atuzaginstat (COR388) / Lighthouse Pharma - LARVOL DELTA

Effect of the P. gingivalis (Pg) gingipain inhibitor atuzaginstat on neuropsychiatric symptoms in Pgpositive mild-moderate AD patients and distress in their caregivers: Analysis of the NPI-12 in the Phase 2/3 GAIN trial (CTAD 2026) - No abstract available

Clinical • P2/3 data • Psychiatry

Red Complex Pathogens, Periodontal Dysbiosis and Periodontal Therapy in Alzheimer's Disease and Dementia. (PubMed, J Clin Med) - "Notably, direct targeting of a single periodontal pathogen has not shown clinical benefit, as the gingipain inhibitor atuzaginstat failed in the GAIN trial, contrasting with the modest success of amyloid-targeting therapies. Current evidence supports graded plausibility rather than causal certainty, and a registered multi-database systematic review with neurological endpoints is needed before meta-analytic clinical claims can be made."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Dental Disorders • Periodontitis

Lighthouse Pharmaceuticals Reports New Evidence that Gingipain Inhibition Benefits Neuropsychiatric Symptoms and Reduces Caregiver Distress in P. gingivalis-Positive Alzheimer's Disease at AAIC 2026 (Yahoo Finance) - "The findings, being presented at the Alzheimer's Association International Conference (AAIC) 2026, build on previously reported results showing that atuzaginstat slowed cognitive decline by 57% (p=0.02) on the ADAS-Cog11 in a prespecified subgroup of Pg-positive patients...New analyses of Neuropsychiatric Inventory (NPI) subdomain data showed significant benefits in agitation/aggression, disinhibition, elation/euphoria, and apathy after 48 weeks of treatment compared with placebo. These benefits were accompanied by significant reductions in caregiver distress, suggesting meaningful improvements for both patients and their families. In Pg-negative patients, no significant benefit was observed in reduction of neuropsychiatric symptoms or caregiver distress."

P2/3 data • Alzheimer's Disease

Gingipains as macromolecular mediators at the periodontal-brain interface: Mechanistic, diagnostic, and therapeutic evidence in Alzheimer's and Parkinson's diseases. (PubMed, Int J Biol Macromol) - "Therapeutically, small-molecule gingipain inhibitors have shown neuroprotective effects in preclinical models (e.g., atuzaginstat/COR388 failed primary endpoints in the Phase 2/3 GAIN trial but demonstrated subgroup benefits in P. gingivalis-positive participants; the next-generation inhibitor LHP588 is advancing in the Phase 2 SPRING trial). While associative and mechanistic evidence is compelling, definitive causation in humans and disease-modifying efficacy require further validation through biomarker-guided clinical trials. Precision inhibition of gingipains represents a promising upstream strategy for addressing a potentially modifiable microbial contributor at the oral-brain interface."

Journal • Alzheimer's Disease • CNS Disorders • Dental Disorders • Inflammation • Movement Disorders • Parkinson's Disease • Periodontitis • NLRP3

Effect Of The P. Gingivalis (Pg) Gingipain Inhibitor Atuzaginstat On Neuropsychiatric Symptoms In Pg-positive Mild-moderate AD Patients (AAIC 2026) - No abstract available

Clinical • Psychiatry

Unraveling the oral microbiome's role in Alzheimer's disease: From pathophysiology to therapeutic potential. (PubMed, Alzheimers Dement) - "Gingipain inhibitors (e.g., COR388), nitrate-reducing probiotics, and integrated dental-neurology care are promising interventions to disrupt the oral-brain axis. We advocate for oral microbiome screening in high-risk populations (apolipoprotein E ε4 carriers, diabetics) and interdisciplinary approaches to AD prevention."

Journal • Review • Alzheimer's Disease • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Diabetes • Hypertension • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • APOE

Porphyromonas gingivalis, neuroinflammation and Alzheimer's disease. (PubMed, Niger J Physiol Sci) - "In addition, some treatment methods could modulate the adverse effects of P. gingivalis like probiotic dietary supplements, maintaining personal hygiene, as well as gingipain inhibitors which modulate cytokines through blocked Aβ production, ApoE proteolysis, and reduced neuroinflammation. In addition, therapeutic compounds like COR388 and COR286, as gingipain inhibitors, prevent P. gingivalis colonization in the brain and have a beneficial action in some conditions like aspiration pneumonia, low birth rate, rheumatoid arthritis, PerioD and AD."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Dental Disorders • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Inflammatory Bowel Disease • Metabolic Disorders • Movement Disorders • Obesity • Oncology • Parkinson's Disease • Periodontitis • Pneumonia • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Targeted Protein Degradation • APOE

Phase 1 SAD/MAD data and Phase 2 study design for LHP588, a second-generation gingipain inhibitor for the treatment of P. gingivalis-positive Alzheimer's dementia (CTAD 2023) - P1, P2/3 | "LHP588 was well-tolerated in healthy volunteers without evidence of hepatic safety signals to date, and its PK profile was supportive of once daily dosing. The Phase 2 trial of LHP588 will be similar in design to the prior atuzaginstat study but will be restricted to subjects with Pg+ saliva. gingivalis, Alzheimer’s."

P1 data • P2 data • Alzheimer's Disease • CNS Disorders • Dementia • Developmental Disorders • Infectious Disease • Inflammation

The gingipain inhibitor atuzaginstat and results of the GAIN trial (AAIC 2023) - "Since the patients most likely to benefit from the results of the clinical trials underway are those with mild-to-moderate AD, more studies are being planned. Atuzaginstat can address the ongoing need for treatment for most patients for whom anti-amyloids are not suitable."

Alzheimer's Disease • Dental Disorders • Hepatology • Infectious Disease • Periodontitis

Phase 2 Study Design and New Data from the Phase 1 SAD/MAD Trial of LHP588, A Second-Generation Gingipain Inhibitor for the Treatment of P. Gingivalis - Positive Alzheimer Dementia (AAIC 2023) - "Conclusion : LHP588 was well-tolerated in healthy volunteers without evidence of hepatic safety signals to date, and its PK profile was supportive of once daily dosing. The Phase 2 trial of LHP588 proposed to start in late 2023 will be similar in design to the prior atuzaginstat study but will be restricted to subjects with Pg + saliva."

New P1 trial • P1 data • P2 data • Alzheimer's Disease • CNS Disorders • Dementia • Infectious Disease • Inflammation • Targeted Protein Degradation

Phase 2 Study Design and New Data from the Phase 1 SAD/MAD Trial of LHP88, a Second-Generation Gingipain Inhibitor for the Treatment of P. Gingivalis-Associated Dementia (ASCP 2023) - "LHP588 was well tolerated in healthy volunteers without evidence of hepatic safety signals to date, and its PK profile was supportive of once daily dosing, with 10x lower liver metabolite levels. Chronic toxicology and rodent metabolite studies are also supportive of safety and progression to Phase 2. Clinical results with the first generation gingipain inhibitor atuzaginstat informed the new study design for precision enrollment and efficacious exposures."

New P1 trial • P1 data • P2 data • Alzheimer's Disease • CNS Disorders • Dementia

Phase 2 Study Design and New Data from the Phase 1 SAD/MAD Trial of LHP88, a Second-Generation Gingipain Inhibitor for the Treatment of P. Gingivalis-Associated Dementia (ASCP 2023) - "LHP588 was well tolerated in healthy volunteers without evidence of hepatic safety signals to date, and its PK profile was supportive of once daily dosing, with 10x lower liver metabolite levels. Chronic toxicology and rodent metabolite studies are also supportive of safety and progression to Phase 2. Clinical results with the first generation gingipain inhibitor atuzaginstat informed the new study design for precision enrollment and efficacious exposures."

New P1 trial • P1 data • P2 data • Alzheimer's Disease • CNS Disorders • Dementia

New Biomarker Data from the GAIN Trial of atuzaginstat (COR388) Link Target Inhibition with Efficacy in Reducing Cognitive Decline in P. gingivalis Infected Subjects with Mild-Moderate Alzheimer’s Disease (AAIC 2022) - No abstract available

Biomarker • Clinical • Alzheimer's Disease • CNS Disorders

COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease. (PubMed, Expert Opin Investig Drugs) - "gingivalis is opsonized by Aβ42, is capable of entering the brain, and is an accelerant of neuropathologies in rodent models of AD. Thus, in our opinion, this bacteria is highly likely to be a pathogen capable of initiating or precipitating the progression of AD, which agrees with the pathogen hypothesis of clinical AD development."

Journal • Alzheimer's Disease • CNS Disorders • Dental Disorders • Immunology • Infectious Disease • Inflammation • Periodontitis

Cortexyme to Participate at 4th International Conference on Porphyromonas gingivalis and Related Species in Oral and Systemic Diseases (Businesswire) - “Cortexyme, Inc…announced that the company will participate at The 4th International Conference on Porphyromonas gingivalis and Related Species in Oral and Systemic Diseases (PgLouisville2022) taking place May 15-17, 2022 in Louisville, Kentucky. Cortexyme’s clinical advisory board member Mark Ryder, D.M.D., will provide an overview of GAIN Trial results and biomarker data examining the role of P. gingivalis in oral and systemic diseases.”

Biomarker • P2/3 data • Alzheimer's Disease • CNS Disorders

Cortexyme Provides New GAIN Trial Data at AD/PD 2022 Demonstrating Potential Benefit of Lysine Gingipain Inhibition in Mild to Moderate Alzheimer’s Population (Businesswire) - P2/3 | N=643 | GAIN (NCT03823404) | Sponsor: Cortexyme Inc. | “Target engagement and biomarker data expands understanding of the role of P. gingivalis and the potential benefit of lysine gingipain inhibition. Biomarker data and correlations to clinical outcomes consistent with the gingipain hypothesis. Cortexyme, Inc…presented new target engagement and biomarker data from the GAIN Trial at the AD/PD™ 2022 International Conference on Alzheimer’s and Parkinson’s Diseases….GAIN Trial findings support that atuzaginstat engaged the target, inhibiting lysine gingipains, which are essential to the survival of P. gingivalis. Lysine gingipain inhibition by atuzaginstat resulted in a 30% to 50% slowing of cognitive decline in the participants with high P. gingivalis load.”

P2/3 data • Alzheimer's Disease • CNS Disorders

Cortexyme to Present New GAIN Trial Data at AD/PD 2022 (Businesswire) - “Cortexyme, Inc…announced that the company will participate at the AD/PD™ 2022 International Conference on Alzheimer’s and Parkinson’s Diseases, which is a hybrid event taking place March 15-20, 2022 in Barcelona, Spain, as well as virtually. Cortexyme’s chief medical officer Michael Detke, MD, PhD, will present new GAIN Trial results and biomarker data examining the role of P. gingivalis in Alzheimer’s disease and the P. gingivalis-positive population, in addition to sharing study data that reinforces the efficacy of the company’s first-in-class gingipain inhibitor in slowing cognitive decline in Alzheimer’s disease with P. gingivalis. These new data analyses will be reviewed at AD/PD 2022 and at additional conferences as more data becomes available throughout 2022.”

Biomarker • P2/3 data • Alzheimer's Disease • CNS Disorders

GAIN Trial: Phase 2/3 Study of COR388 in Subjects With Alzheimer's Disease (clinicaltrials.gov) - P2/3 | N=643 | Completed | Sponsor: Cortexyme Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Jan 2022

Trial completion • Trial completion date • Alzheimer's Disease • CNS Disorders

ADDITIONAL DATA FROM THE PHASE 2/3 GAIN TRIAL OF COR388 (ATUZAGINSTAT) FOR THE TREATMENT OF MILD-MODERATE ALZHEIMER’S DISEASE (ADPD 2022) - P2/3 | "Atuzaginstat slowed cognitive decline in Alzheimer’s disease with P. gingivalis by approximately 50% on ADAS-cog. Additional analyses are pending and will be shared."

P2/3 data • Alzheimer's Disease • CNS Disorders

Increased levels of phospho-tau217 in neuron cultures and CVN mice infected with Porphyromonas gingivalis. (PubMed, Alzheimers Dement) - "P. gingivalis infected neuronal cell cultures and chronically infected CVN mice display elevated p-tau217. In vitro this was apparent at low infection levels that might reflect the physiological level of gingipain exposure. Phospho-tau217 is emerging as a specific biomarker for AD and these results further validate P. gingivalis-infected neuron cultures and mice as models for AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Infectious Disease • NOS2

Cortexyme Announces Clinical Hold on Atuzaginstat’s Investigational New Drug Application (Businesswire) - “Cortexyme, Inc…announced that the company received a letter from the U.S. Food and Drug Administration (FDA) on January 25, 2022 placing a full clinical hold on atuzaginstat’s (COR388) Investigational New Drug application (IND 134303). The company plans to provide additional updates pending continued engagement with FDA….The company intends to prioritize development of its next generation gingipain inhibitor, COR588, in Alzheimer’s disease. COR588 is currently completing a Phase 1 SAD/MAD study and results are expected in the second quarter 2022.”

FDA event • P1 data • Alzheimer's Disease • CNS Disorders

Top-line Results from the GAIN Trial: A Phase 2/3 Study of Atuzaginstat in Mild to Moderate Alzheimer’s Disease (CTAD 2021) - No abstract available

Late-breaking abstract • P2/3 data • Alzheimer's Disease • CNS Disorders

Cortexyme’s Atuzaginstat Slowed Cognitive Decline in Participants With Alzheimer’s Disease and P. Gingivalis Infection in Phase 2/3 GAIN Trial: Additional Top-line Data Presented at CTAD 2021 (Businesswire) - “Cortexyme, Inc…will present additional data from its Phase 2/3 GAIN Trial at the 14th Clinical Trials on Alzheimer's Disease Conference (CTAD 2021) as a part of the meeting’s Late-Breaking Readout Roundtable program today, Thursday, November 11, 2021, at 11:35 a.m. Eastern Time taking place in Boston, Massachusetts, as well as virtually. The presentation will expand on previously reported top-line results that demonstrated the relationship between the reduction of Porphyromonas gingivalis (P. gingivalis) infection and the slowing of cognitive decline in Alzheimer’s disease with atuzaginstat treatment in a prespecified population of patients based on diagnosis of infection.”

Late-breaking abstract • P2/3 data • Alzheimer's Disease • CNS Disorders

Cortexyme's Alzheimer's treatment fails to meet main goals in study (Yahoo Finance) - “Cortexyme Inc said on Tuesday its experimental oral pill failed to meet the main goals of improving cognitive and functional abilities in patients with mild-to-moderate Alzheimer's disease in a study. The drug, atuzaginstat, is designed to target the P. gingivalis bacteria found in the brain of patients suffering from the memory robbing disease. The mid-to-late stage study tested 643 patients and did not meet statistical significance in its goals, according to two scales measuring disease progression. In a group of patients with the bacteria detected in their saliva, the drug showed 57% slowing of cognitive decline on a commonly used test but failed to show significant benefits on another scale…”

Clinical data • Alzheimer's Disease • CNS Disorders

Cortexyme Reports GAIN Trial Data Demonstrated Relationship Between Reduction of P. gingivalis Infection and Slowing of Alzheimer’s Disease Progression (Businesswire) - P2/3, N=643; GAIN (NCT03823404); Sponsor: Cortexyme; "Cortexyme...reported top-line results from its Phase 2/3 GAIN Trial, a double-blind, placebo-controlled study evaluating the efficacy of atuzaginstat (COR388)...The 643-participant study in mild to moderate patients with Alzheimer’s disease did not meet statistical significance in its co-primary cognitive and functional endpoints as measured by ADAS-Cog11 and ADCS-ADL at end of the treatment period in the overall cohort....Significant benefits in this subgroup were not seen on the other co-primary, ADCS-ADL. The cognitive benefit of atuzaginstat in patients with high P. gingivalis infection was reinforced by similar results in multiple pre-specified infection related subgroups and with multiple methods of analysis."

P2/3 data • Alzheimer's Disease • CNS Disorders