BEAM-302 Receives FDA IND Clearance for AATD, a Genetic Disorder Affecting the Liver and Lungs

The FDA cleared an investigational new drug application (IND) for BEAM-302 for the treatment of alpha-1 antitrypsin deficiency (AATD). Currently, the agent is being evaluated in an ongoing open-label, dose exploration, dose expansion phase 1/2 clinical trial to test its safety, tolerability, pharmacodynamics, pharmacokinetics, and efficacy.¹

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AATD is an inherited genetic disorder that affects the lungs and/or liver, leading to early-onset emphysema—a chronic lung disease that damages air sacs in the lungs and causes difficulty breathing—and liver disease—a broad term that encompasses liver-based conditions such as hepatitis, metabolic dysfunction-associated steatohepatitis, cirrhosis, and inflammatory conditions. The most severe form of AATD occurs when a patient has a point mutation in both copies of the SERPINA1 gene at the amino acid 342 position (E342K), which causes AAT to misfold, accumulating inside liver cells rather than being secreted. This results in very low levels—measuring about 10% to 15%—of circulating AAT.^1,2

In addition to resulting in lower levels, the PiZ AAT protein variant is also less enzymatically effective compared with wildtype AAT protein, and because of this, the lung is left unprotected from neutrophil elastase, resulting in progressive, destructive changes in the lung that can result in the need for lung transplants. The mutant protein also accumulates in the liver, causing liver inflammation and cirrhosis, ultimately causing liver failure or cancer. For these reasons, patients will have to undergo a liver transplant. There are currently no approved curative treatments for patients with AATD.^1,2

BEAM-302 is a liver-targeting lipid-nanoparticle (LNP) formulation of base editing reagents designed to convert the mutant PiZ to the corrected PiM isoform. Patients who are homozygous for this mutation (PiZZ) represent the majority of patients living with severe AATD disease. The correction of the PiZ mutation is expected to be durable based on preclinical and clinical evidence.¹

Part A of the clinical trial is designed to evaluate patients with AATD who have lung disease, whereas part B will evaluate patients with AATD who have mild to moderate liver disease, with or without lung disease. The dose expansion portions of the trial will identify the optimal dose to move forward in development. As of March 10, single-ascending fixed doses of 15 mg (n = 3), 30 mg (n = 3), and 60 mg (n = 3) of BEAM-302 were administered via intravenous infusion in patients in part A.³

The initial safety and efficacy data from the phase 1/2 trial of BEAM-302 established clinical proof of concept as a potential treatment for AATD and for in vivo base editing. The preliminary findings showed that BEAM-302 was well-tolerated, and single doses lead to durable, dose-dependent correction of the mutation that causes AATD.³

Following a single infusion of BEAM-302, rapid, durable, and dose-dependent increases in total AAT, new production of corrected M-AAT, and decreases in mutant Z-AAT were observed in circulation. Additionally, changes in total AAT were observed by turbidimetry assays as early as day 7. This plateaued around day 21 and was maintained for the duration of follow-up (up to month 6 in the 15-mg cohort, month 2 in the 30-mg cohort, and day 28 in the 60-mg cohort). Increased total AAT was functional as determined by both neutrophil elastase inhibition and neutrophil elastase binding assays.³

All adverse events (AEs) were considered mild to moderate, with no serious AEs and dose-limiting toxicities reported at the time of data cut-off. Grade 1 asymptomatic alanine transaminase and aspartate aminotransferase elevations and transient grade 1 infusion-related reactions were observed in some patients.³

“The FDA’s clearance of our IND for BEAM-302 is a significant step toward advancing the development of this potential breakthrough treatment for patients living with AATD in the US,” Giuseppe Ciaramella, PhD, president of Beam Therapeutics, said in a news release. “Earlier this month, we shared groundbreaking initial safety and efficacy data from our global phase 1/2 study of BEAM-302, showcasing the first ever clinical genetic correction of a disease-causing mutation. As we move forward, we’re laser-focused on progressing this trial to enroll and dose more patients, activating more sites in new geographies, and preparing to present updated data in the second half of the year.”¹

REFERENCES

1. Beam Therapeutics. Beam Therapeutics Announces Clearance of Investigational New Drug Application for BEAM-302 for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD) by the United States (U.S.) Food and Drug Administration. News release. March 27, 2025. Accessed March 28, 2025. https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-announces-clearance-investigational-new-drug

2. Beam Therapeutics. Broad and diversified portfolio. Accessed March 28, 2025. https://beamtx.com/pipeline/

3. Beam Therapeutics. Beam Therapeutics Announces Positive Initial Data for BEAM-302 in the Phase 1/2 Trial in Alpha-1 Antitrypsin Deficiency (AATD), Demonstrating First Ever Clinical Genetic Correction of a Disease-causing Mutation. News release. March 10, 2025. Accessed March 28, 2025. https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-announces-positive-initial-data-beam-302-phase