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
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 
Published: December 2024

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 &lt;4 RBC units ≤8 weeks prior to first dose) achieved transfusion independence (TI; transfusion-free for ≥8 consecutive weeks during the Core Period) with tebapivat 5 mg QD. The safety profile was consistent with data reported in healthy volunteers.
Methods: Given that the 5 mg daily dose was well tolerated in the phase 2a part of the study, this phase 2b, open-label, multicenter trial (NCT05490446) will explore efficacy at 3 additional higher dose levels. Patients will receive 1 of 3 dose levels (Dose Levels 1-3) for up to 24 weeks (Core Period). Enrollment will be sequential, starting with Dose Level 1; enrollment in subsequent dose levels will begin once the last patient has enrolled in the prior dose level. Approximately 60 patients (20 per dose level) are planned to be enrolled. Key inclusion criteria include: aged ≥18 years; documented LR-MDS (IPSS-R risk score ≤3.5 and &lt;5% blasts); hemoglobin (Hb) &lt;10 g/dL in the 4-week Screening Period; LTB or high transfusion burden (HTB; ≥8 RBC units ≤16 weeks and ≥4 RBC units ≤8 weeks prior to first dose). Patients can be ESA relapsed/refractory or naïve and there is no erythropoietin level cutoff. Key exclusion criteria include: history of acute myeloid leukemia; secondary MDS; prior exposure to a PK activator, including tebapivat in the phase 2a portion of this trial; prior exposure to disease-modifying agents including imetelstat, lenalidomide, hypomethylating agents, and immunosuppressive therapies; treatment with ESAs ± granulocyte colony-stimulating factor &lt;28 days prior to first dose; treatment with luspatercept &lt;65 days prior to first dose.
The primary endpoint is TI (transfusion-free for ≥8 consecutive weeks [TI8] during the Core Period). The proportion of patients who achieve TI8 will be summarized and the 2-sided 95% exact CI (using the Clopper-Pearson method) calculated for each dose level. Secondary endpoints include: safety; change from baseline in Hb concentration; change from baseline in total transfused RBC units from Weeks 8-24; TI for ≥12 consecutive weeks; proportion of patients (HTB only) with ≥50% reduction in total transfused RBC units for ≥12 consecutive weeks compared with baseline; duration of TI. Patients who complete the Core Period will be eligible to continue receiving tebapivat (at the discretion of the investigator) for up to 156 weeks in the Extension Period. The phase 2b portion of the study will be initiated in the second half of 2024.
Conclusions: This phase 2b study will evaluate the efficacy and safety of tebapivat at higher QD doses in patients with anemia due to LR-MDS. Further information is available at https://clinicaltrials.gov/study/NCT05490446.