Pelabresib

Pelabresib (CPI-0610; PELA) is an investigational oral small-molecule drug designed to inhibit bromodomain and extra-terminal domain (BET)-mediated gene transcription involved in the pathogenesis of myelofibrosis (MF) and other myeloproliferative neoplasms. Developed by Constellation Pharmaceuticals, a Novartis company, pelabresib targets epigenetic pathways to modulate oncogenic and inflammatory gene expression, offering a novel therapeutic approach for MF patients with limited treatment options.

As of May 2025, pelabresib is in Phase III clinical trials for MF and has shown promising results in combination with ruxolitinib, a Janus kinase inhibitor (JAKi), but is not yet approved for clinical use.

Pelabresib is a selective inhibitor of BET proteins (BRD2, BRD3, BRD4, BRDT), which regulate gene expression by binding to acetylated histones. In MF, BET proteins drive the expression of genes involved in nuclear factor kappa B (NF-κB) signaling, proinflammatory cytokine production (e.g., IL-6, TNF-α), and aberrant megakaryopoiesis, contributing to bone marrow fibrosis, splenomegaly, and systemic symptoms. By inhibiting BET proteins, pelabresib downregulates these pathogenic pathways, reducing cytokine levels, improving bone marrow function, and alleviating symptoms. Preclinical studies demonstrated synergistic effects when combined with JAKi like ruxolitinib, enhancing suppression of oncogenic and inflammatory signaling.

Preclinical studies established pelabresib’s efficacy in MF models. In JAK2V617F-mutant mouse models, pelabresib reduced spleen weight by 30–40% and decreased bone marrow fibrosis compared to controls, with significant reductions in IL-6 and TNF-α levels. Combination with ruxolitinib further decreased spleen size (up to 60%) and normalized megakaryocyte morphology. In vitro studies on MF patient-derived CD34+ cells showed pelabresib downregulated MYC and BCL2 expression, inducing apoptosis in malignant clones. Pharmacokinetic studies confirmed oral bioavailability, with a half-life of ~6 hours, supporting a once-daily dosing regimen. These findings justified clinical development, particularly in combination with JAKi.

Pelabresib is being evaluated in multiple clinical trials, primarily for MF.

A phase one study of pelabresib in patients with relapsed/refractory lymphomas found pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily.

The MANIFEST study (NCT02158858), a global, open-label, Phase II clinical trial, investigates pelabresib as monotherapy and in combination with ruxolitinib in MF patients, including those intolerant, refractory, or ineligible for JAKi. The study includes four arms: monotherapy in JAKi-experienced patients (Arms 1 and 2), combination with ruxolitinib in JAKi-naïve patients (Arm 3), and monotherapy in high-risk essential thrombocythemia (Arm 4).

The MANIFEST-2 study (NCT04603495), a Phase III clinical trial, is a randomized, double-blind trial comparing pelabresib plus ruxolitinib to placebo plus ruxolitinib in JAKi-naïve MF patients, with a primary endpoint of spleen volume reduction ≥35% (SVR35) at 24 weeks.