzalutamide. Based on the Phase 1b data, the Company initiated
the Phase 2 portion of ProSTAR in late 2018. The Phase 2 portion of
the trial is evaluating CPI-1205 in combination with an ARS
inhibitor as a second-line treatment for patients with mCRPC. The
Company will collect and analyze biomarker and other translational
data in Phase 2 to better define which patients may be most likely
to respond to treatment with CPI-1205. Two randomized arms of Phase
2 are studying CPI-1205 in combination with enzalutamide versus
enzalutamide alone.In addition, because of the activity seen in the
abiraterone arm in the Phase 1b portion of ProSTAR, the Company has
also initiated a Phase 2 arm to evaluate CPI-1205 in combination
with abiraterone in second-line mCRPC patients. According to a
recent study by the laboratory of Dr. Kim Chi of the Vancouver
Prostate Centre, few patients responded to treatment with
abiraterone after experiencing disease progression on enzalutamide.
For this reason, we have not instituted an additional control arm.
In the Chi study, out of 101 patients receiving abiraterone after
experiencing disease progression on enzalutamide, no patients
achieved an 80% reduction in PSA levels and only 4% achieved a 50%
PSA reduction.1 The patient population in the Chi study had
baseline characteristics that are different from those in the Phase
1b portion of ProSTAR, and more similar to those that are expected
to be in ProSTAR Phase 2. For example, unlike ProSTAR Phase 1b, in
which patients had been previously treated with a range of
therapies – including 36% who had received chemotherapy – ProSTAR
Phase 2, like the Chi study, is enrolling only patients receiving
second-line therapy with no prior chemotherapy in order to focus on
activity in that patient population.
- The Company expects to provide an initial update from the Phase
2 portion of ProSTAR in the second half of 2019.
For more information on the Phase 1b portion of ProSTAR, please
see the poster here.
1 D Khalaf et al., Phase 2 randomized cross-over trial of
abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients
(pts) with metastatic castration resistant prostate cancer (mCRPC):
results for 2nd-line therapy, poster presented at 2018 American
Society of Clinical Oncology meeting.
Discovery Pipeline
Constellation is presenting two additional posters at the
American Association for Cancer Research meeting that speak to the
depth and breadth of the Company’s product pipeline and its
expertise in epigenetics. Poster 4351/11, Single-cell RNA
sequencing reveals transcriptomic heterogeneity in response to
epigenetic inhibitors, will be presented at the 1PM-5PM EDT poster
session on April 2. Poster 4722/12, Efficacy of novel EP300/CBP
histone acetyltransferase inhibitor in hormone responsive breast
cancer, will be presented at the 8AM-12PM EDT poster session on
April 3.
About ProSTAR
ProSTAR is an open-label Phase 1b/2 clinical trial of CPI-1205,
a potent and highly selective small-molecule EZH2 inhibitor, in
patients with metastatic castration-resistant prostate cancer
(mCRPC) in the second-line setting. The ProSTAR study is evaluating
CPI-1205 in combination with either enzalutamide or abiraterone /
prednisone (“abiraterone”), which are androgen receptor signaling
(ARS) inhibitors, in mCRPC patients who experienced disease
progression while receiving the other ARS inhibitor.
About mCRPC
Metastatic castration-resistant prostate cancer (mCRPC) is an
advanced form of prostate cancer and is defined by disease
progression despite treatment with androgen depletion therapy
(ADT). mCRPC may present as one or any combination of the
following: a continuous rise in serum levels of PSA, progression of
known metastases, or appearance of new metastases. Prognosis is
associated with several factors, including the ability to perform
certain daily activities and the presence of bone pain. Additional
symptoms commonly include anemia (low levels of healthy red blood
cells), weight loss, fatigue, hypercoagulability (abnormal blood
coagulation), and increased susceptibility to infection. mCRPC
presents as a spectrum of disease, ranging from patients without
symptoms but rising PSA levels despite ADT to patients with
metastases and significant debilitation.
About Constellation Pharmaceuticals
Constellation Pharmaceuticals is a clinical-stage
biopharmaceutical company developing novel therapeutics that
selectively modulate gene expression to address serious unmet
medical needs in patients with cancer. The Company has a deep
understanding of how epigenetic and chromatin modifications in
cancer cells and in the tumor and immune microenvironment play a
fundamental role in driving disease progression and drug
resistance. Constellation is driving development of the EZH2
inhibitors CPI-1205 and CPI-0209 for the treatment of metastatic
castration-resistant prostate cancer and other cancers as well as
the BET inhibitor CPI-0610 for the treatment of myelofibrosis. The
Company is also applying its broad research and development
capabilities to explore other novel targets that directly and
indirectly impact gene expression to fuel a sustainable pipeline of
innovative small-molecule product candidates.
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
that involve substantial risks and uncertainties, including
statements regarding the implications of preliminary clinical data,
the development status of the Company’s product candidates, the
Company’s plans for future data presentations, its anticipated
achievement of milestones, including determination of proof of
concept and its financial guidance regarding the period in which it
will have capital available to fund its operations. All
statements, other than statements of historical facts, contained in
this press release, including statements regarding the Company’s
strategy, future operations, future financial position, prospects,
plans and objectives of management, are forward-looking statements.
The words “anticipate,” “believe,” “continue,” “could,” “estimate,”
“expect,” “intend,” “may,” “plan,” “potential,” “predict,”
“project,” “should,” “target,” “will,” “would” and similar
expressions are intended to identify forward-looking statements,
although not all forward-looking statements contain these
identifying words. Any forward-looking statements are based on
management’s current expectations of future events and are subject
to a number of risks and uncertainties that could cause actual
results to differ materially and adversely from those set forth in,
or implied by, such forward-looking statements. These risks and
uncertainties include, but are not limited to, risks associated
with Constellation’s ability to: obtain and maintain necessary
approvals from the FDA and other regulatory authorities; continue
to advance its product candidates in clinical trials; whether
preliminary or interim results from a clinical trial will be
predictive of the final results of the trial; replicate in later
clinical trials positive results found in preclinical studies and
early-stage clinical trials of CPI-1205, CPI-0610 and its other
product candidates; advance the development of its product
candidates under the timelines it anticipates, or at all, in
current and future clinical trials; obtain, maintain or protect
intellectual property rights related to its product candidates;
manage expenses; and raise the substantial additional capital
needed to achieve its business objectives. For a discussion of
other risks and uncertainties, any of which could cause the
Company’s actual results to differ from those contained in the
forward-looking statements, see the “Risk Factors” section, as well
as discussions of potential risks, uncertainties, and other
important factors, in the Company’s most recent filings with the
Securities and Exchange Commission. In addition, the forward-
looking statements included in this press release represent the
Company’s views as of the date hereof and should not be relied upon
as representing the Company’s views as of any date subsequent to
the date hereof. The Company anticipates that subsequent events and
developments will cause the Company’s views to change. However,
while the Company may elect to update these forward-looking
statements at some point in the future, the Company specifically
disclaims any obligation to do so. CPI-1205, CPI-0610, CPI-0209,
and other product candidates are investigational in nature and have
not yet been approved by the FDA or other regulatory
authorities.
Contact Ronald Aldridge Senior Director,
Investor RelationsConstellation Pharmaceuticals+1
617-714-0539ron.aldridge@constellationpharma.com
Lauren ArnoldMedia RelationsMacDougall Biomedical
Communications+1 781-235-3060larnold@macbiocom.com
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