Publikationsdatum:
2020-11-05
Beschreibung:
I NTRODUCTION: The hallmark of sickle cell disease (SCD) is hemoglobin S (HbS) polymerization upon deoxygenation, resulting in red blood cell (RBC) sickling, oxidative damage, membrane damage, hemolysis, cell adhesion, and vaso-occlusion. Exacerbating the pathogenesis of SCD, the HbS RBC has [1] increased (↑) 2,3-DPG with decreased (↓) O2 affinity (↑ P50) and [2] ↓ RBC ATP. FT-4202, a small molecule allosteric activator of erythrocyte pyruvate kinase (PKR), increases PKR activity resulting in ↓ 2,3-DPG levels and ↑ ATP levels in RBCs. In healthy volunteer (HV) studies (Kalfa et al. Blood 2019), FT-4202 was well tolerated, demonstrating physiologic responses (↓ 2,3-DPG and ↑ ATP) with biologic effects including ↑ O2 affinity, ↓ reticulocytes (P 1 g/dL, % reticulocytes decreased, and markers of hemolysis were improved after 14 days of treatment (compared to pre-treatment levels). Hematologic parameters returned to pre-treatment levels 4 to 7 days post-treatment (data not shown) without clinical AEs. Functional studies in the 2 pts with increased Hb showed improved RBC deformability (↓ PoS) and improved RBC membrane function while on study treatment relative to pre-treatment and/or post-treatment. CONCLUSION: FT-4202 has a favorable safety profile in pts with SCD receiving a single dose or up to 14 days of dosing. A single dose of FT-4202 led to decreased 2,3-DPG and increased ATP, resulting in increased O2 affinity, decreased PoS, improved RBC deformability, and improved RBC membrane function. Initial blinded results of daily dosing with 300 mg FT-4202/placebo over 14 days show improvement in both hematologic and hemolytic parameters in 2 of 3 pts with SCD, along with improved RBC functional studies, suggesting the pharmacodynamic consequences of PKR activation may be of clinical benefit in SCD. Multiple-dose cohorts are ongoing to further evaluate the safety, PK/PD, and biological activity of FT-4202 following daily administration in pts with SCD; updated data will be presented. Disclosures Brown: Imara, Inc.: Consultancy, Research Funding; Forma Therapeutics, Inc,: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis, Inc.: Consultancy, Research Funding. Kalfa:Agios Pharmaceuticals, Inc: Consultancy, Research Funding; Forma Therapeutics, Inc: Research Funding. Kuypers:Forma Therapeutics, Inc.: Research Funding. Saraf:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding. Estepp:Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; ASH, NHLBI: Research Funding. Malik:Aruvant Sciences, CSL Behring: Patents & Royalties; Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy. Ribadeneira:Forma Therapeutics, Inc.: Current Employment. Forsyth:Forma Therapeutics, Inc.: Current Employment. Schroeder:Forma Therapeutics, Inc.: Current Employment. Wu:Forma Therapeutics, Inc.: Current Employment. Kelly:Forma Therapeutics, Inc.: Current Employment. Telen:Forma Therapeutics: Research Funding; GlycoMimetics Inc.: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: 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.
Print ISSN:
0006-4971
Digitale ISSN:
1528-0020
Thema:
Biologie
,
Medizin
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