Higher Ocrelizumab Exposure May Better Control Disability Progression in MS

Higher levels of ocrelizumab are associated with a lower risk for disability progression in patients with relapsing and primary progressive MS.

At higher levels, ocrelizumab exposure is associated with lower rates of disability progression among patients with multiple sclerosis (MS), according to study findings published in the journal Neurology Neuroimmunology & Neuroinflammation.

An intravenous dose of ocrelizumab at 600 mg every 6 months has been associated with significant benefits for reducing disability progression. In the literature, body mass index (BMI)-by-treatment interactions have been reported, suggesting that higher ocrelizumab exposure among patients with lower BMIs (≤25 kg/m2) leads to more pronounced effects.

To better explore this relationship, researchers sourced data from 3 pivotal phase 3 trials: the OPERA I (ClinicalTrials.gov Identifier: NCT01247324), OPERA II (ClinicalTrials.gov Identifier: NCT01412333), and ORATORIO (ClinicalTrials.gov Identifier: NCT01194570). The outcomes of interest in this analysis were 24-week confirmed disability progression (CDP), magnetic resonance imaging (MRI) outcomes, and adverse events among ocrelizumab exposure quartile groups. Disability progression was measured using the Expanded Disability Status Scale (EDSS) and ocrelizumab exposure was defined as the average ocrelizumab serum concentration.

Stratified by ocrelizumab exposure, patients were divided into 4 quartiles with each quartile comprised 196-197 patients with relapsing MS (RMS) and 120-121 patients with primary progressive MS (PPMS). The ocrelizumab serum concentrations among the RMS and PPMS groups were:

  • <15.4 mg/mL and <15.8 mg/mL for quartile 1;
  • 15.4-<18.7 mg/mL and 15.8-<18.9 mg/mL for quartile 2;
  • 18.7-<22.2 mg/mL and 18.9-<23.2 mg/mL for quartile 3, and
  • ³22.2 mg/mL and ³23.2 mg/mL for quartile 4, respectively.
Higher ocrelizumab exposure and greater B-cell depletion may be important for the control of disability progression.

In general, quartiles 1 and 2 had more patients who were men, had higher BMI, and lived in the United States.

In RMS, there was a trend that higher B-cell levels associated with greater CDP rates at week 24 and compared with the control group, patients with greater reductions in B-cell levels had greater risk reduction in disability at 24 weeks (hazard ratio [HR], 0.38 vs 0.73).

The 24-week CDP outcome was more favorable with higher ocrelizumab exposure, in which quartiles 4 (hazard ratio [HR], 0.34; 95% CI, 0.17-0.70; P =.004) and 3 (HR, 0.47; 95% CI, 0.25-0.87; P =.002) were favored over the comparator arm among patients with RMS and quartile 4 (HR, 0.55; 95% CI, 0.36-0.83; P =.005) was favored among the patients with PPMS. A significant treatment-by-BMI effect was observed among the RMS group (P =.016) but not the PPMS group (P =.39).

After pooling quartiles 1 with 2 and 3 with 4, high ocrelizumab exposure associated with a lower rate of new and enlarging T2 lesions (rate ratio [RR], 0.46; 95% CI, 0.24-0.86; P =.01) and the percentage change in white matter volume (mean difference [MD], -0.18; 95% CI, -0.31 to -0.04; P =.0111) compared with the low exposure groups among patients with RMS relative to the trial’s comparator treatment group.

Among quartiles 1 and 4, the rates of:

  • serious adverse events (rate, RMS: 5.5 vs 2.2 per 100 person-years [py]; PPMS: 12.1 vs 7.5 per 100 py);
  • infections (rate, RMS: 80.9 vs 83.6 per 100 py; PPMS: 73.7 vs 75.7 per 100 py);
  • serious infection (rate, RMS: 1.7 vs 0.6 per 100 py; PPMS: 2.7 vs 1.9 per 100 py); and
  • infusion-related reactions (rate, RMS: 41.2% vs 34.0%; PPMS: 39.2% vs 38.8%) did not differ significantly, respectively.

The major limitation of this study was the pooling of data from distinct trials.

Researchers noted, “A consistent trend of higher ocrelizumab exposure leading to greater reduction in risk of CDP was observed, particularly in the relapsing MS trials, and was not associated with a higher rate of adverse events.”

“Higher ocrelizumab exposure and greater B-cell depletion may be important for the control of disability progression,” they concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Neurology Advisor


Hauser SL, Bar-Or A, Weber MS, et al. Association of higher ocrelizumab exposure with reduced disability progression in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. Published online February 15, 2023. doi:10.1212/NXI.0000000000200094