CAMBRIDGE, Mass., Nov. 15, 2018 (GLOBE NEWSWIRE) — Constellation Pharmaceuticals, Inc., (Nasdaq: CNST) a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, will make a presentation on its EZH2 inhibition program in prostate cancer at an upcoming biomedical conference.
Bill Bradley, Ph.D., Associate Director, Translational Sciences, at Constellation, will give a poster presentation at the EORTC / NCI / AACR Molecular Targets and Cancer Therapeutics Symposium in Dublin, Ireland, on November 16. The presentation is titled “EZH2 Inhibition as an Effective Treatment for Metastatic Castration-Resistant Prostate Cancer.” The presentation discusses preclinical evidence showing the effectiveness of the EZH2 inhibitor CPI-1205 in treating metastatic castration-resistant prostate cancer (mCRPC) dependent on androgen receptor signaling (ARS). CPI-1205 was shown to combine synergistically with ARS inhibitors, such as enzalutamide or abiraterone acetate, to inhibit the growth of prostate cancer cell models and also was effective in overcoming mechanisms of resistance to ARS inhibitors. The poster also includes transcriptomic analysis, including single-cell RNA sequencing, highlighting the mechanisms by which CPI-1205 and its combination with ARS inhibitors restrict prostate cancer growth. The data shown in the poster supports the potential of EZH2 inhibition as a therapeutic approach for the mCRPC patient population and contributes to the rationale for Constellation’s ProSTAR trial of the EZH2 inhibitor CPI-1205 used in combination with ARS inhibitors.
About EZH2 Inhibition in Prostate Cancer
EZH2 is an enzyme that acts as an epigenetic writer and normally regulates gene expression by placing one or more methyl groups on a histone protein, leading to the suppression of gene expression programs. While this effect of EZH2 on gene expression is a normal part of cellular development, some cancers depend on an abnormal pattern of gene expression and re-direct EZH2 to genes that become abnormally repressed. Cancer cells with these abnormal gene expression programs may be more resistant to anti-cancer therapies.
There is a strong association between EZH2 expression and disease progression in metastatic castration-resistant prostate cancer (mCRPC), and a therapeutic approach that targets EZH2 may result in better outcomes than those achieved with approved therapeutic agents that treat mCRPC. In prostate cancer, the androgen receptor is a key regulator of gene expression and acts as the mediator of androgen signaling in prostate cells. The AR signaling pathway is the primary pathway used by prostate cancer cells to promote tumor growth. We believe that EZH2, by suppressing certain gene sets, enhances AR signaling, which can lead to increased tumor growth. In preclinical studies, we observed enhanced gene expression changes in prostate cancer cells treated with a combination of enzalutamide and CPI-1205 as compared to enzalutamide treatment alone. This corroborates our hypothesis that EZH2 functionally cooperates with androgen receptor signaling to promote prostate cancer growth.
We also believe that EZH2 is utilized by prostate cancer cells to establish resistance to ARS inhibitors. We have observed in preclinical studies that EZH2 inhibitors, such as CPI-1205, in combination with ARS inhibitors synergistically killed tumor cells and demonstrated activity in models that are resistant to ARS inhibitors.
About CPI-1205
CPI-1205 is a small molecule designed to promote anti-tumor activity by specifically inhibiting EZH2, an enzyme that suppresses target gene expression. In preclinical studies, we observed that CPI-1205 inhibited tumor growth as a single agent and synergistically enhanced the efficacy of cancer therapies, including ARS inhibitors in a prostate cancer model and immune checkpoint inhibitors in other solid tumor models. Based on these observations and the limited options for patients who progress on ARS inhibitors or immune checkpoint inhibitors, we have prioritized clinical development of CPI-1205 as a combination therapy with ARS inhibitors in prostate cancer and immune checkpoint inhibitors in solid tumors. We are currently conducting the ProSTAR trial. We previously completed a Phase 1 clinical trial of CPI-1205 as a monotherapy in patients with relapsed B-cell lymphoma in which CPI-1205 demonstrated clinical activity and was well tolerated.
About the ProSTAR Clinical Trial
ProSTAR is an open-label Phase 1b/2 clinical trial of CPI-1205 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in combination with enzalutamide or abiraterone acetate, which are second-generation ARS inhibitors, in patients with mCRPC who previously progressed on treatment with either abiraterone acetate or enzalutamide. Patients who have previously progressed on treatment with abiraterone acetate are treated with a combination of enzalutamide and CPI-1205, and patients who previously progressed on treatment with enzalutamide are treated with a combination of abiraterone acetate and CPI-1205. In the Phase 1b portion of this trial, we aim to establish safety, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and a recommended Phase 2 dose of CPI-1205 with these agents. Based on results from the Phase 1b trial, we expect to select either abiraterone acetate or enzalutamide to be combined with the optimal dose regimen of CPI-1205 for the Phase 2 portion of the trial. In the Phase 2 trial, we will assess response rate as the primary endpoint, defined as the proportion of patients who have any of (i) a prostate-specific-antigen reduction of 50% or more from baseline, (ii) a decline of 30% or more in circulating-tumor-cell count from baseline or (iii) for patients with measurable soft tissue disease, an objective response, defined as a complete response or partial response per RECIST 1.1 criteria.
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.
Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the anticipated presentation of preclinical data, and its potential implications in the treatment of diseases. All statements, other than statements of historical facts, contained in this press release, including statements regarding the Company’s strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Constellation’s ability to: obtain and maintain necessary approvals from the FDA and other regulatory authorities; continue to advance its product candidates in clinical trials; replicate in later clinical trials positive results found in preclinical studies and early-stage clinical trials of CPI-1205, CPI-0610 and its other product candidates; advance the development of its product candidates under the timelines it anticipates, or at all, in current and future clinical trials; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties, and other important factors, in the Company’s most recent filings with the Securities and Exchange Commission. In addition, the forward- looking statements included in this press release represent the Company’s views as of the date hereof and should not be relied upon as representing the Company’s views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Company’s views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. CPI-1205, CPI-0610, CPI-0209, and other product candidates are investigational in nature and have not yet been approved by the FDA or other regulatory authorities.
Contact
Ronald Aldridge
Investor Relations
Constellation Pharmaceuticals
+1 617-714-0539
[email protected]
Lauren Arnold
Media Relations
MacDougall Biomedical Communications
+1 781-235-3060
[email protected]
