Evaluation of BMS-986446, an Anti-MTBR Tau Monoclonal Antibody, in Early Alzheimer's Disease: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study

The primary objective of this study is to evaluate the change in **thinking** and general functioning at Week 76, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), in participants with early Alzheimer's disease. This is clinically relevant as it aims to assess the efficacy of the anti-MTBR tau monoclonal antibody, BMS-986446, in potentially slowing cognitive decline and functional deterioration in this patient population.

Secondary objectives include measuring the build-up of **tau** in the brain using a position emission tomography (PET) scan. Additionally, the integrated Alzheimer’s Disease Rating Scale (iARDS) will be utilized to assess the effect of the study drug on delaying the worsening of symptoms related to cognitive and general functioning. These objectives are crucial for understanding the broader impact of the treatment on disease progression and symptom management.

The clinical trial for **Early Alzheimer’s Disease** involves a total of 391 participants. The study population includes both male and female subjects, with an age range primarily encompassing older adults, as indicated by the age range categories provided. Participants were selected based on specific criteria, including mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia, consistent with the National Institute on Aging and the Alzheimer's Association core clinical criteria. The trial does not focus on a vulnerable population, and participants are expected to have a Global Clinical Dementia Rating score between 0.5 to 1.0, with evidence of Alzheimer's pathology. Additionally, participants must demonstrate objective impairment in episodic memory and have a Mini Mental Status Examination score ranging from 22 to 30. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures a representative sample of individuals affected by early stages of Alzheimer's disease, aiming to assess changes in thinking and general functioning over the course of the trial.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, and tolerability of BMS-986446, an anti-MTBR tau monoclonal antibody, in participants with early **Alzheimer's disease**. The trial is set to commence recruitment on August 30, 2024, and is expected to conclude by November 16, 2027. The primary objective is to assess the change in thinking and general functioning at Week 76, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary endpoints include changes in brain tau deposition, integrated Alzheimer's Disease Rating Scale (iADRS) score, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog14) score, Mini Mental State Examination (MMSE) score, and Alzheimer's Disease Cooperative Study-instrumental Activities of Daily Living scale (ADCS-iADL) score.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia, a Global Clinical Dementia Rating (CDR) score of 0.5 to 1.0, and evidence of Alzheimer's disease pathology. The study will include follow-up visits at regular intervals to monitor the participants' health and response to the treatment. The end-of-study visit will occur at Week 76, marking the completion of the treatment period. The expected length of participant involvement is approximately 76 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures.

The investigational product, BMS-986446, will be administered intravenously as a solution for injection. Participants will be randomly assigned to receive either the active treatment or a placebo, ensuring the study's double-blind nature. The trial will also utilize Florquinitau F-18 for imaging purposes, and sodium chloride as a placebo. The study is not classified as a low-intervention trial and is categorized as a Phase II trial. Participants' involvement will be closely monitored to ensure adherence to the protocol and to address any potential safety concerns promptly.

The clinical trial involves the administration of **Florquinitau F-18**, a radiopharmaceutical agent used as an experimental medication. Florquinitau F-18 is provided in a **solution for injection** form, with each vial containing 10 mL. The active substance, **Florquinitau (18F)**, is a chemically synthesized compound. The administration route is **intravenous**, and the dosing schedule is determined by the study protocol, with a maximum daily dose and total dose amount set at 9999 mg/L and mmol/g, respectively. Participant compliance with the dosing regimen is monitored throughout the study period.

**PRX005** is another experimental medication used in this trial. It is a monoclonal antibody targeting the microtubule-binding region of tau protein, provided as a **solution for injection** with a concentration of 50 mg/mL. The active substance, **PRX005**, is of protein origin. The administration is conducted via the **intravenous** route. The dosing schedule is aligned with the study protocol, with a maximum daily and total dose amount of 9999 mg/mL. Compliance with the administration schedule is closely monitored to ensure adherence to the study protocol.

**Sodium Chloride** is utilized as a non-experimental treatment in this study, serving as a placebo. The pharmaceutical form and specific details regarding the administration route and dosage are not applicable. Sodium Chloride is included to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. Compliance with the administration of Sodium Chloride is monitored to maintain the integrity of the study design.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints, focusing on participants with early Alzheimer's disease. The primary endpoint is the mean change from baseline at Week 76 in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. This endpoint will evaluate changes in thinking and general functioning, providing a comprehensive measure of disease progression.

Secondary endpoints include the mean change from baseline at Week 76 in several other measures: brain tau deposition as measured by PET scan, the integrated Alzheimer’s Disease Rating Scale (iADRS) score, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog14) score, the Mini Mental State Examination (MMSE) score, and the Alzheimer’s Disease Cooperative Study-instrumental Activities of Daily Living scale (ADCS-iADL) score. These endpoints will provide additional insights into cognitive and functional changes in participants.

The efficacy parameters will be collected and analyzed at the end of the treatment period, which is Week 76. The Clinical Dementia Rating Scale and other validated scales will be utilized to ensure accurate and reliable measurement of cognitive and functional outcomes. The use of PET scans will allow for the assessment of **brain tau deposition**, a key biomarker in Alzheimer's disease. This comprehensive approach will enable a thorough evaluation of the treatment's impact on disease progression and patient outcomes.