Beam Therapeutics has acknowledged the death of a patient in a Phase I/II trial assessing the base editing therapy candidate BEAM-101—a death the company said was likely caused by the preconditioning regimen that preceded dosing, and not the treatment.
The patient died four months after BEAM-101 infusion “due to respiratory failure that was determined by the investigator to be likely related to busulfan conditioning and deemed unrelated to BEAM-101,” Beam said in a statement.
The patient who died is one of six patients to have been dosed with BEAM-101 in the Phase I/II BEACON trial (NCT05456880). Beam disclosed the death on the day it announced initial efficacy data for BEAM-101 from the BEACON trial, a single-arm, open-label clinical trial designed to assess the safety and efficacy of a single dose of BEAM-101 in patients with sickle cell disease (SCD) with severe vaso-occlusive crises (VOCs).
Beam stated that the death has been reviewed by the BEACON trial’s Data Safety Monitoring Committee and the FDA. Beam said the FDA has allowed the company to continue the trial without any changes to the study protocol.
“Today’s conditioning regimens are associated with significant toxic effects,” Beam acknowledged on its website. “Future improved conditioning regimens that produce fewer toxic effects could potentially be paired with BEAM-101 and with other future programs.”
The death comes at a time when researchers across industry and academia are seeking less toxic alternatives to busulfan as a bone conditioning regimen, a crucial component of cell and gene therapy protocols.
“This is a very sad development, especially in light of the recent setbacks we have seen in the sickle cell community,” Sharl S. Azar, MD, medical director, Massachusetts General Hospital (MGH) Comprehensive Sickle Cell Disease Treatment Center, told GEN.
Azar cited in part the revocation of conditional marketing authorization for Novartis’ Adakveo® (crizanlizumab-tmca) by the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA) this year, and the European Medicines Agency last year.
The agencies concluded that the benefits of Adakveo did not outweigh its risks, according to the regulator, after the drug failed a Phase III trial by failing to show a statistically significant reduction in VOCs. Adakveo patients averaged 2.5 VOCs leading to a visit to their healthcare provider during their first year of treatment, vs. an average 2.3 for placebo patients.
Also cited by Azar was Pfizer’s recent withdrawal of Oxbryta® (voxelotor), the marketed SCD therapy that it inherited when it acquired the drug’s original developer, Global Blood Therapeutics (GBT) in 2022 for $5.4 billion. Pfizer voluntarily withdrew Oxbryta in the United States and all other markets where it has been approved, just hours after European regulators disclosed that 16 patients dosed with the drug in a pair of clinical trials had died.
Busulfan has always generated significant setbacks as a conditioning regimen, Azar noted, in large part due to its impact on fertility.
“We grieve”
“This new announcement is disappointing, and we grieve for the tragic loss of any of our warriors. It’s very important that our warriors do not lose hope in light of this,” Azar said.
“This is the type of information that allows us to continue to hone our tools and assure that we are delivering better and safer therapies for sickle cell disease,” Azar added. “I encourage patients to reach out to their sickle cell providers to discuss this news.”
Vivien Sheehan, MD, PhD, director, translational sickle cell disease research at Emory University School of Medicine, told GEN, that researchers would prefer to replace busulfan as a preconditioning agent if they could.
“The potential loss of fertility and mucositis are certainly concerning to patients. An immunotherapy approach would be preferred,” Sheehan said.
Sheehan cited the use of anti-CD117a and melphalan in other trials of SCD therapies, by researchers who reasoned that the approaches resulted in lower toxicity.
Among genetic therapy developers that have worked to create nongenotoxic autologous ex vivo HSC therapies is Beam itself. Its nongenotoxic approach, called ESCAPE, uses base editing to prevent the gene-edited HSCs from producing an antibody, c-Kit (CD117), which is antagonistic to an essential HSC growth factor called stem cell factor.
Blocking this binding is designed to starve the cell, preventing proliferation and growth. As a result, unedited resident HSCs will be inhibited by the antibody, while the edited transplanted HSCs will be free to grow. Importantly, the edit only alters a single amino acid in CD117, which allows the receptor to still function by binding to other growth factors critical for the development of hematopoietic lineages.
Mephalan is designed to impede the growth of cancer cells, which are eventually destroyed by the body. However, the growth of normal cells may also be affected by melphalan, which is sold under the brand name Evomela® by Acrotech Biopharma and as Alkeran® by GlaxoSmithKline (GSK).
“I don’t think they will supplant busulfan,” Sheehan added.
Ex vivo therapy
BEAM-101 is an ex vivo therapy designed to produce base edits that are intended to potentially alleviate the effects of sickle cell disease by mimicking genetic variants seen in individuals who have hereditary persistence of fetal hemoglobin.
During Beam’s third-quarter earnings call, executives said the cause of idiopathic pneumonia syndrome was based on the timing and extensive clinical work-up on the patient.
Before the death, the patient’s blood appeared to be correcting and normalizing, suggesting the BEAM-101 drug product was working, Sami Corwin, PhD, an analyst with William Blair, highlighted from the call in a research note.
“While the patient death is unfortunate, we see the event as highlighting the need for less-toxic preconditioning options,” Corwin observed.
According to Beam, no Grade 3 or higher adverse events (AEs) or serious AEs related to treatment with BEAM-101 were seen in any of the six patients dosed with the treatment. The initial safety profile for the patients was consistent with busulfan conditioning and autologous hematopoietic stem cell transplantation (HSCT).
All six dosed patients achieved their target cell dose with either 1 or 2 mobilization cycles.
The four patients who had one month or more of follow-up achieved neutrophil engraftment at a median of 17 (15–19) days, and platelet engraftment at a median 20 (11–34) days. All four patients experienced rapid and robust fetal hemoglobin (HbF) induction by Month 1 (>60%) and corresponding sickle hemoglobin (HbS) reduction (≤36%) in non-transfused blood, which was sustained over time, Beam reported.
