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THE PHASE 2/3 GAIN TRIAL OF THE FIRST-GENERATION P. GINGIVALIS GINGIPAIN INHIBITOR ATUZAGINSTAT IN MILD-TO-MODERATE PROBABLE ALZHEIMER’S DISEASE: NEW CEREBROSPINAL FLUID BIOMARKER DATA

Michael Detke — Marwan Sabbagh2, Joanna Bolger1, Mark Ryder3, Craig Mallinckrodt4, Florian Ermini1, Casey Lynch1, Stephen Dominy1 1Lighthouse Pharma, 2Barrow Neurological Institute, 3UCSF, 4Pentara Corporation

2026 ASCP Annual Meeting

Background

Porphyromonas gingivalis (Pg), best known for its role as a keystone pathogen in chronic periodontitis, has emerged as a promising target in the treatment of Alzheimer’s disease (AD) through epidemiological, pathological, and mechanistic preclinical studies. We developed an orally bioavailable investigational small-molecule, COR388 (atuzaginstat), that specifically targets and inhibits lysine-gingipain (Kgp), the major protease virulence factor of Pg. We tested atuzaginstat in the GAIN trial, a randomized, double-blind, placebo-controlled phase 2/3 trial (NCT03823404) of a low-dose and high-dose over 48 weeks in participants with mild-moderate AD (N = 643). The primary ITT prespecified cognitive endpoint, ADAS-Cog11 was not met. However, in a prespecified subgroup analysis, Pg detected in saliva (PG-DS), both doses of atuzaginstat engaged the Kgp target and demonstrated a dosedependent effect on ADAS-Cog11, slowing cognitive decline in participants with Pg-positive saliva (n = 244) in the high-dose group by 57% (p = 0.020). In the low-dose group, cognitive decline was slowed by 42% (p = 0.066). Here, we present CSF AD biomarker data from the GAIN study that shows a disease-modifying effect of atuzaginstat on CSF p-tau181. This finding informed the design of the Phase 2 study of LHP588, a second-generation Kgp inhibitor with an improved liver safety profile. The LHP588 study in Pg-positive mild-moderate AD, known as the SPRING Trial (NCT06847321), is ongoing after receiving $49.2M in funding from the National Institute on Aging (NIA).

Methods

The GAIN trial SAP prespecified an exploratory analysis of CSF Aβ-42/40 ratio, ptau181 concentration, and total tau concentration. CSF was collected at baseline (N = 491) and end of study. Using ELISA assays, the mean percent change from baseline at Week 48 was analyzed separately for each biomarker using ANCOVA with fixed effects of treatment group, ApoE4 status, acetylcholinesterase inhibitor and/or memantine usage, site-country, and baseline value for each biomarker as a covariate for the ITT population and prespecified PG-DS subgroup.

Results

P-tau181 levels were observed to increase in both the ITT and Pg-positive-saliva placebo groups from baseline to week 48. In the ITT group, the p-tau181 increase was significantly inhibited in the atuzaginstat 40 mg BID arm (p = 0.048, n = 79), and there was a statistical trend of the 40 mg BID dose to inhibit the p-tau181 increase in the Pg-positive-saliva subgroup (p = 0.083, n = 34). The atuzaginstat 80 mg BID treatment arms had fewer evaluable subjects and did not reach statistical significance in the ITT group (p = 0.174, n= 65) or the Pgpositive-saliva subgroup (p = 0.778, n = 20).

Conclusions

Longitudinal p-tau181 levels were observed to increase in CSF from baseline to week 48 in both the ITT and PG-DS placebo groups, while no significant longitudinal changes were detected for Aβ-42/Aβ40 or total tau. This pattern of longitudinal increase in CSF p-tau181 levels during cognitive decline without a concomitant change in Aβ42 or total tau has been previously reported. The data suggest that Pg infection was driving the increase in CSF p-tau181 levels during the length of the GAIN trial. Based on these results, in the phase 2 study of LHP588 in Pg-positive mild-moderate AD, inclusion criteria include Pg-positive saliva, but also high plasma p-tau-217 levels that will allow us to test the hypothesis that p-tau217 may be a pharmacodynamic biomarker of LHP588 activity.