MPN-375 BET Inhibitor Pelabresib (CPI-0610) Combined With Ruxolitinib in Patients With Myelofibrosis - JAK Inhibitor-Naïe or With Suboptimal Response to Ruxolitinib - Preliminary Data From the MANIFEST Study

Context: Myelofibrosis is characterized by splenomegaly, symptoms, cytopenias, and bone marrow (BM) fibrosis. Pelabresib is an investigational, oral, small-molecule BET inhibitor designed to selectively inhibit the BD1 and BD2 bromodomains of BET proteins. Objective: Evaluation of pelabresib combined with ruxolitinib in patients with myelofibrosis. Design: In Arm 3 of the Phase 2 MANIFEST study (NCT02158858), JAKi-naïve myelofibrosis patients are treated with pelabresib combined with ruxolitinib. In Arm 2, myelofibrosis patients with suboptimal response to ruxolitinib are treated with pelabresib as 'add-on' to ruxolitinib (Arm 2A: transfusion-dependent [TD]; Arm 2B: non-TD). The primary endpoints are ≥35% spleen volume reduction (SVR35) at Week 24 for Arms 3 and 2B and TD to transfusion independence (TI) in Arm 2A. The key secondary endpoint is ≥50% total symptom score reduction (TSS50) at Week 24; in Arm 2A, SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated. Results: As of September 2021, at Week 24 in Arm 3 (N=84), 68% (57/84) of patients achieved SVR35 (median change: -50%), and 56% (46/82) of patients achieved TSS50 (median change: -59%). At Week 24 in Arm 2 (N=86), 20% (16/81; 17% in Arm 2A and 26% in Arm 2B) of patients achieved SVR35 (median change: -18%), and 37% (30/81) of patients achieved TSS50 (median change: -47%). In Arm 2A, the TD to TI rate was 16% (6/38). At Week 24, BM fibrosis improvement ≥ 1 grade was achieved in 28% (16/57) and 26% (12/47) of patients in Arms 3 and 2, respectively. Hematologic treatment-emergent adverse events (TEAEs) included thrombocytopenia, in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) of patients, and anemia, in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) of patients in Arms 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely resulted in discontinuation. Conclusions: In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxolitinib in JAKi treatment-naïve patients with myelofibrosis (NCT04603495).