Beam Therapeutics’ experimental gene-editing therapy for sickle cell disease now has its first cut of patient data showing signs of treating the rare blood disorder in a way that could differentiate it from currently available gene therapies, but the early results reported Tuesday also include a fatality attributed to a drug used to prepare patients for the one-time treatment.
Beam’s therapy, BEAM-101, is made by harvesting a patient’s stem cells and editing them in a lab using a technology called base-editing. Base editing enables precise edits to a single base in a genome. By contrast, double-stranded breaks in DNA made by the CRISPR technology have the potential to cause unwanted or off-target edits. The precision of base-editing is intended to be safer. In sickle cell disease, the Cambridge, Massachusetts-based company’s treatment is intended to increase production of functional hemoglobin, which could in turn inhibit the process by which red blood cells take on the rigid, crescent shape characteristic of the disorder.
Of the 35 patients enrolled in BEAM-101’s open-label Phase 1/2 study, eight have been dosed with the therapy as of a July 2 cutoff date. Beam said there were no serious adverse events reported in six patients who could be evaluated for safety. The patient who died experienced respiratory failure four months after infusion with BEAM-101. Beam said trial investigators determined this complication was likely due to busulfan, a chemotherapy.
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Infusing edited cells into the patient is just one part of a broader, multi-step process. One of those steps is a conditioning regimen that depletes a patient’s cells to help ensure that the newly infused cells can take their place, which is called engraftment. Busulfan is widely used in the conditioning of patients receiving stem cell transplants and gene therapy procedures. Respiratory complications are a known risk of the toxic drug, which is also used to condition sickle cell disease patients before they’re infused with the FDA-approved CRISPR gene therapies Casgevy, from Vertex Pharmaceuticals, and Lyfgenia, from Bluebird Bio.
The BEAM-101 trial has efficacy data for four patients. With the caveat that these are preliminary data from a small number of patients, the results are encouraging. All four experienced engraftment of neutrophils and platelets within one month of receiving the therapy, Beam said. The therapy led to higher levels of fetal hemoglobin and lower levels of sickle-shaped cells. Beam also said signs of red blood cell destruction had normalized for all four patients and there were no cases of vaso-occlusive crises (VOCs), a complication that develops when sickled red blood cells impede blood flow, depriving organs of oxygen. Beam said data from more patients with longer follow-up will be presented next month during the annual meeting of the American Society of Hematology.
The investment firm William Blair see some early signs of differentiation for BEAM-101. In a note sent to investors, analyst Sami Corwin said the Beam therapy’s ability to elicit higher fetal hemoglobin levels, resulting in lower sickle cell hemoglobin, could translate into extended VOC-free intervals that preserve organ health in the long term. Corwin also said the measures of higher fetal hemoglobin and lower sickle cell hemoglobin closely mimic what’s observed in asymptomatic sickle cell mutation carriers, which could result in a differentiated product profile in the long term.
Regarding the deceased patient, Corwin said lung toxicity is a known complication of busulfan, and it can occur months to years following treatment. She added that prior to the death, this patient’s blood appeared to be correcting and normalizing, which suggests BEAM-101 was working.
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“While the patient death is unfortunate, we see the event as highlighting the need for less toxic preconditioning options, and we think Beam is leading the space in this regard,” Corwin wrote.
That less toxic option comes from another BEAM program called Engineered Stem Cell Antibody Paired Evasion, or ESCAPE, which is intended to avoid the need for busulfan. ESCAPE has two components, Beam explained in an investor presentation. The first, BEAM-103, is a monoclonal antibody that leads old and diseased cells to be suppressed and eliminated, making room for edited cells to replace them. The edited patient cells make up the second component, BEAM-104. Modifications to those cells include an edit to avoid binding to BEAM-103. By escaping the antibody, BEAM-104 cells can multiply and engraft.
Beam has preclinical proof-of-concept date for ESCAPE. In tests in two monkeys, each receiving different dose levels of the ESCAPE regimen instead of busulfan, Beam said the antibody-based conditioning was well tolerated with no need for supportive care. Beam also said both monkeys showed rapid increases in fetal hemoglobin levels that reached about 55% measured 35 weeks after administration of the therapy. More data for ESCAPE are set to be presented at the ASH conference.
“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, president of Beam, said in a prepared statement.
Image: Meletios Verras, Getty Images
