Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Patients with Myelofibrosis: Results of the MANIFEST-2 Randomized, Double-Blind, Phase 3 Study

Background

• Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and MF-associated symptoms. These hallmarks result from dysregulation of the JAK/STAT pathway and BET-mediated MF target gene modulation.
• Pelabresib (CPI-0610; pela) is an investigational oral small-molecule drug designed to inhibit BET-mediated gene transcription involved in MF pathogenesis. Preclinical data support the potential of combining pela with therapies that target overlapping pathways, such as JAK/STAT, to improve response by inhibiting the molecular drivers of MF.
• The Phase 3 MANIFEST-2 trial was initiated based on compelling data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pela and ruxolitinib (rux) in JAK inhibitor (JAKi) treatment-naïve patients (pts) with MF.
• In Arm 3 of MANIFEST, primary endpoint analyses at 24 Weeks (Wks) for the 84 pts enrolled reported SVR35 (≥35% reduction in spleen volume from baseline) in 68% of pts and TSS50 (≥50% reduction in Total Symptom Score [TSS] from baseline) in 56% of pts (Mascarenhas, et al. 2023).

Methods

• Key eligibility criteria include a DIPSS score of Intermediate-1 (Int-1) or higher, platelet count ≥100 × 109/L, spleen volume ≥450 cm3 by CT or MRI, ≥2 symptoms with an average score ≥3 or a TSS of ≥10 using the MFSAF v4.0, peripheral blast count <5% and an ECOG performance status ≤2.
• Patient randomization was stratified by DIPSS risk category (Int-1 vs Int-2 vs High), platelet count (>200 × 109/L vs 100–200 × 109/L) and spleen volume (≥1800 cm3 vs <1800 cm3).
• Double-blind treatment of pela (125–175 mg) or placebo was administered once daily for 14 consecutive days, followed by a 7-day break, which is considered one cycle of treatment. Rux (5–25 mg) was administered twice daily based on platelet counts and spleen response for all 21 days of the cycle.
• The primary endpoint is SVR35 response at Wk 24.
• Secondary endpoints include TSS50, percentage change in TSS, safety, pharmacokinetics, changes in bone marrow fibrosis, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 wks.

Results

• A total of 591 pts were screened at 138 sites. Following the screening process, 431 pts from North America, Europe, Asia and Australia were randomized.
• The majority of pts presented with DIPSS Int-1 or -2, had a platelet count above 200 × 109/L and spleen volume below 1800 cm3.
• The study opened for enrolment in November 2020; the first patient received their initial treatment on April 22, 2021, and the last patient received their first treatment on March 2, 2023. The last patient is expected to reach the 24-wk primary endpoint on August 31, 2023, following which a primary analysis will occur. As of June 27, 2023, there were 383 pts ongoing in the study.

Conclusions

• Pelabresib in combination with ruxolitinib compared with placebo in combination with ruxolitinib in JAK inhibitor treatment-naïve patients at Week 24:
  • Significantly reduced splenomegaly (SVR35: 66% vs 35%; p<0.001)
  • Demonstrated strong trends in reducing the mean absolute TSS (p=0.0545) and improving TSS50 response
  • Doubled the percentage of patients with dual SVR35 / TSS50 response
• Fewer anemia adverse events, higher rates of hemoglobin responses and less patients with transfusion requirement
• The safety profile appeared generally comparable to the established safety profile of ruxolitinib with fewer grade ≥ 3 events
• Pelabresib in combination with ruxolitinib showed reduction of pro-inflammatory cytokines, and improvement in bone marrow fibrosis and anemia response, addressing the four hallmarks of myelofibrosis
• These results support a potential paradigm shift in the treatment of patients with myelofibrosis

Rampal R, Grosicki S, Chraniuk D et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, Phase 3 study. Presented at: 65th ASH Annual Meeting and Exposition, December 9-12, 2023. San Diego, California.