Beam Therapeutics Eyes Sickle Cell BLA as Alpha-1 Gene-Editing Program Advances

Key Points

• Beam Therapeutics said its sickle cell disease candidate, risto-cel, could be ready for a BLA filing as early as the end of this year, highlighting continued progress in the company’s hematology pipeline.
• The company’s alpha-1 antitrypsin deficiency program, BEAM-302, is advancing toward dose selection, with executives saying 60 mg appears to be the preferred dose after showing strong biomarker improvements and no meaningful added benefit from higher or repeat dosing.
• Beam said it has FDA alignment on an accelerated approval path for BEAM-302 and plans to enroll 50 patients with one year of follow-up, while also monitoring liver biopsies to assess whether the therapy improves both lung and liver disease.

Beam Therapeutics NASDAQ: BEAM Chief Executive Officer John Evans said the company is advancing its base-editing platform across hematology and liver disease programs, with a potential biologics license application for its sickle cell disease candidate possible as early as the end of this year.

Speaking at RBC Capital Markets’ Global Healthcare Conference in a discussion with Senior Biotechnology Research Analyst Luca Issi, Evans described Beam as a “next-generation gene-editing company” focused on base editing, a form of CRISPR designed to make permanent single-letter changes in genes without creating a double-strand break.

Evans said that distinction could allow Beam to make “more therapeutic edits” and “more precise edits,” including correcting mutations back to normal rather than only knocking genes out.

Alpha-1 Program Shows Dose Selection Progress

A major focus of the discussion was BEAM-302, Beam’s program for alpha-1 antitrypsin deficiency. Evans said the program is designed to correct the single-letter misspelling in the alpha-1 gene back to normal, which he said is the first time anyone has been able to do so.

Evans said earlier data showed that a 60-milligram dose achieved alpha-1 levels above 11 micromolar, a threshold he described as important because carriers who do not have the disease generally live above that line, while patients with progressive lung and liver damage are usually below it.

According to Evans, additional dose exploration around 60 milligrams, including a 75-milligram dose and a two-dose 60-milligram regimen, did not produce meaningful additional pharmacodynamic benefit. He said the results confirmed that 60 milligrams is the dose Beam wants to use.

Evans said the larger data set showed the 60-milligram dose produced an average alpha-1 level of 16 micromolar, with normal M protein levels above 90% and Z protein reduced by 84%.

“We had clearly and dramatically changed the disease physiology to at least a carrier physiology,” Evans said, adding that this supports Beam’s view that treated patients should not experience progressive disease going forward.

Safety and Redosing Discussed

Issi asked about tolerability of a second 60-milligram dose, which Evans said was not as well tolerated as the first. Evans said it was difficult to know why, noting that preclinical data suggested eight weeks should have been enough time for the first lipid nanoparticle dose to clear. However, he said alpha-1 livers may differ in physiology and macrophage biology, potentially retaining some sensitivity.

Evans characterized the observed events as manageable. He said Beam saw higher infusion-related reactions, such as grade two events treated with Motrin, and one patient with a grade three AST/ALT elevation that was asymptomatic, did not require hospitalization, did not involve bilirubin changes and resolved quickly.

Evans said he did not believe the findings indicate that lipid nanoparticle redosing is not possible. He noted that Beam still plans to redose patients who previously received subtherapeutic 15-milligram and 30-milligram doses with the selected 60-milligram dose.

On liver enzyme elevations, Evans said the pattern Beam observed was consistent with a “classic LNP signal,” in which liver enzymes rise quickly and then fall quickly. He said the key safety considerations are rapid improvement within days and no bilirubin change, which he said Beam observed.

Bystander Editing and Protein Function

Evans also addressed investor questions about bystander editing. He said BEAM-302 can create a mixture of corrected M protein and an M variant, a result Beam has known about and characterized over time.

Evans said Beam has shown that the variant is secreted normally, is functional and has a structure comparable to normal M protein. He also said the variant position is commonly varied in the human population and that the specific variant Beam creates is found in people and is not associated with disease.

He pointed to functional data showing direct inhibition of human neutrophil elastase using serum from treated patients, which he said demonstrated that the protein mixture created by the therapy is functional.

Regulatory Path and Liver Endpoints

Evans said Beam has alignment with the FDA on an accelerated approval path for BEAM-302, describing it as a “classic accelerated approval” strategy rather than one reliant on newer regulatory mechanisms. He said the company is working with stable FDA review teams and that the agency’s main request was for 12 months of follow-up because alpha-1 levels can vary over time.

Evans said Beam plans to enroll 50 patients and follow them for one year before submitting the data. He said the biomarker package includes total alpha-1 levels, M protein levels, percentage of M protein, reduction in Z protein, protein functionality and inducibility.

On liver benefit, Evans said Beam believes BEAM-302 could help both lung and liver manifestations of alpha-1 antitrypsin deficiency by raising functional alpha-1 and lowering Z protein. He said Beam is conducting biopsies in Part B patients before treatment and at six and 12 months to assess whether aggregates resolve and whether fibrosis changes over time.

Evans said the Part B patients, who have more advanced liver disease, have so far tolerated the drug similarly to Part A patients, supporting an all-comer Cohort C.

Sickle Cell Program and Pricing Outlook

Evans said Beam’s ex vivo sickle cell disease program, risto-cel, could have a BLA filing as early as the end of this year. He said Beam believes it has a strong manufacturing process, with a vein-to-vein time of just over four months, which he said could allow patients to be treated quickly and predictably.

Evans said risto-cel is aimed at severe sickle cell patients who may be candidates for a transplant-based option, while Beam also continues to work on in vivo approaches that could reach a broader sickle cell population over time.

On pricing, Evans said Beam would price a one-time alpha-1 therapy higher than one year of augmentation therapy, but said payers are sophisticated and evaluate long-term pharmacoeconomic value. He cited sickle cell disease as an example where high lifetime costs have supported genetic medicine pricing, while noting that it is too early to discuss specific pricing for alpha-1.

Evans said Beam believes alpha-1 antitrypsin deficiency has a strong value story because a one-time therapy could potentially address both lung and liver disease.

About Beam Therapeutics NASDAQ: BEAM

Beam Therapeutics, Inc NASDAQ: BEAM is a biotechnology company dedicated to developing precision genetic medicines through its pioneering base editing platform. Headquartered in Cambridge, Massachusetts, with additional research facilities in Philadelphia, the company focuses on engineering molecular editors capable of making precise single-nucleotide changes in DNA. By harnessing its proprietary base editing technology, Beam aims to correct or disrupt disease-causing genetic variants at their source, offering the potential for novel therapies in areas with significant unmet medical need.

Founded in 2017 as a spin-out from Harvard University and the Broad and Whitehead Institutes, Beam was co-founded by leading academic researcher David R.

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