Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis

by Selleckchem | Jul 02 2023

Purpose of review: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, and inflammatory cytokine overproduction, resulting in progressive cytopenias, splenomegaly, and high symptom burden. Current backbone of care includes JAK inhibitor (JAKi) therapy, which offers limited benefits and significant discontinuation rates. Targeting the epigenetic modifiers bromodomain and extra-terminal domain (BET) proteins is a novel approach for harnessing the expression of genes involved in critical oncogenic signalling pathways implicated in MF and other malignancies. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF.

Recent findings: BET inhibition has been shown to target multiple MF driver mechanisms in preclinical studies, with synergistic results using combination therapy with JAKi. Pelabresib is currently being evaluated in the phase II MANIFEST study as monotherapy and in combination with ruxolitinib for MF. Interim data showed favourable responses in symptoms and spleen volume after 24 weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these encouraging results, the Phase III MANIFEST-2 study was initiated. Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.

Comments:

Title: Pelabresib (CPI-0610): A Promising BET Inhibitor for the Treatment of Myelofibrosis

Abstract: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, inflammatory cytokine overproduction, and megakaryocyte atypia. Current treatment options, primarily JAK inhibitors (JAKi), have limited efficacy and significant discontinuation rates. The targeting of bromodomain and extra-terminal domain (BET) proteins, through the use of the investigational small-molecule BET inhibitor Pelabresib (CPI-0610), offers a novel therapeutic approach for MF. This review explores the preclinical and clinical data on Pelabresib, focusing on its efficacy and safety profile in MF.

Introduction: Myelofibrosis (MF) is a hematological disorder characterized by bone marrow fibrosis, abnormal megakaryocyte proliferation, and dysregulated cytokine production. These pathological features lead to cytopenias, splenomegaly, and a high symptom burden for affected individuals. The current standard of care for MF primarily involves JAK inhibitors (JAKi), which provide limited benefits and often require discontinuation due to side effects or lack of response. Therefore, there is a need for alternative treatment options that can improve outcomes for MF patients.

BET Inhibition in Myelofibrosis: Preclinical studies have demonstrated that BET inhibition targets multiple driver mechanisms implicated in MF. By blocking BET proteins, the expression of genes involved in critical oncogenic signaling pathways can be modulated. In combination with JAKi therapy, BET inhibition has shown synergistic effects, further supporting its potential as a therapeutic strategy for MF.

Pelabresib (CPI-0610) in Myelofibrosis: Pelabresib is an oral small-molecule BET inhibitor currently under investigation for the treatment of MF. In the phase II MANIFEST study, Pelabresib is being evaluated as monotherapy and in combination with the JAK inhibitor ruxolitinib. Interim data from this study have shown promising results, with favorable responses observed in symptom control and spleen volume reduction after 24 weeks of treatment. These improvements were correlated with reductions in bone marrow fibrosis and mutant allele fraction.

Future Directions: Based on the encouraging results from the MANIFEST study, the Phase III MANIFEST-2 study has been initiated to further evaluate the efficacy and safety of Pelabresib. If the results continue to show positive outcomes, Pelabresib may offer an innovative treatment approach for MF, either as a monotherapy or in combination with the current standard of care.

Conclusion: Pelabresib, an investigational BET inhibitor, holds promise as a therapeutic option for patients with MF. The preclinical and clinical data suggest that targeting BET proteins could effectively modulate the expression of genes involved in MF pathogenesis. The ongoing clinical trials will provide further insights into the efficacy and safety profile of Pelabresib and its potential role in the management of MF.