On June 3, 2019 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported the presentation of updated interim data from MANIFEST, the Company’s Phase 2 clinical trial of CPI-0610 in MF (Press release, Constellation Pharmaceuticals, JUN 3, 2019, View Source [SID1234536803]). The interim data, which highlight the tolerability and potentially disease-modifying activity of CPI-0610, were presented in a poster at the annual meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.
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"We are excited by these interim data from the MANIFEST trial, which indicate that CPI-0610 is generally well-tolerated and showed signs that it is an active therapeutic agent for the treatment of myelofibrosis, both as a monotherapy and in combination with a standard-of-care JAK inhibitor," said Adrian Senderowicz, M.D., Chief Medical Officer at Constellation Pharmaceuticals. "Moreover, as these data highlight improvements across key hallmarks of myelofibrosis, we believe that CPI-0610 has the potential to address a broad range of unmet needs in patients with this difficult-to-treat cancer. We look forward to the continued evaluation of CPI-0610 in this ongoing Phase 2 trial and to providing additional data from MANIFEST later this year."
The data were gathered from 44 patients enrolled as of April 17, 2019. Twelve patients received 24-week assessments and 16 patients received 12-week assessments. Below is a summary of results from the interim update across primary and secondary endpoints from the trial:
14 of 16 evaluable patients demonstrated spleen volume reductions. Overall, the median best on-trial spleen volume change from baseline was -19.2%.
Of these 16 evaluable patients, 11 were evaluable for improvement in Total Symptom Score (TSS) according to the Myelofibrosis Symptom Assessment Form, Version 4.0. Six of the 11 (55%) evaluable patients achieved greater than 50% TSS improvement from baseline as a best response.
All of these 16 patients were evaluable for Patient Global Impression of Change (PGIC). Fifteen of 16 (94%) evaluable patients reported improvements in PGIC, of which 10 reported feeling either "much improved" or "very much improved" and no patients reported feeling worse following treatment.
Of 12 evaluable patients who received at least 24 weeks of treatment, three were severely anemic and dependent on red-blood-cell transfusions at baseline. Of these three patients, two converted to transfusion independence. These two patients have remained transfusion independent for more than 69 and 24 weeks, respectively, as of April 17, 2019, and remain on trial.
Ten patients were evaluable for bone marrow fibrosis, of which six (60%) experienced improvement in bone marrow morphology of at least one point on a scale of 0-3. Four of these six patients exhibited improvements within six months of starting CPI-0610 therapy.
Based on the interim data, CPI-0610 was generally well-tolerated, both as a monotherapy and in combination with ruxolitinib. Overall, the most commonly reported side effects (≥10%) were diarrhea, vomiting, upper respiratory tract infection, headache, epistaxis, fatigue, dysgeusia, cough and pruritis. Grade 3 or greater treatment-emergent adverse events were only reported in the combination arm, and those reported in more than one patient included thrombocytopenia, anemia, and decreased platelet counts, each of which was reported in two patients. There was one patient death, which the Company assessed as unlikely to have been related to CPI-0610. The combination therapy of CPI-0610 and ruxolitinib showed a non-cumulative, manageable, and mostly reversible asymptomatic thrombocytopenia.
Each of the first four patients enrolled in MANIFEST, of which two received CPI-0610 as a monotherapy and two received CPI-0610 in combination with ruxolitinib, remained on therapy and had been treated for approximately 16 and 20 months, respectively, as of April 17, 2019.
Please see the poster in the Investors & Media section of Constellation’s website for additional details.
As previously announced in November 2018, Constellation expanded the MANIFEST trial to include a third cohort, designed to evaluate CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK-inhibitor-naïve patients with advanced MF. The Company has begun treating patients in this arm of the trial and expects to provide initial results from this cohort, as well as additional data from the ruxolitinib-resistant and -refractory (second-line) cohorts, in the fourth quarter of 2019.
Investor Event
Constellation will host an analyst/investor meeting, with an accompanying conference call and webcast, to discuss this interim update in the Jackson Park D room at Hyatt Regency McCormick Place in Chicago at 8:00 AM EDT/7:00 AM CDT on June 4, 2019. The agenda of the meeting 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 interim data from the MANIFEST clinical trial presented in a poster at ASCO (Free ASCO Whitepaper) on June 3
A panel discussion with two key opinion leaders in MF:
Dr. Srdan Verstovsek, a medical oncologist at the University of Texas MD Anderson Cancer Center and an investigator in the MANIFEST trial; and
Dr. Raajit Rampal, a hematologic oncologist at Memorial Sloan Kettering Cancer Center
The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source Participants may also access the event and participate in the live question-and-answer session by dialing (877) 473-2077 (domestic) or (661) 378-9662 (international) and referring to conference ID 1295319.
Medical Presentation at EHA (Free EHA Whitepaper)
Dr. Ronald Hoffman of Mt. Sinai Health System, an investigator in the MANIFEST trial, will make an oral presentation on this interim update of MANIFEST at the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting at 12:15 PM CEST/6:15 AM EDT on June 15, 2019. Slides from the presentation will be posted to Constellation’s website.
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, either as a monotherapy or in combination with ruxolitinib, in a second-line setting in patients with MF who are refractory to or intolerant of or have relapsed or lost response to ruxolitinib. Patients in the two second-line arms are being stratified based on transfusion-dependent status. The primary endpoint for the cohorts with transfusion-dependent patients is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for the patients who were not transfusion-dependent at baseline is spleen volume reduction. In addition, the Company added a third arm designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK-1/2-inhibitor-naïve MF patients.