Pelabresib (CPI-0610) As Add-on to Ruxolitinib in Myelofibrosis: Durability of Response and Safety Beyond Week 24 in the Phase 2 MANIFEST Study

Background: Myelofibrosis (MF) is largely characterized by bone marrow (BM) fibrosis, splenomegaly and cytopenias. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (eg NF-κB target genes, MYC and BCL-2) and often lead to myeloproliferation and cytopenias.

Although the current standard of care for MF is treatment with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX), many patients (pts) experience a suboptimal response to RUX monotherapy or must discontinue treatment due to cytopenias and therefore there is a significant unmet need for new therapies in this population. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100).

Aims: In the ongoing, open-label Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. In Arm 2 of MANIFEST, pts with suboptimal/lost response to RUX are treated with PELA as 'add-on’ to RUX. In this abstract we will discuss results from the September 2021 data cut; updated data with longer follow-up on efficacy (≥35% reduction in spleen volume from baseline [BL; SVR35], ≥50% total symptom score reduction from BL [TSS50], duration of response and BM fibrosis improvement) and safety data from the planned July 2022 data cut will be presented.

Methods: Pts in Arm 2 are stratified as transfusion dependent (TD; Arm 2A) and nontransfusion dependent (non-TD; Arm 2B). The primary endpoints are conversion from TD to transfusion independence (TI) in Arm 2A (TD cohort) and SVR35 at Week (Wk) 24 for Arm 2B (non-TD cohort). The secondary endpoints include TSS50 per MF Symptom Assessment Form v4.0 at Wk 24 and SVR35 at Wk 24 in Arm 2A (TD cohort). BM biopsies to assess BM fibrosis, durability of responses and safety data are evaluated. Data reported here are from the September 2021 data cut.

Results: At Wk 24 in Arm 2 (N=86), 20% (16/81) of pts achieved SVR35 (Figures 1 and 2); 17% for Arm 2A (TD cohort) and 26% for Arm 2B (non-TD cohort). SVR35 at any time was achieved by 30% (24/81) of pts. At Wk 24, 27% (22/81) pts achieved ≥25% reduction in spleen volume from BL (SVR25); 26% (14/54) pts in Arm 2A (TD cohort) and 30% (8/27) pts in Arm 2B (non-TD cohort). Median spleen volume reduction for the full Arm 2 cohort was -18% at Wk 24. Durable (up to Wk 60) spleen volume reductions were observed as depicted in mean spleen volume change over time, and spleen volume reduction deepened over time (Figure 1). Twenty percent (16/80) pts had SVR35 response at Wk 48. In Arm 2A (TD cohort), the TD to TI rate was 16% (6/38). TSS50 at Wk 24 was 37% (30/81); 36% for Arm 2A (TD cohort) and 39% for Arm 2B (non-TD cohort). A total of 54% (46/86) of pts achieved TSS50 at any time. Median total symptom score reduction was -47% at Wk 24. As of data cut off, the median follow-up time was 24.4 (23.0-30.7) months and median treatment duration was 14.0 (8.4-20.6) months.

After 24 wks of treatment, BM fibrosis improvement by ≥1 grade was achieved in 26% of evaluable pts by central pathology review; 50% of pts maintained the improvement at the next available assessment or longer. A total of 39% of pts achieved ≥1 grade improvement at any time (best response).

The two most common hematologic treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia, reported in 52% (Grade ≥ 3: 33%) pts, and anemia, reported in 27% (Grade ≥ 3: 19%) pts. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely a reason for treatment discontinuation. A total of 20 pts (23%) reported TEAEs that led to PELA discontinuation. Serious adverse events reported in ≥3 pts were anemia (6 pts), respiratory tract infections (4 pts) and urinary tract infections (3 pts).

Conclusions: Based on these preliminary Phase 2 data, PELA as 'add-on’ to RUX in pts with a suboptimal/lost response to RUX monotherapy resulted in durable splenic and symptom responses, deepening of spleen responses over time, and was generally well tolerated. Additionally, improvement in BM fibrosis, as a marker of disease modification, was observed in 39% of treated pts.

Harrison:Sierra: Honoraria; Promedior: Membership on an entity's Board of Directors or advisory committees; EHA: Other: Leadership role; Keros: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings, Research Funding; Galecto: 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; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; MPN voice: Other: Leadership role; Incyte: Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees. Kremyanskaya:BMS: Research Funding; Chimerix: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; Kronos: Research Funding; Incyte: Consultancy, Research Funding; Kura: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Ionis: Research Funding. Bose:Incyte: Honoraria, Research Funding; Promedior: Research Funding; Ionis: Research Funding; Telios: Research Funding; Sierra Oncology (now GSK): Consultancy; Astellas: Research Funding; NS Pharma: Research Funding; Novartis: Honoraria; BMS: Consultancy, Research Funding; Pfizer: Research Funding; AbbVie: Consultancy; Cogent: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Kartos: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Disc Medicine: Research Funding; Karyopharm: Consultancy; Pharma Essentia: Honoraria; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Honoraria, Research Funding. Gupta:Sierra Oncology: Consultancy; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Roche: Other: Participation on a Data Safety or Advisory board; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board. Rampal:CTI: Consultancy; Disc Medicines: Consultancy; Gilead: Consultancy; Galecto: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy; Stemline: Consultancy, Research Funding; Blueprint: Consultancy; Sierra Oncology: Consultancy; Sunimoto Dainippon: Consultancy; Promedior: Consultancy; PharmaEssentia: Consultancy; Zentalis: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Research Funding; Novartis: Consultancy; Celgene/BMS: Consultancy; Incyte: Consultancy, Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding. Lambert:Bristol-Meyer-Squibb: Other: Travel and conference fees; Takeda: Other: Travel and conference fees; Kite-Gilead: Consultancy, Honoraria. Talpaz:SDp: Membership on an entity's Board of Directors or advisory committees; Kirin: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Other: Grant/research support ; IMAGO: Consultancy; BMS: Consultancy; Takeda: Other: Grant/research support . Vannucchi:Blueprint: 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; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. 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. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Verstovsek:Sierra Oncology: Consultancy, Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Novartis: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Incyte: Consultancy, Research Funding; CTI BioPharma Corp.: Research Funding; AstraZeneca: Research Funding; Blueprints Medicines Corp.: Research Funding; ItalPharma: Research Funding; Constellation Pharmaceuticals: Consultancy; Gilead: Research Funding; Pragmatist: Consultancy. Mesa:Promedior: Research Funding; CTI: Research Funding; AOP: Consultancy; Genotech: Research Funding; Samus: Consultancy, Research Funding; AbbVie: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; Celgene: Research Funding; Incyte: Consultancy, Research Funding; Geron: Consultancy; Blueprint: Consultancy; Bristol Myers Squibb: Consultancy; LaJolla Pharmaceutical: Consultancy; Sierra Oncology: Consultancy, Research Funding; Roche: Consultancy; Novartis: Consultancy; Gilead: Research Funding; Imago: Research Funding. Colak:MorphoSys AG: Current holder of stock options in a privately-held company, Other: Stock options; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Current Employment. Klein:Constellation Pharmaceuticals, Inc., a MorphoSys Company: Current Employment; MorphoSys AG: Other: Stock options. Dutta:MorphoSys AG: Current Employment. Mascarenhas:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy; Prelude Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen: Research Funding; Forbius: Research Funding; Merck: Research Funding; PharmaEssentia: Consultancy, Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy; GSK: Consultancy; AbbVie: Consultancy, Research Funding; Galecto: Consultancy; Kartos: Consultancy, Research Funding; Merus: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Roche: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.