MK-2214 for Alzheimer's Disease

Recruiting at 15 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: Anti-amyloid therapy, Immunosuppressants

Disqualifiers: Suicidal ideation, Cancer, HIV, others

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

48 Participants Needed

Trial Summary

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

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently receiving aducanumab or another anti-amyloid therapy, or if you are on systemic immunosuppression.

What data supports the effectiveness of the drug MK-2214 for Alzheimer's Disease?

Research on similar treatments, like tacrolimus (FK506), shows that targeting the calcineurin-Pin1 signaling pathway can reduce Alzheimer's prevalence, as seen in organ transplant patients. Additionally, masitinib, another drug in trials, has shown positive effects on cognitive functions in Alzheimer's patients. ^{1 2 3 4 5}

How does the drug MK-2214 for Alzheimer's disease differ from other treatments?

The research does not provide specific information about MK-2214, but it highlights the need for treatments targeting multiple pathways in Alzheimer's disease, such as the multitarget approach of Kai-Xin-San (KXS) and the selective inhibition of JNK3, which are different from single-target therapies. ^{6 7 8 9 10}

What is the purpose of this trial?

This trial is testing a new drug called MK-2214 to see if it is safe and how it behaves in the body. It targets adults with early memory and thinking problems, like mild cognitive impairment or mild-to-moderate Alzheimer's Disease. Researchers want to know if the drug reaches helpful levels in the brain fluid and stays there long enough to potentially help these conditions.

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with mild cognitive impairment or mild-to-moderate Alzheimer's Disease who are in good health, have a BMI between 18.5 and 35 kg/m2, and show a history of gradual cognitive decline over at least one year. Participants must score within certain ranges on mental state and ischemic assessments.

Inclusion Criteria

Participant is in overall good health based on medical history and laboratory safety tests

BMI between 18.5 and 35 kg/m^2

Have a Mini-Mental State Examination (MMSE) >12 at the prestudy visit

Exclusion Criteria

Based on clinical interview and Columbia-Suicide Severity Rating Scale (C-SSRS), has reported suicidal ideation with intent, with or without a plan or method

History of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food

I am on ongoing medication for an active autoimmune disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MK-2214 or placebo as an IV infusion on Days 1, 29, and 57

12 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

approximately 42 weeks

Treatment Details

Interventions

• MK-2214
• Placebo

Trial Overview The study tests the safety and effects of MK-2214 on patients with Alzheimer's-related cognitive issues. It measures how much drug reaches the brain fluid and its impact compared to a placebo (a substance with no therapeutic effect).

Participant Groups

Group I: MK-2214 Experimental Treatment 1 Intervention

Participants will receive MK-2214 administered in escalating doses as an intravenous (IV) infusion on Days 1, 29, and 57.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive placebo as an IV infusion on Days 1, 29, and 57.

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

Tacrolimus (FK506), an FDA-approved calcineurin inhibitor, can be safely delivered to APP/PS1 mice using time-release pellets, leading to normalization of calcineurin activity and significant reduction of Alzheimer's disease (AD) pathologies such as synapse loss and neuroinflammation.

The treatment with FK506 not only alleviated cognitive impairment and neuroinflammation but also preserved normal immune responses, suggesting it could be a promising early intervention for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response. Stallings, NR., O'Neal, MA., Hu, J., et al.[2023]

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]

In a 30-week study involving 663 patients with mild to moderate Alzheimer's disease, high-dose tacrine (up to 160 mg/d) showed significant improvements in cognitive function and quality of life compared to placebo, particularly on measures like the Clinician Interview-Based Impression (CIBI) and Alzheimer's Disease Assessment Scale (ADAS-Cog).

While tacrine was effective, it was associated with some adverse effects, including liver enzyme elevations and gastrointestinal issues, which were reversible upon stopping the medication, indicating a need for monitoring but not necessarily compromising its overall safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. Knapp, MJ., Knopman, DS., Solomon, PR., et al.[2022]

In a preliminary study of 16 patients with early Alzheimer's disease, the p38α kinase inhibitor neflamapimod showed potential to improve episodic memory function, with significant increases in memory scores observed at 28 and 84 days.

While there were no overall group effects on brain amyloid plaque load, a responder analysis indicated that some patients experienced a reduction in amyloid signal, suggesting a possible impact on β-amyloid production that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease. Scheltens, P., Prins, N., Lammertsma, A., et al.[2022]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response. [2023]

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

Masitinib for the treatment of Alzheimer's disease. [2021]

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

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

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

A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. [2022]

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

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease. [2022]

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

Classic Prescription, Kai-Xin-San, Ameliorates Alzheimer's Disease as an Effective Multitarget Treatment: From Neurotransmitter to Protein Signaling Pathway. [2020]

7. France pubmed.ncbi.nlm.nih.gov

Discovery of novel imidazole chemotypes as isoform-selective JNK3 inhibitors for the treatment of Alzheimer's disease. [2022]

8. China pubmed.ncbi.nlm.nih.gov

[Modified Kaixin San improves memory and synaptic damage of mice with Alzheimer's disease by modulating αCaMKⅡ-PSD95 protein binding through inhibition of neuroinflammation:a study of mechanism]. [2022]

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

Different protection of K252a and N-acetyl-L-cysteine against amyloid-beta peptide-induced cortical neuron apoptosis involving inhibition of MLK3-MKK7-JNK3 signal cascades. [2023]

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

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