Beam Therapeutics has reported the death of a patient enrolled in its Phase I/II BEACON trial evaluating BEAM-101, a base editing therapy candidate for sickle cell disease (SCD). The company stated that the death was likely a consequence of the preconditioning regimen, specifically busulfan, administered before the BEAM-101 infusion, and not a direct result of the treatment itself. The patient succumbed to respiratory failure four months after receiving BEAM-101.
The death occurred in one of six patients dosed in the BEACON trial (NCT05456880), a single-arm, open-label study assessing the safety and efficacy of a single dose of BEAM-101 in SCD patients experiencing severe vaso-occlusive crises (VOCs). The company disclosed the death alongside initial efficacy data for BEAM-101.
Regulatory and Expert Perspectives
Both the BEACON trial’s Data Safety Monitoring Committee and the FDA have reviewed the case. The FDA has permitted Beam Therapeutics to continue the trial without modifications to the study protocol.
Sharl S. Azar, MD, medical director at Massachusetts General Hospital (MGH) Comprehensive Sickle Cell Disease Treatment Center, commented on the broader implications for the SCD community, especially in light of recent setbacks such as the revocation of marketing authorization for Novartis’ Adakveo® (crizanlizumab-tmca) and Pfizer’s withdrawal of Oxbryta® (voxelotor).
The Challenge of Conditioning Regimens
Beam Therapeutics acknowledged the inherent risks associated with current conditioning regimens, stating, "Today’s conditioning regimens are associated with significant toxic effects." The company emphasized the potential for future improved conditioning regimens with fewer toxic effects to be paired with BEAM-101 and other programs.
Researchers are actively seeking less toxic alternatives to busulfan, a crucial component of cell and gene therapy protocols. Busulfan's impact on fertility is a significant concern.
Vivien Sheehan, MD, PhD, director of translational sickle cell disease research at Emory University School of Medicine, noted the preference for replacing busulfan with less toxic alternatives, such as immunotherapy approaches involving anti-CD117a and melphalan.
BEAM-101 and the ESCAPE Approach
BEAM-101 is an ex vivo therapy designed to introduce base edits that mimic genetic variants observed in individuals with hereditary persistence of fetal hemoglobin, potentially mitigating the effects of sickle cell disease. Beam is also developing a non-genotoxic approach called ESCAPE, which uses base editing to prevent gene-edited HSCs from producing c-Kit (CD117), an antibody antagonistic to stem cell factor.
Initial Data and Future Directions
According to Beam, no Grade 3 or higher adverse events (AEs) or serious AEs related to BEAM-101 treatment were observed in any of the six patients. The initial safety profile was consistent with busulfan conditioning and autologous hematopoietic stem cell transplantation (HSCT).
All six patients achieved their target cell dose, and the four patients with at least one month of follow-up experienced neutrophil engraftment at a median of 17 days and platelet engraftment at a median of 20 days. These patients also demonstrated rapid and robust fetal hemoglobin (HbF) induction and corresponding sickle hemoglobin (HbS) reduction.
