A Multi-Center, Double-Blind, Placebo-Controlled, Phase II Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of RO7268489, A Monoacylglycerol Lipase Inhibitor, as Add-On Therapy to Ocrelizumab, in Participants with Progressive Forms of Multiple Sclerosis

The primary objective of this study is to assess the efficacy of RO7268489, a monoacylglycerol lipase inhibitor, as add-on therapy to ocrelizumab in adults with progressive forms of multiple sclerosis (PMS) on disability progression. This evaluation is clinically relevant as it addresses the need for therapeutic strategies to mitigate disability accumulation in patients with progressive disease phenotypes who are receiving anti-CD20 therapy.

The secondary objectives include: • To assess the effect of RO7268489 on cognition in adults with PMS receiving ocrelizumab • To assess the pharmacodynamics of RO7268489 in adults with PMS receiving ocrelizumab • To assess the safety and tolerability of RO7268489 in adults with PMS receiving ocrelizumab • To assess the plasma pharmacokinetics (PK) of RO7268489 in adults with PMS receiving ocrelizumab

The clinical trial enrolled a total of **140 participants** diagnosed with **progressive forms of multiple sclerosis (PMS)**. The study population consisted of adults aged **18 to 60 years**, inclusive, with both male and female subjects eligible for participation. Participants were required to have an **Expanded Disability Status Scale (EDSS)** score between 3.0 and 6.0 at screening, indicating moderate disability levels. A key selection criterion was documented evidence of **disability progression** independent of relapse activity over the 2 years preceding enrollment. All participants were receiving or had received **ocrelizumab** treatment, with specific provisions for those who had discontinued the medication more than 2 years prior to screening, provided the discontinuation was unrelated to safety or efficacy concerns and **B cell counts** were normalized. Participants were required to comply with wearing a **digital gait assessment device** throughout the study period as specified in the protocol. The trial included vulnerable populations as defined by regulatory standards.

This is a multi-center, **double-blind**, **placebo-controlled**, **Phase II** clinical trial designed to evaluate the safety, **pharmacokinetics**, **pharmacodynamics**, and efficacy of **RO7268489**, a **monoacylglycerol lipase inhibitor**, as add-on therapy to **ocrelizumab** in participants with **progressive forms of multiple sclerosis**. The trial employs a **randomized** design to assess the therapeutic potential of RO7268489 when administered in combination with ocrelizumab compared to placebo. The study is estimated to commence recruitment in February 2027 and is projected to conclude in May 2030, representing an overall trial duration of approximately 3 years.

The investigational medicinal products include **Ocrevus** 300 mg concentrate for **solution for infusion** containing ocrelizumab, administered via the **intravenous** route at a maximum daily dose of 600 mg and a maximum total dose of 5400 mg over a treatment period of 48 months. RO7268489 is provided as hard capsules for **oral** administration in multiple formulations. A placebo formulation of RO7268489 is also utilized to maintain blinding. Ocrelizumab is a protein-based therapeutic agent, while RO7268489 is a small molecule chemical compound.

The primary objective of the trial is to assess the efficacy of RO7268489 in adults with progressive multiple sclerosis receiving ocrelizumab on disability progression. The **primary endpoint** is the time from randomization to the first occurrence of composite **confirmed disability progression** confirmed for at least 12 weeks (cCDP12) according to at least one of three criteria: 12-week confirmed disability progression (CDP12), 12-week confirmed increase in **Timed 25-Foot Walk Test** (T25FWT), or 12-week confirmed increase in **9-Hole Peg Test** (9-HPT). Secondary endpoints include time to 24-week confirmed worsening in **Symbol Digit Modalities Test** (SDMT), plasma **2-arachidonoylglycreol** (2-AG) levels and changes from baseline, and comprehensive safety assessments.

Eligible participants must be aged 18 to 60 years at the time of consent and have progressive multiple sclerosis in accordance with the revised 2017 McDonald criteria. An **Expanded Disability Status Scale** (EDSS) score between 3.0 and 6.0 inclusive at screening is required. Documented evidence of disability progression independent of relapse activity over the 2 years before screening must be present according to protocol-specified criteria. Participants who previously received ocrelizumab and discontinued it more than 2 years prior to screening must have stopped for reasons unrelated to safety or lack of efficacy and must have normal B cell count at screening. Agreement to wear a digital gait assessment device as per study protocol is mandatory.

Safety assessments throughout the trial include monitoring the incidence, severity, and causal relationship of **adverse events**, incidence of treatment discontinuations due to adverse events, changes in vital signs and **ECG** parameters, incidence of abnormal laboratory findings, and proportion of participants with suicidal ideation or behavior as assessed by the **Columbia-Suicide Severity Rating Scale** (C-SSRS). Pharmacokinetic evaluations involve measurement of plasma concentrations of RO7268489 and its metabolites as appropriate. Participants are expected to remain in the study for the duration of the treatment period, which may extend up to 48 months for ocrelizumab treatment. Early termination from the study may occur due to adverse events, lack of efficacy, withdrawal of consent, protocol violations, or investigator decision based on safety concerns.

The experimental treatment **Ocrevus** (ocrelizumab) is administered as a 300 mg **concentrate for solution for infusion**. The product is supplied by Roche Registration GmbH and has been relabeled and repackaged for clinical trial use. The active substance **ocrelizumab** is a protein-based therapeutic agent. Ocrevus is administered via the **intravenous route**. The maximum daily dose is **600 mg**, with a maximum total dose of **5400 mg** over the treatment period. The maximum treatment duration is **48 weeks**. This medicinal product is used as add-on therapy in participants with progressive forms of **multiple sclerosis**.

The experimental investigational medicinal product **RO7268489** is a **monoacylglycerol lipase inhibitor** classified as a small molecule. It is formulated as **hard capsules** for oral administration. The product is supplied by F. Hoffmann-La Roche Ltd and is available in multiple formulations identified by sponsor product codes RO 726-8489/F09-01, RO 726-8489/F10-01, RO 726-8489/F11-01, and RO 726-8489/F12-01. The active substance RO7268489 is of chemical origin. The medicinal product is administered via the **oral route**. The maximum treatment period for each formulation is **1 day**. RO7268489 is being evaluated as add-on therapy to ocrelizumab in this clinical trial.

A **placebo** comparator for RO7268489 is included in the study design. The placebo is used to maintain the double-blind nature of the trial and to provide a control group for assessing the efficacy and safety of the active investigational medicinal product. The placebo formulation is designed to match the appearance of the active RO7268489 capsules to ensure adequate blinding of study participants and investigators.

The primary efficacy endpoint is the time from randomization to the first occurrence of composite confirmed disability progression confirmed for at least 12 weeks (cCDP12). This composite endpoint is defined by at least one of the following three criteria: 12-week confirmed disability progression (CDP12), 12-week confirmed increase in Timed 25-Foot Walk Test (T25FWT), or 12-week confirmed increase in 9-Hole Peg Test (9-HPT). Secondary efficacy endpoints include the time from randomization to the first occurrence of 24-week confirmed decrease of at least 4 points (worsening) in Symbol Digit Modalities Test (SDMT). Additionally, plasma 2-arachidonoylglycreol (2-AG) levels and change from baseline in plasma 2-AG levels will be assessed as secondary endpoints. Plasma concentrations of RO7268489 and its metabolite(s) will also be measured as appropriate.