Pelabresib Generates Excitement in Myelofibrosis


In an interview with Targeted Oncology, Joseph M. Scandura, MD, PhD, discussed research on pelabresib for the treatment of patients with myeloproliferative neoplasms.

Joseph M. Scandura, MD, PhD thumbnail

Joseph M. Scandura, MD, PhD

Multiple studies are evaluating pelabresib (CPI-0610) for the treatment of patients with myeloproliferative neoplasms (MPNs). With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. Scandura, MD, PhD, reflected on its potential role for patients with myelofibrosis and studies evaluating the agent.

Pelabresib is an oral, small-molecule, investigational BET inhibitor. The agent works by downregulating NF-κB and signals other relevant genes involved in myelofibrosis disease pathways.

In the ongoing, global, nonrandomized, multicohort, open-label, phase 2 MANIFEST study (NCT02158858), investigators are assessing pelabresib as a monotherapy and in combination with ruxolitinib (Jakafi) in patients with myelofibrosis.1

The study is evaluating the efficacy of the JAK inhibitor combination therapy vs pelabresib alone for treatment-naïve or pretreated patient populations, and involved 4 separate cohorts. Patients with JAK inhibitor-pretreated myelofibrosis were given pelabresib, patients with ruxolitinib-pretreated myelofibrosis were given pelabresib plus ruxolitinib, patients with JAK inhibitor naïve myelofibrosis were given pelabresib plus ruxolitinib, and patients with essential thrombocythemia were given pelabresib alone.

According to data from the trial presented at the 2023 EHA Congress, by the data cutoff of July 29, 2022, 7 of the 20 patients enrolled in the study were treated for at least 6 months. Fourteen patients continued to receive pelabresib. Findings showed that pelabresib plus ruxolitinib demonstrated durable improvements in spleen volume and total symptom score among those enrolled. The confirmed complete response rate was 40% and the partial hematologic response rate was 20%, respectively.

Another study evaluating pelabresib is the ongoing, randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495).2 Here, patients with JAK inhibitor-naïve myelofibrosis are being randomized 1:1 and treated with upfront pelabresib plus ruxolitinib vs ruxolitinib alone.

Patient enrollment in this study was completed in May 2023. Topline findings are expected to be released in late 2023.

Blood Cancer: © Hadi -

Blood Cancer: © Hadi -

In an interview with Targeted OncologyTM, Scandura, Weill Cornell Medicine, discussed research on pelabresib for the treatment of patients with MPNs.

Targeted Oncology: Can you discuss pelabresib and its mechanism of action?

Scandura: Pelabresib is a first-in-class oral inhibitor of BET proteins, primarily those containing the BD1 and BD2 domains. It's being developed currently in myelofibrosis. It has been tested in other diseases, but it has shown significant activity in myelofibrosis. I believe that it's going forward in that area and represents the first of what is potentially multiple drugs hitting these same epigenetic pathways.

What sets it apart from other agents for patients with MPNs?

Well, it's the first drug that hits the BET inhibitors. It's among the first epigenetic modifiers, and these are pathways that affect how genes are packaged and expressed, turned on, and turned off. In all myeloid malignancies, in fact in all cancers, epigenetic abnormalities are much more common than genetic abnormalities and exactly how to target them has been a challenge. This particular pathway has been shown to be kind of hyperactivated in myelofibrosis. This inhibitor has shown some activity, both in terms of single-agent use and in combination with standard JAK inhibitor therapy.

Can you explain some of the recent research on pelabresib?

John Mascarenhas, MD, [presented] an update of the long-term follow-up of patients treated with the combination of ruxolitinib with pelabresib–ruxolitinib being a first-in-class and standard-of-care JAK inhibitor. What he's showing are the remarkable early responses that have been observed and are being maintained through the most recent follow-up. Then, Claire Harrison, MD, FRCP, FRCP, [presented] data on another arm of the phase 2 study where in pelabresib was added to ruxolitinib in people who are not achieving an adequate response.

I have presented an update on the translational work related to pelabresib trying to understand what some of these markers are, and these changes were observed in the bone marrow. From that standpoint, I think that’s where the excitement was generated with pelabresib. It's 1 of the first agents that has been able to reverse fibrosis in the marrow in a sizable percentage of patients. Of course, this disease is myelofibrosis, so the idea of reducing fibrosis is appealing.

The reality of it is we don't know, besides that kind of intuitive appeal, what it means when patients respond and have reversion of fibrosis in terms of long-term outcomes or in terms of what that goes along with our patients feeling better. [Those are] some of the other measures of response correlating with the marrow response.

What are some key takeaways regarding pelabresib and its development?

The first one is that we need to wait for the data to mature. My personal bias is all of these biomarkers are invaluable until we know outcomes such as survival or time to treatment failure or event-free survival. Until we know that, we are just kind of stuck in this circular loop of what should be, what we hope will be, what our intuitive beliefs are, but we do not really know what any of these things mean until we have those outcomes. That just takes time.

The nice thing is there are a number of phase 3 studies, randomized trials, collaborative studies. MANIFEST-2 is a randomized phase 3 study, and that will allow us to address and follow up on some of these findings, and hopefully get to those answers about whether or not these changes that we're observing in the short-term are predicting these long-term beneficial outcomes. It just takes time for that data to mature.

Passamonti F, Patriarca A, Knapper S, et al. Pelabresib (CPI-0610) monotherapy in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: preliminary results from MANIFEST study. Presented at: 2023 EHA Congress; June 8-11,2023;Frankfurt,Germany. Abstract S168.
Harrison CN, Gupta VK, Gerds AT, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. Future Oncol. 2022;18(27):2987-2997. doi:10.2217/fon-2022-0484
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