Results from a Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Tebapivat (AG-946) in Patients with Sickle Cell Disease
Authors: Xu Julia Z , Novelli Enrico M , Ribeil Jean-Antoine , Glenthøj Andreas , Gopal Srila , Al-Samkari Hanny , Idowu Modupe , Despotovic Jenny , Patil Spurthi , Dai Xiaoshu , Al Masud Abdullah , Callaghan Michael , El Rassi Fuad 
Published: December 2024

Introduction: Prior studies in patients (pts) with sickle cell disease (SCD) have shown that pyruvate kinase activation increases adenosine triphosphate (ATP), leading to stabilization of membrane integrity and increased survival of red blood cells, and decreases 2,3-diphosphoglycerate (DPG), thus preventing the polymerization of sickle hemoglobin (HbS) in its deoxygenated state. Mitapivat, a pyruvate kinase activator, has demonstrated clinically meaningful improvement in hemoglobin (Hb) response and improvements in hemolysis and erythropoiesis in phase (Ph) 2 trials. Tebapivat (formerly AG-946) is an oral, potent, allosteric pyruvate kinase activator that is under clinical investigation as a potential therapy for rare anemias, including SCD. Results from the randomized, double-blind, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) parts of the Ph 1 study (NCT04536792) in healthy volunteers have been previously reported. Here, we report safety, pharmacokinetic (PK), and pharmacodynamic (PD) results from the non-randomized, open-label, third part of the Ph 1 study in adult pts with SCD.

Aims: To identify a well-tolerated and pharmacologically active dose of tebapivat in pts with SCD.

Methods: Two dose levels of tebapivat were evaluated. Adult pts (18-70 years) with sickle cell anemia (HbSS or HbS/beta[0]-thalassemia) and adequate organ function received 2 mg or 5 mg tebapivat once daily (QD) for 28 days, with a further 28-day observational safety follow-up. The primary objective was to identify a range of well-tolerated and pharmacologically active dose(s) of tebapivat for the treatment of pts with SCD. Secondary endpoints included type, severity, and relationship of adverse events (AEs) and serious AEs (SAEs), change from baseline in Hb and markers of hemolysis and erythropoiesis, change over time in PD concentrations (2,3-DPG and ATP), and plasma PK parameters.

Results: Sixteen adult pts with SCD received at least one dose of either 2 mg QD (n=8) or 5 mg QD (n=8) oral tebapivat. Median age (range) was 33.5 years (19-51), 50.0% were male, 81.3% were Black or African American. Mean (Standard Deviation [SD]; range) baseline Hb concentration was 7.96 g/dL (1.03; 6.80-10.31). Seven (43.8%) pts (4 [50.0%] in the 2 mg cohort, 3 [37.5%] in the 5 mg cohort) had vaso-occlusive crises in the 12 months prior to initiating the trial. Ten (62.5%) pts (4 [2 mg], 6 [5 mg]) were taking stable-dose hydroxyurea for ≥3 months prior to initiating tebapivat. There were no imbalances between dose cohorts in demographics or disease characteristics deemed to have an impact on the interpretation of the results. All pts (100.0%) experienced at least one treatment-emergent AE (TEAE). The most common TEAEs were sickle cell anemia with pain crises (7 [43.8%] pts; 4 [50.0%] in the 2 mg cohort, 3 [37.5%] in the 5 mg cohort]), and upper respiratory tract infection (3 [18.8%] pts; 1 [12.5%] in the 2 mg cohort, 2 [25.0%] in the 5 mg cohort). Two (25.0%) pts in the 2 mg cohort and 1 (12.5%) pt in the 5 mg cohort experienced a SAE of sickle cell anemia with pain crises during the 28-day off-treatment safety follow-up, with the SAE in the 5 mg cohort considered treatment-related. Six (37.5%) pts experienced Grade ≥3 TEAEs (3 in each cohort). No dose-limiting toxicities, TEAEs leading to discontinuation of treatment, or deaths, were reported in either cohort. At the end of the 28-day treatment period, the mean (SD) change from baseline for Hb was 1.2 (0.41) g/dL in the 2 mg cohort and 1.9 (0.69) g/dL in the 5 mg cohort. On Day 28 (pre-dose), the mean (SD) percent increase in ATP from baseline was 46.3% (29.08) and 67.8% (30.92), and the mean (SD) percent reduction in 2,3-DPG from baseline was 20.91% (7.10) and 29.44% (12.67), for the 2 mg and 5 mg cohorts, respectively. Improvements in markers of hemolysis (lactate dehydrogenase and bilirubin) and erythropoiesis (reticulocytes) were also observed at Day 28.

Conclusions: Tebapivat was well tolerated in pts with SCD receiving either 2 mg or 5 mg QD for 28 days. This study provides further evidence that PK activation may have beneficial effects in pts with SCD.