A Phase 2B, Open-Label Multicenter Study of Tebapivat (AG-946), a Potent Pyruvate Kinase Activator, in Patients with Anemia Due to Lower-Risk Myelodysplastic Syndromes

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.6708-6708
• Main Authors: Zeidan, Amer M., Sekeres, Mikkael A., Al-Samkari, Hanny, Carraway, Hetty E., DeZern, Amy E., Mittelman, Moshe, Little, Meredith, Beynon, Vanessa, Dai, Xiaoshu, Sommakia, Sal, Despotovic, Jenny M., Patel, Parija, Dibacco, Melissa, Fattizzo, Bruno, Stein, Eytan M., Sallman, David, Kulasekararaj, Austin G., Platzbecker, Uwe, Fenaux, Pierre
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-203073

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow neoplasms characterized by dysplasia in hematopoietic cells, ineffective erythropoiesis, and progressive cytopenias. Median age at diagnosis is above 70 years. According to the revised International Prognostic Scoring System (IPSS-R), patients with IPSS-R score ≤3.5 are generally considered to have lower-risk MDS (LR-MDS). Anemia is the most common cytopenia in LR-MDS, occurring in up to 90% of patients, with more than half becoming red blood cell (RBC) transfusion-dependent. Anemia in MDS is associated with increased morbidity and mortality, and transfusions are associated with complications such as alloimmunization and iron overload, negatively impacting quality of life and healthcare resource use. Erythropoiesis-stimulating agents (ESAs) have long been used as first-line therapy, but less than 40% of patients respond, and the median duration of response is less than 18 months. Unmet needs for novel agents remain in patients with anemia due to LR-MDS who do not respond to ESAs or other approved therapies. Tebapivat (formerly AG-946) is a potent, investigational, oral, once-daily (QD) activator of pyruvate kinase (PK), including the RBC-specific (PKR) and M2 (PKM2) isoforms. Tebapivat had a positive impact on the glycolytic pathway (PK activity, PK/hexokinase activity ratio, PK stability, and adenosine triphosphate [ATP]) in in vitro LR-MDS studies, as well as improved erythroblast maturation in two MDS mouse models. In a 16-week phase 2a study of patients with anemia due to LR-MDS, 4/10 patients with low transfusion burden (LTB; 3-7 RBC units within 16 weeks and