Evaluation of Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Versus Intravenous Ocrelizumab in Multiple Sclerosis Patients

The primary objective of this study is to demonstrate the **pharmacokinetics** (PK) non-inferiority of the subcutaneous (SC) formulation of **ocrelizumab** in patients with **Multiple Sclerosis** (MS). This is clinically relevant as it aims to establish that the SC administration of ocrelizumab is as effective in terms of PK parameters as the intravenous (IV) formulation, potentially offering a more convenient administration route for patients.

Secondary objectives include:

• Determining the maximum serum concentration (Cmax) of ocrelizumab SC in patients with MS.
• Evaluating the radiological effects of ocrelizumab SC compared with ocrelizumab IV in patients with MS.
• Evaluating and comparing the safety profile after administration of ocrelizumab SC versus ocrelizumab IV and assessing the safety of ocrelizumab SC at the selected dose in patients with MS.
• Evaluating the immune response to ocrelizumab SC and IV, and rHuPH0.
• Evaluating the effect of ocrelizumab SC compared with IV ocrelizumab on the pharmacodynamics (PD) marker for the mechanism of action of ocrelizumab, specifically B cell depletion.
• Evaluating biomarkers that are predictive of response to ocrelizumab, are early surrogates of efficacy, are associated with progression to a more severe disease state, can provide evidence of ocrelizumab activity, or can increase the knowledge and understanding of disease biology.

The clinical trial involves a total of **69 participants** diagnosed with **Multiple Sclerosis (MS)**, specifically targeting individuals with primary progressive MS (PPMS) or relapsing forms of MS (RMS) as per the revised McDonald 2017 criteria. The study population includes both male and female subjects, aged between **18 to 65 years**, who are neurologically stable for at least 30 days prior to both screening and baseline. Participants are required to have an Expanded Disability Status Scale (EDSS) score ranging from 0 to 6.5 at screening. The trial population was selected based on specific criteria, including disease duration from the onset of MS symptoms of less than 15 years for those with an EDSS score below 2.0 at screening. Women of childbearing potential are required to adhere to specific contraceptive measures during the treatment period and for a designated period after the final dose of ocrelizumab. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study aims to demonstrate the pharmacokinetics non-inferiority of the subcutaneous formulation of ocrelizumab in this patient group.

The clinical trial is designed as a **Phase III**, non-inferiority, randomized, open-label, parallel group, multicenter study. It aims to investigate the pharmacokinetics, pharmacodynamics, safety, and radiological and clinical effects of subcutaneous **ocrelizumab** versus intravenous ocrelizumab in patients with **Multiple Sclerosis (MS)**. The trial is expected to run from April 30, 2022, to March 31, 2025. Participants will be randomly assigned to receive either the subcutaneous or intravenous formulation of ocrelizumab. The primary objective is to demonstrate the pharmacokinetics non-inferiority of the subcutaneous formulation in patients with MS.

The study will include several visits, starting with a screening visit to confirm eligibility based on criteria such as age, diagnosis of primary progressive MS or relapsing forms of MS, and neurological stability. Participants will then undergo baseline assessments before the initiation of treatment. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and pharmacokinetic parameters. These visits will include assessments such as brain MRI scans at Weeks 8, 12, and 24, and evaluations of adverse events and vital signs. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the long-term effects of the treatment.

Participant involvement is expected to last up to 96 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will assess primary endpoints such as the serum ocrelizumab area under the concentration-time curve after subcutaneous administration compared to intravenous infusion from Day 1 to Week 12. Secondary endpoints include the maximum serum concentration of ocrelizumab, the number of new or enlarging T2 lesions, and the incidence of treatment-emergent antidrug antibodies.

The clinical trial involves the administration of **ocrelizumab**, a monoclonal antibody, in different formulations and routes to evaluate its pharmacokinetics, pharmacodynamics, safety, and clinical effects in patients with **multiple sclerosis**. The experimental medication is provided in two pharmaceutical forms: a **solution for injection** and a **concentrate for solution for infusion**. The solution for injection is administered subcutaneously, while the concentrate for solution for infusion is administered intravenously.

The first experimental treatment involves the subcutaneous administration of ocrelizumab, identified by the sponsor product code RO 496-4913/F09-01. This formulation is a solution for injection, developed by F. Hoffmann-La Roche Ltd. The dosing schedule for this formulation is not explicitly detailed in terms of milligrams per administration, but the maximum treatment period is specified as 96 weeks. The subcutaneous route is intended to provide a convenient alternative to intravenous administration, potentially improving patient compliance.

The second experimental treatment is another subcutaneous formulation of ocrelizumab, identified by the sponsor product code RO 496-4913/F09-02, also developed by F. Hoffmann-La Roche Ltd. Similar to the first subcutaneous formulation, this treatment is administered as a solution for injection. The maximum treatment period for this formulation is also 96 weeks, and it shares the same characteristics and administration route as the first subcutaneous formulation.

The third experimental treatment involves the intravenous administration of ocrelizumab, marketed under the name Ocrevus 300 mg concentrate for solution for infusion. This formulation is developed by Roche Registration GmbH and is administered as a solution for infusion. The maximum daily dose for this formulation is 300 mg, with a total maximum dose of 600 mg over a treatment period of 2 weeks. The intravenous route is the traditional method of administration for ocrelizumab, providing a controlled delivery of the medication directly into the bloodstream.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The trial aims to demonstrate the non-inferiority of the subcutaneous formulation compared to the intravenous formulation in terms of pharmacokinetics, while also assessing safety and clinical outcomes.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the serum ocrelizumab area under the concentration-time curve (AUC[w1-12]) after subcutaneous (SC) administration compared to intravenous (IV) infusion from Day 1 to Week 12. This will evaluate the pharmacokinetic non-inferiority of the SC formulation of ocrelizumab in patients with **Multiple Sclerosis** (MS).

Secondary endpoints include a range of pharmacodynamic, radiological, and safety measures. These include the maximum serum concentration (Cmax) of ocrelizumab SC, the total number of T1Gd+ lesions detected by brain magnetic resonance imaging (MRI) at Weeks 8 and 24, and the total number of new or enlarging T2 lesions detected by brain MRI at Weeks 12 and 24 relative to the previous scan. Safety will be assessed by the incidence and severity of adverse events, determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, changes from baseline in targeted vital signs and clinical laboratory test results, and the incidence of treatment-emergent antidrug antibodies (ADAs) to ocrelizumab and antibodies to rHuPH20. Additionally, the percentage of patients achieving CD19+ B cell level <5 cells/microliter at Weeks 12, 24, 48, and/or 96, and levels of biomarkers such as neurofilament light (NfL) in serum will be compared between dosing arms at specified timepoints.