Alvelestat (MPH-966): A Comprehensive Profile of an Investigational Oral Neutrophil Elastase Inhibitor for Alpha-1 Antitrypsin Deficiency

I. Executive Summary

Alvelestat, also identified by the development codes AZD-9668 and MPH-966, is an investigational, orally bioavailable, small molecule drug engineered as a selective and reversible inhibitor of human neutrophil elastase (NE).[1] The primary therapeutic focus for alvelestat is the treatment of lung disease associated with severe Alpha-1 Antitrypsin Deficiency (AATD-LD), a rare, genetic condition characterized by progressive lung destruction.[4] By directly targeting the protease-antiprotease imbalance that defines AATD-LD pathophysiology, alvelestat aims to inhibit the enzymatic activity of NE and thereby mitigate the ongoing destruction of lung tissue, offering a potential disease-modifying approach.[3]

The clinical development program, led by Mereo BioPharma, has yielded critical insights from two complementary Phase 2 studies, ASTRAEUS and ATALANTa. These trials demonstrated a clear dose-dependent efficacy profile. The higher dose of 240 mg administered twice daily (BID) resulted in statistically significant reductions in key biomarkers of both NE activity and active elastin degradation, namely Aα-Val360 and desmosine. In contrast, the lower 120 mg BID dose, while effectively suppressing the target enzyme, did not consistently translate this suppression into a significant impact on these downstream markers of disease activity.[5] Furthermore, encouraging signals of clinical benefit were observed in patient-reported outcomes, specifically improvements in the St. George's Respiratory Questionnaire (SGRQ) scores.[4]