Early use of Ocrevus (ocrelizumab) significantly slows shrinkage of the thalamus — a brain region involved in sensory and motor functions — in people with relapsing forms of multiple sclerosis (MS) and primary progressive MS (PPMS), according to new analyses from three Phase 3 trials that compared immediate use with a two-year delay.
These data also suggested that initial (baseline) thalamic volume may be used as a predictor of disability progression in relapsing MS patients.
Findings were presented by Douglas Arnold, MD, with McGill University’s Montreal Neurological Institute and Hospital, in Canada, at the MSVirtual2020 that ran Sept. 11–13. It marked the 8th joint meeting of the American (ACTRIMS) and European (ECTRIMS) Committees for Treatment and Research in MS.
Arnold is also president and CEO of NeuroRx Research, a company focused on advanced image analysis techniques of the central nervous system (the brain and spinal cord) to provide outcome data.
His oral presentation was titled “Reduced thalamic atrophy in patients initiating earlier versus delayed ocrelizumab therapy: results from the OLE of OPERA I/II and ORATORIO” (abstract # FC03.05).
The thalamus is a brain structure that not only serves as a kind of relay and integration center for sensory information other than smell, but also is involved in motor control, alertness, memory, and cognition.
In MS patients, thalamic shrinkage, or atrophy, occurs early and consistently over the course of the disease. Its integrity is affected both directly by neuronal death, and indirectly by lesions in other brain areas that connect with the thalamus.
“Pathological studies have revealed a loss of up to one-third of neurons in the thalamus” of MS patients, Arnold said.
Loss of thalamic volume is “associated with disability progression, both physical and cognitive,” he added, and may be “a particularly useful marker of the biological effects of the disease and also of the effects of treatments.”
In a Roche-funded study, Arnold and colleagues compared the effectiveness of early and delayed treatment with Ocrevus at slowing thalamic shrinkage in relapsing MS and PPMS patients who participated in Phase 3 clinical trials of this medication.
Ocrevus, developed by Roche’s subsidiary Genentech, is approved in the U.S. and European Union to treat adults with relapsing forms of MS (clinically isolated syndrome, relapsing-remitting MS and active secondary progressive MS), as well as those with PPMS.
In the OPERA studies, 1,656 relapsing MS patients were treated either with Ocrevus or Rebif (interferon beta-1a; an approved therapy marketed by EMD Serono) for 96 weeks (about 1.8 years). EMD Serono is known as Merck KGaA outside the U.S. and Canada.
In ORATORIO, 732 PPMS patients were assigned to either Ocrevus or a placebo for at least 120 weeks (about 2.3 years).
After completing the trials, participants were invited to enter an open-label extension period, in which all would be treated with Ocrevus.
The current analysis included data from the completed two-year double-blind part of all three studies, and from their ongoing extension phases, totaling about four (ORATORIO) to six years (OPERA) of data.
In terms of patient characteristics, ORATORIO participants were older, more often male, and had higher disability (as assessed with the expanded disability status scale) and a smaller average brain volume than those in the OPERA trials.
Mean normalized thalamic volume at the trial’s start, when accounting for co-variates, was not significantly different between OPERA and ORATORIO trial patients. But when looking at thalamic volume over time, researchers found that patients who were initially assigned to Ocrevus had significantly lesser thalamic atrophy than those switching to Ocrevus two years later.
Early Ocrevus treatment resulted in a 16% lower thalamic atrophy in relapsing MS patients, compared with those initially treated with Rebif, and a 25% lower thalamic volume loss in PPMS patients compared with those initially on placebo.
Changes in thalamic volumes were also similar between OPERA and ORATORIO patients on Ocrevus since study start. However, in the first two years of the trials and compared with patients given Ocrevus from the start, relapsing MS patients initially on Rebif appeared to show a greater loss of thalamic volume than PPMS patients on a placebo (43% vs. 35%).
Arnold noted that this was consistent with an acceleration of thalamic atrophy when initiating interferon therapy, an effect known as pseudoatrophy — a rapid, short-term drop in brain volume over a few months when patients start an anti-inflammatory therapy.
This Rebif-associated pseudoatrophy appeared to be reversed after patients switched to Ocrevus, but thalamic volume never reached the values seen in patients continuously treated with Ocrevus.
Overall, “in the open-label extension of the Phase 3 OPERA I and III and ORATORIO trials, patients with relapsing MS and PPMS who were initially randomized to [Ocrevus] experienced less thalamic volume loss compared with those initiating [Ocrevus] later,” Arnold said.
The team also found that baseline thalamic volume was significantly associated with different measures of disability progression in both the OPERA and ORATORIO trials.
Notably, relapsing MS patients with baseline thalamus volume lower than the median were significantly more likely to have confirmed disability progression during their trial’s first two years (the double-blind period) than those with larger thalamus. No similar association was found for PPMS patients in ORATORIO.
According to Arnold, these findings suggest that initial thalamic volume may be used to predict disability progression in people with relapsing forms of MS.
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