In a field bubbling with preclinical data and ideas on complex genome edits—including rewriting chunks of DNA—Beam Therapeutics has shown that just one nucleotide change can change an entire life.
At the 66th Annual Meeting and Exposition for the American Society of Hematology (ASH) in San Diego, California, Beam Therapeutics provided its first data on BEACON, the company’s clinical trial on sickle cell disease that uses base editing ex vivo on autologous hematopoietic stem cells (HSCs).
Results from the first seven patients show that BEAM-101 can significantly change the hemoglobin profile and provide rapid engraftment with a low number of neutropenic days—even one patient who died two months into the trial, which was deemed to be from respiratory failure caused by the conditioning agent, not the therapeutic.
“I think that the [BEACON] data… and a relatively increased and high probability of technical success… but also the progress that’s been made in the field and a very clear regulatory pathway in the U.S. with the FDA that has now been validated in the industry gives BEAM-101 a very clear path forward,” said Beam CEO John Evans in an investor meeting in San Diego attended by Inside Precision Medicine, referencing the FDA approval of Vertex’s Exa-cel (Casgevy) and Bluebird Bio’s Lovo-cel (Lyfgenia) in December 2023.
In addition, Beam showed new preclinical data for its Engineered Stem Cell Antibody Evasion (ESCAPE) conditioning platform, demonstrating that their approach enabled engraftment of base-edited hematopoietic stem cells (HSCs) and induced robust, durable production of fetal hemoglobin (HbF) in a non-human primate (NHP) model.
Honoring the patient
In addition to delivering a comprehensive presentation on the BEACON trial’s safety and efficacy, Matthew M. Heeney, MD, associate chief of Hematology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who led the Beam-sponsored trial, provided a detailed account of the patient who died during the trial.
Patient #3, a 21-year-old female homozygous for the sickling mutation (βs/βs), appeared to benefit from treatment with BEAM-101. She exhibited several signs of a successful treatment, including a rapid increase in fetal hemoglobin (HbF) and neutrophil and platelet engraftment.
However, nearly two months after receiving the BEAM-101 infusion, she was admitted to the hospital with fever, vomiting, and diarrhea, followed by respiratory distress and multiple pulmonary infiltrates. After infection and hemorrhage were ruled out, she was sent home on Day 82 with steroids and a non-invasive ventilator (nocturnal BiPAP). Only four days later, she was readmitted with progressive respiratory distress, acute lung injury, and pneumomediastinum consistent with idiopathic pneumonia syndrome (IPS), necessitating mechanical ventilation. She died shortly after, about four months after receiving the BEAM-101 infusion, of refractory respiratory failure.
In response to a question from Inside Precision Medicine on the thoroughness of the investigation into the patient’s death, CMO Amy Simon, MD, a physician-scientist with decades of experience in respiratory care, reviewed several findings that supported, in her opinion, the claim that the patient died of respiratory failure caused by busulfan treatment and not due to the base editing. Her assessment was in line with that of the clinical trial data monitoring (DMC) for the BEACON trial, which stated, “The occurrence of severe pulmonary toxicity is in keeping with known risks with busulfan.”
Simon explained that all indicators pointed to the effectiveness of BEAM-101. Even in the patient’s extreme duress, there was no evidence of several cellular phenotypes associated with sickle cell disease, including red blood cell “sickling” and adhesion. “There was no evidence of sickling whatsoever in that patient, despite being critically ill; that’s really important,” Simon told Inside Precision Medicine. “There’s a huge stress to the patient who was hypoxemic… and despite that, there was no evidence of sickling, which in itself is quite amazing.”
ESCAPE from chemotherapy
President Giuseppe Ciaramella, PhD, gave a short presentation with updates on ESCAPE, Beam’s efforts towards a non-genotoxic approach to stem cell transplants.
“Conditioning is an important step—it’s a critical step in transplants in general—to generate that niche within which the edit itself can actually engraft and ultimately provide the benefit for the long term,” said Giuseppe Ciaramella, PhD, president of Beam Therapeutics. “Typically, the conditioning agent that is most used is busulfan, and this agent was launched in the mid-1950s. If you think about it, there hasn’t been much difference since the ’50s in transplants that could benefit patients.”
Though busulfan continues to be used in patients treated by Casgevy and shows positive safety and efficacy in hundreds of patients, this conditioning agent is chemotherapeutic by nature. Beam has sought to move HSC transplants into an era that does not use a chemotherapeutic for conditioning, which it is doing with ESCAPE.
This non-chemotherapeutic approach combines conditioning with an antibody, known as BEAM-103, that blocks the interaction between a stem cell growth factor and its HSC receptor, CD117, from the HSCs with BEAM-104, which combines BEAM-101 with another base edit that protects this antibody that is simultaneously given to HSCs ex vivo. ESCAPE is a multistep approach where patients are first treated with BEAM-103 to remove resident HSCs and then treated with both BEAM-103 and BEAM-104 to enrich for edited HSCs to engraft in the bone marrow.
“In terms of the next steps, we have essentially studied the phase one enabling studies for the antibody only, which we plan to take into a health quality study to determine essentially not only the safety but also the PK/PD (pharmacokinetics-pharmacodynamics) understanding of those regimens that we would like to then use in human studies, in parallel with conducting additional NHP studies better to refine the pre- and transplant regimen for the antibody,” said Ciaramella. “When we combine those two, we will go directly to patients that will use both the antibody and the dual-edited cells for the next set of studies.”
One is good, two is better
Evans said that BEAM-101 and ESCAPE are fully resourced, so there’s no resource competition between them, and emphasized that the two trials are, in some ways, synergistic.
“You can’t overstate the efficiency between the two [programs],” said Evans. “Almost anything that ESCAPE needs, we’re putting it in place with BEAM-101, so you get twice as much leverage from that investment. It’s not only going to move BEAM-101 forward, which has the potential to be a near-term market entry.”
Evans continued, “BEAM-101 will be followed by ESCAPE, which has the potential to eliminate chemotherapy from transplants altogether and dramatically expand or reach a base editing. From there, should ESCAPE work, we have the platform to do many different things in hematology, which is quite exciting.”
To prepare for these clinical trials, Beam had the foresight to develop a manufacturing facility to support BEAM-101 and ESCAPE through clinical trials and beyond, which, Evans told Inside Precision Medicine, was brought to the table early on by Ciaramella during preclinical stages.
“Our North Carolina facility is designed to do not only the clinical supply but also the commercial supply,” Ciaramella said. “We already have both the process and the capacity to support the launch for some time. We also added an additional suite to take what we expect to be the demands even beyond that.”
Beyond Sickle Cell
Evans reminded the audience that Beam’s vision is to provide life-long cures for patients with serious diseases. “This is a real mission that we think is achievable given the technologies we now have,” said Evans. “These would be potentially one-time curative and transformative therapies. Of course, we’re beginning with rare and genetic diseases today, but we do see the potential to enforce more common disorders over the long term.”
