Recombinant AAT-Fc fusion protein INBRX-101 achieves normal serum AAT levels in patients with alpha-1 antitrypsin deficiency (AATD)

AATD is a genetic disorder characterized by low levels of AAT causing emphysema, loss of lung function, and decreased survival. Plasma-derived AAT (pdAAT) therapy is approved in many countries but access ex-US remains limited due to cost/supply. Here we describe the recombinant human AAT-Fc fusion protein, INBRX-101, designed to safely achieve and maintain AAT levels within the normal range (>20 µM) using every 3 wk dosing. This study is an open-label, international Phase 1 designed to assess safety, PK/PD, and immunogenicity of INBRX-101 (NCT03815396). AATD patients were administered single or multiple doses of 10, 40, 80 or 120 mg/kg INBRX-101 via IV infusion. As of November 2021, 24 AATD patients have been dosed INBRX-101 at 10 mg/kg (n=6), 40 mg/kg (n=6), 80 mg/kg (n=6) and 120 mg/kg (n=6). INBRX-101 has been well tolerated without serious adverse reactions or severe drug-related adverse events. Serum antigenic PK and functional AAT levels were assessed in 21 AATD patients. Dose-dependent increases in INBRX-101 exposure were observed. Terminal half-life was 15 – 19 days. Accumulation of functional AAT levels was observed following multiple doses of 40 mg/kg or 80 mg/kg every 3 wks. Trough levels of functional AAT exceeded those achieved by current pdAAT therapies. INBRX-101 maintains normal AAT serum levels (>20 µM) with every 3-wk dosing, with potential for longer intervals.