Key messages
– Ocrelizumab is a recently approved medicine to treat people with multiple sclerosis (MS). In relapsing-remitting MS (where people experience flare-ups of symptoms), ocrelizumab probably substantially reduces flare-ups, may substantially reduce worsening of symptoms, and probably makes little or no difference to unwanted effects compared with interferon beta-1a (a standard treatment for MS), 96 weeks after treatment starts.
– Compared to placebo (a dummy medicine) after 120 weeks of treatment for primary progressive MS (where people's symptoms worsen gradually), ocrelizumab may reduce worsening of symptoms. Ocrelizumab probably increases unwanted effects but makes little or no difference to the number of serious unwanted effects.
– We need more, better-designed studies to test the effectiveness of ocrelizumab and measure unwanted effects.
What is multiple sclerosis?
MS is a condition where the body's immune system mistakenly attacks the nerves in the brain and spinal cord (the central nervous system). This damage prevents messages travelling from the central nervous system to other parts of the body. It causes a range of potential symptoms from pins and needles to difficulties with balance and walking.
There are several types of MS. In relapsing-remitting MS, people have 'flare-ups' of disease followed by periods of recovery. In primary progressive MS, people's symptoms gradually worsen over time.
What is ocrelizumab?
Ocrelizumab is a medicine that has been recently approved to treat relapsing-remitting MS and primary progressive MS. It is a disease-modifying therapy, which is a type of medicine that treats the underlying symptoms of MS. Ocrelizumab targets white blood cells in the body's immune system. It sticks to a type of these cells called B cells, and stops them attacking the central nervous system. This prevents inflammation and nerve damage, reducing the number and severity of relapses and slowing the worsening of symptoms.
What did we want to find out?
We wanted to find out if ocrelizumab is more effective than any other medicine or placebo in people with relapsing-remitting MS and primary progressive MS.
We were interested in how many people:
– had symptom flare-ups;
– had worsening symptoms;
– experienced unwanted effects; and
– stopped treatment due to unwanted effects.
What did we do?
We searched for studies that compared ocrelizumab against any other medicine or placebo for people with a confirmed diagnosis of relapsing-remitting MS or primary progressive MS. People in the studies could be any age or sex, could have mild or severe symptoms, and could have had MS for any length of time.
We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found four studies with 2551 people with MS. The largest study included 732 people and the smallest included 163 people. The studies were in countries around the world, but mostly in the USA. One study lasted for 24 weeks; two studies for 96 weeks; and one study for at least 120 weeks. Pharmaceutical companies funded the four studies.
Three studies compared ocrelizumab with interferon beta-1a in people with relapsing-remitting MS. Interferon beta-1a is an older type of disease-modifying therapy. One study compared ocrelizumab with placebo for people with primary progressive MS.
Main results
Ocrelizumab compared with interferon beta-1a for people with relapsing-remitting MS, after 96 weeks of treatment:
– probably substantially reduces the number of people who had flare-ups;
– may substantially reduce the number of people whose symptoms got worse;
– probably makes little or no difference to unwanted effects; and
– may substantially reduce the number of people who stopped having treatment due to unwanted effects.
Ocrelizumab compared with placebo for people with primary progressive MS, after 120 weeks of treatment:
– may reduce the number of people whose symptoms got worse;
– probably increases unwanted effects; and
– may make little or no difference to the number of serious unwanted effects and the number of people who stopped having treatment due to unwanted effects.
What are the limitations of the evidence?
Our confidence in the results is moderate to low for several reasons. First, people dropped out of the studies unevenly, which meant more people had one treatment than the other. Second, there was not enough information about some of our points of interest to allow us to draw conclusions for outcomes, there was not enough information available for us to be confident in the results. Finally, changes in symptoms shown by scans could have been due to causes other than disease progression.
How up-to-date is this evidence?
The evidence is up-to-date to 8 October 2021.
For people with RRMS, ocrelizumab probably results in a large reduction in relapse rate and little to no difference in adverse events when compared with interferon beta-1a at 96 weeks (moderate-certainty evidence). Ocrelizumab may result in a large reduction in disability progression, treatment discontinuation caused by adverse events, number of participants with gadolinium-enhancing T1 lesions on MRI, and number of participants with new or enlarging T2-hyperintense lesions on MRI, and may result in little to no difference in serious adverse events (low-certainty evidence).
For people with PPMS, ocrelizumab probably results in a higher rate of adverse events when compared with placebo for at least 120 weeks (moderate-certainty evidence). Ocrelizumab may result in a reduction in disability progression and little to no difference in serious adverse events and treatment discontinuation caused by adverse events (low-certainty evidence).
Ocrelizumab was well tolerated clinically; the most common adverse events were infusion-related reactions and nasopharyngitis, and urinary tract and upper respiratory tract infections.
Ocrelizumab is a humanised anti-CD20 monoclonal antibody developed for the treatment of multiple sclerosis (MS). It was approved by the Food and Drug Administration (FDA) in March 2017 for using in adults with relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only disease-modifying therapy (DMT) approved for PPMS. In November 2017, the European Medicines Agency (EMA) also approved ocrelizumab as the first drug for people with early PPMS. Therefore, it is important to evaluate the benefits, harms, and tolerability of ocrelizumab in people with MS.
To assess the benefits, harms, and tolerability of ocrelizumab in people with RRMS and PPMS.
We searched MEDLINE, Embase, CENTRAL, and two trials registers on 8 October 2021. We screened reference lists, contacted experts, and contacted the main authors of studies.
All randomised controlled trials (RCTs) involving adults diagnosed with RRMS or PPMS according to the McDonald criteria, comparing ocrelizumab alone or associated with other medications, at the approved dose of 600 mg every 24 weeks for any duration, versus placebo or any other active drug therapy.
We used standard methodological procedures expected by Cochrane.
Four RCTs met our selection criteria. The overall population included 2551 participants; 1370 treated with ocrelizumab 600 mg and 1181 controls. Among the controls, 298 participants received placebo and 883 received interferon beta-1a. The treatment duration was 24 weeks in one study, 96 weeks in two studies, and at least 120 weeks in one study. One study was at high risk of allocation concealment and blinding of participants and personnel; all four studies were at high risk of bias for incomplete outcome data.
For RRMS, compared with interferon beta-1a, ocrelizumab was associated with: 1. lower relapse rate (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.52 to 0.73; 2 studies, 1656 participants; moderate-certainty evidence); 2. a lower number of participants with disability progression (hazard ratio (HR) 0.60, 95% CI 0.43 to 0.84; 2 studies, 1656 participants; low-certainty evidence); 3. little to no difference in the number of participants with any adverse event (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 1651 participants; moderate-certainty evidence); 4. little to no difference in the number of participants with any serious adverse event (RR 0.79, 95% CI 0.57 to 1.11; 2 studies, 1651 participants; low-certainty evidence); 5. a lower number of participants experiencing treatment discontinuation caused by adverse events (RR 0.58, 95% CI 0.37 to 0.91; 2 studies, 1651 participants; low-certainty evidence); 6. a lower number of participants with gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) (RR 0.27, 95% CI 0.22 to 0.35; 2 studies, 1656 participants; low-certainty evidence); 7. a lower number of participants with new or enlarging T2-hyperintense lesions on MRI (RR 0.63, 95% CI 0.57 to 0.69; 2 studies, 1656 participants; low-certainty evidence) at 96 weeks.
For PPMS, compared with placebo, ocrelizumab was associated with: 1. a lower number of participants with disability progression (HR 0.75, 95% CI 0.58 to 0.98; 1 study, 731 participants; low-certainty evidence); 2. a higher number of participants with any adverse events (RR 1.06, 95% CI 1.01 to 1.11; 1 study, 725 participants; moderate-certainty evidence); 3. little to no difference in the number of participants with any serious adverse event (RR 0.92, 95% CI 0.68 to 1.23; 1 study, 725 participants; low-certainty evidence); 4. little to no difference in the number of participants experiencing treatment discontinuation caused by adverse events (RR 1.23, 95% CI 0.55 to 2.75; 1 study, 725 participants; low-certainty evidence) for at least 120 weeks. There were no data for number of participants with gadolinium-enhancing T1 lesions on MRI and number of participants with new or enlarging T2-hyperintense lesions on MRI.