Beam Therapeutics has set its sights on an accelerated approval of its base editing therapy for the severe form of alpha-1 antitrypsin deficiency (AATD) following a positive Phase I/II trial readout.
In the open-label, dose exploration and dose expansion study (NCT06389877), 29 patients have been treated with BEAM-302, an in vivo liver-targeting lipid-nanoparticle (LNP) formulation designed to correct the underlying SERPINA1 gene mutation (PiZ) in the liver.
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After treatment with a single dose of BEAM-302 in Part A, the steady-state circulating total AAT mean was 16.1 µM in the 60mg cohort and 14.4 µM in the 75mg cohort.
In the multi-dose cohort, patients achieved a mean of 16.5 µM total AAT at day 84, 28 days after the second 60 mg dose. Across all cohorts, increased total AAT in circulation was functional as demonstrated by a neutrophil elastase inhibition assay.
Mutant Z-AAT was also reduced after treatment with BEAM-302, with a mean reduction of 84% in the 60mg cohort and 79% in the 75mg cohort. In the multi-dose cohort, the mean reduction in Z-AAT was 80%.
In regards to M-AAT production, the steady-state mean proportion was 94% in the 60mg cohort and 91% in the 75mg cohort. In the multi-dose cohort, the mean proportion of M-AAT was 93%.
Adverse events (AEs) were mild to moderate, with no serious AEs reported and no dose-limiting toxicities as of the data cutoff. All ALT/AST elevations were asymptomatic and did not require treatment.
Dr Jeffrey Teckman, professor of paediatrics, Saint Louis University School of Medicine, said: “What makes BEAM-302 particularly compelling is its ability to directly correct the underlying genetic mutation in the SERPINA1 gene that drives both lung and liver manifestations of the disease. By enabling the liver to produce corrected M-AAT for the first time while reducing the toxic mutant protein, this approach has the potential to fundamentally transform how we as clinicians treat AATD and represents a meaningful advance for patients.”
Based on this data, the company has selected 60mg as the optimal biological dose to advance into pivotal development.
Following feedback from the US Food and Drug Administration (FDA), Beam will pursue an accelerated approval pathway for BEAM-302 based on a primary endpoint of AAT biomarkers evaluated over 12 months.
To support a future biologics licensing application (BLA) submission, the company anticipates enrolling approximately 50 additional patients with AATD-associated lung disease, with or without liver disease, in an expansion of the ongoing open-label Phase I/II trial.
According to GlobalData’s Alpha-1 Antitrypsin Deficiency (AATD): Opportunity Analysis and Forecast to 2031 report, the AATD market in the two major markets of the US and Germany will increase from $1.2bn in 2021 to $3.48bn in 2031.
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