ASP-8731 (HRS-6719/ML-0207): A Comprehensive Review of a Discontinued BACH1 Inhibitor for Sickle Cell Disease

1. Executive Summary

ASP-8731, also identified by the synonyms ML-0207 and HRS-6719, was an orally administered small molecule inhibitor of BTB domain and CNC homolog 1 (BACH1) under development for the treatment of sickle cell disease (SCD). Originating from Mitobridge, Inc., later acquired by Astellas Pharma Global Development, Inc., ASP-8731 aimed to address SCD pathophysiology by derepressing NRF2-mediated pathways. This was hypothesized to increase the expression of antioxidant genes and, critically, fetal hemoglobin (HbF), thereby mitigating oxidative stress, inflammation, vaso-occlusion, and anemia associated with SCD.

Preclinical studies, encompassing in vitro experiments with human cell lines (including SCD patient-derived cells) and in vivo assessments in the Townes-SS humanized mouse model of SCD, demonstrated promising activity. ASP-8731 was shown to upregulate antioxidant markers, reduce inflammatory mediators, decrease vaso-occlusion, and induce HbF expression, both alone and in combination with hydroxyurea. These findings provided a strong rationale for clinical investigation.

Astellas initiated a Phase 1 clinical trial (NCT05167526) in March 2022 to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP-8731 in healthy adult volunteers. Despite receiving Orphan Drug Designation from the U.S. FDA for sickle cell anemia in September 2022, the Phase 1 study was terminated prematurely in March 2023 because "protocol defined stopping criteria" were met. The specific adverse events or findings that triggered these criteria have not been publicly disclosed. Consequently, Astellas officially discontinued the development of ASP-8731 for SCD in April 2023.