Abstract Background Alpha-1 antitrypsin deficiency (AATD) is a genetic disease resulting in decreased circulating functional levels of alpha-1 antitrypsin (AAT), an important protease inhibitor that protects tissue, particularly the lungs, from protease-mediated degradation. Individuals with AATD-associated emphysema have historically been treated with plasma-derived AAT, requiring weekly infusions. A recombinant AAT-Fc fusion protein, efdoralprin alfa, is currently being studied in clinical trials. Here, we sought to delineate a normal range of functional AAT (fAAT) that can be used to assess how effectively therapies restore fAAT to the normal range. Methods Self-reported healthy individuals from Massachusetts were recruited to serve as donors to delineate a reference interval (RI), with requirements for ≥ 75% of individuals to be White. The Mayo Clinic analyzed blood samples from each donor to confirm wildtype Pi*MM phenotype and assess total AAT protein levels using the A1ALC test and a Siemens nephelometry assay, respectively. Samples were assessed for fAAT at BioAgilytix using a validated anti-neutrophil elastase capacity assay with WHO International AAT standards. Verification cohorts were recruited from geographically distinct regions (Florida and California) to confirm that the Massachusetts cohort was representative of the broader population. Results Of 237 individual donors in the RI cohort, 211 with confirmed wildtype Pi*MM phenotype were used to calculate the RI. The central 95% range (2.5th percentile to 97.5th percentile) of fAAT concentration was 23.8–42.4 µM, with 23.8 µM designated as the lower limit of normal (LLN). Although one of the Florida verification cohorts was not included because of inability to verify sample-handling procedures, the LLN determined from the RI cohort was in alignment with the other two verification cohorts. In addition, the lower bound for total AAT protein from the RI cohort was 106 mg/dL. This value was consistent with two larger published datasets, supporting the representativeness of the RI cohort. Conclusions The fAAT RI and LLN delineated by this study can be applied directly to clinical trials to evaluate the pharmacodynamic effect of AATD therapies, and, in conjunction with clinical trial pharmacokinetic data, can be used to support dosing decisions for patients with AATD.
Merdek et al. (Thu,) studied this question.