BMN-349: An Investigational Oral Chaperone for Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

1. Executive Summary

BMN-349 is an investigational, orally bioavailable small molecule therapeutic candidate currently under development by BioMarin Pharmaceutical.[1] This agent is designed to function as an Alpha-1 Antitrypsin (A1AT) modulator and protein folding stabilizer, specifically acting as a molecular chaperone. Its primary pharmacological target is the misfolded Z-mutant A1AT (Z-AAT) protein, the accumulation of which is central to the pathogenesis of Alpha-1 Antitrypsin Deficiency (AATD)-associated liver disease.[1] Consequently, the principal therapeutic indication for BMN-349 is AATD-associated liver disease.[2]

As of early 2025, BMN-349 has progressed into Phase 1 clinical development. An ongoing clinical trial, identified as NCT06738017, is actively evaluating the safety, tolerability, and pharmacokinetic profile of BMN-349 in adult participants who are either homozygous for the Z mutation (PiZZ genotype) or heterozygous (PiMZ genotype) with concurrent metabolic dysfunction-associated steatohepatitis (MASH).[4] Preclinical investigations have provided encouraging results, particularly studies conducted in the PiZ mouse model of AATD. These studies have demonstrated the potential of BMN-349 to reduce the accumulation of Z-AAT polymers within hepatocytes and to enhance the secretion of Z-AAT into the circulation.[5]