Epigenetic regulators change the architecture of chromatin by either adding, binding to, or removing chemical tags, allowing it to adopt an open configuration to facilitate gene expression or, conversely, a closed configuration to suppress gene expression. Abnormal cells, such as proliferating cancer cells, can usurp these epigenetic mechanisms, ultimately leading to disease. Epigenetic regulators also govern the differentiation of immune cell populations by promoting and suppressing certain genes that are specific for each type of immune cell. Because epigenetic regulators control gene expression in many types of cells, they play a role in many different diseases and are potentially attractive drug targets.

Applying Translational Expertise

The first epigenetic inhibitors caused broad changes to gene expression across thousands of genes, resulting in unintended and often undesirable effects. The next phase focused on targeted epigenetic regulators in genetically defined cancer contexts, specifically on mutated regulators with abnormal function that cancer cells depend on for growth. These genetically defined approaches underestimate the potential of identifying, and specifically targeting, epigenetic regulators in cancer.

Constellation Pharmaceuticals has an integrated epigenetics platform designed to overcome these shortcomings. We combine our understanding of transcriptional regulation by epigenetic regulatory proteins with our knowledge of the assays that are appropriate for identifying the relevant chemical matter involved in target modulation; this is supported by our extensive library of small molecules, including commercially sourced and in-house synthesized compounds; a library of chemical probes comprising selective and potent inhibitors of specific epigenetic regulators; and a translational element.

The latter builds on our experience working with epigenetic pathways and targets. We have a staff of approximately 20 translational scientists with the expertise needed to make the connections between epigenetic regulation and specific diseases. This translational approach is informing the next wave of our discovery efforts.

Our novel therapeutics target the writer, reader, and eraser classes of epigenetic regulators and selectively modulate gene expression. Epigenetic writers chemically modify chromatin, readers recognize chemical modifications on chromatin and bind to these modifications using specialized protein domains, and erasers remove chemical modifications from chromatin. Each activity leads to modification of the chromatin architecture and thus impacts gene transcription.

We are focused on targets whose inhibition modulates gene expression in a highly selective manner; that have broad development opportunities, including biomarker-defined contexts; and whose inhibition may reprogram immune cells in the tumor microenvironment to enhance anti-tumor activity. These distinct classes of epigenetic regulators are broadly druggable, and selective reprogramming of gene expression is a promising therapeutic approach to both induce cancer cell killing and enhance anti-tumor immunity.

Targeting chromatin modification creates broader opportunities for restoring desired genetic outcomes in many different diseases without the need to target specific mutated genes. However, tying the effects within specific contexts to specific patient populations and constructing disease models and assays that will provide the relevant context are crucial.

Inhibiting BET Readers in Myelofibrosis

Bromodomain and extra-terminal domain (BET) proteins act as epigenetic readers, transmitting the signal carried by acetylated lysine residues on histones and transcribing it into various phenotypes. Abnormal BET function has been implicated in cancer through several means, including chromosomal translocation, gene amplification, and gene overexpression.

Dysregulated BET signaling is involved in a number of diseases, including myelofibrosis (MF), by promoting the generation of aberrant megakaryocytes from hematopoietic stem cells. The two approved therapies are both JAK1/2 inhibitors and generally offer symptomatic improvement, but many patients receiving treatment do not respond well, while responders can develop resistance within five years.

CPI-0610 is a potent small molecule designed to selectively inhibit the function of BET proteins to decrease the expression of abnormally expressed genes in cancer. In so doing, the compound may impede the differentiation of myeloid cells to megakaryocytes, a key hallmark of the disease. Constellation is exploring the hypothesis that these myeloid cells may proceed down a different pathway.

Our preclinical studies and translational insights from our first-in-human study of CPI-0610 led us to prioritize the clinical development of CPI-0610 in myelofibrosis. We are currently conducting a global phase II study of CPI-0610 in patients with MF to investigate its performance, alone and in combination with ruxolitinib in both first-line and second-line contexts. Preliminary data presented in December 2019 showed evidence of activity across a broad range of MF parameters in JAK-inhibitor-naïve and ruxolitinib-resistant or -intolerant patients. Evidence of activity included spleen volume reductions, symptom improvements, conversion of transfusion-dependent patients to transfusion independence, hemoglobin increases, and improvements in bone marrow fibrosis. We believe that the combination of CPI-0610 and ruxolitinib could transform the standard of care in first-line MF, providing greater activity than ruxolitinib alone, with lower levels of anemia that could help some patients initiate treatment earlier or continue treatment longer.

Inhibition of EZH2 in Prostate Cancer

EZH2 is a component of the polycomb repressive complex 2 (PRC2), which is responsible for healthy embryonic development. As an epigenetic writer, EZH2 methylates histones, leading to the suppression of gene expression, and abnormal EZH2 function has been implicated in specific cancers.

Prostate cancer is the second most common type of cancer among men in the United States and the second leading cause of cancer death in this population. In prostate cancer, the androgen receptor signaling (ARS) pathway is the primary driver of tumor growth in prostate cancer. Evidence suggests that EZH2 enhances AR signaling, which may lead to increased tumor growth, and that EZH2 is utilized by prostate cancer cells to establish resistance to ARS inhibitors.

CPI-1205 is a small molecule EZH2 inhibitor that has been shown to inhibit tumor growth as a single agent and to enhance the efficacy of cancer therapies, including ARS inhibitors, in a preclinical prostate cancer model. We have prioritized clinical development of CPI-1205 as a combination therapy with ARS inhibitors in prostate cancer. We are currently conducting the ProSTAR phase Ib/II clinical trial of CPI-1205 in combination with second-generation ARS inhibitors (enzalutamide or abiraterone) in metastatic castration-resistant prostate cancer. In the phase Ib portion of the study, we observed deep and durable responses, including 80% reductions in prostate-specific antigen, in subsets of a heterogeneous population of advanced mCRPC patients in combination with either abiraterone or enzalutamide. In phase II, we continue to gather data, including on the durability of response and on biomarkers that could suggest which patient populations are most likely to benefit. Phase II data will be presented in mid-2020.

CPI-0209 is our second-generation EZH2 inhibitor designed to achieve comprehensive target coverage through extended on-target residence time. Once CPI-0209 binds to EZH2, it remains bound for months. The compound has demonstrated more robust anti-tumor activity compared with first-generation EZH2 inhibitors in preclinical models of multiple cancer types. We are studying CPI-0209 in a phase I/II clinical trial in advanced solid tumors.

Looking Toward the Future

Going forward, we will continue to build on our strong scientific roots in epigenetics while leveraging our growing translational expertise to explore programs from a disease strategy perspective, enabling us to branch into other areas and ensure the future of the company from a sustainable development and commercial perspective. Our goal is to become a fully integrated discovery, development, and commercial organization in oncology.