Disability Builds in Relapsing MS in Ways Not Tied to Relapses, Analysis Finds

Disability appears to mostly accumulate in people with relapsing forms of multiple sclerosis (MS) in a progressive manner — rather than being due to relapses, a pooled analysis of patients in two Ocrevus (ocrelizumab) clinical trials shows.

These findings, indicating that disease progression underlies relapsing MS as well, “challenge the current clinical distinction of relapsing and progressive forms of multiple sclerosis,” the researchers wrote.

“We provide evidence that, in a typical population with relapsing MS, 80% to 90% of overall disability accumulation occurred independently of relapses,” they wrote. “This observation, obtained in the setting of 2 state-of-the-art prospective phase 3 trials, challenges the current paradigm of a dichotomy” in disease course between these two MS forms.

The study, “Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials,” was published in the journal JAMA Neurology.

New symptoms in MS are considered to either occur in isolated attacks and build up in a stepwise manner (relapsing MS), or build up continuously over time, independent of relapses, as a consequence of progressive disease.

Relapsing and progressive MS are generally regarded as distinct clinical entities, with patients accumulating disability through different mechanisms. But increasing evidence supports relapsing MS patients also worsening over time, even when relapses are well under control.

Researchers in five countries set out to investigate how relapse-associated worsening (RAW) and steady progression independent of relapse activity (PIRA) contribute to overall disability accumulation in relapsing MS.

Pooled data from two identical and randomized Phase 3 trials — OPERA I (NCT01247324) and OPERA II (NCT01412333) — investigating Ocrevus against Rebif (interferon beta-1a) were used.  These data used were collected between August 2011 and April 2015, and analyses took place between July 2015 and February 2020.

Trial results led to Ocrevus’ approval for relapsing forms of MS, such as clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. The therapy, developed by Genentech, a member of the Roche Group, is also approved for primary progressive MS based on data from a separate trial.

This pooled analysis covered 1,656 of the 2,096 patients enrolled in the OPERA trials, treated either with Ocrevus every six months or Rebif three times a week for 96 weeks (about 1.8 years). It findings also show Ocrevus as superior to Rebif at lowering a risk of disability accumulation.

Overall disability worsening was determined via a composite outcome called confirmed disability accumulation (CDA), which takes into account overall function on the expanded disability status scale (EDSS) as well as upper and lower extremity function. Ability in the upper extremities were measured using the 9-hole peg test (9HPT), an investigator-administered test of fine finger movements, and for lower extremities using timed 25 foot walk (T25FW), which assesses the time taken to safely walk 25 feet.

Results showed that most first events of disability accumulation were due to PIRA events, meaning that most patients were progressing independent of relapses.

In fact, 88% of patients on Ocrevus and 78% of those given Rebif with a first event of composite disability accumulation in their trial’s first 12 weeks did so due to continuous disability progression rather than a relapse.

Likewise, disability accumulation after a first disability event within 24 weeks was attributed to a PIRA event in 89.1% of patients on Ocrevus and 80.6% of those on Rebif.

Only a small group of patients had disability accumulation after both PIRA and RAW events — 4.4% by week 12 and 5% by week 24 — suggesting these events did not overlap in most people in these trials.

Relapses were more frequent in the Rebif group compared with the Ocrevus group. But while 29.7% of patients on Ocrevus with relapses experienced disability accumulation in CDA after 12 weeks, only 16.6% had disability accumulation due to RAW events. A similar trend was seen in patients on Rebif: 38.9% of those with relapses had CDA increases, of which 18.8% were found to be due to RAW events.

More than half of RAW events were driven by worsening in overall function, or increases in the EDSS scores, while these accounted for less than 30% of PIRA events, the researchers stated. Rather, PIRA events were mostly due to worsening in T25FW scores.

Factors predicting CDA and PIRA events were essentially the same, the team noted. These included male sex, longer duration of MS symptoms, greater number and volume of brain lesions seen on an MRI, lower brain volume, and higher disability burden, among many others.

In contrast, only the presence of T1 gadolinium-enhancing MRI lesions (active lesions) was associated with both relapse and RAW events.

Ocrevus was better than Rebif at preventing disability accumulation, lowering the risk of a CDA event at week 12 by 33%, and by 30% at week 24. It also significantly lowered the risk of PIRA events — by 22% at both weeks 12 and 24 — and RAW events — by 53% at week 12 and 59% at week 24.

“Our results show that most overall disability accumulation in RMS [relapsing MS] is attributable to an underlying progressive disease course independent of relapse activity, challenging the current phenotypical distinction of relapsing and progressive forms of MS,” the researchers wrote.

Such a finding “strongly supports that MS may be a single disease continuum with an underlying progressive disease course and a highly variable superimposed accumulation of disability resulting from relapses with incomplete recovery,” they added.

“In this study, ocrelizumab was superior to interferon β-1a in preventing confirmed disability accumulation, irrespective of its association with relapses,” the team concluded.