The primary analysis shows that more drug exposure does not necessarily mean better disease control, as higher doses of ocrelizumab removed more circulating B cells without improving disability outcomes in MS.
Efficacy and safety of weight-adjusted high-dose ocrelizumab in relapsing (MUSETTE) and primary progressive (GAVOTTE) multiple sclerosis: two multicenter, randomized, double-blind, parallel-group phase 3b studies. Image credit: Camptoloma / Shutterstock
In a recent study published in lancetResearchers investigated whether high, weight-adjusted doses of ocrelizumab could better control disability progression in multiple sclerosis (MS). The study used data from two parallel Phase 3b clinical trials, MUSETTE and GAVOTTE, both of which compared dose escalation to the approved 600-milligram dose in patients with relapsed or newly diagnosed progressive disease.
The study results revealed that higher doses were associated with greater depletion of target immune cells in blood tests but did not provide an additional clinical benefit in slowing the accumulation of damage, indicating that the currently prescribed standard dose of 600 mg remains the favored standard regimen.
background
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, progressive condition in which the body’s immune system mistakenly damages the myelin sheath covering nerve fibers in the central nervous system (CNS). The disease manifests phenotypically as visual problems, sensory changes, movement disorders, cognitive/mood changes, or severe fatigue, depending on the specific neurological damage and the extent of disease progression.
Clinically, studies have shown that MS is traditionally divided into relapsing-remitting, secondary-progressive, and primary-progressive phenotypes, but this study focuses on two clinically important populations: relapsing MS and PPMS. A review on this topic highlights that although modern disease-modifying therapies are excellent at controlling acute inflammation and relapse, slowing long-term disability progression independent of relapse remains a major unmet urgent medical need.
Ocrelizumab is a humanized anti-CD20 monoclonal antibody designed to target and deplete CD20-expressing B cells, white blood cells that are central to autoimmune diseases. The drug was previously approved for both relapsing multiple sclerosis (RMS) and PPMS at standard doses of 600 milligrams (mg) given every six months.
Retrospective analyzes of patients regularly given ocrelizumab suggest that disability progression is slower in those with higher drug exposure, but these observations and the resulting hypothesized association between dose and MS outcome remained untested.
About research
This study aimed to elucidate this knowledge gap and inform future MS interventions by using data from two international, randomized, double-blind, phase 3b clinical trials, MUSETTE and GAVOTTE. The MUSETTE study was specific to RMS and included 860 patients with RMS. The GAVOTTE trial focused on PPMS patients (n = 753). Both cohorts consisted of participants aged 18 to 56 years.
Participants were assigned in a 2:1 ratio to receive either a weight-adjusted high dose of ocrelizumab or a standard dose of 600 mg intravenous infusion every 24 weeks. To account for differences in participant weight, high-dose (experimental) cohort patients weighing less than 75 kg received 1200 mg, and patients weighing 75 kg or more received 1800 mg.
The primary endpoint of this study was time to onset of composite confirmed disability progression (CCDP) at 12 weeks. CCDP was tracked using the Expanded Disability Status Scale (EDSS) to measure physical impairment, the timed 25-foot walk test (T25FWT) to assess participants’ walking speed, and the 9-hole peg test (9HPT) as a proxy for manual dexterity.
Secondary outcomes of this study included monitoring participants’ structural brain volumes using high-resolution magnetic resonance imaging (MRI) and estimating neuroaxonal damage using blood levels of neurofilament light chain (NfL).
Research results
Results revealed that higher doses of ocrelizumab resulted in greater CD20-expressing B cell clearance (as expected), but that higher doses did not provide superior disease control compared to the standard dose of 600 mg.
In the MUSETTE (RMS) trial, 34% (198 of 577) of high-dose patients experienced disability progression over 12 weeks, compared with 37% (104 of 283) in the standard group (hazard ratio (HR) 0.93, p = 0.53). Results from the GAVOTTE trial (PPMS) confirmed these patterns. 47% (235 of 500) of high-dose participants progressed compared to 49% (124 of 253) in the standard group (HR 0.95; p = 0.64).
Blood-associated B cell count data revealed a significantly higher proportion of patients in the high-dose group with <0.441 cells per microliter (μL) at week 120 (38% vs. 15% in the MUSETTE group and 31% vs. 20% in the GAVOTTE group). However, this did not lead to improved clinical function. Both groups experienced a significant reduction in markers of nerve damage, with blood NfL decreasing by 37% at week 48 in both MUSETTE treatment groups (p<0.0001).
Encouragingly, the safety profile and serious infection rates remained similar across treatment groups, and no new safety concerns were identified in either trial.
conclusion
This study demonstrates that increasing doses of ocrelizumab leads to greater depletion of peripheral B cells, but this does not improve MS outcome or reduce disability progression.
These findings suggest that the benefits of higher intervention doses may be reaching a therapeutic limit in MS management, and further indicate that measurement of circulating B cell concentrations may be an insufficient basis for clinical decisions, as improved peripheral clearance does not equate to better protection against brain tissue loss. The results also suggest that further progress may require targeting CNS compartmentalized B cells or non-B cell-mediated neurodegenerative mechanisms that contribute to disease progression.
This study supports the standard dose of 600 mg as a currently approved treatment with a favorable benefit and risk profile based on current knowledge of MS.
