Results from the first clinical trial of bitopertin for steroid-relapsed/refractory Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is an inherited anemia characterized by ribosome defects that reduce globin chain production, producing an excess of toxic heme. Bitopertin selectively reduces heme synthesis, rebalances globin-heme production, and improves anemia in model systems. We report the first clinical trial of bitopertin for the treatment of steroid-relapsed/refractory DBA. This was an open-label, intrapatient dose-escalation study in 15 heavily pretreated, transfusion-dependent adult DBA patients (ClinicalTrials.gov NCT05828108). Bitopertin dosing increased monthly (5 mg escalating to 60 mg, daily), followed by 3-months maintenance. Primary endpoint was response (hemoglobin level, erythrocyte transfusions). Secondary endpoints were safety (adverse events, AE) and tolerability. Twelve patients completed the full 8-month course (2 discontinued early for non-bitopertin-related serious AE (SAE), 1 lost-to-follow-up). All 12 patients reached the planned 60-mg maximum dose. Two de-escalated to 40 mg (1 grade-2 dizziness, 1 concern for loss of early effect). Seven SAEs were reported, all unlikely/unrelated to bitopertin. Plasma drug levels were consistent with prior studies. At 10 mg daily and greater, all patients reached levels consistent with EC₅₀. There was a time-dependent/dose-dependent reduction of reticulocyte hemoglobin content. There were no clinical responses. Bitopertin is safe, bioavailable, and well-tolerated in steroid-refractory DBA. Although bitopertin did not result in transfusion-independence, iron overload, marrow hypocellularity and prior steroid failure reflect a cohort with long-standing disease and minimal hematopoietic marrow reserve. Additionally, based on model systems, dosing may have escalated too rapidly, missing a potential lower effective dose. Future studies will test slower dose escalation of bitopertin as a steroid-sparing agent for steroid-responsive DBA patients.