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ASH 2021 | MANIFEST update: pelabresib clinical and pathological investigations

Srdan Verstovsek, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, TX, shares preliminary findings from the ongoing Phase II MANIFEST study (NCT02158858) of pelabresib with and without ruxolitinib for the treatment of myelofibrosis (MF). Pelabresib is a first-in-class, selective small-molecule BET inhibitor, shown to modify the expression of genes involved in NFκB signaling in patients with MF. The multi-arm study investigated pelabresib as a single agent in patients intolerant or refractory to ruxolitinib, or as an add on in patients receiving ruxolitinib with a suboptimal response. Updated data showed that, in both trial arms, pelabresib reduced bone marrow fibrosis, decreased megakaryocyte density and increased erythroid progenitor numbers. Additionally, treatment was able to reduce spleen volume and improve symptoms. Dr Verstovsek outlines the plans for a Phase III trial of pelabrasib. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

Pelabresib or CPI-0610 is a BET, bromodomain inhibitor, one of the epigenetic modifiers. It alters the expression of genes in the bone marrow. And we know that epigenetic modifiers are active in myeloproliferative neoplasms. They may do a lot of good things. Well, this drug has been tested in a multi-arm, Phase II open label study as a single agent in myelofibrosis patients after ruxolitinib. Ruxolitinib is a standard practice, first line, JAK/STAT inhibitor, but it doesn’t work forever...

Pelabresib or CPI-0610 is a BET, bromodomain inhibitor, one of the epigenetic modifiers. It alters the expression of genes in the bone marrow. And we know that epigenetic modifiers are active in myeloproliferative neoplasms. They may do a lot of good things. Well, this drug has been tested in a multi-arm, Phase II open label study as a single agent in myelofibrosis patients after ruxolitinib. Ruxolitinib is a standard practice, first line, JAK/STAT inhibitor, but it doesn’t work forever. So after ruxolitinib, pelabresib as a single agent is active, a very good drug for control of the spleen and symptoms in about a quarter of the patients. And it may improve the anemia as well, which is an extra bonus. Now it’s been studied also, and I presented some of these results in combination with ruxolitinib in the frontline setting from the very first day, the two together were given to patients and the improvement in the spleen and improvement in symptoms were much better than what you would expect with ruxolitinib alone.

And again, it can improve the anemia which we haven’t seen with any other therapies. Therefore, through all these different arms of the open label Phase II study, we got very good knowledge that this drug is active, it can be easily combined with ruxolitinib and the plan is, it’s already happening actually, a Phase III study for possible approval of pelabresib. This is the prospective randomized placebo control study in a frontline setting from day one, combination of pelabresib and ruxolitinib versus ruxolitinib alone, to see whether the spleen and symptoms response will be better than ruxolitinib alone. And from my perspective, also looking whether anemia will improve because we don’t have any anemia drugs at all and the JAK inhibitors typically lower the red blood cell count, so it’s a problem. So all these characteristics give us enthusiasm for the drug to be possibly in the near future, approved as a new therapy in combination with JAK inhibitors for myelofibrosis patients.

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