Constellation Pharmaceuticals Enhances and Expands Phase 2 MANIFEST Study of CPI-0610 in Myelofibrosis

Published: Oct 10, 2018

CAMBRIDGE, Mass.,  (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, today announced several planned updates to the Phase 2 portion of its ongoing MANIFEST study, an open-label Phase 1/2 clinical trial of its BET inhibitor CPI-0610 in MF.

MANIFEST is evaluating CPI-0610, either as a monotherapy or in combination with ruxolitinib, in patients with MF who are refractory or intolerant or have relapsed or lost response to the standard of care. Based on encouraging preliminary data in this trial, Constellation is amending the design of each second-line cohort to stratify all patients enrolled in the study based on transfusion dependence status. In addition, the Company is amending the design of MANIFEST to include a third cohort designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK 1/2-inhibitor-naïve MF patients.

The Company made these updates based on the unmet medical need for disease-modifying therapies in myelofibrosis, especially among patients requiring red-blood-cell transfusions. The changes are intended to enhance the clinical trial design by providing additional measures of potential clinical benefit and to expand the potential addressable patient population for CPI-0610.

“We are encouraged by the preliminary data from MANIFEST, which may indicate synergistic and disease-modifying effects of CPI-0610 in myelofibrosis,” said Adrian Senderowicz, Senior Vice President and Chief Medical Officer of Constellation Pharmaceuticals. “We are enhancing the study’s design to better measure these potential effects. Among the key goals of MANIFEST are identifying the most appropriate endpoints and patient populations for future pivotal studies. We continue to look forward to determining proof of concept for CPI-0610 in MF by mid-2019.”

MANIFEST Enhancements

The Phase 2 proof-of-concept portion of MANIFEST in a second-line setting is designed to study the anti-tumor activity and safety of the BET inhibitor CPI-0610 in treatment of patients with MF as a monotherapy and in combination with the JAK-1/2 inhibitor ruxolitinib. This portion of the study had been expected to enroll 70 patients (35 on monotherapy and 35 on combination therapy) to evaluate safety, pharmacokinetics, reduction in spleen volume, and patient-reported symptom improvement in all enrolled patients, as well as improvements in red-blood-cell transfusion independence rate in patients who were transfusion-dependent at baseline. Preliminary data from this trial demonstrated spleen volume reduction, symptom improvement, and positive hemoglobin effects, which Constellation believes may be the result of improved hematopoiesis. In addition, as Constellation reported previously, one of four patients treated with CPI-0610 was transfusion-dependent at baseline and later converted to transfusion independence. 

As a result of this positive preliminary hematological data, all enrolled patients in both the combination and monotherapy arms will now be stratified by transfusion dependence status, with each cohort expected to enroll up to 16 transfusion-dependent patients and up to 25 non-transfusion-dependent patients. Proof of concept in these cohorts will be based on conversion to transfusion independence and other factors in transfusion-dependent patients; and by reduction in spleen volume, patient-reported symptom improvement, and other factors in non-transfusion-dependent patients.

In addition, Constellation is adding a third cohort to this trial, which will evaluate treatment with CPI-0610 in combination with ruxolitinib as first-line therapy in up to 43 JAK 1/2-inhibitor-naïve MF patients. This cohort will only enroll anemic patients. Constellation’s current plan for a potential pivotal trial of CPI-0610 as a first-line treatment would be to enroll all-comers. Proof of concept for this cohort will be measured by reduction in spleen volume, patient-reported symptom improvement, and other factors.

The Company expects to update this protocol change at https://clinicaltrials.gov under study ID NCT02158858 in the near future.

Conference Call/Corporate Presentation

Constellation’s CEO Jigar Raythatha and CMO Adrian Senderowicz will host a conference call to discuss this protocol change in greater detail at 8:30 AM EDT on Thursday, October 11. To participate in the conference call, please dial (877) 473-2077 (US) or +1(661) 378-9662 (international) and refer to conference ID 4165317. A live webcast will be available in the investor section of the company's website. The webcast will be archived for 60 days following the call. Constellation has posted an updated version of its corporate presentation in the investor section of the company’s website. 

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.

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