Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise

• Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously reported data and differentiated from standard of care
  
• Spleen responses demonstrated in non-transfusion-dependent second-line patients as a monotherapy and add-on to ruxolitinib
• Conversion to transfusion independence and improvements in hemoglobin levels and bone marrow fibrosis suggest possible disease-modifying effects of CPI-0610
• EZH2 inhibitor CPI-0209 is prioritized for further clinical development               

CAMBRIDGE, Mass., June 12, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. CNST today announced that three posters relating to the MANIFEST clinical trial of CPI-0610 in myelofibrosis (MF) were published online in association with the European Hematology Association (EHA) annual meeting. The data in these posters are based on a data cutoff of April 17, 2020, and reflect an analysis of clinical activity in 51 first-line (1L) and 73 second-line (2L) patients. 

"I'm encouraged that the initial signals of activity with CPI-0610, such as spleen and symptom responses, that were presented last December at ASH continue to be observed in a larger dataset presented in these EHA posters," said Claire Harrison, D.M. (Oxon.), Professor of Haematology and a MANIFEST investigator. "In addition, we continue to see signals of disease modification, such as increases in hemoglobin, conversions of transfusion-dependent patients to transfusion independence, and bone marrow fibrosis improvements. If corroborated in further testing, these data suggest that CPI-0610 could potentially change the treatment paradigm in MF."

"We are excited about the emerging profile of CPI-0610," said Jigar Raythatha, Chief Executive Officer of Constellation Pharmaceuticals. "Our goal is to drive CPI-0610 to registration and to transform the standard of care in myelofibrosis and potentially other hematologic diseases."

Data Highlights

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

• 37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen volume reduction of 51%
• 19 of 30 evaluable patients (63%) achieved SVR35 at 24 weeks (the primary endpoint for Arm 3) and had a median spleen volume reduction of 53%
• 17 of 29 evaluable patients (59%) achieved a 50% improvement in Total Symptom Score (TSS50) at 24 weeks and had a median TSS improvement of 64%
• No evidence of correlation between SVR35 response and baseline risk status, platelet count, or spleen volume

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

• 3 of 14 (21%) evaluable transfusion-dependent (TD) patients converted to transfusion independence (TI), the primary endpoint for cohort 1A
• 5 of 21 (24%) evaluable non-TD patients achieved SVR35 (the primary endpoint for cohort 1B) and 9 of 19 (47%) evaluable non-TD patients achieved TSS50 at 24 weeks
• 11 of 19 (58%) non-TD patients on treatment for at least 12 weeks without any transfusions achieved a ≥1.5 g/dL mean increase in hemoglobin

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

• 11 of 32 (34%) evaluable TD patients converted to TI, the primary endpoint for cohort 2A
• 4 of 18 (22%) evaluable non-TD patients achieved SVR35 (the primary endpoint for cohort 2B) and 7 of 19 (37%) evaluable non-TD patients achieved TSS50 at 24 weeks

Safety

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

Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 43 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (14.0%), anemia (9.3%), diarrhea (4.7%), and respiratory tract infection (2.3%). Six patients discontinued treatment because of TEAEs. There were no Grade 4 or Grade 5 TEAEs.

Among the most common TEAEs in 70 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (22.9%), anemia (7.1%), fatigue (5.7%), diarrhea (4.3%), respiratory tract infections (4.3%), nausea (2.9%), and abdominal pain (1.4%). Grade 4 TEAEs included thrombocytopenia (1.4%) and anemia (1.4%). Seven patients discontinued treatment due to TEAEs, including four Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), and disease progression.  

Among the most common TEAEs in 64 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (15.6%), respiratory tract infections (3.1%), and thrombocytopenia (1.6%). Grade 4 TEAEs included thrombocytopenia (3.1%), anemia (1.6%), and respiratory tract infection (1.6%). Four patients discontinued treatment due to TEAEs, including two Grade 5 TEAEs, each due to multi-organ failure due to sepsis.

For further details, please see the EHA poster presentations here.

EHA Poster Presentations

TITLE: CPI-0610, A Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK Inhibitor Treatment Naive Myelofibrosis Patients: Update of MANIFEST Phase 2 Study (Presentation Code: EP1084)

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 (Presentation Code: EP1091)

TITLE: CPI-0610, Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, as "Add-on" to Ruxolitinib (Rux), in Advanced Myelofibrosis Patients with Suboptimal Response: Update of MANIFEST Phase 2 Study (Presentation Code: EP1083)

Session: Myeloproliferative Neoplasms—Clinical

Date and Time: June 12, 2020, 8:30 AM CEST/2:30 AM EDT

Investor Event

Constellation will host a virtual analyst/investor event and conference call on June 12 at 8:00 AM EDT to discuss the data from these three posters relating to the MANIFEST clinical trial for CPI-0610 being presented at the European Hematology Association meeting. The agenda of the event will include:

• An overview of myelofibrosis (MF) and the potential impact of Constellation's BET inhibitor CPI-0610 in treating MF
• A review of the data from the MANIFEST clinical trial presented in the EHA posters
• A live question-and-answer session

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 6275774.

EZH2 Program Prioritization

Constellation today announced that it plans to prioritize further clinical development of its next-generation EZH2 inhibitor CPI-0209. The decision is based on a recent data cut and review of ProSTAR, the ongoing Phase 1b/2 clinical study evaluating CPI-1205, a small-molecule inhibitor of EZH2, combined with enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). The data did not demonstrate the definitive signal of activity necessary to advance the program into pivotal studies in mCRPC. A full data set from ProSTAR will be presented at a future medical meeting.

"We thank the patients and investigators who participated in ProSTAR," said Jigar Raythatha. "While we are disappointed with the outcome of this study, we remain committed to EZH2 as an important cancer target and will apply the learnings from ProSTAR to our second-generation EZH2 inhibitor, CPI-0209. We believe the deeper and more durable target engagement as well as the improved metabolic properties that CPI-0209 demonstrated in preclinical studies give it the potential to be a best-in-class EZH2 inhibitor for use in a broad range of cancer types. CPI-0209 is progressing through the dose escalation portion of a phase 1/2 clinical trial, and we expect to determine a recommended Phase 2 dose later in the year."

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 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 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 inhibitors CPI-1205 and CPI-0209 for the treatment of metastatic castration-resistant prostate cancer and other cancers. 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, Company's plans, strategies and prospects for its business and statements regarding the development status 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, CPI-1205 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, CPI-1205 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 March 31, 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

Ronald Aldridge
Senior Director, Investor Relations
Constellation Pharmaceuticals
+1 617-714-0539
ron.aldridge@constellationpharma.com

Lauren Arnold
Media Relations
MacDougall Biomedical Communications
+1 781-235-3060
larnold@macbiocom.com