Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Acquired Marrow Failure Syndromes, MDS, Bone Marrow Failure Syndromes, Clinical Research, Chronic Myeloid Malignancies, drug development, hematopoiesis, Diseases, Therapies, Myeloid Malignancies, Biological Processes
Methods: This ph 2a/2b multicenter study consists of an open-label, proof-of-concept (ph 2a) study and a double-blind, randomized, placebo (PBO)-controlled (ph 2b) study evaluating efficacy and safety of AG-946 in adult pts with anemia due to LR-MDS (Figure). Pts are categorized based on TF burden (non-TF-dependent [NTD], low TF burden [LTB], and high TF burden [HTB]), defined along with primary endpoints by International Working Groups 2018 criteria. Key inclusion criteria: age ≥18 years; documented LR-MDS IPSS-R (risk score ≤3.5 and <5% blasts); hemoglobin (Hb) <11.00 g/dL; and NTD (<3 RBC units within 16 wks and 0 RBC units within 8 wks prior to first dose of AG-946) or either LTB (3–7 RBC units within 16 wks and <4 RBC units within 8 wks prior to first dose), or (for ph 2b only) HTB (≥8 RBC units within 16 wks and ≥4 RBC units within 8 wks prior to first dose). Key exclusion criteria: history of acute myeloid leukemia; secondary MDS; and prior exposure to PK activator, disease-modifying agents, or treatment for high-risk MDS. Before receiving the first dose of AG-946, EPO or G-CSF must have been stopped for ≥28 days and luspatercept for ≥65 days. In ph 2a, 20 pts will receive 5 mg AG-946 QD for up to 172 wks (16-wk core and 156-wk extension period [EP]). Ph 2a primary endpoints: Hb response (≥1.5 g/dL average increase above baseline [BL] from Wk 8 to Wk 16) and in pts with LTB TF independence (TI), defined as TF-free for ≥8 consecutive wks during the core period. Ph 2a secondary endpoints: safety, Hb change from BL, Hb 1.0+ response, ≥50% reduction in total transfused RBC units for ≥8 consecutive wks, and pharmacokinetics/pharmacodynamics. If the ph 2a study meets prespecified criteria, the ph 2b study will enroll 96 pts to be randomized (1:1:1:1) to receive AG-946 (2 mg, 3 mg, or 5 mg QD) or PBO for up to 180 wks (24-wk double-blind and 156-wk EP). Ph 2b primary endpoint: modified hematologic improvement-erythroid (mHI-E) response during the double-blind period (ie, Hb response for ≥8 consecutive wks in NTD pts, TI in pts with LTB, and ≥50% reduction in total transfused RBC units for ≥8 consecutive wks in pts with HTB). Ph 2b secondary endpoints: safety, TI, time to first mHI-E-response, and maximum duration of mHI-E response. Pts who complete the ph 2a core period or the ph 2b double-blind period will be eligible to receive AG-946 in the EP.
Results: Global site recruitment is in progress.
Conclusions: This ph2a/2b global study aims to provide proof-of-concept and evaluate efficacy and safety of AG-946, an investigational, once-daily, activator of PKR, vs PBO in adult pts with anemia due to LR-MDS.
Disclosures: Al-Samkari: Forma: Consultancy; Moderna: Consultancy; Dova: Consultancy, Research Funding; argenx: Consultancy; Rigel: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding. Fenaux: AbbVie, BMS, Janssen, Jazz, Novartis: Consultancy, Honoraria, Research Funding. Sekeres: Kurome: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Stein: Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Auron Therapeutics: Current equity holder in private company; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy; Syndax: Consultancy, Research Funding; Bayer: Research Funding. Sallman: Lixte: Patents & Royalties: LB-100; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syntrix Pharmaceuticals: Research Funding; Nemucore: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Brunner: Janssen: Research Funding; AstraZeneca: Research Funding; Celgene/BMS: Consultancy, Research Funding; GSK: Research Funding; Keros Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Taiho: Consultancy; Novartis: Consultancy, Research Funding; Agios: Honoraria; Acceleron: Honoraria; Aprea: Research Funding. Gurov: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yin: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Frisbie: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Xiao: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bhatia: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Beynon: Agios: Current Employment, Other: Stockholder. Wind-Rotolo: Agios Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Dibacco: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Silence Therapeutics: Honoraria; Takeda: Honoraria; Geron: Honoraria; Novartis: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Abbvie: Honoraria.
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