On May 10, 2021 Constellation Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported its first-quarter 2021 financial results (Press release, Constellation Pharmaceuticals, MAY 10, 2021, View Source [SID1234579551]). The Company also provided updates on its product candidates pelabresib and CPI-0209.

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"Over the last year, we have advanced the development of pelabresib as a novel therapy for myelofibrosis, and we are pleased to be dosing patients in the Phase 3 MANIFEST-2 trial. Today we are also excited to announce progress on the Phase 2 development plan for our second generation EZH2 inhibitor, CPI-0209. We have determined the recommended Phase 2 dose and the expansion cohorts are open for enrollment, with the first patient dosed. We believe that CPI-0209 provides potential opportunities to treat a wide range of oncology patients," said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. "These are important achievements in moving forward with our goal of becoming a fully integrated hematology / oncology company with a sustainable product pipeline."

Program Updates
pelabresib

Dosing underway in the Phase 3 MANIFEST-2 clinical trial
On May 12, the Company expects the following three abstracts to be published in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting, related to MANIFEST, the ongoing Phase 2 clinical trial of pelabresib:
TITLE: Pelabresib (CPI-0610) improved anemia associated with myelofibrosis: interim results from MANIFEST Phase 2 study (Abstract Code: EP1077)
TITLE: Clinical benefit of pelabresib (CPI-0610) in combination with ruxolitinib in JAK inhibitor treatment naïve myelofibrosis patients: Interim efficacy subgroup analysis from Arm 3 of MANIFEST Phase 2 study (Abstract Code: EP1085)
TITLE: BET inhibitor pelabresib decreases inflammatory cytokines, improves bone marrow fibrosis and function, and demonstrates clinical response irrespective of mutation status in myelofibrosis patients (Abstract Code: EP1080)
CPI-0209

The Company established the recommended Phase 2 dose (RP2D) of CPI-0209 monotherapy as 350 mg once daily. In the Phase 2 expansion cohorts, the Company plans to study CPI-0209 as a monotherapy in patients with cancers such as urothelial, ovarian clear cell and endometrial, where ARID1A mutations are prevalent, and lymphomas, where EZH2 mutations are prevalent. The first patient has been dosed in the expansion cohorts.
On April 10, a poster published in association with the American Association for Cancer Research (AACR) (Free AACR Whitepaper) provided preclinical data suggesting that CPI-0209 has therapeutic potential in androgen receptor-positive prostate cancer.
On May 19, the Company expects the following abstract for a poster to be published in association with the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting related to the Phase 1 portion of the Phase 1/2, clinical trial of CPI-0209:
TITLE: Phase 1/2 first-in-human (FIH) study of CPI-0209, a novel small molecule inhibitor of enhancer of zeste homolog 2 (EZH2) in patients with advanced tumors (Abstract Code: 3104)
Milestones

The Company anticipates achieving the following milestones during 2021:

Pelabresib – Provide MANIFEST translational data update mid-year
Pelabresib – Provide MANIFEST clinical data update and update on new indications by end of year
CPI-0209 – Provide Phase 1 data update by mid-year
CPI-0209 – Provide update on monotherapy cohorts from Phase 2 by end of year
First Quarter 2021 Financial Results

Cash, cash equivalents, and marketable securities as of March 31, 2021, were $382.1 million, a decrease of 9.3% compared to December 31, 2020, primarily due to operating expenses.
Research and development (R&D) expenses increased 53.3% year over year to $30.8 million in the first quarter of 2021, mainly due to increased clinical trial expenses.
General and administrative (G&A) expenses grew 59.8% year over year to $9.4 million in the first quarter of 2021, primarily due to building out the organization of the company.
The net loss attributed to common shareholders increased 57.5% year over year to $40.1 million for the first quarter of 2021, mainly due to increased R&D and G&A expenses. The net loss per share attributable to common shareholders increased 37.7% to $0.84 per share due to an increased net loss, partially offset by an increase in weighted average shares outstanding.
Financial Guidance

Constellation expects that its current cash, cash equivalents, and marketable securities will fund operations into mid-2023.

For further information, please refer to the financial statements filed with the SEC on Form 10-Q, including notes to the financials.

Conference Call

Constellation will host a conference call at 8:00 AM EDT on May 10, 2021, to discuss its clinical programs and financial results. The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source 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 8798968.

About MANIFEST-2

MANIFEST-2 is a global, blinded, randomized Phase 3 clinical trial with pelabresib 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 pelabresib + 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 MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of pelabresib 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 CPI-0209 clinical trial

The Phase 2 portion of the Phase1/2 clinical trial of CPI- 0209 is an open label, single arm study, enrolling up to 29 patients per cohort in the following tumor types: relapsed urothelial carcinoma with known ARID1A mutation; relapsed ovarian clear cell carcinoma with known ARID1A mutation; relapsed endometrial carcinoma with known ARID1A mutation; relapsed or refractory lymphomas of either B-cell or T-cell histology. The goal of these cohorts is to establish the safety and establish the antitumor activity of CPI-0209 as a monotherapy for patients with these tumor types.