Gene editing therapy bombshell: A trial participant has died

On November 5, 2024, Eastern Time, Beam Therapeutics (Beam) announced preliminary results from several clinical studies that it will present at the 66th American Society of Hematology (ASH) Annual Meeting. Among them, the I/II phase single-arm BEACON study of its key project BEAM-101 showed that a trial participant died of respiratory failure four months after receiving BEAM-101 infusion.

Beam Therapeutics was established in 2017 by pioneers in the field of gene editing, including MIT professor Feng Zhang, Harvard professor David Liu, and J. Keith Joung. In February 2020, Beam raised $180 million in an initial public offering and successfully listed on NASDAQ, becoming the first base editing technology company to go public. Currently, it has 7 projects in various stages in its pipeline. The disclosure of the trial participant's death in BEAM-101, the company's core project, is also the first time this clinical data has been publicly disclosed.

However, unexpectedly, despite the death of a trial participant in the study, investors did not lose confidence in Beam. Among all 18 rating institutions, 50% of the securities firms still gave buy recommendations (this article does not provide any investment advice).

The participant died, but it was not the fault of the product

BEAM-101 is an autologous CD34+ base editing therapy developed for the treatment of sickle cell disease (SCD) and is the first single-base gene-edited drug approved by the FDA for IND.

The preliminary data disclosed this time is from the I/II phase single-arm BEACON study, which aims to evaluate the safety and efficacy of BEAM-101 in SCD patients with severe vaso-occlusive crises (VOCs). Currently, 6 trial participants have been treated. To allow the edited cells to successfully engraft in the bone marrow and start producing healthy blood cells, patients need to be preconditioned with Busulfan before cell infusion (Busulfan is mainly used to reduce the number of cells in the patient's own bone marrow to "make room" for the new cells that are about to be produced).

The effective data disclosed this time is based on the follow-up data of 4 trial participants for 1 to 6 months. The analysis results show that the 4 trial participants reached neutrophil and platelet engraftment (early important markers, indicating the preliminary recovery of the patient's hematopoietic function) at a median of 17 days (15-19 days) and 20 days (11-34 days), respectively. Moreover, within one month after treatment, the levels of fetal hemoglobin (HbF) in the bodies of the 4 trial participants significantly increased (>60%) compared to the baseline, while the levels of sickle hemoglobin (HbS) in the non-transfused blood of the patients significantly decreased (≤36%). In addition, hemolysis markers have been normalized or improved in all 4 patients. Overall, the preliminary clinical data of BEAM-101 are excellent, successfully achieving its predetermined trial objectives. Beam's previous trial objective was to increase HbF levels to at least 60% while reducing HbS to 40% or lower.

The safety data disclosed this time comes from 6 trial participants. The results show that none of the participants experienced grade ≥3 adverse events (AEs) or serious adverse events related to BEAM-101 treatment, and no patients experienced VOCs. There was one case of trial participant death, but the researchers judged that it might be related to Busulfan preconditioning, not due to BEAM-101 treatment. The official press release explained that the participant died of respiratory failure four months after receiving BEAM-101 infusion, but in fact, pulmonary complications are a known risk in patients who undergo bone marrow ablation and stem cell transplantation with chemotherapy drugs (such as Busulfan), and this risk can indeed lead to death in very rare cases.

Therefore, accepting BEAM's statement that the death of one trial participant is not a serious adverse event related to the treatment, the efficacy and safety of BEAM-101 do show certain therapeutic potential.

Strong competitors

At the end of 2023, Casgevy (Vertex/CRISPR) and Lyfgenia (bluebird) were approved by the FDA for marketing, both for the treatment of SCD. Among them, Casgevy is the first therapy approved by the FDA using CRISPR/Cas9 gene-editing technology.

BEAM-101 uses single-base gene-editing technology, which is an improved CRISPR/Cas9 gene-editing technology. Traditional CRISPR gene-editing technology uses the Cas9 enzyme to cut the DNA double strand at the mutation site, forming a DNA double-strand break, triggering the cell repair mechanism, and ultimately leading to gene function loss/change. Beam believes that this repair will disrupt the gene sequence at the cutting site, leading to different levels of cell effectiveness. In contrast, single-base editing technology does not cut DNA but uses enzymes to edit and transform the bases in DNA (for example, from A to G), and the entire process does not involve DNA double-strand breaks, thus avoiding the variations that may be introduced during the repair process, reducing the risk of potential harmful chromosomal rearrangements, and achieving higher precision and consistency.

Although the disclosed study has a small sample size and a short follow-up time, the preliminary data show that BEAM-101 is indeed one of the potential new treatment options for SCD. From the effectiveness data, the HbF levels of the 4 trial participants who received follow-up increased by 60% or more compared to the baseline, showing potential to compete with Casgevy. It is reported that Casgevy achieved and maintained HbF levels of 42% to 44% in a 24-month study.

In summary, many analysts are positive about Beam's future. Analysts at BMO Capital Markets believe that the preliminary clinical data of BEAM-101 show a clear advantage over other gene-editing therapies, and they believe that the death of the trial participant caused by chemotherapy should not affect everyone's trust in the potential of this technology.

【Editor’s note】The above content (~5300 words) is a quick translation of a Chinese article (posted on 2024-11-06) by DrugTimes team. To read the original article, please click here . All comments are warmly welcome. Many thanks!