A patient with sickle cell disease (SCD) participating in Beam Therapeutics' Phase 1/2 BEACON clinical trial (NCT05456880) evaluating BEAM-101, an investigational base-edited autologous hematopoietic stem cell (HSC) therapy, has died due to complications related to the busulfan-conditioning regimen. The trial's investigators determined that the patient's death, caused by respiratory failure four months post-treatment, was linked to the conditioning regimen rather than the HSC therapy itself. This adverse event underscores the inherent risks associated with myeloablative chemotherapy in transplant settings. Updated data from the BEACON trial will be presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2024.
Known Risks of Myeloablative Conditioning
Myeloablative chemotherapy, such as busulfan, carries a known risk of potentially fatal pulmonary complications, albeit rare. According to Beam Therapeutics, the patient's death aligns with the established risk profile of busulfan. As of the data cut on July 2, 2024, six patients had been treated in the BEACON trial. Beam Therapeutics reported that no grade 3 or higher adverse events were attributed to BEAM-101 itself in these patients.
John Evans, MBA, CEO of Beam Therapeutics, acknowledged the risks associated with myeloablative transplant with chemotherapy, stating, "This is a sad outcome and it really underscores the real risks of doing myeloablative transplant with chemotherapy. These risks are well known. This includes significant toxicities that are possible and the rare, but real, risk of mortality."
Beam's ESCAPE Approach
Beam Therapeutics is also developing an Engineered Stem Cell Antibody Evasion (ESCAPE) approach, which aims to circumvent the need for busulfan conditioning. This method uses a CD117 monoclonal antibody for conditioning instead of busulfan. The monoclonal antibody depletes diseased cells before therapy administration. ESCAPE involves base-editing of HBG1/2 promoters in autologous CD34+ hematopoietic stem and progenitor cells to induce fetal hemoglobin (HbF), similar to BEAM-101. Additionally, ESCAPE edits a single epitope on CD117 in these cells to prevent targeting by the CD117 monoclonal antibody used for conditioning.
Evans noted the potential of the ESCAPE approach: "This is clearly the future. It would not only make this process much safer for all patients because you’ve gotten rid of chemotherapy, it also expands the addressable population by 3- to 4-fold."
Preclinical ESCAPE Data
Preclinical data in non-human primates (NHPs) demonstrated the potential of the ESCAPE approach. One NHP received 10 mg/kg of the monoclonal antibody, and another received 25 mg/kg, seven days before base-edited cell administration. Additional monoclonal antibody doses were administered post-cell administration to maintain a competitive advantage for the base-edited cells. The conditioning regimen was well-tolerated, and supportive care was unnecessary. After 35 weeks, approximately 85% of red blood cells in the NHPs expressed HbF.
Giuseppe Ciaramella, PhD, President of Beam, stated, "Our proof-of-concept data for ESCAPE in non-human primates demonstrate that base editing could enable antibody conditioning and engraftment for stem cell transplant without chemotherapy, a potential breakthrough in the field of hematology and for patients. Along with the strong translation from preclinical to clinical of our BEAM-101 program, these data reflect the potential of base editing to enable new therapeutic possibilities for people suffering from serious diseases."
