Beam's Base-Editing Sickle Cell Therapy Shows Potential, Marred by Fatality

Beam Therapeutics has unveiled initial data from its experimental gene-editing therapy, BEAM-101, designed to treat sickle cell disease. The early findings suggest it holds promise in addressing the rare blood disorder differently than existing gene therapies. However, the preliminary results, shared on Tuesday, also reported a patient fatality linked to a drug used in preparing patients for the therapy.

BEAM-101 operates by extracting a patient’s stem cells and performing precise edits using a base-editing technology. This method aims to correct a single base in the genome without causing the double-stranded breaks in DNA that CRISPR technology might induce, which can lead to off-target effects. The precision of base-editing is anticipated to be safer. Beam Therapeutics, based in Cambridge, Massachusetts, aims for its treatment to enhance the production of functional hemoglobin, potentially preventing red blood cells from adopting the rigid, sickle shape typical of the disease.

The BEAM-101 trial, an open-label Phase 1/2 study, has enrolled 35 patients, with eight having received the therapy by the July 2 cutoff. According to Beam, six of these patients, who could be assessed for safety, did not experience serious adverse events. However, one patient who received the treatment died from respiratory failure four months post-infusion, a complication attributed to the chemotherapy drug busulfan. This drug is commonly employed in the conditioning process to deplete a patient’s cells before the introduction of edited stem cells, facilitating their engraftment. While busulfan is used in treatments for sickle cell disease, including the FDA-approved CRISPR gene therapies Casgevy and Lyfgenia, its respiratory risks are well-documented.

Four patients in the BEAM-101 trial have shown encouraging efficacy data. Beam reported that all four experienced successful engraftment of neutrophils and platelets within a month of therapy. The treatment led to increased levels of fetal hemoglobin and a decrease in sickle-shaped cells. Additionally, markers of red blood cell destruction normalized, and none of the patients experienced vaso-occlusive crises (VOCs), which can occur when sickled red blood cells block blood flow and deprive organs of oxygen. Beam plans to present more extensive data from additional patients at the upcoming American Society of Hematology meeting.

Investment firm William Blair noted some early signs that BEAM-101 might offer distinct advantages. Analyst Sami Corwin highlighted that the therapy’s ability to increase fetal hemoglobin while reducing sickle cell hemoglobin could potentially lead to longer VOC-free periods, preserving organ health over time. Corwin also pointed out that the observed hemoglobin changes in treated patients resemble those in individuals who carry the sickle cell trait but do not exhibit symptoms, suggesting a unique product profile for BEAM-101.

In response to the patient’s death, Corwin acknowledged the known risk of lung toxicity associated with busulfan. She also noted that the patient’s blood parameters were normalizing prior to the fatal incident, indicating the therapy's effectiveness. Corwin emphasized the necessity for less toxic preconditioning options and recognized Beam’s efforts in this area.

Beam is developing an alternative conditioning regimen, Engineered Stem Cell Antibody Paired Evasion (ESCAPE), to eliminate the need for busulfan. ESCAPE comprises two components: BEAM-103, a monoclonal antibody that suppresses and eliminates old and diseased cells, and BEAM-104, edited patient cells designed to evade BEAM-103 binding. This evasion allows BEAM-104 cells to proliferate and engraft.

In preclinical tests with two monkeys, Beam’s antibody-based conditioning in the ESCAPE regimen was well tolerated, with no supportive care required. The treated monkeys showed significant increases in fetal hemoglobin levels, reaching approximately 55% after 35 weeks. Beam plans to present additional ESCAPE data at the ASH conference.

Giuseppe Ciaramella, President of Beam, expressed optimism about the ESCAPE data, suggesting that base editing could facilitate stem cell transplant conditioning and engraftment without chemotherapy, potentially revolutionizing hematology treatments and patient care.