An update and baseline data from the phase 2/3 GAIN trial of COR388 (atuzaginstat), a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s disease

Abstract

AbstractBackgroundThe novel mechanism of action of atuzaginstat is based on the discovery of gingipains, toxic protease virulence factors from the bacterial pathogen Porphyromonas gingivalis (Pg), in >90% of Alzheimer’s disease (AD) brains. Gingipain levels correlated with AD diagnosis and tau and ubiquitin pathology, and oral infection of mice with Pg results in classic AD pathology that can be blocked by atuzaginstat, an irreversible lysine‐gingipain inhibitor. Pg is best known for its role in periodontal disease. Atuzaginstat was well tolerated in phase 1, including trends of efficacy on clinical scales, and significant improvement on a computerized speech assessment and two relevant biomarkers.MethodsThe Phase 2/3 GAIN trial, designed to be potentially pivotal, completed enrollment in November 2020. 642 subjects (aged 55‐80; mild‐moderate AD with MMSE 12‐24) were randomized to one of two doses of atuzaginstat (40mg or 80mg BID) or placebo. The co‐primary endpoints are mean change in ADAS‐Cog 11 and ADCS‐ADL from baseline to 48 weeks. Additional endpoints include change in CDR‐SB, MMSE, NPI, Winterlight Speech Assessment, CSF and oral biomarkers, MRI and other measures.ResultsBaseline data show that the 642 randomized subjects are: 56.9% female, 64.3% ApoE4 positive, 49.5% mild (MMSE = 19‐24) and 50.5% moderate (12‐18). 73.2% of subjects received symptomatic AD co‐medications. New baseline biomarker data from the full set of subjects in the study will be shared, including anti‐Pg IgG, amyloid‐β peptide ratio 42/40, and phospho tau. 233 GAIN trial patients are also participating in a dental sub‐study, and while not selected for periodontal disease, approximately 90% have moderate ‐ severe periodontitis.ConclusionsEnrollment of the GAIN trial was completed in November 2020, and top‐line efficacy data are expected December Q4 2021. An interim analysis in December 2020 indicated that the study should continue as planned without sample size adjustment. Subjects enrolled exhibit baseline characteristics consistent with AD and with Pg infection, indicating an appropriate population to test the efficacy and safety of atuzaginstat in mild‐moderate AD. The high correlations of AD, periodontal disease, and Pg infections observed in GAIN replicates findings by others and supports a causal role of Pg in AD.