LHP588 for Alzheimer's Disease

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Lighthouse Pharmaceuticals, Inc.

Must not be taking: Anti-amyloid beta antibodies

Disqualifiers: Cancer, Cardiovascular, Neurologic, Psychiatric, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 23

Duration: 48 weeks

300 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This study is to test LHP588 in persons who have mild to moderate Alzheimer's disease (AD) who have shown progressive mental decline in the last year and who have P. gingivalis infection. P. gingivalis infection has been linked to the development of dementia. LHP588 is designed to target the P. gingivalis bacterium, to potentially help to halt or slow down the progression of AD and its symptoms. A saliva test will be done to determine P. gingivalis infection. Tests for AD include standard questionnaires such as MMSE and a blood test for pTau 217. Treatment will be blinded, meaning the participant and the doctor will not know if the participant is receiving LHP588 or placebo. The total time for participation in the study may be up to 64 weeks. This includes a screening period (to ensure the participant is suitable for the study and the study is suitable for the participant) of up to 12 weeks, a treatment period of up to 48 weeks, and a safety follow-up period of 4 weeks after the last dose of the study drug to check the participant's overall health. Treatment is a once-a-day capsule. Caregiver participation is required. The study requires the participant to visit the study center (with the caregiver) at least 20 times within 64 weeks (this does not include any unplanned visits that may be recommended by the study doctor). In addition, the study doctor or clinic staff will contact the participant via phone at least 1 time.

Will I have to stop taking my current medications?

The trial allows participants to continue taking acetylcholinesterase inhibitors and/or memantine if the dose has been stable for 90 days and no changes are planned during the study. However, if you are on other medications, especially anti-amyloid beta antibodies or other disease-modifying treatments for dementia, you may need to stop them to participate.

Is LHP588 safe for humans?

There is no specific safety data available for LHP588, but a similar drug, idalopirdine, was found to be generally safe and well-tolerated in long-term studies for Alzheimer's disease, with some patients experiencing mild increases in liver enzymes. ^{1 2 3 4 5}

How does the drug LHP588 differ from other Alzheimer's treatments?

LHP588 may be unique in its potential mechanism involving lysosomal pathways, as lysosome-associated membrane protein 1 (LAMP1) is implicated in Alzheimer's disease pathology, particularly in amyloid plaque formation. This approach could differ from existing treatments that primarily focus on neurotransmitter modulation or amyloid-beta clearance. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with mild to moderate Alzheimer's Disease who have experienced mental decline in the past year and tested positive for P. Gingivalis infection. Participants must be able to take a daily capsule and commit to frequent study center visits with caregiver support.

Inclusion Criteria

Plasma pTau217 above cutoff

Modified Hachinski score ≤4 at screening

Saliva rinse sample positive for P. gingivalis

Exclusion Criteria

I have not had cancer treatment in the last 5 years.

I do not have major neurological or psychiatric illnesses like schizophrenia or Parkinson's.

Other criteria in the Investigator's judgment that may interfere with the ability to participate in the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

up to 12 weeks

At least 2 visits (in-person)

Treatment

Participants receive LHP588 or placebo once daily for 48 weeks, with evaluations including medical history, physical exams, and cognitive assessments

48 weeks

At least 20 visits (in-person), 1 contact (phone)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person), 1 contact (phone)

What Are the Treatments Tested in This Trial?

Interventions

• LHP588

Trial Overview The study tests LHP588, aimed at targeting P. Gingivalis bacteria linked to dementia, against a placebo. The goal is to see if it can slow down Alzheimer's progression. It involves blind treatment over up to 64 weeks, including assessments like MMSE and blood tests.

How Is the Trial Designed?

Group I: LHP588 50 mg Experimental Treatment 1 Intervention

Group II: LHP588 25 mg Experimental Treatment 1 Intervention

Group III: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Lighthouse Pharmaceuticals, Inc.

Lead Sponsor

Trials

1

Recruited

300+

Published Research Related to This Trial

In a one-year study involving 51 older adults with Alzheimer's disease, nizatidine did not show any significant effect on delaying cognitive decline compared to a placebo.

Despite initial hopes for nizatidine as a treatment to slow symptom progression in Alzheimer's, the trial results indicate it is ineffective for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine. Carlson, MC., Tschanz, JT., Norton, MC., et al.[2019]

In a study of 1332 patients with Alzheimer's disease or other dementias in France, the prevalence of adverse drug reactions (ADRs) was found to be 5.0%, with serious ADRs occurring in 31.9% of cases, highlighting the potential risks associated with medication in this population.

The most common ADRs were gastrointestinal, central nervous system, and psychiatric disorders, with anti-dementia and psychotropic drugs being the most frequently implicated, indicating a need for careful monitoring and prescribing practices in patients with dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross-sectional study. Laroche, ML., Perault-Pochat, MC., Ingrand, I., et al.[2013]

Idalopirdine, when used as an adjunctive therapy in patients with mild to moderate Alzheimer's disease, demonstrated good tolerability over an extended period of up to 18 months, with treatment-emergent adverse events reported in 51-59% of patients, but no new safety concerns were identified.

Despite its safety profile, idalopirdine did not show consistent efficacy benefits when added to donepezil or memantine, indicating that while it is safe for long-term use, it may not provide significant therapeutic advantages in treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-Label, Multicenter, Phase III Extension Study of Idalopirdine as Adjunctive to Donepezil for the Treatment of Mild-Moderate Alzheimer's Disease. Frölich, L., Atri, A., Ballard, C., et al.[2020]

In a study involving 487 patients with Alzheimer's dementia and psychosis, aripiprazole at 10 mg/day significantly improved psychotic symptoms and agitation compared to placebo, demonstrating its efficacy in this population.

While aripiprazole was generally safe, there were reports of cerebrovascular adverse events, particularly at higher doses, highlighting the need for careful monitoring when prescribing atypical antipsychotics to elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses. Mintzer, JE., Tune, LE., Breder, CD., et al.[2022]

Idalopirdine, a selective 5-HT6 receptor antagonist, showed no significant overall efficacy in improving cognitive function in Alzheimer's disease patients compared to placebo, based on a meta-analysis of 4 randomized controlled trials involving 2,803 participants.

While idalopirdine may have some effectiveness at higher doses and in patients with moderate Alzheimer's, it is associated with a higher risk of adverse events, including elevated liver enzymes and vomiting, raising concerns about its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of idalopirdine for Alzheimer's disease: a systematic review and meta-analysis. Matsunaga, S., Fujishiro, H., Takechi, H.[2020]

This study quantified lysosomal vesicles at amyloid plaques in the human hippocampus, revealing that both diffuse and neuritic plaques contain LAMP1-positive vesicles, indicating their potential role in Alzheimer's disease.

Unlike mouse models, not all amyloid plaques in humans accumulated lysosomal vesicles, suggesting differences in the disease mechanisms between species and highlighting the spatial distinction between lysosomal vesicle accumulation and phospho-tau presence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus. Hassiotis, S., Manavis, J., Blumbergs, PC., et al.[2023]

In Alzheimer's disease (AD) stages I-IIA/B and V-VIC, there is a significant upregulation of LAMP-1 mRNA and protein levels in the frontal cortex, indicating a potential role of lysosomes in the disease process.

LAMP-1 expression is associated with specific neuronal changes, such as granulovacuolar degeneration, and its presence in microglia suggests involvement in the clearance of amyloid burden, highlighting its potential role in the turnover of beta-amyloid and hyperphosphorylated tau in AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lysosome-associated membrane protein 1 (LAMP-1) in Alzheimer's disease. Barrachina, M., Maes, T., Buesa, C., et al.[2010]

Research in Alzheimer's disease models shows that age-related increases in β-amyloid peptide (Aβ) near synapses lead to early synapse dysfunction, indicating a critical role of Aβ in the disease's progression.

The study reveals that Aβ accumulation at synapses is linked to plaque formation and is influenced by synaptic activity, suggesting that understanding the normal function of amyloid precursor protein (APP) could help develop therapies to counteract synapse dysfunction in Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The inside-out amyloid hypothesis and synapse pathology in Alzheimer's disease. Gouras, GK., Willén, K., Faideau, M.[2014]

Alzheimer's disease (AD) is a leading cause of dementia, affecting a significant portion of the elderly population, and current treatments like memantine and acetylcholinesterase inhibitors only alleviate symptoms without curing the disease.

Recent clinical trials are exploring new therapeutic approaches targeting key pathological features of AD, including promising Phase III trials for passive immunotherapy against amyloid-β peptides and small molecules aimed at inhibiting tau aggregation and BACE activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug candidates in clinical trials for Alzheimer's disease. Hung, SY., Fu, WM.[2018]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross-sectional study. [2013]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Open-Label, Multicenter, Phase III Extension Study of Idalopirdine as Adjunctive to Donepezil for the Treatment of Mild-Moderate Alzheimer's Disease. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of idalopirdine for Alzheimer's disease: a systematic review and meta-analysis. [2020]

6. France pubmed.ncbi.nlm.nih.gov

Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Lysosome-associated membrane protein 1 (LAMP-1) in Alzheimer's disease. [2010]

8. Switzerland pubmed.ncbi.nlm.nih.gov

The inside-out amyloid hypothesis and synapse pathology in Alzheimer's disease. [2014]

9. England pubmed.ncbi.nlm.nih.gov

Drug candidates in clinical trials for Alzheimer's disease. [2018]