What was it about the science Constellation Pharmaceuticals is pursuing that made you want to return to lead the company?

Constellation was started by a group of venture capital firms around the area of epigenetics. They recognized that the potential for small molecule inhibitors to control gene expression through epigenetic mechanisms can be powerful in combating disease, so my first iteration with Constellation was about building an extensive discovery platform. This helped us identify novel development candidates. When I returned to Constellation four years later, the company had progressed to the point where it had taken those programs through the initial phases of clinical development.

It was evident to me that there was enormous power behind the discovery platform that helped us identify which targets could be important and in identifying molecules that can serve as drug candidates. Our early phase 1 data suggested that these molecules were active as single agents in combating cancer. However, what was missing was a translational element that could help us connect the dots between the basic biology and our target patient population. In some areas that is obvious because if you have a monogenic disease and you are targeting the gene mutation you can see your impact. But by nature, epigenetics is the opposite. We are controlling gene transcription without impacting the underlying genetics, which means that the investment in translational science to connect the dots to your patient population becomes much more important.

This was an opportunity in the field of epigenetics that Constellation could capture and we turned the focus of the company to translation. In thinking about the diseases in which we could make the most impact, we realized it was not in the areas where we saw initial activity in the clinic, so we pivoted to identify novel applications and supplement that with translational science information.

How do you intend to position Pelabresib as the future backbone of therapy for myelofibrosis?

Currently, the approved standard of care therapies are JAK inhibitors, ruxolitinib, based on an ability to shrink the size of the spleen and to help patients’ symptom load decrease. However, bone marrow fibrosis progresses and hematologic function continues to worsen. One of the side effects of ruxolitinib is anemia.

Our vision is to help enhance the responses seen with ruxolitinib, thereby increasing the magnitude and duration of response. We also think there is the possibility of completely modifying the course of the disease, so you can reverse the damage that is being done to the marrow. Ultimately, we want to treat more patients, so those patients who are in “watch and wait” mode can be treated earlier because there is potential to modifying the course of the disease. Also, because we stave off anemia, patients will be able to be treated in combination with ruxolitinib for a longer period. In addition, there are certain conditions where ruxolitinib is not used, such as in patients who may be too anemic or patients who see suboptimal responses. We think these are potential areas where patients may be able to use pelabresib as a monotherapy or in combination with other agents. We continue to learn more as we further develop this drug candidate.

What is Constellations’s approach to discovery and how do you think creatively about development strategies?

Discovery is our lifeblood. Everything that we have progressed into the clinic has been homegrown. We recently nominated a new development stage candidate - CPI-482, which is an LSD1 inhibitor. This underscores our strategy to investment in translational science. CPI-482 has a significant effect on myeloid biology, which could help us move into adjacencies and complimentary spaces to pelabresib.

What is driving interest in Constellation from public markets investors?

The enthusiasm for Constellation is driven largely by the potential for our lead program today. Myelofibrosis is very exciting for a multitude of reasons. There is high unmet need, a reasonable number of patients and treatment typically is needed for years. This translates into a very big opportunity for us as a company and our shareholders. I think a lot of the excitement from our investors was generated when they dug into the data that we presented, and they see pelabresib as a game changer, initially in myelofibrosis but then there is potential beyond that. Our discovery engine also fuels future value generating potential that we look to unlock for our investors.