A Phase 2a/2b Multicenter Study of AG-946 in Patients with Anemia Due to Lower-Risk Myelodysplastic Syndromes

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by ineffective erythropoiesis, dysplasia, and progressive cytopenias. Overall survival and risk of leukemic transformation can be evaluated by the Revised International Prognostic Scoring System (IPSS-R). For lower-risk MDS (LR-MDS), anemia is the most common symptom and occurs in approximately 90% of patients (pts), half of whom will develop red blood cell (RBC) transfusion (TF) dependence. Primary therapeutic strategies are limited for pts with anemia due to LR-MDS and include erythropoiesis-stimulating agents or TF. Additional treatments are indicated only in specific MDS subtypes, with limited responses achieved. Unfortunately, all pts eventually require subsequent therapies. Currently, there is tremendous need for novel therapies for pts with LR-MDS. Acquired pyruvate kinase (PK) deficiency has been observed in MDS, suggesting direct involvement of RBC-specific PK (PKR), a key glycolytic enzyme, in MDS-associated anemia pathogenesis. AG-946 is an investigational, potent, small-molecule, allosteric activator of wild-type and mutated PKR isoforms. AG-946 may enhance RBC functionality and survival by increasing glycolysis and ATP production, and may improve differentiation of erythroid cells in bone marrow, potentially improving anemia caused by ineffective erythropoiesis in MDS. In a phase (ph) 1 study, 5 mg of AG-946 once daily (QD) demonstrated near maximal pharmacodynamic activity (predicted to provide ~95% of the maximal effect in increasing ATP according to a pharmacokinetic-pharmacodynamic modeling), and was safe and tolerable in healthy volunteers. 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. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal