BMN 349 / BioMarin - LARVOL DELTA

Study of BMN 349 Single Dose in PiZZ and PiMZ/MASH Adult Participants (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: BioMarin Pharmaceutical | N=12 ➔ 6 | Trial completion date: Sep 2025 ➔ Aug 2026 | Trial primary completion date: Sep 2025 ➔ Aug 2026 | Recruiting ➔ Active, not recruiting

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Alpha-1 Antitrypsin Deficiency • Metabolic Dysfunction-Associated Steatohepatitis • Pulmonary Disease • Respiratory Diseases

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

Journal • Preclinical • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Inflammation • Liver Failure • Pulmonary Disease • Respiratory Diseases • SERPINA1

Study of BMN 349 Single Dose in (PiZZ) and (PiMZ) Adult Participants (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: BioMarin Pharmaceutical

New P1 trial • Alpha-1 Antitrypsin Deficiency • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Pulmonary Disease • Respiratory Diseases

BMN 349, A SMALL MOLECULE FOR ALPHA-1 ANTITRYPSIN ASSOCIATED LIVER DISEASE, STABILIZES HUMAN Z-AAT AND REDUCES SEVERITY OF LIVER DISEASE IN THE PIZ MOUSE MODEL (AASLD 2024) - "BMN 349 stabilizes monomeric human Z-AAT, blocking formation of polymers and allowing for normal secretion to plasma. This appears to reduce pro-necro-inflammatory processes in hepatocytes. The reduction in ER stress and UPR biomarkers in BMN 349-treated mice suggests that diminishing the accumulation of Z-AAT in the liver reduces pathways that may lead to hepatocyte cell death."

Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • CALR • HSPA5 • SERPINA1

BIOANALYTICAL . METHODS: TO ASSESS PHARMACOKINETICS AND PHARMACODYNAMICS OF BMN 349, A SMALL MOLECULE THERAPEUTIC FOR ALPHA1 ANTITRYPSIN DEFICIENCY (AASLD 2024) - "We developed and validated a suite of bioanalytical methods to measure pharmacokinetics and pharmacodynamics of BMN 349 in human plasma. These assays will be used to support clinical development of BMN 349 to treat humans with AATD."

PK/PD data • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • ELANE

PLASMA PROTEOMIC PROFILING IDENTIFIES PROTEIN LEVEL CHANGES ASSOCIATED WITH ALPHA-1 ANTITRYPSIN DEFICIENCY LIVER DISEASE PATHWAYS (AASLD 2024) - "BMN 349, a small molecule that blocks Z-AAT polymerization, was assessed for its effects on plasma protein levels in PiZ mice... Proteomics in people with AATD and PiZ mice identified circulating proteins associated with pathways known to be dysregulated in AATD liver disease. With further research, a subset of these proteins could serve as noninvasive biomarkers to provide a more complete picture of AATD liver pathogenesis and response to treatment."

Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • SERPINA1

A small molecule chaperone for alpha-1 antitrypsin deficiency-associated liver disease reduces liver polymer burden in the PiZ mouse model (EASL-ILC 2022) - "Taken together, these data indicate that BMN 349 is effective in reducing Z-AAT polymer burden, reversing liver damage, and restoring liver function in the PiZ mouse model."

Preclinical • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • ELANE • HSPA5 • SERPINA1