Pelabresib and Ruxolitinib Show Benefit in Treating Patients With JAK Inhibitor-Naïve Myelofibrosis

Data show that pelabresib (Novartis) in combination with ruxolitinib (Jakafi; Incyte Corp) significantly reduced splenomegaly and improved anemia in patients with myelofibrosis (MF) that have not been previously treated with Janus kinase inhibitors (JAKis). The findings, published in Clinical Lymphoma Myeloma and Leukemia, address treatment approaches for JAKi-naïve patients.¹

The findings underscore the significant clinical benefit of combining pelabresib with ruxolitinib in treating JAKi-naïve myelofibrosis patients. Image Credit: © Viktoriia - stock.adobe.com

MF is a rare, fatal myeloproliferative neoplasm characterized by the overproduction of hematopoietic stem cells leading to reduced blood cell production. Studies have shown that bromodomain and extraterminal domain (BET) and the JAK/STAT pathway are involved in the development and progression of MF. As a result, BET proteins are emerging as a potential target capable of altering the underlying causal mechanism driving MF.²

Pelabresib is an investigational, oral, small molecule bromodomain and extraterminal domain (BET) inhibitor intended to decrease expression of MF target genes. In the global, randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495), researchers investigated the safety and efficacy of pelabresib in combination with ruxolitinib vs ruxolitinib with placebo in patients with JAKi-naïve MF. The primary end point of the study was a ≥35% spleen volume reduction from baseline (SVR35) at week 24, with secondary end points including absolute change in total symptom score (TSS), ≥50% reduction in TSS from baseline (TSS50) at week 24, and safety. Additionally, the researchers assessed hemoglobin response (≥1.5 g/dL mean increase from baseline without transfusions in the prior 12 weeks).^1,3,4

The researchers randomized 430 patients to receive either pelabresib or placebo (daily for 14 consecutive days of 21) with ruxolitinib (twice daily for 21 days [1 cycle]). At 24 weeks, 65.9% of patients in the pelabresib and ruxolitinib arm achieved an SVR35 response compared with 35.2% of patients on the placebo regimen (P < .001). Additionally, patients receiving the pelabresib combination therapy demonstrated a mean absolute change in TSS of −15.99 (1.028) vs −14.05 (0.986), as well as a TSS50 response of 52.3% vs 46.3% (nominal P = .22), compared with the placebo arm. Hemoglobin response was 10.7% (23/214) vs 6.0% (13/216) of patients for pelabresib with ruxolitinib and ruxolitinib with placebo, respectively. Additionally, differences in mean hemoglobin levels were maintained at 48 weeks.¹

Out of 426 patients evaluated for safety, anemia occurred in 43.9% treated with pelabresib and ruxolitinib compared with 54.7% in ruxolitinib and placebo. Other common adverse effects included thrombocytopenia (52.8% vs 37.4%), and diarrhea (23.1% vs 18.7%).¹

The findings underscore the significant clinical benefit of combining pelabresib with ruxolitinib in treating JAKi-naïve patients with myelofibrosis , demonstrating substantial improvements in spleen volume reduction, symptom relief, and anemia management. These data provide hope for improving outcomes and marks an important step forward in the development of better therapies for MF.

REFERENCES

1. Mascarenhas J, Rampal R, Grosicki S, et al. Mpn-135 safety and efficacy of pelabresib in combination with ruxolitinib for jak inhibitor-naïve patients with myelofibrosis: latest data from the phase 3 manifest-2 study. Clin Lymphoma Myeloma Leuk. September 2024. doi:10.1016/S2152-2650(24)01403-4

2. Study findings suggest use of fedratinib as treatment in the second line for myelofibrosis. Pharmacy Times. October 3, 2024. Accessed October 4, 2024. https://www.pharmacytimes.com/view/study-findings-suggest-use-of-fedratinib-as-treatment-in-the-second-line-for-myelofibrosis

3. Pelabresib. Morphosys. Accessed October 4, 2024. https://www.morphosys.com/en/our-pipeline/pelabresib

4. Phase 3 study of pelabresib (cpi-0610) in myelofibrosis (mf) (manifest-2) (manifest-2). ClinicalTrials.gov Identifier: NCT04603495. Updated May 8, 2024. Accessed October 4, 2024. https://clinicaltrials.gov/study/NCT04603495?a=37