Trial Outcomes & Findings for A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS) (NCT NCT04544436)

A total of 864 participants with relapsing multiple sclerosis (RMS) took part in the study at 122 investigative sites across 21 countries. The study is still ongoing.

Participants received double-blinded treatment (DBT) with either ocrelizumab higher dose (1200 milligrams \[mg\] or 1800 mg) based on the participant's body weight (BW) or ocrelizumab 600 mg for a minimum of up to 120 weeks. 4 participants had a major good clinical practice (GCP) violation and were hence excluded from all analysis sets used in this study. Therefore, results are presented for 860 participants.

A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS)

Time to onset of 12-week cCDP=first occurrence of a 12-week cCDP according to at least 1 of the 3 criteria: 1) CDP=12-week confirmed increase (CI) from baseline (FB) in expanded disability status scale (EDSS) score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 12-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 12-week CI of ≥20% FB in Timed 25-foot Walk Test (T25FWT) score OR 3)12-week CI of ≥ 20% FB in 9-hole Peg Test (9-HPT) score. EDSS = disability scale that ranges in 0.5-point steps from 0 \[normal\]-10.0 \[death\]. In T25FWT test participants walked to a 25 foot course as quickly \& safely as possible. Score = average of 2 completed trials (in seconds). In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. In T25FWT \& 9-HPT the longer it took complete test= higher scores, indicating deterioration.

Time to onset of a 24 week cCDP=first occurrence of a 24-week cCDP according to at least 1 of 3 criteria: 1) CDP=24-week CI from baseline in EDSS score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 24-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 24-week CI of ≥20% FB in T25FWT score OR 3) 24-week CI of ≥ 20% FB in 9-HPT score. EDSS = disability scale that ranges in 0.5-point steps from 0 \[normal\]-10.0 \[death\]. In T25FWT test participants walked to a 25 foot course as quickly \& safely as possible. Score = average of 2 completed trials (in seconds). In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. In T25FWT \& 9-HPT the longer it took complete test= higher scores, indicating deterioration.

Time to onset of a 48-week cCDP=first occurrence of a 48-week cCDP according to at least 1 of 3 criteria: 1) CDP=48-week CI from baseline in EDSS score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 48-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 48-week CI of ≥20% FB in T25FWT score OR 3) 48-week CI of ≥ 20% FB in 9-HPT score. EDSS = disability scale that ranges in 0.5-point steps from 0 \[normal\]-10.0 \[death\]. In T25FWT test participants walked to a 25 foot course as quickly \& safely as possible. Score = average of 2 completed trials (in seconds). In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. In T25FWT \& 9-HPT the longer it took complete test= higher scores, indicating deterioration.

Time to onset of 12-week cCDP=first occurrence of a 12-week cCDP according to at least 1 of 3 criteria: 1) CDP=12-week CI from baseline in EDSS score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 12-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 12-week CI of ≥20% FB in T25FWT score OR 3) 12-week CI of ≥ 20% FB in 9-HPT score. EDSS score, T25FWT \& 9-HPT are the same as defined in primary outcome measure. Protocol-defined relapse=occurrence of new or worsening neurological symptoms attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days. Symptoms persist for at least 24 hours \& accompanied by objective neurological worsening consistent with an increase of one of the following: Half a step (0.5 point) on the EDSS; Two points on one of the functional system scores (FSS) (pyramidal, ambulation, cerebellar, brainstem, sensory, or visual); One point on ≥2 more of the FSS.

CDP was defined as a 12-week confirmed increase from baseline in EDSS score of ≥1.0 point in participants with a baseline EDSS score of ≤5.5 or a 12-week CI ≥0.5 points in participants with a baseline EDSS score of \>5.5. The EDSS was used to measure changes in the disability level of participants with MS over time. EDSS is based on a standard neurological examination, incorporating functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral \[or mental\]) that are rated and then scored as a FSS, and ambulation, which is scored as ambulation score. Each FSS is an ordinal clinical rating scale where score range from 0 to 5 or 6, and ambulation score that is rated from 0 to 16. These ratings along with observations and assistive devices were then used to determine the total EDSS score. The total EDSS score ranges from 0 (normal) to 10.0 (death) in 0.5-point steps.

T25FWT test is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant was directed to start at one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly and safely as possible. The Examining Investigator timed the participants from the start of the walk to the end of the 25 feet. The task was immediately administered again by having the participant walk back the same distance. Participants could use assistive devices (e.g., cane, crutch, or rollator) when performing the task. Score was the average of the two completed trials, measured in seconds. The longer it takes to walk, higher the score, indicating deterioration. A 20% change from baseline of the averaged T25FWT was considered clinically meaningful.

Brain volume was measured using magnetic resonance imaging (MRI) scans. Mean difference in annual rate of percent change from baseline in total brain volume between the higher and approved dose of ocrelizumab arms in participants with RMS where no treatment discontinuation nor initiation of alternative MS treatment occurred, are reported.

The SDMT is a performance measure that demonstrated sensitivity in detecting the presence of cognitive impairment and changes in cognitive functioning over time \& in response to treatment. The SDMT presents a series of nine symbols, each paired with a single digit in a key at the top of a standard sheet of paper. Participants were asked to pair specific numbers with given geometric figures within 90 seconds. Responses were collected orally. The score is the number of correctly paired items in 90 seconds with a maximum score of 110 and minimum of 0. Higher scores indicate improvement. A four-point change from baseline was considered clinically meaningful.

The MSWS-12 was a 12-item self-report measure of the impact of MS on the participant's ability to walk during the past 2 weeks. Each item was scored on a 5-point Likert scale ranging from 1 (not at all) to 5 (extremely likely). Scores were summed and linearly converted to a 0-100 scale with higher scores indicating greater impact of MS on walking ability. An 8-point change was considered clinically meaningful.

NfL is a biomarker of neuroinflammation in CSF. Ratio of change from baseline in NfL at Week 48 for RMS participants where no treatment discontinuation nor initiation of alternative MS treatment occurred within the ocrelizumab higher dose arm has been reported. The results correspond to fold change from baseline (ie ratio of adjusted geometric means at week 48 vs baseline).

NfL is a biomarker of neuroinflammation in CSF. Ratio of change from baseline in NfL at Week 48 for RMS participants where no treatment discontinuation nor initiation of alternative MS treatment occurred within the ocrelizumab approved dose arm has been reported. The results correspond to fold change from baseline (ie ratio of adjusted geometric means at week 48 vs baseline).

AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Prevalence of ADAs at baseline was defined as the percentage of participants that is ADA positive at baseline. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer unit (t.u.) greater than the baseline titer result. Percentages have been rounded off.