A Phase 2 Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Study to Evaluate the Efficacy and Safety of MK-2214 in Participants with Early Alzheimer's Disease

The primary objectives of this clinical trial are to compare the efficacy of MK-2214 versus placebo in slowing the progression of tau spreading, as measured by the change from baseline in tau positron emission tomography (PET) standardized uptake value ratio (SUVr), and to evaluate the safety and tolerability of MK-2214. These objectives address the critical need to assess whether MK-2214 can modify the pathological progression of tau pathology in Alzheimer's disease, a key driver of neurodegeneration and cognitive decline.

The secondary objectives include:

• To compare the efficacy of MK-2214 versus placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB).

• To compare the efficacy of MK-2214 versus placebo in slowing the progression of tau spreading, as measured by the change from baseline in the composite tau PET SUVr in Braak region III and IV.

• To compare the efficacy of MK-2214 versus placebo in slowing the progression of tau spreading, as measured by the change from baseline in the composite tau PET SUVr.

• To compare the efficacy of MK-2214 versus placebo in slowing the progression of tau spreading, as measured by the PET SUVr in Braak region I to VI.

• To evaluate the efficacy of MK-2214 versus placebo on the change from baseline in the AD Assessment Scale–Cognitive Subscale 13 (ADAS-Cog13) Total Score.

• To evaluate the efficacy of MK-2214 versus placebo on the change from baseline in the Alzheimer's Disease Cooperative Study Activities of Daily Living for mild cognitive impairment (ADCS-ADL-MCI) score.

• To evaluate the efficacy of MK-2214 versus placebo on the change from baseline in modified integrated Alzheimer's Disease Rating Scale (iADRS) score.

This clinical trial enrolled a total of **283 participants** diagnosed with **Alzheimer's Disease**. The study population included both **male** and **female** subjects comprising **adults** and **elderly** individuals. Participants presented with **mild cognitive impairment** or **mild dementia** due to Alzheimer's Disease. Each participant was required to have a designated study partner capable of fulfilling the study requirements. Subjects receiving approved Alzheimer's Disease therapy for symptomatic treatment were required to maintain a stable dosing regimen for at least 3 months prior to screening. The trial did not involve vulnerable populations.

This is a Phase 2 **randomized**, **placebo-controlled**, **double-blind**, **parallel-group** study designed to evaluate the efficacy and safety of **MK-2214** in participants with early **Alzheimer's disease**. The study aims to compare the efficacy of MK-2214 versus placebo in slowing the progression of tau spreading, as measured by the change from baseline in **tau positron emission tomography (PET)** **standardized uptake value ratio (SUVr)**. Additionally, the study will evaluate the safety and tolerability of MK-2214. The trial is scheduled to commence recruitment in August 2025 and is estimated to conclude in September 2029.

Eligible participants must have **mild cognitive impairment (MCI)** or **mild dementia** due to Alzheimer's disease and must have a designated study partner who can fulfill the requirements of this study. Participants who are receiving an approved Alzheimer's disease therapy for symptomatic treatment must have been on a stable dosing regimen for at least 3 months prior to screening. The study will utilize **MK-2214** administered as a **solution for injection/infusion** via **intravenous infusion**, with a maximum treatment period of 100 weeks. **Florquinitau F18**, a solution for injection containing **florquinitau (18F)**, will be used as an auxiliary medicinal product administered via **intravenous injection** for PET imaging purposes, with a maximum daily dose of 370 **MBq** and a maximum total dose of 1110 MBq over a period of 3 days. A placebo to MK-2214 will be administered to the control group.

The primary endpoints include the change from baseline in tau PET SUVr, the number of participants who experience one or more **adverse events (AEs)**, and the number of participants who discontinue study intervention due to an AE. Secondary endpoints encompass changes from baseline in several clinical and cognitive assessments, including the **Clinical Dementia Rating-Sum of Boxes (CDR-SB)** total score, composite tau PET SUVr in various Braak regions, the **Alzheimer's Disease Assessment Scale–Cognitive Subscale 13 (ADAS-Cog13)** total score, the **Alzheimer's Disease Cooperative Study Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL-MCI)** total score, and the modified **Integrated Alzheimer's Disease Rating Scale (iADRS)** total score.

Participants will undergo a screening visit to determine eligibility for the study. Following enrollment, participants will attend scheduled follow-up visits throughout the treatment period for administration of study intervention, safety assessments, and efficacy evaluations including PET imaging and cognitive testing. An end-of-study visit will be conducted upon completion of the treatment period or upon early termination. The expected length of participant involvement extends up to approximately 100 weeks of treatment, with additional time for screening and follow-up assessments. Participants may be subject to early termination from the study due to adverse events, withdrawal of consent, protocol violations, or other conditions as determined by the investigator or sponsor.

The experimental medication under investigation is MK-2214, a biological product classified as a protein-based therapeutic agent. MK-2214 is supplied as a solution for injection/infusion and is administered via intravenous infusion. The maximum treatment period for MK-2214 is 100 weeks. The product is manufactured by Merck & Co. Inc. and contains MK-2214 as the active substance.

The comparator treatment in this study is placebo to MK-2214, which serves as the control intervention in this randomized, double-blind, parallel-group trial. The placebo is designed to match the experimental medication to maintain blinding throughout the study.

Florquinitau F18 is utilized as an auxiliary agent for diagnostic imaging purposes in this clinical trial. Florquinitau F18, also known as [18F] MK-6240, is a radiopharmaceutical supplied as a solution for injection. The active substance is florquinitau (18F), which is of chemical origin. This agent is administered via intravenous injection for tau positron emission tomography (PET) imaging. The maximum daily dose is 370 MBq (megabecquerels), with a maximum total dose of 1110 MBq over a maximum treatment period of 3 days. Florquinitau F18 is used to measure tau spreading in participants with early Alzheimer's disease by assessing changes in standardized uptake value ratio (SUVr) from baseline.

Efficacy will be assessed through multiple parameters evaluating disease progression and clinical outcomes in participants with early **Alzheimer's disease**. The primary efficacy endpoint is the change from baseline in tau positron emission tomography (PET) standardized uptake value ratio (SUVr), which measures the progression of tau spreading. Additional primary endpoints include the number of participants who experience one or more adverse events and the number of participants who discontinue study intervention due to an adverse event.

Secondary efficacy endpoints comprise several validated clinical and cognitive assessment tools. The Clinical Dementia Rating-Sum of Boxes (CDR-SB) total score will be evaluated for change from baseline to assess overall dementia severity. Cognitive function will be measured using the change from baseline in the Alzheimer's Disease Assessment Scale–Cognitive Subscale13 (ADAS-Cog13) total score. Functional abilities will be assessed through the change from baseline in the Alzheimer's Disease Cooperative Study Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL-MCI) total score. The modified Integrated Alzheimer's Disease Rating Scale (iADRS) total score will be used to evaluate combined cognitive and functional outcomes. Additional tau PET imaging endpoints include the change from baseline in composite tau PET SUVr in Braak Region III and IV, the overall composite tau PET SUVr, and the composite tau PET SUVr in Braak Region I to VI.