A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy, Safety, and Tolerability of BIIB080 in Subjects with Mild Cognitive Impairment Due to Alzheimer’s Disease or Mild Alzheimer’s Disease Dementia

The primary objective of this study is to **characterize the dose-response** in change from Baseline to Week 76 using the Clinical Dementia Rating-Sum of Boxes (CDR-SB) in participants with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia. This is clinically relevant as it aims to determine the optimal dosing of BIIB080, potentially leading to improved management of cognitive decline in Alzheimer's disease.

Secondary objectives include:

• Testing the superiority of at least one dose arm of BIIB080 versus placebo in change from Baseline to Week 76 using CDR-SB.
• Evaluating the efficacy of BIIB080 versus placebo in change from Baseline to Week 76.
• Assessing the safety and tolerability of BIIB080 in participants with mild cognitive impairment due to Alzheimer's disease or with mild Alzheimer's disease dementia.

The clinical trial involves a total of **408 participants** diagnosed with **Mild Cognitive Impairment due to Alzheimer's Disease** or **Alzheimer's Disease Dementia**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific clinical criteria, including a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Memory Index score of ≤85, a Clinical Dementia Rating (CDR) global score of 0.5 for MCI or 0.5 to 1 for mild dementia, and a Mini-Mental State Examination (MMSE) score between 22 and 30. Additionally, evidence of amyloid pathology was required, as determined by positive emission tomography (PET) or cerebrospinal fluid (CSF) sampling. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group study** to evaluate the efficacy, safety, and tolerability of BIIB080 in subjects with mild cognitive impairment due to **Alzheimer's disease** or mild Alzheimer's disease dementia. The primary objective is to characterize the dose-response in change from baseline to Week 76 using the Clinical Dementia Rating-Sum of Boxes (CDR-SB). The trial is expected to run until December 2026, with recruitment having commenced in March 2023. Participants will be involved for a maximum treatment period of 105 weeks.

Study visits are structured to include an initial **screening visit** to confirm eligibility based on criteria such as a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Memory Index score of ≤85, a CDR global score of 0.5 or 1, and evidence of amyloid pathology. Following the screening, participants will undergo regular follow-up visits to monitor changes in cognitive function and assess any treatment-emergent adverse events. The **end-of-study visit** will conclude the participant's involvement, evaluating the primary and secondary endpoints, including changes in CDR-SB and other cognitive assessments.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial involves the administration of BIIB080 via **intrathecal use**, with a placebo group receiving an artificial cerebrospinal fluid diluent. The study aims to provide insights into the potential therapeutic benefits of BIIB080 in altering the progression of cognitive impairment associated with Alzheimer's disease.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **Neuraceq** is a **solution for injection** containing **florbetaben (18F)** as the active substance. It is administered intravenously with a maximum daily and total dose of 300 MBq. The treatment period is limited to one day. This radiopharmaceutical is used for imaging purposes and is produced by Life Radiopharma Berlin GmbH.

**BIIB080** is another experimental medication in the trial, formulated as a **solution for injection**. The active substance is a **2ʹ-O-(2-methoxyethyl) antisense oligonucleotide targeting microtubule-associated protein tau pre-mRNA**. This medication is administered via intrathecal use, with a maximum daily dose of 115 mg and a total dose of 805 mg over a treatment period of 105 days. The product is developed by Biogen Idec Research Limited and is classified as an antisense oligonucleotide.

**MK-6240** is also included in the study, presented as a **solution for injection** with the active substance **6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)-5-isoquinolinamine**. It is administered intravenously, with a maximum daily dose of 185 MBq and a total dose of 370 MBq over a two-day treatment period. This chemical compound is used for imaging and is provided by Biogen Idec Research Limited.

**Vizamyl** is another investigational product, available as a **solution for injection** containing **flutemetamol (18F)**. It is administered intravenously with a maximum daily and total dose of 185 MBq, limited to a one-day treatment period. This radiopharmaceutical is produced by GE Healthcare AS and is used for diagnostic imaging.

The trial also includes a **placebo** for BIIB080, which is an artificial cerebrospinal fluid diluent, formulated as a solution for injection. The placebo is used to maintain the double-blind nature of the study and does not contain any active pharmaceutical ingredient. It is administered in the same manner as BIIB080 to ensure consistency in the trial protocol.

The efficacy of the investigational product BIIB080 in subjects with mild cognitive impairment due to Alzheimer's Disease or mild Alzheimer's Disease dementia will be assessed using several parameters. The primary endpoint is the dose-response in change from Baseline to Week 76 on the **Clinical Dementia Rating-Sum of Boxes (CDR-SB)**. Secondary endpoints include changes from Baseline to Week 76 on the CDR-SB, ADCS-ADL-MCI, ADAS-Cog 13, MMSE, Modified iADRS, and ADCOMS. Additionally, the number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will be recorded.

The efficacy assessments will be conducted at specified timepoints, with the primary and secondary endpoints measured at Baseline and Week 76. The CDR-SB, a validated scale, will be used to evaluate changes in cognitive and functional performance. Other scales such as ADCS-ADL-MCI, ADAS-Cog 13, MMSE, Modified iADRS, and ADCOMS will also be utilized to provide a comprehensive assessment of cognitive and functional changes. Data collection will be performed in a double-blind, placebo-controlled, parallel-group study design to ensure the reliability and validity of the results.