A Randomized, Double-Blind, Placebo-Controlled Study of LHP588 in Subjects with P. gingivalis-Positive Alzheimer's Disease - SUMMARY/ABSTRACT A Randomized, Double-Blind, Placebo-Controlled Study of LHP588 in Subjects with P. gingivalis-Positive Alzheimer's Disease Given the increasing incidence of AD worldwide, there is an urgent unmet need for precision medicine approaches that could prevent or delay cognitive decline experienced by Alzheimer’s disease (AD) patients. Mounting evidence suggests that life exposure to brain-penetrant pathogens could contribute to the etiology of AD. One microbial agent recently associated with AD is Porphyromonas gingivalis (Pg). Pg is best known for its role in chronic periodontitis , but epidemiologic and other studies also strongly imply its contribution to cognitive decline. Critically, Pg virulence factors, proteases called gingipains have been identified in post-mortem AD brains, at rates significantly higher than age-matched controls. Gingipain loads have shown a positive correlation with AD severity, brain tau levels, and ubiquitin pathology. Our team previously developed a small-molecule, brain-penetrant, orally bioavailable, first-generation, covalent gingipain inhibitor called COR388 (atuzaginstat), which mitigated many AD- associated neuropathological features in preclinical in vitro and animal studies. After obtaining U.S. Food & Drug Administration (FDA) permission, we conducted a large, Phase-II/III, placebo-controlled, randomized clinical trial of atuzaginstat administered to mild-to-moderate dementia subjects (MMSE ranging 12-24) for 48 weeks. Target engagement was verified along with dose-dependent reduction of systemic Pg infection. The prespecified subgroup analysis most relevant to the mechanism of action indicated dose-dependent efficacy in patients with Pg-positive (Pg+) saliva (N=242), with a reduction of the AD Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11) scores by 57% compared to baseline (p=0.02). However, because of hepatic safety concerns, development of atuzaginstat was discontinued. We, at Lighthouse Pharmaceuticals, have now developed a second-generation, orally bioavailable gingipain inhibitor called LHP588. Rigorous in vitro and animal studies have demonstrated improved target engagement and reduced toxicity of LHP588 compared to atuzaginstat. In a Phase I study combining a single-ascending-dose and a 10-day multiple-ascending-dose, LHP588 was well tolerated and there was no evidence of hepatic toxicities at any dose. Using our experience with atuzaginstat and the development of LHP588, we formulated the hypothesis that LHP588 can provide increased target engagement with reduced safety risks to slow down cognitive decline in patients suffering from Pg-positive (Pg+) mild-to-moderate AD. To test our hypothesis, we will deploy a rigorously designed Phase II, double-blind, placebo-controlled, randomized, 3-arm, parallel group clinical trial termed SPRING (Stopping PRogression of Porphyromonas gINGivalis-associated AD). Thorough screening will select AD subjects with Pg+ saliva and plasma p-tau-217 levels above 0.42 pg/mL, which is associated with amyloid plaque positivity across racial and ethnic groups. Enrolled study participants (N=300; minimum of 30% of diverse subjects) will be randomized 1:1:1 to 25 or 50 mg LHP588 taken orally once-a-day, or matching placebo, for 48 weeks. Importantly, the FDA provided a “study may proceed” letter after review of our Investigational New Drug (IND) application. In Aim 1, we will assess safety and tolerability in AD subjects administered LHP588. In Aim 2, we will test for target engagement by measuring Pg DNA levels in saliva and anti-Pg IgG levels in serum. In Aim 3, we will determine drug efficacy vs. placebo using clinical assessments of dementia, i.e., cognition (ADAS- Cog11, which is the primary efficacy measure), other clinical measures, biomarkers, including brain atrophy estimated by vMRI, and plasma levels of p-tau-217. Success of our SPRING trial will warrant carrying out at least one larger confirmatory Phase III study for future
