2 large trials back approved dose of Ocrevus for treating MS

Increasing the dose of the infusion therapy Ocrevus (ocrelizumab) does not provide additional benefit compared with the approved regimen in slowing disability progression for people with relapsing forms of multiple sclerosis (MS) or primary progressive MS.

That’s according to final data from two global Phase 3b clinical trials — MUSETTE (NCT04544436) and GAVOTTE trial (NCT04548999) — that followed more than 1,600 adults with these MS types for more than three years.

While high-dose Ocrevus led to greater reductions in B-cells, as had been suggested in previous studies, the data showed that these higher doses were no more effective than the approved dose at controlling disease activity or slowing disease progression. No new safety concerns were identified, according to the researchers.

“Together, MUSETTE and GAVOTTE confirm the favourable benefit-risk profile of the [six-month] dosing regimen of the approved dose of [Ocrevus],” the researchers wrote.

The study, “Efficacy and safety of a bodyweight-adjusted higher dose of ocrelizumab in relapsing (MUSETTE) and primary progressive (GAVOTTE) multiple sclerosis: two multicentre, randomised, double-blind, parallel-group phase 3b trials,” was published in the journal The Lancet. The research was funded by Roche, the parent company of Genentech, which markets Ocrevus.

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An antibody therapy, Ocrevus works by depleting B-cells, which are immune cells that play a key role in the inflammation that drives MS. It is given as two initial 300 mg infusions, followed by 600 mg every six months.

The therapy was approved for relapsing forms of MS and PPMS based mainly on data from the OPERA (NCT01247324 and NCT01412333) and ORATORIO (NCT01194570) trials, also Phase 3 studies. Those results showed Ocrevus’ effectiveness at controlling relapses and reducing disability accumulation.

However, later analyses from these trials suggested that patients who weighed less, and thus were exposed to higher blood levels of Ocrevus, tended to experience greater B-cell depletion and lower rates of confirmed disability progression compared with those with lower drug exposure. That suggested that higher doses might work better.

Trials tested Ocrevus doses in over 1,500 people with MS

The MUSETTE and GAVOTTE trials were launched to test that hypothesis in 860 participants with relapsing forms of MS and 753 with PPMS.

In both studies, participants were randomly assigned to receive either the approved 600 mg dose or a higher dose: 1,200 mg for those weighing less than 75 kg (165 pounds) and 1,800 mg for those weighing 75 kg or more.

The trials were designed to last at least 120 weeks, or about 2.3 years. In MUSETTE, treatment lasted a median of 184 weeks, or 3.5 years, while median treatment duration in GAVOTTE was 174 weeks, or about 3.3 years.

The studies failed to demonstrate that the higher dose was superior to the approved regimen at delaying the time to 12-week composite confirmed disability progression — defined as a worsening in the Expanded Disability Status Scale (EDSS) or in tests of walking ability or manual dexterity sustained for at least 12 weeks, or about three months.

The two dosing regimens also performed similarly across a variety of other measures, including 24- and 48-week confirmed disability progression and disability progression independent of relapse activity (PIRA). Similar outcomes were also seen across doses on assessments of cognitive decline, walking impairment, and brain volume loss. In the MUSETTE trial, relapse rates and signs of disease activity on MRI scans were also similar and low with both treatment regimens.

MUSETTE and GAVOTTE confirm the effects of 600 mg [Ocrevus] — the dose approved for treating [relapsing MS] and PPMS — but do not show improved efficacy on disability progression at the higher dose.

Blood levels of neurofilament light chain, a marker of nerve damage, fell substantially in both treatment groups, decreasing by about 37% in MUSETTE and 20% in GAVOTTE after nearly two years. Again, there were no significant differences between doses, the researchers noted.

Consistent with Ocrevus’ mechanism of action, the higher dose depleted B-cells more extensively than the standard regimen. In MUSETTE, after 120 weeks, 38% of participants receiving the higher dose had undetectable B-cell levels versus 15% of those on the standard dose. In GAVOTTE, the numbers were 31% and 20%, respectively.

However, the greater reduction in circulating B-cells did not translate into better clinical outcomes, the researchers noted.

“The finding that a further reduction in peripheral B-cell levels did not enhance the … impact on disability progression achieved with the 600 mg dose …  raises the possibility that more effective targeting of [brain and spinal cord] inflammation, and addressing both B-cell and non-B-cell-mediated mechanisms … contributing to progression, would be needed to provide additional benefit,” the researchers wrote.

Safety outcomes were comparable between the dosing groups and consistent with the known safety profile of Ocrevus, the team noted. Across both trials, side effects occurred in about 90%-96% of participants and serious adverse events were experienced by 11%-13% of patients. The most common adverse events were infusion-related reactions, COVID-19, and the common cold.

“MUSETTE and GAVOTTE confirm the effects of 600 mg [Ocrevus] — the dose approved for treating [relapsing MS] and PPMS — but do not show improved efficacy on disability progression at the higher dose,” the researchers concluded.