BMN 349, a small molecule inhibitor of Z alpha-1 antitrypsin polymerization, increases secretion and reduces intrahepatic inclusions in a mouse model of disease

BACKGROUND AND AIMS: Alpha-1 antitrypsin (AAT), encoded by the SERPINA1 gene, is primarily synthesized in the liver and secreted into the blood. The SERPINA1 Z allele encodes Z-AAT (Glu342Lys), a variant that self-associates into polymers that are retained in hepatocytes and trigger inflammation and hepatic injury. Targeting and preventing Z-AAT polymerization allows a therapy to directly address the pathophysiology of AAT deficiency (AATD) associated liver disease. APPROACH AND RESULTS: A structure-based design approach was used to develop BMN 349, a small molecule polymerization blocker capable of stabilizing Z-AAT to prevent new polymerization and promote hepatic clearance. BMN 349 bound Z-AAT ~150 times faster in vitro than wild-type M-AAT and promoted secretion and reduced polymer levels in a cell model of Z-AAT deficiency. Crystallography with M-AAT showed that BMN 349 partially displaces a region involved in polymerization, the reactive center loop proximal hinge. Oral dosing in female PiZ transgenic mice with 20-200 mg/kg/day BMN 349 for 30 days was associated with dose-dependent increases in total plasma Z-AAT and concurrent decrease in circulating and liver Z-AAT polymers relative to vehicle-treated controls. Histopathologic and proteomic assessments of liver and plasma samples from these mice showed doses ≥100 mg/kg/day of BMN 349 reduced liver inflammation and improved liver health biomarkers after 30 days. CONCLUSIONS: This study is the first to demonstrate a reduction in Z-AAT polymer burden without altering protein expression. Improvements in liver inflammation and function following BMN 349 treatment support further investigations of its therapeutic benefits for AATD liver disease.