biostudies-literatureRampal RKConstellation Pharmaceuticals, a Novartis CompanyNCI NIH HHS1531-1538https://www.ebi.ac.uk/biostudies/studies/S-EPMC12092244biostudies-literatureUnknown31(5)Janus kinase (JAK) inhibitors provide limited depth and durability of response in myelofibrosis. We evaluated pelabresib-a bromodomain and extraterminal domain (BET) inhibitor-plus ruxolitinib (a JAK inhibitor) compared with placebo plus ruxolitinib as first-line therapy. In this phase 3 study (MANIFEST-2), JAK inhibitor-naive patients with myelofibrosis were randomized 1:1 to pelabresib 125 mg once daily (QD; 50-175 mg QD permitted) for 14 days followed by a 7-day break (21-day cycle), or to placebo in combination with ruxolitinib 10 or 15 mg twice daily (BID; 5 mg QD-25 mg BID permitted). Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS) and TSS50 response (≥50% reduction in TSS fromNature medicinePelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial.PMC12092244P30 CA008748Kiladjian JJLavie DBrown BPalandri FChraniuk DMesa RLucchesi AAlvarez-Larran AVannucchi AMPatriarca ABose POh STHarris MGrosicki SScandura JMGupta VAbruzzese EMascarenhas JLee SEKuykendall ATLi QBoxhammer RRampal RKJegg AMTalpaz MHarrison CNGerds ATKays SKfalsePelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial.Janus kinase (JAK) inhibitors provide limited depth and durability of response in myelofibrosis. We evaluated pelabresib-a bromodomain and extraterminal domain (BET) inhibitor-plus ruxolitinib (a JAK inhibitor) compared with placebo plus ruxolitinib as first-line therapy. In this phase 3 study (MANIFEST-2), JAK inhibitor-naive patients with myelofibrosis were randomized 1:1 to pelabresib 125 mg once daily (QD; 50-175 mg QD permitted) for 14 days followed by a 7-day break (21-day cycle), or to placebo in combination with ruxolitinib 10 or 15 mg twice daily (BID; 5 mg QD-25 mg BID permitted). Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS) and TSS50 response (≥50% reduction in TSS from2025-01-01T00:00:00Z2025 May2026-06-01T10:24:07.929Z2026-04-08T11:27:18.052ZS-EPMC120922444006516910.1038/s41591-025-03572-3