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 therapiesthat 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).

Aims

MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pela + rux versus placebo + rux in JAKi treatment-naïve pts with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pela + rux. Here we present the study design and baseline patient stratification for MANIFEST-2. Results from the primary analysis of MANIFEST-2 will be presented at the ASH Annual Meeting 2023.

Methods

The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a DIPSS score of Intermediate-1 (Int-1) or higher, platelet count ≥100 × 10 9/L, spleen volume ≥450 cm 3 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 × 10 9/L vs 100-200 × 10 9/L) and spleen volume (≥1800 cm 3 vs <1800 cm 3). 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 number of pts assigned to each randomization stratum are presented in Table 1; the majority of pts presented with DIPSS Int-1 or -2, had a platelet count above 200 × 10 9/L and spleen volume below 1800 cm 3. 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.

Conclusion

The Phase 3 MANIFEST-2 study was initiated based on compelling data from the ongoing Phase 2 MANIFEST study, in which the combination of pela and rux in Arm 3 demonstrated significant clinical activity and disease-modifying potential without clinically relevant treatment-limiting toxicity. MANIFEST-2 has completed recruitment and will provide definitive efficacy results of combination therapy in JAKi treatment-naïve pts with MF. As DIPSS Int-1 pts have been excluded or underrepresented in prior randomized trials in MF, MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease. Primary results from the pivotal Phase 3 MANIFEST-2 trial of pela and rux versus placebo and rux in JAKi treatment-naïve pts may have the potential to influence the MF treatment paradigm and will be presented at the ASH Annual Meeting 2023.

Rampal:Celgene-BMS: Consultancy; Kartos: Consultancy; Zentalis: Research Funding; Dainippon: Consultancy; Constellation: Research Funding; Karyopharm: Consultancy; Ryvu: Research Funding; CTI BioPharma Corp: Consultancy; Galecto: Consultancy; Morphosys/Constellation: Consultancy; Sumitomo: Consultancy; Incyte: Research Funding; Stemline: Research Funding; Pharmaessentia: Consultancy; Servier: Consultancy; GSK-Sierra: Consultancy; Zentalis: Consultancy; Incyte: Consultancy. Abruzzese:Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bose:Kartos, Telios, Ionis, Disc, Janssen, Geron: Research Funding; Incyte, BMS, CTI, Morphosys, Blueprint, Cogent, Sumitomo: Honoraria, Research Funding; GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, Morphic: Honoraria. Gerds:AbbVie, Bristol Myers Squibb, Constellation Pharmaceuticals, GlaxoSmithKline, Kartos, Novartis, PharmaEssentia, Sierra Oncology: Consultancy; Accurate Pharmaceuticals, Constellation Pharmaceuticals, CTI BioPharma, Imago BioSciences, Incyte Corporation, Kratos Pharmaceuticals: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri:Novartis, BMS, Celgene, GSK, Amgen, AbbVie, Karyopharm, AOP, Sierra Oncology, Janssen: Consultancy, Honoraria. Gupta:BMS Celgene, Roche, AbbVie, Pfizer, Sierra Oncology, CTI Biopharma, GSK: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Novartis, BMS Celgene, SMP Oncology, AbbVie, Constellation Biopharma, Pfizer, GSK Pharma, CTI Biopharma: Consultancy; BMS, Celgene, Roche, Abb Vie, Pfizer, Sierra Oncology, CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis, BMS Celgene, GSK: Honoraria; GSK: Other: Travel to EHA 2023 for invited talk at GSK sponsored MPN education session ; Novartis, BMS Celgene, Sierra Oncology, AbbVie, Constellation Biopharma, Pfizer, GSK Pharma, CTI Biopharma: Consultancy. Lucchesi:Morphosys: Consultancy; Amgen: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Protagonist: Consultancy; SOBI: Speakers Bureau; Pfizer: Speakers Bureau; Incyte: Speakers Bureau; BMS: Speakers Bureau. Oh:CTI BioPharma, Bristol Myers Squibb, Disc Medicine, Blueprint Medicines, PharmaEssentia, Constellation/MorphoSys, Geron, AbbVie, Sierra Oncology/GSK, Cogent, Incyte, Morphic, Protagonist: Consultancy. Kuykendall:Protagonist Therapeutics, Inc.: Consultancy, Research Funding; AbbVie: Consultancy; GSK: Consultancy; CTI: Consultancy; BMS: Consultancy, Research Funding; Sierra Oncology: Research Funding; Morphosys: Consultancy, Research Funding; Prelude: Research Funding; Incyte: Consultancy; Novartis: Consultancy; Blueprint: Consultancy, Research Funding, Speakers Bureau; Imago: Consultancy. Patriarca:Sanofi: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Sobi: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Alvarez-Larran:AOP: Consultancy. Mesa:AbbVie, CTI, Incyte, Sierra: Consultancy, Honoraria, Research Funding; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Research Funding; Blueprint, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Novartis: Consultancy, Honoraria. Kiladjian:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: 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; AbbVie, AOP Health, Bristol-Myers Squibb, GlaxoSmithKline, Incyte, Novartis, Pharmaessentia.: Consultancy. Talpaz:Sumitomo: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; BMS: Other: Advisory Board Member; Sumitomo: Other: Advisory Board Member; BMS: Research Funding. Harris:Constellation Pharmaceuticals, a MorphoSys Company: Current Employment. Kays:MorphoSys AG: Current Employment. Jegg:MorphoSys AG: Current Employment. Li:MorphoSys US Inc: Current Employment. Brown:Constellation Pharmaceuticals, a MorphoSys Company: Current Employment. Harrison:Morphosys: Honoraria, Speakers Bureau; AOP: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Galecto: Honoraria, Speakers Bureau; CTI: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Mascarenhas:Bristol Myers Squibb, Celgene, Constellation Pharmaceuticals/MorphoSys, CTI BioPharma, Galecto, Geron, GSK, Incyte Corporation, Karyopharm Therapeutics, Novartis, PharmaEssentia, Prelude Therapeutics, Pfizer, Merck, Roche, AbbVie, Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Janssen, Kartos Therapeutics, Merck, Novartis, PharmaEssentia, Roche; Participated in consulting or advisory committees - AbbVie, Bristol Myers Squibb, Celgene, Constellation Pharmac: Research Funding; Incyte, Novartis, Roche, Geron, GSK, Celgene/BMS, Kartos, AbbVie, Karyopharm, PharmaEssentia, Galecto, Imago, Sierra Oncology, Pfizer, MorphoSys, CTI Bio: Consultancy; AbbVie, Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Novartis, Janssen, Kartos Therapeutics, Merck, PharmaEssentia, Roche: Research Funding; GSK: Honoraria; AbbVie, CTI BioPharma Corp, a Sobi company, Geron, GlaxoSmithKline, Imago, Incyte, Kartos, Kayropharm, MorphoSys, Novartis, Pfizer, PharmaEssentia, Sierra: Consultancy.

Figure 1
Figure 1
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2023
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