Updated Results from the Phase 3 Manifest-2 Study of Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor-Naïve Patients with Myelofibrosis

Background Myelofibrosis (MF) is characterized by splenomegaly, MF-associated symptoms, cytopenias (eg, anemia), and impairment of the bone marrow (BM) microenvironment (including fibrosis). Pelabresib (CPI-0610; PELA) is an investigational, oral, small molecule drug that inhibits BET proteins and subsequent BET-mediated gene expression involved in MF pathogenesis. The Phase 3 MANIFEST-2 study (NCT04603495) met its primary endpoint, showing a statistically significant higher proportion of patients (pts) with ≥35% reduction in spleen volume (SVR35) from baseline (BL) at Week (Wk) 24 with PELA+ruxolitinib (RUX) vs placebo (PBO)+RUX (p<0.001) in Janus kinase inhibitor-naïve pts with MF. PELA+RUX also showed a trend toward improved total symptom score (TSS) from BL at Wk 24, as well as improvements in multiple measures of anemia (eg, hemoglobin [Hb] response) and in the BM microenvironment, vs PBO+RUX (Rampal R, et al. Presented at ASH 2023 [Oral 628]). Aim To present follow-up efficacy and safety outcomes at Wk 48 from the Phase 3 MANIFEST-2 study. Methods Eligible pts had a DIPSS ≥intermediate-1 risk, platelet count ≥100 × 109/L, spleen volume ≥450 cm3, ≥2 symptoms with an average score ≥3 or TSS ≥10 by MF Symptom Assessment Form v4.0, peripheral blast count <5%, and ECOG PS ≤2. Pts were randomized 1:1. PELA or PBO was administered once daily for 14 consecutive days of 21-day cycles in combination with RUX, which was administered twice daily for 21-day cycles. Primary endpoint was SVR35 at Wk 24. Key secondary endpoints were absolute change in TSS and ≥50% reduction in TSS from BL (TSS50) at Wk 24. Other prespecified endpoints included SVR35 at Wk 48, absolute change in TSS and TSS50 at Wk 48, Hb response (≥1.5 g/dL mean increase from BL without transfusions in the prior 12 wks), BM fibrosis (BMF), and safety. Mutation profiles were assessed by next-generation sequencing. Informed consent was obtained from all pts. Results As of March 29, 2024, all pts assessed had been followed for ≥48 wks; 58.9% (126/214) and 62.0% (134/216) of pts continued on double-blind treatment in the PELA+RUX and PBO+RUX arms, respectively. Preliminary data are presented here; analyses are ongoing and data points are subject to change. At Wk 48, 56.5% (121/214) vs 37.5% (81/216) of pts had SVR35 responses in the PELA+RUX vs PBO+RUX arms, showing sustained benefit beyond Wk 24. SVR35 responders at any time were 82.2% (176/214) vs 58.3% (126/216) in the PELA+RUX vs PBO+RUX arm; loss of SVR35 response was observed in 13.1% (23/176) vs 19.8% (25/126) of pts in the PELA+RUX vs PBO+RUX arm. At Wk 48, least squares mean (standard error) absolute change in TSS was −16.24 (1.133) vs −14.11 (1.085) in the PELA+RUX vs PBO+RUX arms, with a greater difference in absolute TSS observed between treatment arms at Wk 24 and Wk 48 for pts with higher symptom burden at BL. TSS50 response at Wk 48 was 45.3% (97/214) vs 39.4% (85/216) with PELA+RUX vs PBO+RUX. Dual SVR35 and TSS50 response was observed in 36.0% (77/214) vs 19.0% (41/216) of pts in the PELA+RUX vs PBO+RUX arms at Wk 48. Hb response was observed in 12.6% (27/214; 95% confidence interval [CI], 8.17-17.07) vs 6.9% (15/216; 95% CI, 3.55-10.33) of pts in the PELA+RUX vs PBO+RUX arms, with differences between arms in mean Hb levels maintained at Wk 48; in pts with anemia (Hb BL <10 g/dL), Hb response was observed in 17.9% (12/67; 95% CI, 8.73-27.09) vs 14.1% (10/71; 95% CI, 5.99-22.18) of pts. The trend of higher rate of BMF improvement of ≥1 grade in the PELA+RUX arm vs the PBO+RUX arm continued to be observed at Wk 48. Of 426 pts evaluated for safety, ≥1 treatment-emergent adverse event (TEAE) was reported in 97.6% vs 96.7% of pts in the PELA+RUX vs PBO+RUX arms; Grade ≥3 events were reported in 56.6% vs 62.1% of pts. Rates of the most common TEAEs (≥10%) at Wk 48 in the PELA+RUX vs PBO+RUX arms were similar to rates at Wk 24. Updated efficacy and safety results, including data on BMF, mutational profile, and leukemic transformation, will be presented. Conclusion At Wk 48, PELA+RUX continued to show improvements in spleen volume, TSS, multiple measures of anemia, and the BM microenvironment vs PBO+RUX, impacting the four hallmarks of MF. These data suggest that PELA+RUX could lead to more profound and sustained responses in pts with MF vs PBO+RUX.