Beam Therapeutics has announced promising early clinical trial data for BEAM-101, a novel base editing therapy for sickle cell disease. The data indicates successful editing of stem cells, leading to the production of more durable red blood cells. However, the trial also reported the death of a participant due to lung damage, potentially linked to the chemotherapy drug busulfan, commonly used in stem cell transplants. This highlights both the potential and the challenges of advancing gene editing techniques for severe genetic disorders.
Clinical Trial Results and Fetal Hemoglobin Production
Data from the first four patients with at least one month of follow-up showed that BEAM-101 significantly increased levels of fetal hemoglobin (HbF) and reduced levels of sickled hemoglobin. In two patients with longer follow-up, the treatment nearly eliminated red blood cells expressing only sickled hemoglobin by the second month. This effect is expected to protect patients from vaso-occlusive crises, a hallmark of sickle cell disease. Beam reported that none of the treated patients experienced such crises during the trial period. Participants in the trial, aged 19 to 27, had a history of sickle cell-related pain crises in the two years before enrollment.
Safety Concerns and Busulfan Toxicity
Despite the encouraging efficacy results, the death of one patient from lung damage has raised concerns. The adverse event was attributed to busulfan, a chemotherapy drug used to create space in the bone marrow for the edited stem cells to engraft. Busulfan is known to be toxic, and its use is a common challenge in gene editing therapies for blood disorders. Beam CEO John Evans acknowledged the risks associated with myeloablative transplant using chemotherapy, including potential toxicities and a rare risk of mortality. He emphasized that these risks must be weighed against the severe health threats posed by sickle cell disease, such as strokes and organ damage.
BEAM-104: A Chemotherapy-Free Alternative
To address the safety concerns associated with busulfan, Beam is developing BEAM-104, a second-generation therapy that aims to eliminate the need for chemotherapy. BEAM-104 utilizes an anti-CD117 antibody to suppress and eliminate diseased cells in the bone marrow. The therapy also involves engineered stem cells that are resistant to the antibody. Preclinical testing in monkeys has shown that BEAM-104 can successfully edit stem cells and promote engraftment in the bone marrow using only antibody conditioning. Beam plans to conduct further preclinical testing before initiating a Phase 1 study of the anti-CD117 antibody in healthy volunteers, followed by evaluation of the antibody and stem cell product in patients with sickle cell disease and beta thalassemia.
Implications and Future Directions
The early data from the BEAM-101 trial provides a proof point for Beam's base editing technology in treating sickle cell disease. While the death of a patient highlights the challenges associated with current stem cell transplant procedures, the development of BEAM-104 offers a potential path toward safer and more accessible gene editing therapies. Beam estimates that BEAM-104 is several years behind BEAM-101 in development. The company plans to present additional data from the BEAM-101 trial at the American Society of Hematology's annual meeting in December. Beam has enrolled 35 patients in the expansion cohort of its Phase 1/2 study testing BEAM-101 and will continue to track hemoglobin levels and the proportion of patients who are free of pain crises for 12 or more months.
