Ocrevus Effective in RRMS Patients With Poor Responses to Prior DMTs

Ocrevus (ocrelizumab) safely and effectively prevents relapses and disease progression in relapsing-remitting multiple sclerosis (RRMS) patients who responded poorly to other disease-modifying therapies (DMTs), final two-year data from the CHORDS Phase 3b clinical trial show.

Notably, these benefits also were observed among patients who enrolled in the study based only on subclinical disease activity, highlighting the importance of switching to a new DMT, such as Ocrevus, when others have failed, even in patients without clinical events.

Also, pronounced reductions in relapses and brain lesions were observed after the first six months of treatment, likely representing the time needed for Ocrevus to exert its effects, the researchers noted.

The study, “Ocrelizumab treatment for relapsing-remitting multiple sclerosis after a suboptimal response to previous disease-modifying therapy: A nonrandomized controlled trial,” was published in the Multiple Sclerosis Journal.

Despite significant advancements in MS therapies, many patients still show poor responses to DMTs, with clinical or subclinical disease activity —  progression of brain lesions without overt symptoms.

Switching these patients “to a more effective option, before significant neurological damage has occurred, is critical to minimize disease progression and ensure optimal long-term outcomes,” the researchers wrote.

Developed by Roche’s subsidiary Genentech, Ocrevus is a B-cell depleting DMT approved in the U.S. and European Union for adults with relapsing forms of MS or with primary progressive MS (PPMS). B-cells are a type of immune cell involved in the abnormal immune attacks that drive nerve cell damage in MS.

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The therapy’s benefits in relapsing MS were demonstrated in the OPERA I and II Phase 3 trials (NCT01247324 and NCT01412333), with Ocrevus being superior to Rebif (interferon beta-1a) at reducing relapse rates and disease progression.

The CHORDS Phase 3b study (NCT02637856) evaluated the safety and effectiveness of nearly two years of treatment with Ocrevus in 608 adults with RRMS who had not responded well to a treatment course of at least six months with another DMT. Participants were recruited across 90 study sites in North America.

A poor response was defined as either one or more clinical relapses, or new or enlarging brain lesions, as detected by magnetic resonance imaging (MRI) scans. Ocrevus was administered directly into the bloodstream once every 24 weeks (nearly six months).

Participants’ mean age was 37.2 years and they had been living with an MS diagnosis for a mean of 4.2 years. Most (44.2%) patients qualified for the trial due to MS relapse only, while nearly 30% had subclinical disease activity, based on MRI data only.

Most patients previously received one (55.1%) or two (36.2%) DMTs, with a mean duration of last DMT use of 26.4 months (over two years) and an interval of 1.5 months between last DMT and Ocrevus initiation.

The most frequently used DMTs prior to Ocrevus were glatiramer acetate (sold as Copaxone, with generic also available, 49.3%), dimethyl fumarate (originally marketed as Tecfidera, but generics are now available, 35.4%), and fingolimod (sold as Gilenya among others, 20.1%).

CHORDS’ trial goals

CHORDS’ main goal was to assess the proportion of participants showing no evidence of disease activity (NEDA) at 96 weeks, defined by the absence of relapses, confirmed disability progression, and new or enlarging brain lesions.

This was assessed in the 576 patients (94.7%), excluding those who discontinued treatment early for reasons other than lack of efficacy or death.

Other goals included change in Expanded Disability Status Scale (EDSS) scores, brain volume, and patient-reported outcomes related to the physical and psychological impact of MS and treatment satisfaction.

Results showed that NEDA was achieved by 59% of patients after six months, by 51.2% at nearly one year, and by 48.1% after nearly two years of treatment.

At two years, most patients were free from relapses (89.6%), had no confirmed disability progression for at least 24 weeks (89.6%), and had no T1, or actively inflamed, lesions (95.5%). A total of 59.5% had no new or enlarging T2 lesions, which are those that show up on a scan but might not be sites of active inflammation.

Notably, comparable results were observed for patients who had subclinical disease activity only at study start, and for those who had received one versus more than one prior DMT.

These findings highlighted that Ocrevus “was effective, even in patients without clinically apparent disease, and may suggest the importance of switching patients to a new treatment with subclinical disease activity, not just clinical events,” the researchers wrote.

In addition, adjusted annualized relapse rate was 0.046, with most relapses and MRI-based activity being observed in the first six months, with pronounced reductions afterward.

“This likely reflects the time necessary for [Ocrevus] to exert its pharmacological effects, which is supported by epoch analyses showing a considerable decrease in both relapse and T2 lesion activity after 24 weeks,” the team wrote.

Ocrevus also slightly lessened EDSS-based disability progression, slowed brain shrinkage, reduced patient-reported physical and psychological disability, and improved treatment satisfaction.

Ocrevus’ safety profile was consistent with that reported in previous trials and real-world studies, with no new safety concerns identified and most adverse events (side effects) being mild to moderate in severity. The most common adverse events included infusion-related reactions (43.3%), urinary tract infections (14.8%), and common colds (10.5%).

Serious adverse events were reported by 47 (7.7%) patients. Treatment interruptions or other modifications due to adverse events occurred in 108 (17.8%) patients. Six patients (nearly 1%) discontinued treatment because of nonserious adverse events, and two (0.3%) due to serious adverse events.

These findings, confirming CHORDS’ previous one-year data, support the benefits of switching to Ocrevus in “patients with early RRMS who had a suboptimal treatment response to previous DMT,” the researchers wrote.

Preliminary data from a similar Phase 3b trial in Europe, called CASTING (NCT02861014) showed comparable two-year results, with 52% of RRMS patients achieving NEDA with Ocrevus after a poor response to other DMTs.

Final data “will improve our understanding of [Ocrevus] use in patients who respond poorly to other treatments,” the team concluded.