Study of LHP588 in Subjects With P. Gingivalis-Positive Alzheimer's Disease

This is a randomized, double-blind, placebo-controlled study that will assess the efficacy and safety of LHP588 in participants with evidence of P. gingivalis [Pg] infection and Alzheimer's Disease (AD) according to the National Institute on Aging-Alzheimer's Association (NIA-AA) research criteria. Enrolled participants must also have evidence of P. gingivalis infection as determined by polymerase chain reaction (PCR) of saliva oral rinse and clinical evidence of progressive cognitive decline in the last year. The participant should not have other conditions or brain imaging abnormalities that can explain the symptoms of dementia based on prior imaging and the screening magnetic resonance imaging (MRI). Due to the nature of AD, participants must identify a primary caregiver prior to enrollment in the study who will assist the participant with study participation and attend clinic visits.

The study will consist of the following periods: 1) screening period of up to 12 weeks, 2) double-blind treatment period of 48 weeks (including a 2 week up-titration for the high dose arm), and 3) safety follow-up period of 4 weeks.

The screening period will include at least two office visits during which eligibility will be verified. The first screening visit assessments will be limited to include the Mini-Mental State Examination (MMSE), saliva sample collection to assess Pg positivity, and pTau217 sample collection. The second screening visit will only be scheduled for participants with positive results of Pg infection and pTau217 test, and the rest of the screening procedures will be performed. Screening MRI will be performed as the last eligibility verification assessment.

Participants who meet all eligibility criteria will be randomized in a 1:1:1 fashion to receive LHP588 25 mg, LHP588 50 mg, or placebo, orally, once daily (QD) in a fasted state (at least one hour before or two hours after a meal) for 48 weeks. Dosing should be done at approximately the same time each day. Blood samples for pharmacokinetics levels and biomarkers will be collected during selected visits.

Evaluations will be conducted according to the schedule of assessments and will include: Medical history, physical examination, height, weight, saliva rinse for verification of Pg infection, blood for pharmacokinetic analysis, safely laboratory measures, electrocardiogram, and cognitive and functional scale assessments such as ADAS Cog, administered periodically.

After completion of study treatment, participants will continue to be monitored for 4 weeks and will have a phone call to assess safety at Week 50 and will return for the Safety Follow-up Visit (Week 52).

Inclusion criteria

• AD according to the National Institute on Aging-Alzheimer's Association criteria.
• MMSE scores corresponding to mild and moderate AD.
• Saliva rinse sample positive for P. gingivalis.
• Plasma pTau217 above cutoff.
• Subject and caregiver have provided full written informed consent.
• Background symptomatic therapy with acetylcholinesterase inhibitors, and/or memantine, are allowed if the dose has been stable for 90 days and no changes are planned during the study.
• Modified Hachinski score ≤4 at screening.

Exclusion criteria

• History of cancer requiring systemic therapy in last 5 years.
• Evidence of a clinically significant, unstable cardiovascular, pulmonary, renal, hepatic, gastrointestinal, neurologic, or metabolic disease within 6 months prior to screening.
• Unstable angina, uncompensated and/or symptomatic congestive heart failure (Grade 2 or higher on the New York Heart Association scale) or myocardial infarction within 6 months.
• Acute or poorly controlled blood pressure >180 mmHg systolic or >100 mmHg diastolic at screening visit.
• History or current evidence of major neurological or psychiatric illness such as schizophrenia, bipolar disorder, Parkinson's Disease, other.
• Currently being treated with anti-amyloid beta antibodies or other disease-modifying treatments for dementia.
• Other criteria in the Investigator's judgement that may interfere with the ability to participate in the study.