Assessing the efficacy of Alpha1-Proteinase inhibitor (human) augmentation therapy for Alpha1-Antitrypsin deficiency – Related emphysema: Challenges and opportunities

Clinical benefit of Alpha1-Proteinase Inhibitor (Human) (A1-PI) products for Alpha1-antitrypsin deficiency (AATD) is uncertain, based on a systematic review of observational studies and randomized controlled trials (RCTs) in AATD of Alpha1-Proteinase Inhibitor (Human) (A1-PI) products. At the recommended dose, A1-PI products raise its serum concentration but do not normalize levels. Observational studies suggest A1-PI might modestly slow progression of airflow limitation in patients with intermediate airflow obstruction, a finding not confirmed by three placebo-controlled RCTs of limited power, which showed non-significant rates of forced expiratory volume in 1 second (FEV1) change favoring placebo. These RCTs found trends favoring A1-PI in loss of high-resolution computerized tomographic (HRCT) lung density. While two meta-analyses of HRCT lung density change in RCTs achieved significance favoring A1-PI arms, clinical benefit remains uncertain. HRCT lung density measurements don't distinguish changes in measured density due to fluid shifts into and out of the lungs and changes in lung inflammation from those due to progressive loss of alveolar mass. A meta-analysis of RCTs found exacerbations significantly increased in A1-PI groups compared to placebo. No RCTs have shown favorable effects of A1-PI on mortality, FEV1, six-minute walking distance, quality of life, change in diffusion capacity of carbon monoxide (DLCO), or exacerbation frequency. A fourth RCT comparing two dose regimens of A1-PI is underway. RCTs have not provided evidence of clinical benefit in terms of how patients feel, function, or survive. Results have implications for the design of future clinical trials of A1-PI and potentially other products targeting AATD-associated emphysema.