B24-12 Non-invasive Screening for Advanced Liver Fibrosis in Alpha-1 Antitrypsin Deficiency-Associated Emphysema: Experience From the Phase 2 ASTRAEUS Trial

Rationale The PiZZ mutation is the most common cause of alpha-1 antitrypsin deficiency (AATD)-associated emphysema. Misfolded protein accumulates in the liver leading to fibrosis in approximately 20% of patients. Monitoring for hepatotoxicity is essential in drug development, and underlying significant liver disease can confound safety assessments. Simple serological tools, such as the Fibrosis (FIB)-4 score have demonstrated high negative predictive values for advanced fibrosis in AATD and may be a practical approach to enable prioritization of more time-consuming specialized investigations, such as Transient Elastography (TE). We report use of a FIB-4 screening strategy in the Phase 2 ASTRAEUS trial (NCT03636347). Methods ASTRAEUS was a 12-week trial of alvelestat oral neutrophil elastase inhibitor in PiZZ adults (18-75 years), with severe AAT deficiency (<11μM) and emphysema. All were current non-smokers, without significant alcohol consumption in the previous year (defined as average of > 20 g/day in females, >30 g/day in males). Those with acute/chronic viral hepatitis, other chronic liver diseases, evidence of cirrhosis or clinically relevant liver function test abnormalities were excluded. Full eligibility criteria are published. Screening FIB-4 scoring was performed using the formula: FIB-4 = (Age × AST) / (Platelet count × √ALT). Thresholds applied were: <1.45 “no risk” of advanced fibrosis; ≥1.45 to ≤ 3.25 “inconclusive” (thereby requiring TE evaluation); >3.25 = high risk of advanced fibrosis, excluded from study. Participants with TE >12.5 kPa were also excluded. Results 99 patients were randomized. Mean±SD age was 57.2±9.1 years; BMI 26.1±4.7; FEV1% predicted 58.7±20.7. 60.2% were female. The mean FIB-4 was 1.23±0.44, the majority having scores in the “no risk” range. Thirty participants with “inconclusive” FIB-4 underwent TE with a liver stiffness (mean, SD) of 5.28±1.68 kPa (range: 3.30 to 10.1). FIB-4 and TE were positively correlated (Pearson correlation coefficient r = 0.596, p = 0.0006, Figure). Conclusions FIB-4 is a simple and effective non-invasive method to exclude significant underlying liver disease in AATD. Although the mechanism of hepatic injury in PiZZ AATD may release less ALT, potentially underestimating fibrosis risk, using FIB-4 as a first-line assessment, followed by TE for indeterminant cases, efficiently identifies participants for enrolment, while minimizing unnecessary testing.