Constellation Pharmaceuticals is advancing discovery programs against multiple targets in the reader, writer, and eraser classes of epigenetic proteins. The company has developed proprietary tools and assays to validate the biological function of the members of these target classes. In parallel, we are employing our integrated expertise in biochemistry, biophysics, medicinal chemistry, pharmacology, and translational medicine to rapidly advance our most promising research and development programs through the clinic.
CPI-1205 is a small-molecule that increases the expression of genes that are abnormally suppressed (“turned off or “silenced”) in some cancers. CPI-1205 blocks the activity of an enzyme called Enhancer of Zeste Homolog 2 (EZH2), which is over-expressed or mutated in many solid tumors and hematologic malignancies. EZH2 expression levels strongly correlate with late-stage disease and a poorer prognosis for patients.
Constellation Pharmaceuticals has identified multiple series of programmable small-molecule inhibitors of EZH2. The first of these inhibitors is CPI-1205, which is in clinical trials for patients with metastatic castration-resistant prostate cancer as well as other solid tumors and hematologic malignancies.
In parallel, we are employing our discovery and drug development expertise to advance next-generation EZH2 inhibitors. Data from the leading compounds in this next-generation EZH2 inhibitor portfolio show the ability to engage with EZH2 in different ways to help access additional therapeutic potential in biological contexts not amenable to treatment with first-generation EZH2 inhibitors.
Disclaimer: CPI-1205 is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). CPI-1205 is not available for use outside of a clinical trial setting.
EZH2: A Scientific Overview
EZH2 normally places a small chemical group, called a methyl group, on a histone protein associated with DNA. When the methyl group is placed on the protein, the gene in this location is less likely to be expressed. While this effect of EZH2 on gene expression is a normal part of development, some cancers depend on an abnormal pattern of gene expression caused by EZH2.
Lysine methyltransferases and demethylases have been identified as transcriptional co-regulators by either preserving particular chromatin methylation states or by controlling placement and removal of histone lysine methylation marks to promote dynamic changes in gene expression. EZH2 is an important histone lysine methyltransferase that functions cooperatively as part of a multi-subunit complex known as Polycomb Repressive Complex 2 (PRC2). EZH2 is responsible for methylating a single lysine residue (K27) on the histone H3 N-terminal region.
Further, functional data implicate EZH2 in tumor initiation and progression, stem cell self-renewal, migration, angiogenesis and proper function of activated regulatory T-cell differentiation (Tregs).
CPI-0610 is a small-molecule that inhibits the expression of several genes involved in cancer and fibrosis, including MYC, BCL2, NF-κB and TGF-β-induced collagen genes by binding to a family of proteins known as bromodomain and extra-terminal (BET). CPI-0610 is currently being tested in a Phase 2 study of myelofibrosis, a myeloproliferative and fibrotic disorder.
Disclaimer: CPI-0610 is an investigational medicine and has not been approved by the FDA (or any other regulatory authority). CPI-0610 is not available for use outside of a clinical trial setting.
BET: A Scientific Overview
BET proteins are four closely related bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT), which constitute a subset of the larger family of 47 bromodomain-containing proteins. Bromodomains are acetyl-lysine binding pockets that target bromodomain-containing proteins to histones at distinct genomic locations, thereby affecting chromatin structure and function. The binding of BET protein bromodomains to chromatin regulates gene expression and small-molecule inhibition of that binding results in selective down-regulation of distinct genes. A number of the genes under BET control include key oncogenes, such as MYC, BCL-2, and down-stream NF-kB gene targets, a number of which are important mediators of cancer and inflammation.
Small-molecule inhibition of BET bromodomains leads to selective killing of tumor cells across a broad range of hematologic and solid tumor-derived cell lines. Constellation Pharmaceuticals has deployed its integrated drug discovery product engine, which includes proprietary screening strategies and structure-based drug design to identify novel, potent, and selective inhibitors of BET bromodomains. Our first BET inhibitor, CPI-0610, was evaluated in three separate Phase 1 clinical studies where it demonstrated clinical anti-tumor activity at well-tolerated doses.
In addition to cancer, BET bromodomain inhibition has the potential to be an effective treatment for patients with myelofibrosis. The principal toxicity of treatment with CPI-0610 is reversible thrombocytopenia, and mild thrombocytopenia is observed at doses of CPI-0610 that are relatively low and devoid of any other toxicity. In preclinical models where human stem cells are differentiated ex vivo into megakaryocytes, megakaryocyte differentiation is inhibited at relatively low concentrations of CPI-0610, and at concentrations that correlate with those where thrombocytopenia is observed in patients. BET bromodomain inhibitors are known to cause anti-inflammatory effects due to their ability to inhibit the transcription of a subset of NF-κB-dependent cytokines, like IL-6. Hence BET inhibition, like JAK2 inhibition, may alleviate the constitutional symptoms that afflict patients with this disease. BET bromodomain inhibition also can block the TGF-β-induced secretion of collagen by fibroblasts, raising the possibility of eventually ameliorating the marrow fibrosis that is central to this disease. Thus, BET inhibition impacts several key determinants of myelofibrosis, including inflammation, fibrosis, and megakaryocyte function, potentially resulting in disease amelioration. A phase 1/2 clinical trial utilizing CPI-0610 in patients with myelofibrosis is currently open for enrollment.
Prostate cancer is the most commonly diagnosed cancer among men in the United States. One in eight men will develop invasive prostate cancer in his lifetime, with the risk increasing with age. Most men survive five years or longer following a prostate cancer diagnosis, with the disease eventually progressing in most cases. Estimates suggest more than two million men in the country live with prostate cancer. Approximately 161,000 men will be diagnosed with prostate cancer in 2017, and approximately 26,000 men will die from the disease, according to the American Cancer Society.
As with many cancers, death rates for patients affected by prostate cancer have been going down since the late 1990s, due to the introduction of better diagnostic approaches and new treatments. In the last 10 years, new classes of androgen synthesis inhibitors and androgen receptor inhibitors (together, ARis)—including second-generation ARis abiraterone acetate (marketed as Zytiga® by Janssen) and enzalutamide (marketed as Xtandi® by Astellas and Pfizer)—have been introduced. These treatments have extended survival for patients with metastatic castration-resistant prostate cancer (mCRPC) and have enabled many of these patients to avoid or delay chemotherapy. As a result, some doctors have called ARis the foundation of therapy for mCRPC. Some estimates suggest that 90 percent or more of patients with mCRPC will be prescribed ARis at some point in their course of treatment.
However, resistance to ARis usually develops after a year or two following initiation of therapy, and resistance develops more rapidly to subsequent ARis a patient may be prescribed. Recent research suggests that prostate cancer cells develop ARi resistance by expressing mutated versions of the androgen receptor, overexpressing the androgen receptor, or evolving to a different cellular state that is not dependent on androgen signaling. Scientific understanding of the drivers of resistance to has increased in recent years, and this provides a way to help patients not well-served by existing treatments.
Other Solid Tumors
Independent of tumors with EZH2 overexpression, EZH2 has been shown to be required as part of the transcriptional program that drives regulatory T-cell differentiation (Tregs). Constellation Pharmaceuticals has extended this work by showing that our EZH2 inhibitor CPI-1205 can reduce Treg suppressive capacity and stimulate effector T-cells (Teffs) that are known to be important for strong anti-tumor response in syngeneic, tumor-bearing mouse models. Based on these observations, we are planning further clinical studies with CPI-1205 in combination with other immuno-oncology therapies.
Separately, EZH2 has been shown to be instrumental in other drug resistance contexts, including lung cancer, and breast cancer.
Myelofibrosis (MF) is part of a collection of progressive blood cancers known as myeloproliferative neoplasms. Approximately 3,000 new patients are diagnosed each year, and nearly 13,000 patients are living with MF in the United States. Most patients are 65 years or older at diagnosis, and median survival from diagnosis is approximately five years. Treatment options include cytoreductive therapies like hyroxyurea, interferon and other immunomodulatory agents, spleen debulking or removal, and allogeneic stem cell transplant. Ruxolitinib (marketed as Jakafi® by Incyte) has become the standard-of-care for high- and intermediate-risk patients after approval in 2011 based on pivotal trials that demonstrated reduction in spleen volume and symptom improvement. Despite first line ruxolitinib treatment for high-and intermediate-risk MF, literature suggests that up to 75 percent of patients will face tolerability issues or loss of therapeutic effect within five years.
We are developing our EZH2 inhibitor CPI-1205 as an option for patients that progress after treatment with second generation androgen inhibitors.
The epigenetic regulatory protein EZH2 has been correlated with prostate cancer stage and prognosis. Researchers have identified higher EZH2 expression levels in more advanced prostate cancers, with the highest levels observed in patients with metastatic tumors. Further, high EZH2 expression level in tumor samples was associated with more rapid treatment failure after surgical castration (Varambally et al., Nature 2002). Further research on tumor samples enabled the identification of a “gene signature” linked to genes modulated by EZH2 that has been employed to prospectively classify prostate cancer tumor risk and patient outcomes. Patients with a “high risk” EZH2 gene signature were found to have a lower likelihood of survival (Yu et al., Cancer Research, 2007). Based on these data, we have demonstrated in pre-clinical models the potential for our EZH2 inhibitor CPI-1205 to impact prostate tumors.
Constellation Pharmaceuticals is currently conducting a Phase 1b/2 clinical trial combining CPI-1205 with enzalutamide in patients that no longer respond to abiraterone acetate and in combination with abiraterone acetate in patients that no longer respond to enzalutamide.
In addition, we are developing our BET inhibitor CPI-0610 as an option for patients that continue to experience myelofibrosis symptoms when treated with ruxolitinib (marketed at Jakafi® by Incyte).
In pre-clinical studies, CPI-0610 has shown to inhibit megakaryocyte differentiation—a central cell type implicated in myelofibrosis—at low doses. BET bromodomain inhibitors are also known to cause anti-inflammatory effects due to their ability to inhibit the transcription of a subset of NF-κB-dependent cytokines, like IL-6. BET inhibition, like JAK2 inhibition, may alleviate the constitutional symptoms that afflict patients with myelofibrosis. BET bromodomain inhibition also can block the TGF-β-induced secretion of collagen by fibroblasts, raising the possibility of eventually reducing marrow fibrosis associated with myelofibrosis. BET inhibition impacts several key determinants of myelofibrosis, including inflammation, fibrosis, and megakaryocyte function, potentially resulting in disease amelioration.
Constellation Pharmaceuticals is currently conducting a Phase 1/2 clinical trial utilizing CPI-0610 in patients with myelofibrosis. This trial is currently open for enrollment.