Beam Reports Positive Initial Data for Its in Vivo AATD Gene Editor

Rare Daily Staff

Beam Therapeutics reported positive initial safety and efficacy data from its phase 1/2 trial of its experimental in vivo base editor BEAM-302, establishing clinical proof-of-concept as a potential treatment for the rare liver and lung disease alpha-1 antitrypsin deficiency.

Preliminary results from the first three single-ascending dose cohorts demonstrated that BEAM-302 was well tolerated. Single doses of BEAM-302 led to durable dose-dependent correction of the disease-causing mutation.

Alpha-1 antitrypsin deficiency (AATD) is an inherited genetic disorder that affects the lungs and/or liver, leading to early onset emphysema and liver disease, and for which there are no currently approved curative treatments. 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. This point mutation causes alpha-1 antitrypsin, or AAT, to misfold, accumulating inside liver cells rather than being secreted, resulting in low levels of circulating AAT.

In addition to resulting in lower levels, the PiZ AAT protein variant is less enzymatically effective than wild-type 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 or cancer requiring patients to undergo a liver transplant.

BEAM-302 is a liver-targeting lipid-nanoparticle formulation of a guide RNA and an mRNA encoding a base editor designed to correct the disease-causing PiZ mutation. A one-time A-to-G correction of the PiZ mutation with Beam’s adenine base editor has the potential to reduce the aggregation of mutant simultaneously, misfolded AAT protein that causes toxicity to the liver (Z-AAT), generate therapeutic levels of corrected protein (M-AAT), and increase total and functional AAT in circulation, thereby addressing the underlying pathophysiology of both the liver and lung disease.

In addition, the reduction in circulating PiZ aggregates has the potential to minimize lung inflammation and dysfunction. Because the native AAT gene would be corrected in its normal genetic location, AAT levels are anticipated to increase physiologically in response to inflammation or infection. This is a critical aspect of AAT’s normal function to regulate the body’s inflammatory response, which does not occur with currently approved protein replacement therapies. Based on preclinical and clinical evidence, correction of the PiZ mutation is expected to be durable.

BEAM-302 is being evaluated in a phase 1/2, open-label, dose exploration and dose expansion clinical trial to investigate its safety, tolerability, pharmacodynamics, pharmacokinetics and efficacy. Part A of the trial is designed to evaluate AATD patients with lung disease, and Part B will evaluate AATD patients with mild to moderate liver disease with or without lung disease. The dose expansion portions of the trial will identify the optimal dose to take forward in development.

Treatment with BEAM-302 was well tolerated with an acceptable safety profile at all dose levels explored to date. All adverse events (AEs) were mild to moderate, with no serious AEs reported and no dose-limiting toxicities as of the data cutoff. 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.

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.

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, and expects to report further data at a medical conference in the second half of 2025. In addition, the company plans to dose the first patient in Part B, which will include AATD patients with mild to moderate liver disease, in the second half of 2025.

“The initial data for BEAM-302 demonstrate that the direct correction of the PiZ mutation both increased levels of functional AAT in the blood and reduced the harmful mutant protein which directly contributes to the liver and lung disease in this condition,” said Noel McElvaney, professor of medicine at the Royal College of Surgeons in Dublin, Ireland. “These data represent a major breakthrough in the area of AATD, offering, for the first time ever, an opportunity to simultaneously treat the lung and liver disease associated with the condition by targeting the root cause and the potential for a cure from a single therapeutic administration, something which we have never seen before in a genetic lung disease.”