Constellation Pharmaceuticals Provides Update of MANIFEST Study for CPI-0610 at ASH Meeting

• 67% spleen volume response rate observed in 63 first-line myelofibrosis patients treated with CPI-0610 + ruxolitinib at 24 weeks
• CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings
• Translational data supports potential disease-modifying effects of CPI-0610

CAMBRIDGE, Mass., Dec. 06, 2020 (GLOBE NEWSWIRE) — Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) today announced that two oral presentations and three posters relating to the Phase 2 MANIFEST and the Phase 3 MANIFEST-2 clinical trials of CPI-0610 in myelofibrosis (MF) were presented at the American Society of Hematology (ASH) Annual Meeting and Exposition. The preliminary data in these presentations are based on a data cutoff of September 29, 2020, and reflect an analysis of clinical activity in 63 first-line (1L) and 94 second-line (2L) or later patients.

“We are pleased both with the response rates and consistency of the results we are seeing in MANIFEST,” said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. “In addition, we are excited by results from our translational studies that suggest that CPI-0610 may potentially be a disease modifying therapy that affects all four hallmarks of myelofibrosis. We are pleased to have initiated MANIFEST-2, our global registrational study of CPI-0610, in JAK-inhibitor-naïve MF patients.”

Data Highlights

Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients

• 42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). The median spleen volume reduction was 50%
• 34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total Symptom Scores (TSS50) at 24 weeks. The median TSS reduction was 59%

Arm 1 (2L or later) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients

• 7 of 23 (30%) evaluable patients that were not transfusion dependent at baseline (non-TD) achieved SVR35 at 24 weeks, the primary endpoint for cohort 1B. 10 of 21 (48%) evaluable non-TD patients achieved TSS50 at 24 weeks
• 10 of 20 (50%) evaluable non-TD patients who did not receive transfusions 12 weeks prior to treatment achieved a ≥1.5 g/dL increase in hemoglobin
• 3 of 14 (21%) evaluable transfusion-dependent (TD) patients converted to transfusion independence (TI), the primary endpoint for cohort 1A

Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients

• 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. 8 of 21 (38%) evaluable non-TD patients achieved TSS50 at 24 weeks
• 13 of 36 (36%) evaluable TD patients converted to transfusion independence, the primary endpoint for cohort 2A

Translational data

• In samples from patients in Arm 3, 16 of 48 evaluable patients (33%) had at least one grade improvement in bone marrow fibrosis and in 88% (14/16) of these patients, improvements occurred within six months of starting treatment. Only 2 of 48 patients had worsening in bone marrow fibrosis
• 38 of 116 (33%) patients with evaluable samples across all three treatment arms had a one grade or greater improvement in bone marrow fibrosis. In 84% (32/38) of these patients, improvements occurred within six months of treatment. Only 7 of 116 patients had worsening in bone marrow fibrosis
• Analysis of evaluable patient samples from MANIFEST suggests that CPI-0610 promotes normalization of megakaryocyte and erythroid differentiation and proliferation, which the Company believes may improve bone marrow function and hemoglobin levels, and may ultimately be disease-modifying in patients

Safety

CPI-0610 was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients.

Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (15%), anemia (13%), diarrhea (4%), constipation (2%), respiratory tract infection (2%), and decreased weight (2%). Other Grade 3/4 TEAEs (≥ 5%) include hyperuricemia (9%), hyperkalemia (6%) and dyspnea (6%). Nine patients discontinued treatment because of TEAEs.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (23%), anemia (10%), respiratory tract infections (5%), diarrhea (4%), asthenic conditions (4%), and nausea (3%). Grade 4 TEAEs included thrombocytopenia (3%) and anemia (1%). Nine patients discontinued treatment due to TEAEs, including six Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), disease progression, congestive heart failure, and transformation to AML.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (28%) and thrombocytopenia (5%). Grade 4 TEAEs included thrombocytopenia (3%), anemia (1%), and respiratory tract infection (1%). Two patients discontinued treatment due to TEAEs. In addition, there were two Grade 5 TEAEs, each resulting from multi-organ failure due to sepsis.

ASH Oral Presentations

Title: CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK-Inhibitor-Naïve Myelofibrosis Patients: Update of MANIFEST Phase 2 Study
Oral Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Date and Time: December 5, 2020, 11:30 AM EST
Presenter: Dr. John Mascarenhas, Associate Professor of the Icahn School of Medicine at Mount Sinai

Title: CPI-0610, Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As “Add-on” to Ruxolitinib, in Advanced Myelofibrosis Patients with Suboptimal Response: Update of MANIFEST Phase 2 Study
Oral Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Date and Time: December 5, 2020, 11:45 AM EST
Presenter: Dr. Srdan Verstovsek, Medical Oncologist, MD Anderson Cancer Center

ASH Poster Presentations

Title: CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As Monotherapy in Advanced Myelofibrosis Patients Refractory / Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study
Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Date and Time: Sunday, December 6, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Moshe Talpaz, Professor of Leukemia Research and Professor of Internal Medicine, University of Michigan Medical School

Title: MANIFEST-2, a Global, Phase 3, Randomized, Double-Blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Placebo and Ruxolitinib in JAK-Inhibitor-Naïve Myelofibrosis Patients
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. John Mascarenhas, Associate Professor of the Icahn School of Medicine at Mount Sinai

Title: The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Mohamed Salama, Professor of Pathology and Laboratory Medicine, Mayo Clinic School of Medicine and Chief Medical Officer at Mayo Clinic Laboratories

Title: LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and post-MPN AML in the context of constitutive JAK-STAT pathway activation
Session: 635. Myeloproliferative Syndromes: Basic Science: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Raajit Rampal, Clinical Director of Leukemia Service at Memorial Sloan Kettering Cancer Center

Conference Call  

Constellation will host a virtual analyst/investor event and conference call on December 7, 2020 at 8:00 AM EDT to discuss the data relating to the MANIFEST clinical trial for CPI-0610 being presented at the ASH meeting. The agenda of the event will include:

• An overview of MF and the potential impact of Constellation’s BET inhibitor, CPI-0610, in treating MF
• A review of the clinical and translational data from MANIFEST presented at ASH
• A physician panel discussion and question-and-answer session with Dr. John Mascarenhas, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai – New York and Dr. Serge Verstovsek, Professor of Medicine at University of Texas MD Anderson Cancer Center 

The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at http://ir.constellationpharma.com/events–and–presentations/events. To participate in the live question-and-answer session, please dial (877) 473-2077 (domestic) or (661) 378-9662 (international) and refer to conference ID 7164095.  

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation is also evaluating CPI-0610, either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to TI for 12 consecutive weeks. The primary endpoint for the patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment. 

About MANIFEST-2

MANIFEST-2 is a global, double-blind, randomized Phase 3 clinical study with CPI-0610 in combination with ruxolitinib versus placebo plus ruxolitinib in JAK-inhibitor-naïve patients with primary myelofibrosis or post-ET or post-PV myelofibrosis who have splenomegaly and symptoms requiring therapy. It is designed to enroll approximately 310 patients, randomized 1:1 to the CPI-0610 + ruxolitinib arm or the placebo + ruxolitinib arm. The primary endpoint of the study is a ≥35% reduction in spleen volume (SVR35) from baseline at 24 weeks. A key secondary endpoint of the study is 50% or greater improvement in Total Symptom Score (TSS50) from baseline at 24 weeks. Other endpoints include bone marrow fibrosis grade improvements, duration of transfusion independence, rate of red-blood-cell transfusion for the first 24 weeks, and hemoglobin response.

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 BET inhibitor CPI-0610 for the treatment of myelofibrosis as well as the EZH2 inhibitor CPI-0209 for the treatment of solid tumors. 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 or interim clinical data, the Company’s clinical development and regulatory plans and timelines, and prospects of the Company’s product candidates. 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 the Company’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 data 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-0610 and CPI-0209; 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; raise the substantial additional capital needed to achieve its business objectives; the COVID-19 pandemic and general economic and market conditions. CPI-0610 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 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, including the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2020. 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.  

Contacts 

Kia Khaleghpour, Ph.D. 
Vice President, Investor Relations and Communications 
Constellation Pharmaceuticals 
+1 617-844-6859 
kia.khaleghpour@constellationpharma.com 
  
Lauren Arnold 
Media Relations 
MacDougall Biomedical Communications 
+1 781-235-3060 
larnold@macbiocom.com