Earlier Ocrevus treatment may reduce cerebellar shrinkage in MS
Study shows long-term effects in relapsing MS, PPMS
Early treatment with Ocrevus (ocrelizumab) may help protect the cerebellum, a region of the brain that plays a key role in motor coordination, cognitive function, and emotional regulation, from damage in people with multiple sclerosis (MS), a study suggested.
Data from the clinical studies that supported Ocrevus’ approval showed that patients with relapsing forms of MS and primary progressive MS (PPMS) who began the medication earlier experienced significantly less cerebellar volume loss than those who first received a control treatment or a placebo and started the therapy only in the trials’ open-label extension portions.
These differences were maintained in the long term.
The study, “Short- and long-term effects of early versus delayed treatment with ocrelizumab on cerebellar volume loss in patients with RMS and PPMS,” was published in the Multiple Sclerosis Journal. The research was funded by Roche, the parent company of Ocrevus’ developer Genentech.
MS is a neurological disorder in which the immune system mistakenly attacks the myelin sheath, a fatty coating around nerve fibers that facilitates the communication between nerve cells. This causes regions of damage, which are seen in MRI scans as lesions, and leads to nerve cell death.
Ocrevus treatment trials
When nerve cells and neural connections are lost, the brain and its structures shrink faster than what’s typical with aging. Brain atrophy, or shrinkage, is often used to monitor the degree of neurodegeneration in MS patients.
The cerebellum is increasingly recognized as one of the brain regions affected in all stages of MS, with patients experiencing faster rates of cerebellar volume loss compared with healthy people.
A recent study suggested that Ocrevus, an antibody that aims to deplete B-cells, key drivers of MS inflammation, may help to reduce cerebellar volume loss in people with relapsing forms of MS.
To learn more, an international team of researchers examined data from the three Phase 3 trials that formed the basis for the approvals of Ocrevus — OPERA I (NCT01247324) and OPERA II (NCT01412333) for relapsing forms of MS, and ORATORIO (NCT01194570) for PPMS.
The OPERA trials enrolled more than 1,600 patients who were randomly assigned to receive Ocrevus or Rebif (interferon beta-1a) for 96 weeks (nearly two years) and then entered an open-label extension, in which all are receiving long-term Ocrevus.
The ORATORIO study enrolled 732 participants who received either Ocrevus or a placebo for at least 120 weeks, or about 2.3 years, after which most also entered an open-label extension portion.
All extensions are ongoing. At the time the data for this analysis was gathered, patients from the OPERA trials had been receiving Ocrevus for up to eight years and those from ORATORIO for up to 7.5 years.
In both trials and their extensions, MRI scans were used to monitor cerebellar and overall brain volume at multiple time points.
Results showed that patients with relapsing forms of MS who received Ocrevus in the OPERA trials had 30% less reduction in cerebellar volume after 96 weeks compared with those treated with Rebif in the main trials. Patients in both groups experienced similar rates of cerebellar volume atrophy in the open-label portion, meaning that the differences observed at the end of the main trials were kept until the end of the follow-up period.
In the PPMS group, the initial difference in cerebellar atrophy between Ocrevus and the placebo was lower, at 16%, at the end of the ORATORIO trial and reaching up to 22% during the open-label extension.
Again, patients who eventually transitioned to Ocrevus in the extension started to experience similar cerebellar atrophy at a similar rate as those who had always been on Ocrevus, so the greater early cerebellar volume loss was never reversed after switching.
Volume loss in PPMS vs relapsing MS
Cerebellar volume loss in the extension portions occurred almost twice as fast in PPMS (a reduction of 0.30% per year) compared with relapsing MS (0.18% per year), despite similar initial cerebellar volumes.
The researchers attributed this accelerated decline to continuous and slow inflammatory and neurodegenerative processes that result in faster irreversible tissue loss. In contrast, relapsing forms of MS are primarily driven by acute inflammatory activity, which responds more effectively to therapies like Ocrevus.
Finally, the team found that a greater cerebellar volume at the start of the OPERA trials was linked with better initial scores on certain clinical measures, such as disability levels, dexterity, and walking ability. Such correlations were not observed in the ORATORIO trial.
There was no evidence that initial cerebellar volumes could predict the likelihood of confirmed disability progression in patients with either relapsing forms of MS or PPMS, meaning there’s no “clear evidence to support the routine measurement of cerebellar volume in patients receiving anti-CD20 therapies,” the team wrote.
“Our results show that ocrelizumab helps preserve cerebellar volume and its integrity when treatment is started earlier,” the researchers wrote, adding that more studies are needed to understand how changes in cerebellar atrophy correlate with long-term clinical outcomes.
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