On February 24, 2021 Constellation Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported its fourth-quarter 2020 financial results and provided a business update (Press release, Constellation Pharmaceuticals, FEB 24, 2021, View Source [SID1234575550]).

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"2020 was an important year for Constellation Pharmaceuticals, marked by several presentations of strong data from our MANIFEST clinical trial for pelabresib (formerly CPI-0610), including our oral presentations at the ASH (Free ASH Whitepaper) Annual Meeting," said Jigar Raythatha, President and Chief Executive Officer of Constellation Pharmaceuticals. "We are executing on our recently launched Phase 3 trial, MANIFEST-2 and believe pelabresib has the potential to transform the standard of care in myelofibrosis. We also continue to advance our pipeline of product candidates with CPI-0209 and the newly announced CPI-482."

Pelabresib (CPI-0610)

Constellation presented an update of MANIFEST data in two oral presentations and three posters at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting, which are available on Constellation’s website.
CPI-0209

Patients continue to be advanced through multiple dosing cohorts in the Phase 1 dose escalation portion of a Phase 1/2 clinical trial of the EZH2 inhibitor CPI-0209.
Data from the Phase 1 portion will guide our recommended Phase 2 dose (RP2D) selection for expansion arms in select tumor types.
Clinical data will be supplemented with data on biomarkers to identify patients most likely to benefit.
CPI-482

The Company named CPI-482 as a new development candidate, targeting LSD1. CPI-482 reinforces our commitment to addressing unmet needs in hematologic diseases, particularly myeloproliferative neoplasms (MPNs). Furthermore, our development strategy with CPI-482 will leverage our unique translational research and understanding of epigenetic mechanisms in myeloid cells.
2020 Leadership Updates

Constellation strengthened its senior management team with the appointment of Brendan Delaney as Chief Commercial Officer, effective January 2021. Previously, Mr. Delaney served as Chief Commercial Officer of Immunomedics and Vice President, U.S. Commercial Hematology Oncology at Celgene. Mr. Delaney will build and lead the Company’s commercial organization and pre-launch preparations in support of pelabresib.
Earlier in the year, Constellation appointed Jeffrey Humphrey, M.D. as Chief Medical Officer. Previously, Dr. Humphrey served as Chief Development Officer at Kyowa Kirin Co., where he oversaw the development of over twenty drug candidates including regulatory submissions leading to three drug approvals in the United States and Europe.
2021 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

Fourth Quarter 2020 Financial Results

Cash, cash equivalents, and marketable securities as of December 31, 2020, were $421.4 million. 
Research and development (R&D) expenses increased 47.2% year over year to $27.4 million in the fourth quarter of 2020, mainly due to increased clinical trial expenses.
General and administrative (G&A) expenses grew 56.2% year over year to $8.5 million in the fourth quarter of 2020, primarily due to building out the organization of the company.
The net loss attributed to common shareholders increased 54.4% year over year to $37.4 million for the fourth quarter of 2020, mainly due to increased R&D and G&A expenses. The net loss per share attributable to common shareholders increased by 14.5% to $0.79 per share, due to an increase in net loss and partly off-set by an increase in weighted shares outstanding.
Full Year 2020 Financial Results

Research and development (R&D) expenses increased 43.7% year over year to $95.5 million for full-year 2020, mainly due to increased clinical trial expenses.
General and administrative (G&A) expenses grew 49.8% year over year to $29.3 million for full-year 2020, primarily due to building out the organization of the company.
The net loss attributed to common shareholders increased 47.7% year over year to $126.4 million for full-year 2020, mainly due to increased R&D and G&A expenses. The net loss per share attributable to common shareholders decreased 7.6% to $2.81 per share, largely due to an increase in weighted average shares outstanding as a result of the additional shares issued in June 2020.
Financial Guidance

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

About MANIFEST-2

MANIFEST-2 is a global, blinded, randomized Phase 3 clinical study 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.