A76-16 Quantitative Systems Pharmacology Model Provides Mechanistic Insight Into the Impact of Augmentation Therapy on Lung Density and Lung Function in Alpha-1-Antitrypsin Deficiency

Abstract Introduction/Rationale Alpha-1-antitrypsin deficiency (AATD) is a chronic inherited disorder associated with lung disease. Decreased levels of functional AAT (fAAT) lead to accelerated destruction of lung tissue by serine proteases including neutrophil elastase (NE). AATD is currently treated by augmentation therapy with plasma-derived alpha-1-protease inhibitors (pdA1PI). Recent evidence suggests the potential for clinical benefit by targeting higher functional AAT levels than the historical theoretical threshold of 11 μM. However, studies of higher doses of pdA1PI and their clinical benefit have been limited. Achieving higher fAAT levels has been reported in the Phase 1 clinical study of efdoralprin alfa (NCT03815396). To provide a biologically plausible assessment of the impact of increasing fAAT in AATD patients, we have developed a quantitative systems pharmacology (QSP) model that provides a mechanistic link between AAT levels and specific measures of lung density and lung function that are associated with clinical benefit. Methods The AATD QSP model was developed by integrating multiple published data sources including (1) natural history studies; (2) mechanistic data describing key cell types and inflammatory molecules associated with AATD pathophysiology; and (3) clinical studies of pdA1PI products and efdoralprin alfa. The model describes the biochemical kinetics of AAT regulation of NE activity and resulting effects on elastin. Data were used to establish a plausible link between AAT activity, quantitative CT-measured lung density, and % predicted FEV1 (ppFEV1). A virtual population (VP) of AATD patients was generated that reproduced clinically observed variability in ppFEV1. By leveraging exposure data, the VP was employed to simulate the multiscale response to treatment with pdA1PI products. Results The QSP model represents the spectrum of endogenous AAT levels across genotypes ranging from PiMM (healthy) to PiZZ (most severe deficiency). Through the mechanistic relationship established between biological processes, the model demonstrates how decreasing AAT dynamically leads to increased NE activity, decreased elastin levels, and reduced lung density and function, in alignment with clinical observations from patients with the PiZZ genotype. VP simulations of augmentation therapy adequately recapitulated changes in lung density and function as reported in the RAPID and EXACTLE clinical studies. Conclusions The QSP model establishes a biologically plausible relationship between fAAT levels and changes in lung density and function metrics associated with clinical benefit. The model provides a quantitative framework for assessing novel augmentation therapy regimens and supplementing clinical observations. This abstract is funded by: Sanofi