Constellation Pharma’s president and chief executive officer, Jigar Raythatha, took time out to speak with BioSpace about the company and where it’s headed with the field of epigenetics.
Epigenetics is the study of changes in gene expression that don’t involve changes to the DNA sequence. The most well-known form is DNA methylation, where the addition of a methyl group, a carbon atom with three hydrogen atoms attached, affects whether a gene is turned on and off. There are others, such as chromatin remodeling, histone modification, and non-coding RNA mechanisms.
Because the tools and knowledge of epigenetics is fairly recent, biopharma is just beginning to exploit epigenetics in developing therapeutics for a variety of diseases. One of those companies is Cambridge, Massachusetts-based Constellation Pharmaceuticals. The company’s president and chief executive officer, Jigar Raythatha, took time out to speak with BioSpace about the company and where it’s headed with the field of epigenetics.
At this point, Constellation Pharmaceuticals, which was launched by Third Rock Ventures in 2009, has advanced two programs, soon to be a third, into clinical trials.
“The exciting thing is through the work we’ve done we wholly own our pipeline now, and there are a lot of ways for us to think about creating value for the company going forward,” Raythatha said. “The data we’ve generated now with our initial programs that are in proof-of-concept studies point to the potential for disease-modifying effects and the ability to move into pivotal studies in the near future.”
Part of that ability, Raythatha said, is the company’s focus on translational science and, “thinking through epigenetics and how do we take interesting biology and biochemistry and translate that into who the patients are who are most likely to benefit from intervening in these targets.”
The company’s lead program is CPI-0610, which is a BET inhibitor in Phase II clinical trials in myelofibrosis. Abnormal BET function has been associated with cancer for quite some time. BET proteins control the expression of the target genes of NF-kB, a key immune signaling pathway that is abnormally activated in cancer and immune disorders. The trial is dubbed MANIFEST.
“Several companies have developed BET inhibitors and taken them into the clinic,” Raythatha said, “but most have issues around finding a wide enough therapeutic window and safety margin to pursue them in development, and most have stumbled with that issue. We have what we think is a best-in-class BET inhibitor that has really differentiated itself in that perspective. We have a very wide therapeutic window. We see the same on-target dose-limiting toxicities, but they tend to be reversible, noncumulative, and the potent activity we generate is at a dose level where that toxicity is manageable. We just haven’t seen that replicated in other BET inhibitors.”
So the MANIFEST program is evaluating CPI-0610 in myelofibrosis patients in combination with Incyte’s Jakafi (ruxolitinib), a JAK inhibitor, and as a monotherapy.
MANIFEST is the lead program and the company hopes to move into pivotal Phase III trials with the drug sometime in 2020. Raythatha notes, “CPI-0610 is furthest along. We’ve presented data and have data we have not yet presented. Our goal is to initiate a Phase III study in the frontline scenario and the JAK inhibitor study, mid-2020, and potentially there is an accelerated path based on the Phase II study results that may present itself.”
The second program in Phase II is CPI-1205, which is in the ProSTAR trial. This and at least one other program, CPI-0209, focuses on EZH2. EZH2 acts as what is called an “epigenetic writer.” It regulates gene expression by attaching one or more methyl groups on a histone protein—part of the chromatin structure of DNA—which results in suppressing the gene’s expression. This is a normal part of cellular development, but some cancers re-direct EZH2 to genes that become abnormally repressed.
“EZH2 is very challenging,” Raythatha said, “and while CPI-1205 is very good, it doesn’t cover the target 24/7, and we believe that if you are able to cover the target 24/7, you can extract the entirety of EZH2 biological potential, which greatly expands the opportunities to other avenues.”
Which is why the developed CPI-0209, which is currently in preclinical studies. CPI-1205 is in the ProSTAR trial for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in combination with enzalutamide (Pfizer’s Xtandi) or abiraterone acetate (Janssen Oncology’s Zytiga).
The company also has several other compounds in preclinical development, which Raythatha says is a differentiating factor for the company. “We’re not a one-trick pony. We’re not just one target or one or two mechanisms. We have a very broad portfolio, approaching three programs in the clinic and multiple other programs across a range of different spaces preclinically. So I think we have a unique profile that should appeal, for instance, to potential recruits that we’re trying to bring into the company that can really satisfy a range of different career arcs and trajectories, from early-stage discovery, translational medicine, clinical development, and soon into the commercial realm.”
Which is important, because he notes that they are in the process of positioning the company for building late-stage development and commercialization infrastructure. Which means they expect to accelerate hiring—and, in fact, already have a number of job opportunities posted.
Although the concept of epigenetics has been around for quite some time, with the term coined in 1942 by Conrad H. Waddington, it moved to the forefront in the 1990s with the discovery of the effects of imprinting in cancer and diseases such as Prader-Willi syndrome and Angelman Syndrome. But the tools to exploit epigenetics for the development of therapeutics is only now starting to gain momentum.
“In the grand scheme of things, we’re still in the early phases of the industrialization of epigenetics,” Raythatha said. “These broad areas of biology take a very long time, decades, to unlock the true potential—of the immune system, gene therapies, cell therapies—and we’ve been working on these concepts for multiple decades. We’ve really been working on epigenetics for about 10 years. The strong takeaway is you need to think about who your patients are from the very beginning. In this day and age, we have the tools and technology that really allow us to do some of that fundamental translational work early one, so when you get to the clinic you have real hypotheses to test. That wasn’t available 10 years ago, but it certainly is now.”
