Ocrevus Benefited RRMS Patients Who Responded Poorly to DMTs

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Most relapsing-remitting multiple sclerosis (RRMS) patients switching to Ocrevus (ocrelizumab) following suboptimal responses to other disease-modifying therapies (DMTs) show no evidence of disease activity, according to final two-year data from the European-based CASTING Phase 3b trial.

These clinical benefits, which entail no relapses or disease progression and no new or enlarging brain lesions over the trial’s duration, were observed across a wide range of patient subgroups, regardless of prior treatment background, and were not associated with new safety concerns.

These findings add to results from a parallel Phase 3b study in North America, called CHORDS (NCT02637856), that show the therapy safely and effectively prevented relapses and disease progression for up to two years in this subset of RRMS patients.

Together, the data support the importance of recognizing suboptimal treatment responses and the value of switching to Ocrevus to maintain disease control, the researchers noted.

The study, “Efficacy and Safety of Ocrelizumab in Patients with Relapsing-Remitting Multiple Sclerosis with Suboptimal Response to Prior Disease-Modifying Therapies: Primary Analysis from the Phase 3b CASTING Single-Arm, Open-Label Trial,” was published in the European Journal of Neurology.

Ocrevus, developed by Roche’s subsidiary Genentech, is a B-cell depleting DMT approved for adults with relapsing forms of MS or with primary progressive MS. 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 CASTING Phase 3b clinical trial (NCT02861014), sponsored by Genentech, evaluated Ocrevus’ safety and effectiveness in 680 RRMS patients (436 women and 244 men) who showed suboptimal responses to one (60.4%) or two (39.6%) prior DMTs, received for at least six months.

Mean duration of last DMT was 26.5 months (more than two years), and interferon-based treatments, such as Avonex and Rebif, were the most commonly used DMTs. Use of fingolimod — sold as Gilenya, among others — was associated with more advanced disease relative to other last-used DMTs.

Participants, recruited at 157 study sites across Europe and Turkey, had a mean age of 34.2 years and had been living with an RRMS diagnosis for a mean of 3.7 years. Suboptimal responses were reflected exclusively by clinical relapses in 35% of patients, by subclinical disease activity only — based on brain lesions detected through MRI — in 24.6%, and by both in 40.4%.

After a mean of 1.9 months since the last DMT dose, patients received Ocrevus once every six months for up to 96 weeks (nearly two years). Most (94.3%) completed the two-year treatment, while 39 (5.7%) patients withdrew from the therapy prematurely.

The trial’s main goal was to assess the proportion of participants achieving no evidence of disease activity (NEDA) — a status defined by the absence of relapses, new or enlarging brain lesions, and 24-week confirmed disability progression — after two years.

Patients’ initial (baseline) MRI data were considered after two months of treatment to exclude MRI-based disease activity that is known to occur during that period before Ocrevus’ therapeutic potential kicks in, the team noted.

Results showed that NEDA was achieved by 87.1% of patients after six months, by 82.6% after nearly one year, and by 74.8% after nearly two years of treatment. At two years, higher NEDA rates were found among those recruited due to subclinical disease activity (80.6%) — relative to 75.1% due to relapse only, and 70.5% due to both.

Notably, NEDA rates were higher than 66% across a wide range of disease-related and demographic groups, regardless of prior DMT.

However, NEDA was more likely to be achieved by patients with less disability at enrollment (77.2%), who had received only one previous DMT (77.6%), who had fewer relapses prior to study entry (78.2%), or who were previously treated with interferons (81.1%).

After two years, most patients were free from relapses (89.8%), had no disability progression lasting at least 24 weeks (87.5%), and exhibited no new or enlarging brain lesions (91.5%). Also, the adjusted mean annualized relapse rate was 0.03, the “equivalent to one relapse approximately every 33 years,” the team wrote.

Ocrevus’ therapeutic benefits were associated with a safety profile consistent with that reported in previous trials, 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, common cold, headache, influenza virus infections, and urinary tract infections.

Serious adverse events were reported by 49 (7.2%) patients. Treatment interruptions or other modifications due to adverse events occurred in 102 (15%) patients, most of which were infusion-related reactions.

These findings highlight the benefits of switching to Ocrevus in RRMS patients who show a suboptimal response to other DMTs, and support the use of “an early intensive treatment approach rather than a gradual escalation to therapy in MS,” the researchers wrote.

The fact that higher NEDA rates were observed “in patients enrolled based on MRI activity only, in those with lower baseline disability scores and markers of less active disease, and in patients receiving [Ocrevus] as the first switch versus second switch, demonstrate the importance of identifying and reacting to early suboptimal clinical or subclinical response to a DMT,” the team wrote.

The results also indicate that switching to Ocrevus “is never as effective as earlier treatment, and does not reverse lost function,” they added.

“The highly positive benefit-risk profile seen in this and other clinical studies of [Ocrevus] continues to be evaluated in long-term extension studies,” the researchers wrote.

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