Background: MMB, a novel oral ACVR1/ALK2 and JAK1/2 inhibitor, showed clinical activity on MF symptoms, red blood cell (RBC) transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials, including in MF patients (pts) with thrombocytopenia.
Aims: MOMENTUM is a pivotal phase 3 study of symptomatic and anemic MF pts previously treated with a JAK inhibitor (JAKi) testing MMB vs DAN. This analysis evaluated MOMENTUM pts with baseline (BL) platelet counts (PLT) ≤150 x 109/L on key symptom, anemia, and spleen volume endpoints at 24 weeks (wks).
Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; hemoglobin (Hgb) <10 g/dL; prior JAKi for ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 wks or Gr 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm; PLT ≥25 x 109/L. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks. Primary endpoint: TSS response (≥50% reduction from BL) rate at wk 24. Key secondary endpoints, assessed sequentially at wk 24: RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Informed consent was obtained from all participants.
Results: 64% of the MOMENTUM pts had BL PLT of ≤150 x 109/L. Of this subset, 60 (74%) of 81 MMB pts and 25 (58%) of 43 DAN pts completed the 24-week randomized treatment (RT) phase. In this subset, median BL TSS were 29 (MMB) and 24 (DAN), Hgb were 7.9 (MMB) and 8.0 (DAN) g/dL, and PLT were 67 x 109/L (MMB) and 64 x 109/L (DAN). BL mean spleen volume was 2504 (MMB) and 2282 (DAN) cm3. Prior JAKi was ruxolitinib in 124 pts (100%) and fedratinib in 6 pts (5%); mean duration of prior JAKi was 136 weeks. Efficacy results are in Table. These results are consistent with the overall intent-to-treat (ITT) analysis set (N=195). Most common Gr ≥3 treatment-emergent adverse events (TEAEs) in the RT phase were thrombocytopenia (MMB, 31%; DAN, 16%) and anemia (MMB, 7%; DAN, 14%); Gr ≥3 bleeding events occurred in 9% of MMB and 5% of DAN pts. TEAEs led to study drug discontinuation in 15% of MMB and 19% of DAN pts, and serious TEAEs were reported in 36% of MMB and 40% of DAN pts, in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN [HR (95% CI)=0.490 (0.195, 1.235)]. Additional analyses of pts with BL PLT <100 x 109/L (N=100) and BL PLT <50 x 109/L (N=31) show similar treatment effects of MMB vs DAN.
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Summary/Conclusion: In thrombocytopenic MF pts who were symptomatic and anemic, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses and showed comparable safety and favorable survival. MMB may address a critical unmet need in thrombocytopenic MF pts. NCT04173494.