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.

Mechanism of Action

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

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.

Clinical Development

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.

A third study, NCT06401356, is ongoing to provide continued access to treatment with pelabresib for patients who previously received pelabresib in a parent study and to continue collecting safety and efficacy information, such as a patient's leukemia-free survival and overall survival status during and after the treatment is ended.

NCT02158858, a phase one/two open-label, sequential dose escalation study of pelabresib in patients with previously treated acute leukemia, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, and myelofibrosis is ongoing.

Efficacy

In the MANIFEST study, pelabresib demonstrated clinical activity across patient subgroups. In Arm 3 (JAKi-naïve, combination with ruxolitinib), 67% of evaluable patients (42/63) achieved SVR35 at 24 weeks, with a median spleen volume reduction of 50%. Additionally, 57% (34/60) achieved a ≥50% reduction in Total Symptom Score (TSS50), indicating significant symptom relief. Central pathology review confirmed bone marrow fibrosis improvement in 33% of patients within 6 months.

In MANIFEST-2, pelabresib plus ruxolitinib achieved a 65.9% SVR35 rate at 24 weeks compared to 35.2% for placebo plus ruxolitinib, with durable responses (13.4% vs. 27.8% response loss in responders). TSS50 rates were 52.3% vs. 46.3%, though not statistically significant (p=0.216).Subgroup analyses showed consistent benefits regardless of mutation status (e.g., ASXL1), age, or risk score, suggesting broad applicability.

Safety and Tolerability

Pelabresib is generally well-tolerated, with a manageable safety profile.

In the MANIFEST study, common adverse events (AEs) included fatigue, nausea, and decreased appetite, with thrombocytopenia being dose-dependent, reversible, and non-cumulative. The recommended Phase II dose (RP2D) is 125 mg daily for 14 days, followed by a 7-day break, balancing efficacy and safety.

In MANIFEST-2, the combination with ruxolitinib showed similar AEs, with no significant increase in severe toxicities compared to ruxolitinib alone.

Long-term data from the continued access study (NCT06401356) are being collected to assess rare or delayed toxicities, but preliminary results suggest pelabresib’s safety supports its use in combination regimens.

Background

Myelofibrosis is a rare, chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms (e.g., fatigue, night sweats). Most patients harbor mutations in JAK2, CALR, or MPL genes, driving aberrant cytokine signaling and megakaryocyte proliferation. While JAKi like ruxolitinib improve symptoms and spleen size, many patients develop resistance or intolerance, and disease modification remains elusive. Pelabresib emerged to target BET proteins, which regulate proinflammatory and oncogenic pathways beyond JAK signaling, offering a complementary mechanism to address these limitations. Initial development by Constellation Pharmaceuticals began in 2012, with clinical trials launched in 2014 to explore its potential in MF and other hematologic malignancies.

Regulatory Status

As of May 2025, pelabresib has not received regulatory approval from agencies like the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA).

The FDA granted pelabresib Orphan Drug Designation in 2019 for MF, recognizing its potential for a rare disease with unmet needs. Fast Track designation was also granted in 2022 to accelerate development.

Discussions with regulatory bodies are ongoing to define endpoints (e.g., SVR35, OS) for approval in JAKi-naïve MF patients.

Comparison with Other Therapies

Pelabresib offers a distinct mechanism compared to other MF therapies. Unlike JAKi (e.g., ruxolitinib, fedratinib, pacritinib), which target JAK-STAT signaling, pelabresib addresses epigenetic dysregulation via BET inhibition, complementing JAKi effects. Compared to imetelstat, a telomerase inhibitor approved for MDS, pelabresib shows stronger spleen and symptom responses in JAKi-naïve patients but lacks direct OS data. Navitoclax, a BCL2 inhibitor, targets apoptosis but has higher hematologic toxicity. Pelabresib’s synergy with ruxolitinib provides an advantage over monotherapy JAKi in achieving deeper responses, particularly in high-risk MF. However, its efficacy in JAKi-refractory patients is less robust than in naïve populations, positioning it as a combination rather than standalone therapy.

References

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