Patient With Sickle Cell Disease Dies From Complications Related to Busulfan-Conditioning Following Treatment With Beam’s Base-Editing HSC Therapy BEAM-101
The patient died of respiratory failure 4 months after receiving BEAM-101.
A patient treated for sickle cell disease (SCD) in the context of Beam Therapeutics’ phase 1/2 BEACON clinical trial (NCT05456880), which is evaluating the company’s investigational base-edited autologous hematopoietic stem cell (HSC) therapy BEAM-101, has died.1
The patient’s death was deemed by the trial’s investigatory to be related to the busulfan-conditioning regimen that patients must receive prior to administration of BEAM-101, rather than to the HSC therapy itself. Specifically, the patient died of respiratory failure 4 months after receiving BEAM-101. Myeloablating chemotherapy such as busulfan is known to be capable of leading to fatal pulmonary complications in rare cases, and as such the patient’s death is not outside of the known risk profile of busulfan. The patient was 1 of 6 patients to have been treated in BEACON as of a July 2, 2024, data cut. Beam noted that no adverse events of grade 3 or greater severity deemed related to BEAM-101 itself were reported in these patients. Updated from the trial will be presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7 to 10, 2024, in San Diego, California.
“This is a sad outcome and it really underscores the real risks of doing myeloablative transplant with chemotherapy,” John Evans, MBA, the chief executive officer of Beam, said in an interview with BioPharma Dive.2 “These risks are well known. This includes significant toxicities that are possible and the rare, but real, risk of mortality.”
Notably, at ASH, Beam Therapeutics will also be presenting preclinical data on its Engineered Stem Cell Antibody Evasion (ESCAPE) approach, which is a similar approach to treating SCD as BEAM-101, but circumvents the need for busulfan conditioning. Specifically, the ESCAPE approach involves the use of a CD117 monoclonal antibody for conditioning in place of busulfan conditioning. The monoclonal antibody acts to deplete diseased cells prior to administration of the therapy itself. In addition to base-editing of HBG1/2 promoters in autologous CD34+ hematopoietic stem and progenitor cells to induce fetal hemoglobin (HbF), as is done in BEAM-101, ESCAPE also involves editing of a single epitope on CD117 in these cells in order to prevent them from being targeted by the CD117 monoclonal antibody used for conditioning.
“This is clearly the future,” Evans added in the interview with BioPharma Dive.2 “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.”
The preclinical data tested the ESCAPE approach in nonhuman primates (NHPs). The research involved treatment of 1 NHP with a dose of 10 mg/kg of the monoclonal antibody and another NHP with a dose of 25 mg/kg of the monoclonal antibody, 7 days before administration of the base-edited cells. Additional doses of the monoclonal antibody were given after the base-edited cell administration to continue to provide a “competitive advantage” for the base-edited cells. Beam reported that the conditioning regimen was well-tolerated and that supportive care was unnecessary. Furthermore, at 35 weeks after treatment with ESCAPE cells, the NHPs showed approximately 85% of red blood cells expressing HbF.
“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,” Giuseppe Ciaramella, PhD, the president of Beam, said in a statement.1 “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.”
