A 2-Part, Multicenter, Randomized, Blinded, Active-Controlled Phase 2 Study to Sequentially Evaluate the Safety and Efficacy of BIIB091 Monotherapy and BIIB091 Combination Therapy With Diroximel Fumarate in Participants With Relapsing Forms of Multiple Sclerosis

The primary objective of this study is to investigate the **safety** and tolerability of BIIB091 monotherapy in participants with relapsing forms of multiple sclerosis (RMS). This is clinically relevant as it aims to establish the safety profile of BIIB091, which is crucial for determining its potential as a therapeutic option for RMS. Additionally, the study seeks to evaluate the effects of BIIB091 combination therapy with Diroximel Fumarate (DRF) compared with the DRF monotherapy arm on the key Magnetic Resonance Imaging (MRI) measure of active Central Nervous System (CNS) inflammation, which is important for understanding the efficacy of the combination therapy in reducing CNS inflammation.

Secondary objectives include: - Evaluating the effects of BIIB091 monotherapy on MRI measures of active CNS inflammation. - Assessing the effects of BIIB091 combination therapy with DRF compared with the DRF monotherapy arm on additional MRI measures of active CNS inflammation. - Investigating the safety and tolerability of BIIB091 combination therapy with DRF in participants with RMS.

The clinical trial involves a total of **80 participants** diagnosed with **Relapsing Forms of Multiple Sclerosis**, including both **relapsing-remitting multiple sclerosis** and active secondary progressive multiple sclerosis, as per the 2017 Revised McDonald criteria. The study population comprises both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on specific criteria, including a time since multiple sclerosis symptom onset of less than 20 years and an expanded disability status scale score between 0 and 5.0 at screening and baseline. The trial does not include a vulnerable population. Participants must have experienced at least one clinical relapse within the past 24 months, with additional MRI evidence of disease activity. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to assess the safety and tolerability of BIIB091 monotherapy and its combination with Diroximel Fumarate, focusing on the effects on active central nervous system inflammation as measured by MRI.

The clinical trial is designed as a **randomized**, **blinded**, active-controlled Phase 2 study to evaluate the safety and efficacy of BIIB091 monotherapy and its combination with **Diroximel Fumarate** in participants with relapsing forms of **Multiple Sclerosis**. The trial is structured in two parts, with the primary objective of Part 1 being to assess the safety and tolerability of BIIB091 monotherapy. Part 2 aims to evaluate the effects of BIIB091 in combination with Diroximel Fumarate compared to Diroximel Fumarate monotherapy, focusing on the key **Magnetic Resonance Imaging (MRI)** measure of active **Central Nervous System (CNS)** inflammation. The trial is expected to commence recruitment on September 1, 2023, and conclude by November 9, 2026, with an estimated duration of 48 weeks for each participant's involvement.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a diagnosis of relapsing-remitting multiple sclerosis or active secondary progressive multiple sclerosis, and an **Expanded Disability Status Scale (EDSS)** score between 0 and 5.0. Following the screening, eligible participants will be randomized into one of the treatment arms. The study does not include a placebo control group; however, placebo is used for masking purposes. Participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including the number of new T1 **Gadolinium-Enhancing (GdE)** lesions and other MRI measures. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

Participant involvement may be terminated early if they experience serious adverse events or if they no longer meet the study criteria. The primary endpoints include the number of participants with adverse events and serious adverse events in Part 1, and the cumulative number of new T1 GdE lesions in Part 2. Secondary endpoints encompass various MRI measures and changes in cardiac parameters. The trial is not classified as low intervention and is conducted to investigate the safety and efficacy of potential therapeutic regimens for relapsing forms of multiple sclerosis.

The clinical trial involves the administration of **BIIB091**, an experimental medication formulated as a **tablet**. The active substance in BIIB091 is (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide. This chemical compound is administered orally with a maximum daily dose of 700 mg and a total maximum dose of 235.2 g over a treatment period of 48 weeks. The medication is provided by Biogen Idec Research Limited and is classified as a small molecule.

**Diroximel fumarate** is another experimental treatment used in this study, provided in the form of gastro-resistant hard capsules. The active substance, diroximel fumarate, is administered orally with a maximum daily dose of 924 mg and a total maximum dose of 310.4 g over a 48-week period. This chemical compound is supplied by Biogen Netherlands B.V. and is also classified as a small molecule.

For auxiliary purposes, **Clariscan 0.5 mmol/ml** is used, which is a solution for injection containing the active substance **gadoteric acid**. This chemical compound is administered via injection, with a focus on its role in imaging procedures rather than as a therapeutic agent. The product is provided by GE Healthcare Buchler GmbH & Co. KG.

Another auxiliary treatment is **Solu-Moderín 125 mg**, a solution for injection containing the active substance **methylprednisolone**. This chemical compound is administered via injection with a maximum daily dose of 1000 mg and a total maximum dose of 5000 mg over a 5-day period. The product is supplied by Pfizer, S.L.

The study employs a **placebo** for masking purposes only. All participants are randomized to one of the active treatment arms, and no participant receives placebo treatment exclusively. The placebo is not used as a control group in this study.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the number of participants with adverse events (AEs) and serious adverse events (SAEs) in Part 1, and the cumulative number of new T1 **Gadolinium-Enhancing (GdE) Lesions** in Part 2. Secondary endpoints for Part 1 include the cumulative number of new T1 GdE lesions, cumulative number and volume of new or enlarging T2 hyperintense lesions, mean change from baseline in QT interval corrected for heart rate using Fridericia's formula (QTcF), RR, PR, QRS, and QT intervals, number of participants with change from baseline in heart rate, and number of participants with clinically significant electrocardiogram (ECG) abnormalities. For Part 2, secondary endpoints include the cumulative number and volume of new or enlarging T2 hyperintense lesions, number of participants with AEs and SAEs, number of participants with change from baseline in QTcF, RR, PR, QRS, and QT intervals, number of participants with change from baseline in heart rate, and number of participants with ECG abnormalities as assessed by 12-lead ECG measurements.