MK-1167 for Alzheimer's Disease

Recruiting at 32 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Merck Sharp & Dohme LLC

Must be taking: Acetylcholinesterase inhibitors

Disqualifiers: Stroke, CNS disease, Seizures, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

Researchers want to learn if giving MK-1167 (the study medicine) along with acetylcholinesterase inhibitor (AChEI) therapy can improve symptoms of Alzheimer's disease dementia (AD dementia), such as memory and mental activity. AD dementia is the most common type of dementia. AChEI therapy is the standard treatment for AD dementia. The goals of this study are to learn: * If at least one dose level (amount) of MK-1167 works to improve a person's memory and thinking compared to a placebo * About the safety of MK-1167 and if people tolerate it

Do I need to stop my current medications for the trial?

The trial requires participants to continue using acetylcholinesterase inhibitors (AChEI) therapy for Alzheimer's disease dementia, so you will not need to stop this medication. The protocol does not specify about other medications.

What data supports the effectiveness of the drug MK-1167 for Alzheimer's disease?

The research on M1 muscarinic agonists, which are similar to MK-1167, shows they can enhance cognitive function and reduce Alzheimer's disease markers in animal models. This suggests that MK-1167 might also be effective in targeting Alzheimer's symptoms. ^{1 2 3 4 5}

How does the drug MK-1167 differ from other Alzheimer's treatments?

MK-1167 is unique because it targets the M1 muscarinic receptor, which is involved in memory and cognition, and has the potential to modify the disease by reducing harmful proteins like beta-amyloid and tau in the brain, unlike many current treatments that only address symptoms. ^{1 2 6 7 8}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for people with mild to moderate Alzheimer's Disease dementia, specifically stages 4 or 5. Participants must have a Mini-Mental State Examination score of 12-24 and be on standard acetylcholinesterase inhibitor therapy. They also need a study partner who knows them well enough to provide detailed information about their daily functioning.

Inclusion Criteria

I have someone who knows me well and can provide detailed information about my daily life and health for the study.

My condition is in the mild to moderate stages of Alzheimer's Disease.

My mental state score is between 12 and 24.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MK-1167 or placebo once daily for up to approximately 24 weeks

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• MK-1167 (Monoclonal Antibodies)

Trial Overview The study is testing whether MK-1167 can improve memory and thinking in those with AD dementia when taken alongside standard AChEI therapy. It aims to determine the effectiveness of at least one dose level of MK-1167 compared to a placebo, as well as its safety and tolerability.

Participant Groups

Group I: MK-1167 3 mg Experimental Treatment 1 Intervention

Participants receive 3 mg of MK-1167 once daily (QD) for up to approximately 24 weeks.

Group II: MK-1167 1 mg Experimental Treatment 1 Intervention

Participants receive 1 mg of MK-1167 QD for up to approximately 24 weeks.

Group III: MK-1167 0.3 mg Experimental Treatment 1 Intervention

Participants take 0.3 mg of MK-1167 QD for up to approximately 24 weeks.

Group IV: Placebo Placebo Group 1 Intervention

Participants take placebo QD for up to approximately 24 weeks.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a randomized, double-blind trial involving 240 participants with mild-to-moderate Alzheimer's disease, the selective M1 muscarinic positive allosteric modulator MK-7622 did not show any significant improvement in cognitive function or daily living activities after 12 and 24 weeks of treatment.

The study was halted for futility, and a higher percentage of participants taking MK-7622 discontinued due to adverse events compared to those on placebo (16% vs 6%), indicating potential safety concerns with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer's disease. Voss, T., Li, J., Cummings, J., et al.[2022]

AF267B, an M1-selective muscarinic agonist, has shown promise in reducing beta-amyloid levels in both rabbits and triple transgenic mice models of Alzheimer's disease, indicating its potential as a cognitive enhancer and disease modifier.

The mechanism of action for AF267B involves the activation of M1 mAChR, which leads to reduced cognitive deficits and decreases in both beta-amyloid and tau pathologies, highlighting its role in targeting key hallmarks of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

M1 muscarinic agonists target major hallmarks of Alzheimer's disease--the pivotal role of brain M1 receptors. Fisher, A.[2008]

In an 11-week study involving 181 patients with mild to moderate Alzheimer's disease, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid modulator LY451395 did not show significant improvement in cognitive function compared to placebo, as measured by the ADAS-Cog scale.

While there were some marginal improvements in neuropsychiatric symptoms after 8 weeks of treatment, the overall safety profile was similar between LY451395 and placebo, with most adverse events being mild.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AMPA potentiator treatment of cognitive deficits in Alzheimer disease. Chappell, AS., Gonzales, C., Williams, J., et al.[2022]

The study evaluated halogenated thiophene chalcone-based molecules as dual inhibitors of human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) for potential Alzheimer's disease treatment, finding moderate ChE inhibition with IC50 values between 14-70 µM.

Among the compounds tested, T8 and T6 exhibited the strongest inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively, suggesting that T8 could be further optimized for better AChE inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones. Parambi, DGT., Aljoufi, F., Murugaiyah, V., et al.[2019]

Memantine, a drug that blocks NMDA receptors, showed a small but significant benefit in patients with moderate-to-severe Alzheimer's disease after 28 weeks, with a mean difference of 0.3 in the global score compared to placebo.

Patients taking memantine experienced less deterioration in daily living activities, with a score change of 2.1 compared to 3.4 in the placebo group, highlighting its potential as a valuable treatment option in a field with limited effective medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is memantine a breakthrough in the treatment of moderate-to-severe Alzheimer's disease? Doggrell, S.[2019]

Chronic activation of the M1 muscarinic acetylcholine receptor using the agonist VU0364572 in 5XFAD mice prevented memory impairments and reduced levels of harmful amyloid-beta (Aβ) proteins, suggesting a neuroprotective effect against Alzheimer's disease.

The study indicates that M1 activation not only helps maintain cognitive function but also decreases the presence of oligomeric Aβ, highlighting its potential as a dual-action treatment for both symptoms and underlying pathology in early Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model. Lebois, EP., Schroeder, JP., Esparza, TJ., et al.[2018]

AF267B, a selective M1 muscarinic agonist, has shown promise in reducing key Alzheimer's disease (AD) hallmarks, such as beta-amyloid levels and tau hyperphosphorylation, while also improving cognitive deficits in various animal models, indicating its potential efficacy as a treatment.

The compound demonstrated a wide safety margin and effectively penetrated the central nervous system, making it a unique candidate for clinical trials aimed at addressing multiple aspects of AD pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

M1 muscarinic agonists target major hallmarks of Alzheimer's disease--an update. Fisher, A.[2022]

M1 muscarinic acetylcholine receptor (mAChR) dysfunction in Alzheimer's disease is linked to increased beta-amyloid and tau protein levels, which contribute to cognitive decline.

M1-selective muscarinic agonists, such as AF102B and AF150(S), show promise in improving cognitive function and regulating beta-amyloid and tau protein levels in animal models, suggesting they may offer a unique therapeutic approach compared to traditional acetylcholinesterase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists. Fisher, A.[2019]

References

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

Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer's disease. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

M1 muscarinic agonists target major hallmarks of Alzheimer's disease--the pivotal role of brain M1 receptors. [2008]

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

AMPA potentiator treatment of cognitive deficits in Alzheimer disease. [2022]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones. [2019]

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

Is memantine a breakthrough in the treatment of moderate-to-severe Alzheimer's disease? [2019]

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

Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model. [2018]

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

M1 muscarinic agonists target major hallmarks of Alzheimer's disease--an update. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists. [2019]