Pelabresib is an investigational oral therapy emerging as a new approach in the treatment landscape for certain blood cancers. As a novel small-molecule drug, it represents a targeted strategy in oncology. This article provides a general overview of pelabresib, covering its intended use, how it functions at a cellular level, outcomes from its clinical studies, potential adverse effects, and its current stage of development.
What Pelabresib Is and What It Treats
Pelabresib (CPI-0610) is an investigational oral small-molecule drug designed to inhibit bromodomain and extra-terminal (BET) proteins. It is being developed to treat myelofibrosis (MF), a rare and chronic blood cancer.
Myelofibrosis is a myeloproliferative neoplasm (MPN) where the bone marrow produces too many abnormal blood cells. In MF, scar tissue develops in the bone marrow, leading to abnormal blood cell production, an enlarged spleen, and systemic symptoms. Myelofibrosis is characterized by significant bone marrow scarring and an enlarged spleen, distinguishing it from other MPNs.
How Pelabresib Works
Pelabresib functions as a BET inhibitor, targeting BET proteins that regulate gene expression by binding to acetylated histones. By inhibiting these proteins, pelabresib disrupts chromatin remodeling and can reduce the expression of genes that promote cell growth in certain cancers.
In myelofibrosis, BET proteins activate pathways like nuclear factor kappa B (NF-κB) signaling and produce inflammatory cytokines. These processes drive disease progression, leading to bone marrow fibrosis, an enlarged spleen, and other symptoms. Pelabresib aims to reduce these inflammatory signals and improve bone marrow function, offering a complementary approach to existing treatments by addressing epigenetic dysregulation.
Clinical Trial Results
Clinical trials for pelabresib have focused on its effectiveness, particularly in combination with ruxolitinib, a Janus kinase (JAK) inhibitor commonly used for myelofibrosis. The Phase 3 MANIFEST-2 study investigated pelabresib plus ruxolitinib in patients with myelofibrosis who had not previously received JAK inhibitor treatment. This trial demonstrated that the combination therapy significantly improved spleen volume reduction and symptom burden.
The primary endpoint of the MANIFEST-2 study was a 35% or greater reduction in spleen volume (SVR35) at 24 weeks. In this trial, 65.9% of patients receiving pelabresib plus ruxolitinib achieved SVR35, compared to 35.2% in the placebo group. This represents a notable improvement in spleen response. While the total symptom score (TSS) reduction of at least 50% (TSS50) at 24 weeks was numerically better with the combination therapy, it did not reach statistical significance.
Further analyses indicated improvements in other disease hallmarks, including bone marrow fibrosis and levels of proinflammatory cytokines. The combination led to greater reductions in NF-κB-regulated cytokines. These findings suggest that pelabresib, when combined with ruxolitinib, could provide more profound and sustained responses in patients with myelofibrosis.
Potential Side Effects
Pelabresib has been associated with side effects observed during clinical trials. The most commonly reported hematologic side effects include thrombocytopenia (a reduction in platelet count) and anemia (a decrease in red blood cells).
In the MANIFEST-2 trial, thrombocytopenia occurred in 52.8% of patients receiving pelabresib plus ruxolitinib, with 13.2% experiencing severe (Grade 3 or higher) cases. Anemia was reported in 44.8% of patients in the pelabresib combination arm, with 23.1% being Grade 3 or higher.
Non-hematologic side effects observed in trials include gastrointestinal issues such as diarrhea, nausea, and constipation. Other common non-hematologic events include fatigue, musculoskeletal pain, and respiratory tract infections. A small percentage of patients may require dose reductions or discontinuation due to adverse events. The overall safety profile of the pelabresib and ruxolitinib combination has been consistent with previous studies, with no new safety signals emerging.
Current Development Status
Pelabresib is currently in Phase 3 clinical trials for myelofibrosis. The MANIFEST-2 study met its primary endpoint, showing significant improvements in spleen volume reduction.
The manufacturer is preparing regulatory filings for submission to health authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). While initial indications suggested submissions in mid-2024, the company awaits 48-week follow-up data to finalize filing plans. This additional data is expected to provide a more comprehensive understanding of pelabresib’s profile, supporting its potential for approval as a new treatment option for myelofibrosis.