Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, today provided an update on progress in the MANIFEST Phase 2 clinical trial of CPI-0610 in myelofibrosis (MF).
The Company also reviewed its 2018 accomplishments and announced its data disclosure plans for 2019.
As of December 10, 2018, each of the first four ruxolitinib-resistant second-line MF patients in MANIFEST remained on study. The two patients treated with a combination of CPI-0610 and ruxolitinib (i.e., CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. The two patients treated with CPI-0610 monotherapy have been treated for over 12 months. Each of the four patients has shown a reduction in spleen volume and improved hemoglobin levels. One of the combination therapy patients was transfusion dependent before therapy and converted to being transfusion independent after CPI-0610 was added to the patient’s regimen. As of our data cutoff, this patient’s response has persisted free of transfusions for over 52 weeks. Additionally, bone marrow biopsies before and after treatment were analyzed for the two patients on monotherapy, and both demonstrated a one-grade improvement in bone marrow fibrosis score as well as associated improvements in hemoglobin and platelets. Taken together, these results suggest that CPI-0610 may be modifying the underlying course of the disease in these ruxolitinib-resistant MF patients.
The Company has now opened 16 clinical trial sites in the U.S., Canada, and E.U. and enrolled 18 patients in MANIFEST. Only one patient has discontinued treatment, which was due to a non-drug-related serious adverse event. The recommended Phase 2 dose of CPI-0610 in the MANIFEST study is 125 mg once daily (may be titrated up), which is below the maximum tolerated dose of 225 mg once daily. Furthermore, in a Phase 1 clinical trial of CPI-0610, the Company also showed that the dose-limiting toxicity of thrombocytopenia was reversible and non-cumulative. Taken together, preliminary data suggest that CPI-0610 may have a wider therapeutic window and the potential for a differentiated toxicity profile relative to some other BET inhibitors, based on their published data.
Additional 2018 Accomplishments
‘During 2018, we generated encouraging preliminary clinical data for both CPI-0610 and CPI-1205, which led the Company to expand both clinical programs,’ said Jigar Raythatha. ‘We are particularly excited by the preliminary Phase 2 results we have seen thus far in CPI-0610 that demonstrate potential disease-modifying effects rather than primarily addressing the symptoms of the disease. In addition, we advanced CPI-0209, our second-generation EZH2 inhibitor that has the potential to broaden the patient populations treated with EZH2 inhibition, into IND-enabling development during the year.’
CPI-0610
Constellation announced that it enhanced and expanded the MANIFEST Phase 2 trial in October to stratify for transfusion dependence status. The Company also announced the planned initiation of a new arm to determine whether the combination of CPI-0610 and ruxolitinib in ruxolitinib-naive MF patients could improve on the benefit of ruxolitinib alone in first-line treatment of myelofibrosis.
Constellation announced that the FDA granted Fast Track status for CPI-0610 in myelofibrosis in November, a designation that facilitates the development and expedites the review of drugs to treat serious or life-threatening diseases and to fill unmet medical needs.
CPI-1205
Thirty-six patients have been enrolled in the Phase 1b portion of the ProSTAR clinical trial of CPI-1205 in metastatic castration-resistant prostate cancer (mCRPC) in combination with either abiraterone or enzalutamide. Constellation established the safety, pharmacokinetics, and pharmacodynamics of CPI-1205 in both the enzalutamide and the abiraterone arms. The Company also observed evidence of clinical activity in both arms.
Constellation announced the initiation of the Phase 2 portion of ProSTAR in December. Based on the clinical activity and safety profile demonstrated by CPI-1205 with either abiraterone or enzalutamide in the Phase 1b portion, Constellation expanded the Phase 2 portion of ProSTAR to study both combinations, i.e., a randomized trial of CPI-1205 + enzalutamide versus enzalutamide alone, as well as a single arm of CPI-1205 + abiraterone. While a low response rate and a short duration of response have been observed in clinical trials of second-line treatment of mCRPC generally, the unmet need in this setting is particularly great with abiraterone alone. Dosing has begun in the enzalutamide arm and will soon begin in the abiraterone arm.
CPI-0209
The Company nominated CPI-0209 as a development candidate in April. Preclinical data demonstrated that CPI-0209 engaged EZH2 more comprehensively and durably and produced more rapid tumor regression with lower and less frequent dosing compared with first-generation EZH2 inhibitors.
Corporate Development
Constellation completed a crossover financing in April and an initial public offering in July, together raising $160 million. As a result of these successful financings, Constellation expects to be able to fund its operations into the second quarter of 2020.
Constellation strengthened its management team by appointing a General Counsel and a Chief Scientific Officer. In addition, the Company expanded the board with appointments of two executives with extensive industry experience in prostate cancer and myelofibrosis.
A Look Ahead at 2019
‘2018 was all about execution, and we reached each of the business and R&D milestones that we set out to achieve for ourselves and our shareholders,’ continued Mr. Raythatha. ‘We expect 2019 to be an important year focused on data, as we are set up to deliver results from our ongoing studies throughout 2019.’
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