Beam Therapeutics Reports Clinical Proof-Of-Concept Data for BEAM-302 in Alpha-1 Antitrypsin Deficiency Trial

Eight months after dosing the first patient with BEAM-302, Beam Therapeutics has shared exciting safety and efficacy data indicating that a base-editing approach could transform treatment for patients with alpha-1 antitrypsin deficiency.

By: Karen O'Hanlon Cohrt - Mar. 12, 2025

Lay summary - promising clinical trial results for base-editing treatment for alpha-1 antitrypsin deficiency

Beam Therapeutics has announced encouraging results from its clinical trial of an experimental therapy known as BEAM-302. BEAM-302 is being developed for the genetic disease alpha-1 antitrypsin deficiency, which is caused by mutations in a protein known as AAT. The clinical trial results so far show that BEAM-302 can correct the most common AAT mutation using a gene-correction technology known as base editing. In patients with alpha-1 antitrypsin deficiency, a single treatment of BEAM-302 increased the levels of healthy protein and reduced harmful mutated protein by up to 78%, with only mild side effects reported.

Unlike the approved protein replacement therapies that are lifelong and don't address the liver complications associated with alpha-1 antitrypsin deficiency, BEAM-302 corrects the mutation directly, allowing natural protein production. Beam Therapeutics plans to continue and expand the trial to include patients with liver disease later in 2025, while several other companies advance similar genetic approaches for this condition.

Beam Therapeutics has announced positive initial data from its Phase 1/2 clinical trial of BEAM-302 in patients with alpha-1 antitrypsin deficiency (AATD). The results, which were shared in a press release published on Monday, demonstrate the first-ever clinical genetic correction of a disease-causing mutation through base-editing technology.

Single dose of BEAM-302 led to durable, dose-dependent correction of disease-causing mutation

Since the first patient was dosed in July 2024, preliminary results from the first three single-ascending dose cohorts now show that treatment with BEAM-302 led to durable, dose-dependent correction of the disease-causing PiZ mutation. The data also show that a single dose of BEAM-302 led to measurable increases in total and functional alpha-1 antitrypsin (AAT) protein and decreases in mutant Z-AAT in circulation across all three dose levels (15 mg, 30 mg, and 60 mg). Of note, the third dose level (60 mg) achieved a mean total AAT of 12.4μM at Day 28, which exceeds the protective therapeutic threshold of 11μM necessary for clinical benefit. This cohort also demonstrated a reduction in mutant Z-AAT of up to 78%.

Safety-wise, BEAM-302 is reported to be well tolerated at all dose levels explored to date. All reported adverse events were mild to moderate, with no serious adverse events or dose-limiting toxicities reported as of the February 26, 2025 data cutoff. According to the press release, the most common side effects were Grade 1 asymptomatic elevations in liver enzymes (ALT and AST) and transient Grade 1 infusion-related reactions, none of which required treatment.

BEAM-302 addresses the underlying cause of AATD

As described in a previous article, BEAM-302 is an in vivo 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. BEAM-302 is designed to make a single A-to-G correction of the PiZ mutation in the SERPINA1 gene.

By correcting PiZ at the DNA level, BEAM-302 has demonstrated its potential to provide multiple therapeutic benefits from a single administration; it reduces the amount of misfolded Z-AAT in circulation, generates therapeutic levels of corrected protein (M-AAT), and increases total and functional AAT above the protective threshold.

An important distinction from current augmentation therapies is that the correction occurs in the native genetic location, which should allow AAT levels to increase physiologically in response to inflammation or infection. This is a critical aspect of AAT's normal function that is not possible with protein replacement approaches.

AATD is a genetic condition that increases the risk of developing severe lung and liver disease, including emphysema (lung), cancer, and organ failure. The disease arises through mutations in the SERPINA1 gene, which either reduce the quantity of AAT produced by the liver, completely inhibit its production, or alter its structure, preventing release from the liver. In healthy individuals, AAT functions as an anti-protease by inhibiting the activity of neutrophil elastase. Neutrophil elastase is secreted by white blood cells as a normal part of the immune response during infection, but if not tightly controlled by AAT it can attack healthy tissues. Deficient or dysfunctional AAT leads to lung damage and the accumulation of abnormal protein in the liver, causing hepatic damage over time. Most individuals living with severe AATD are homozygous for the PiZ mutation, which is known as p.Glu366Lys (and also referred to as E342K).

AATD affects approximately 1 in 1,500 to 3,500 individuals with European ancestry, while 100,000 individuals are estimated to be homozygous for PiZ in the United States alone. The disease is incurable and current treatment approaches predominantly aim to control symptoms and reduce risk factors. Augmentation or protein replacement therapy, a lifelong treatment involving the administration of AAT protein derived from donor blood, can increase AAT levels in the lungs and slow lung damage, though it does not prevent liver damage. Lung and liver transplants may be an option for patients with severe disease, although donor organs are not easy to obtain and the surgeries are not without complications.

Dose escalation continues, with further clinical data expected later this year

Based on these encouraging results, Beam plans to continue the dose-escalation portion of Part A of the ongoing Phase 1/2 trial, including enrolling and dosing a fourth dose cohort. The company expects to report updated data at a medical conference in the second half of 2025.

Additionally, Beam plans to initiate Part B of the trial, which will include AATD patients with mild to moderate liver disease with or without lung disease, in the second half of 2025. This expansion will help to determine whether BEAM-302 can effectively address both the liver and lung manifestations of AATD.

Other advanced gene-editing programmes for AATD

While BEAM-302 is the only base-editing candidate in the clinic for AATD, Wave Life Sciences is advancing an RNA-editing oligonucleotide WVE-006 through clinical trials in AATD (Phase 1 and Phase 1/2 trials ongoing) and Korro Bio received regulatory clearance in Australia late in 2024 to initiate a Phase 1/2 trial of its ADAR candidate KRRO-110 in patients with AATD.

Boston- and Germany-based biotech startup AIRNA is also preparing to bring an ADAR candidate for AATD into the clinic in 2025. You can read more about AIRNA's approach to genetic medicine in our recent interview with Co-founder Thorsten Stafforst and CEO Kris Elverum.

Stay tuned for more updates

We will continue to update you on the BEAM-302 trial and other gene-editing trials as new details emerge. In the meantime, you can find all of our coverage on clinical-stage gene editing programmes here.

For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.

ArticleNewsClinical News UpdatesAlpha-1 Antitrypsin Deficiency, AATDBase editorsBeam Therapeutics Inc.