Introduction: MMB, an oral JAK1, JAK2, and ACVR1 inhibitor, showed clinical activity on MF symptoms, red blood cell (RBC) transfusion requirements (anemia), and spleen volume in the prior phase 3 SIMPLIFY trials. The pivotal phase 3 MOMENTUM study (NCT04173494) of MF patients (pts) previously treated with a JAK inhibitor (JAKi) testing MMB vs DAN met the primary endpoint of total symptom score (TSS) response and all key secondary endpoints as demonstrated by improvements in symptoms, anemia, and spleen volume at Week (Wk) 24. Here we provide updated efficacy and safety results after all pts completed their Wk 48 assessment on the MOMENTUM study, including data specific to thrombocytopenic pts.

Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; TSS ≥10; hemoglobin (Hgb) <10 g/dL; platelets (PLT) ≥25 x 109/L; 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. Prior JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg daily plus DAN placebo or DAN 600 mg daily plus MMB placebo for 24 wks, after which pts could receive open-label (OL) MMB. Pts crossing over from DAN received OL MMB 200 mg daily. Pts could roll over to the extended access study after Wk 48. Assessments: Pt-reported symptoms using an eDiary and spleen volume by MRI or CT. Wk 48 endpoints included duration of TSS response (≥50% reduction from baseline [BL]), duration of transfusion independence (TI) response (no RBC transfusions in 12 wks prior and Hgb ≥8 g/dL), duration of splenic response (≥35% reduction from BL), overall and leukemia-free survival (OS, LFS).

Results: As of May 17, 2022, 93 of 130 (72%) MMB pts [MMB→MMB] and 41 of 65 (63%) DAN pts [DAN→MMB] entered the OL period. All pts received OL MMB, including 4 pts on the DAN arm who crossed over early due to splenic progression. Mean MMB duration of MMB→MMB pts was 48 wks and DAN→MMB pts was 24 wks. Duration of response analyses for Wk 24 responders revealed few loss-of-response events: of TSS responders, 1 of 32 (3%) MMB→MMB and 0 of 6 DAN→MMB had TSS ≥BL; of TI responders, 4 of 40 (10%) MMB→MMB and 3 of 13 (23%) DAN→MMB had a RBC transfusion or Hgb <8 g/dL; and of spleen responders, 0 of 30 MMB→MMB and 0 of 2 DAN→MMB had splenic volume ≥BL. TSS over time for W24 TSS responders is shown in Figure 1.

Most common Gr ≥3 TEAEs in the OL phase, similar to the RT phase, were thrombocytopenia (MMB→MMB, 9%; DAN→MMB, 15%) and anemia (MMB→MMB, 9%; DAN→MMB, 2%). Gr ≥3 infections occurred in 19% of MMB→MMB and 10% of DAN→MMB pts, including Gr ≥3 (all nonfatal) COVID-19 infections in 5% of MMB→MMB pts only. Peripheral neuropathy (PN) was seen in 2 (2%) MMB→MMB (both Gr ≤2) and 1 (2%) DAN→MMB (Gr 1) pts in the OL phase, and none discontinued MMB due to PN. Overall, TEAEs led to MMB discontinuation in 18% of MMB→MMB and 10% of DAN→MMB pts in the OL phase.

Median follow-up for OS was 51 wks (range 6-84 wks) for MMB-randomized and 53 wks (range 4-97 wks) for DAN-randomized pts. A previously reported trend toward improved OS up to Wk 24 was seen with MMB vs DAN (HR=0.506, p=0.0719); after all pts crossed over to OL MMB at Wk 24, OS and LFS curves for MMB→MMB and DAN→MMB arms converged (HR=0.945, 95% CI=0.528, 1.693; HR=0.830, 95% CI=0.473, 1.4555).

60 of 81 (71%) MMB pts [MMB→MMB] and 29 of 43 (67%) DAN pts [DAN→MMB] with BL PLT ≤150 x 109/L entered the OL phase. Efficacy results of this thrombocytopenic subgroup in the OL period are consistent with the overall ITT analysis set. Most common Gr ≥3 TEAEs in the OL phase were thrombocytopenia (MMB→MMB, 13%; DAN→MMB, 21%) and neutropenia (MMB→MMB, 8%; DAN→MMB, 0%); Gr ≥3 bleeding events occurred in 8% of MMB→MMB and 3% of DAN→MMB pts. TEAEs led to MMB discontinuation in 17% of MMB→MMB and 10% of DAN→MMB pts in the OL phase.

Efficacy and safety analyses of pts with BL PLT <100 x 109/L (N=70) and BL PLT <50 x 109/L (N=19) are also consistent with the ITT. Improved OS and LFS were seen with MMB→MMB vs DAN→MMB for BL PLT <50 x 109/L (HR=0.123; 95% CI=0.014, 1.082 for both OS/LFS; Figure 2).

Additional analyses, including PK, genomic, and biomarker results, will be reported.

Conclusions: In these initial analyses of response duration, OL MMB maintained symptom, TI, and spleen responses with continued good survival and safety in the ITT (symptomatic and anemic MF pts) and in those with low PLT. MMB may address a critical unmet need, particularly in MF pts with anemia, including those with severe thrombocytopenia.

Figure 1
Figure 1
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Gerds:Kratos Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Imago BioSciences: Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Accurate Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys/Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Bristol Myers Squibb: Consultancy; AOP: Consultancy; CTI: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Blueprint: Consultancy; Geron: Consultancy; LaJolla Pharmaceutical: Consultancy; Roche: Consultancy; Incyte: Consultancy, Research Funding; Samus: Consultancy, Research Funding; Genotech: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Research Funding; Imago: Research Funding. Vannucchi:Roche: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; AOP Orphans Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees, Other: NA; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Other: NA; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Al-Ali:Kartos: Membership on an entity's Board of Directors or advisory committees; AOP: Consultancy, Other: Support for attending meetings and/or travel; Abbvie, BluePrint, Takeda, Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; BMS: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Incyte, Deutsche Leukämie und Lymphom Stiftung, East German Study Group for Hematology and Oncology: Research Funding; Sierra Oncology: Other: Medical Writing. Kuykendall:Pharmaessentia: Consultancy, Honoraria, Speakers Bureau; Imago Biosciences: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Blueprint: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; GSK - Sierra Oncology: Consultancy, Honoraria, Other: Research Support, Speakers Bureau; Prelude Pharmaceuticals: Other: Research Support; BMS: Consultancy, Honoraria, Other: Research Support, Speakers Bureau; Morphosys: Other: Research Support; Protagonist: Other: Research Support; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau. Iurlo:Novartis, BMS, Celgene, Incyte, Pfizer: Honoraria. Goh:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Medical Pharma: Membership on an entity's Board of Directors or advisory committees; NS Pharma: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Antengene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Research Funding; Abbvie: Honoraria; Astellas: Honoraria. Fox:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. McLornan:CELGENE BMS: Research Funding, Speakers Bureau; ABBVIE: Speakers Bureau; NOVARTIS: Honoraria, Research Funding, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau. Perkins:Sierra Oncology: Honoraria, Other: Support for present manuscript; Celgene: Other: Support for meetings and/or travel; Abbvie: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yoon:Roche-Genetech: Research Funding; Yuhan Pharmaceutical: Research Funding; Tikaros: Consultancy; Novartis: Consultancy; Kyowa Kirin: Research Funding; Amgen: Consultancy; Astellas Pharma: Consultancy; Janssen Pharmaceutical: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Chugai Pharmaceutical: Consultancy. Gupta:Roche: Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Donahue:Sierra Oncology: Current Employment. Kawashima:Sierra Oncology: Current Employment. Verstovsek:Sierra Oncology: Consultancy, Research Funding; Roche: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Novartis: Consultancy, Research Funding; CTI BioPharma Corp.: Research Funding; Constellation Pharmaceuticals: Consultancy; Genentech: Research Funding; ItalPharma: Research Funding; Incyte: Consultancy, Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Pragmatist: Consultancy.

Author notes

*

Asterisk with author names denotes non-ASH members.

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2022
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