Beam Therapeutics' BEAM-302 Shows Promising Results for Alpha-1 Antitrypsin Deficiency

Beam Therapeutics, a biotechnology company specializing in precision genetic medicines through base editing, recently presented additional data from its Phase 1/2 clinical trial of BEAM-302 at the 2025 Alpha-1 Foundation 7th Global Research Conference and 10th Patient Congress in Lisbon, Portugal. The data, which were presented on April 5, 2025, offer a glimpse into the potential of BEAM-302 as a groundbreaking treatment for alpha-1 antitrypsin deficiency (AATD), a genetic disorder that affects the lungs and liver, leading to early onset emphysema and liver disease.

AATD is caused by mutations in the SERPINA1 gene, which either reduce the quantity of alpha-1 antitrypsin (AAT) produced by the liver, completely inhibit its production, or alter its structure, preventing release from the liver. The most severe form of AATD arises when a patient has a point mutation in both copies of the SERPINA1 gene at amino acid 342 position (E342K, also known as the PiZ mutation or the “Z” allele). This point mutation causes alpha-1 antitrypsin to misfold, accumulating inside liver cells rather than being secreted, resulting in very low levels (10%-15%) of circulating AAT. In addition to resulting in lower levels, the PiZ AAT protein variant is also less enzymatically effective compared to wildtype AAT protein. As a consequence, the lung is left unprotected from neutrophil elastase, resulting in progressive, destructive changes in the lung, such as emphysema, which can result in the need for lung transplants. The mutant AAT protein also accumulates in the liver, causing liver inflammation and cirrhosis, which can ultimately cause liver failure, requiring patients to undergo liver transplants.

BEAM-302 is a liver-targeting lipid-nanoparticle (LNP) formulation of base editing reagents designed to correct the PiZ mutation found in the majority of severe homozygous AATD patients. By correcting the PiZ mutation at the DNA level, BEAM-302 has the potential to be a one-time therapy that simultaneously reduces the amount of Z-AAT in circulation, generates therapeutic levels of corrected protein (M-AAT), and increases total and functional AAT in circulation above the 11µM protective threshold, thereby addressing the underlying pathophysiology of both the liver and lung disease.

The data presented at the conference showed that a single dose of BEAM-302 led to durable, dose-dependent increases in total and functional AAT, production of corrected M-AAT, and decreases in mutant Z-AAT in circulation across the initial three dose levels. The third dose level of 60 mg achieved a mean total AAT of 12.4µM at Day 28, exceeding the protective therapeutic threshold, and reduced mutant Z-AAT up to 78%. Additionally, the 60 mg cohort showed that corrected M-AAT reached 91% of total AAT in circulation at Day 28, and a 79% mean decrease in mutant Z-AAT was observed at Day 28.



The safety profile of BEAM-302 was also encouraging. All adverse events were mild to moderate, with no serious adverse events or dose-limiting toxicities reported. Grade 1 asymptomatic alanine transaminase (ALT) and aspartate aminotransferase (AST) elevations and transient Grade 1 infusion-related reactions were observed in some patients and did not require treatment.

The data presented at the conference support continued dose escalation, with updated data from Part A of the Phase 1/2 trial expected to be presented at a medical conference in the second half of 2025. Beam Therapeutics has also initiated a fourth cohort evaluating 75 mg of BEAM-302 and plans to report additional data in the second half of 2025. The company has received FDA clearance for BEAM-302's IND, allowing U.S. site activation, and plans to begin Part B of the trial, including AATD patients with mild to moderate liver disease, in the second half of 2025.

The potential long-term benefits for patients are significant. By correcting the PiZ mutation at the DNA level, BEAM-302 has the potential to provide a durable cure for AATD. This could dramatically improve both clinical outcomes and healthcare economics for the approximately 100,000 individuals in the U.S. with the PiZZ genotype. The correction of the PiZ mutation is expected to be durable based on preclinical and clinical evidence, allowing AAT levels to increase physiologically in response to inflammation or infection, which is a critical aspect of AAT's normal function that is not possible with currently approved protein replacement therapies.

In conclusion, the data presented at the 2025 Alpha-1 Foundation 7th Global Research Conference and 10th Patient Congress offer a promising glimpse into the potential of BEAM-302 as a groundbreaking treatment for AATD. The durable, dose-dependent correction of the PiZ mutation, along with the favorable safety profile, support continued dose escalation and the potential for a one-time therapy that addresses the underlying pathophysiology of both the liver and lung disease. The long-term benefits for patients could be significant, offering a durable cure for AATD and dramatically improving both clinical outcomes and healthcare economics.