Effectiveness of Ocrelizumab in Primary Progressive Multiple Sclerosis: a Multicenter, Retrospective, Real-world Study (OPPORTUNITY)

Abstract

Ocrelizumab is a recombinant humanized monoclonal antibody selectively targeting CD20-expressing B cells. The effect of ocrelizumab on primary progressive multiple sclerosis (PPMS) has been evaluated during phase 3 trials that enrolled patients under 55 years with a maximum Expanded Disability Status Scale (EDSS) of 6.5. However, little is known on older disabled patients with longer disease duration. We aimed to assess the clinical effectiveness of ocrelizumab in PPMS patients out of the ORATORIO eligibility criteria. This multicenter retrospective study collected data about the effectiveness of ocrelizumab in PPMS patients who received treatment between May 2017 and June 2022 in the Italian MS centers contributing to the Italian MS Registry who adhered to the Compassionate Use Program. The confirmed EDSS worsening (CEW) (defined as either a ≥ 1-point or ≥ 2-point increase in EDSS score from baseline that was confirmed at T12 and T24) was calculated. At the date of data extraction, out of 887 PPMS patients who had received ocrelizumab, 589 (mean age 49.7 ± 10.7 years, 242 (41.1%) females) were enrolled. The mean follow-up period was 41.3 ± 12.3 months. A total of 149 (25.3%) received ocrelizumab according to the ORATORIO criteria (ORATORIO group) and 440 (74.7%) outside the ORATORIO criteria (non-ORATORIO group). No differences in terms of cumulative probabilities of 12 and 24 months of CEW of ≤ 1 point were found between ORATORIO and non-ORATORIO groups. Cox regression analyses showed that age older than 65 years (HR 2.51, 25% CI 1.07-3.65; p = 0.01) was associated with higher risk of CEW at 24 months. Patients not responding to ORATORIO criteria for reimbursability may benefit from ocrelizumab treatment, as disease activity, disease duration, and EDSS seem to not impact the disability outcome. Our results may suggest to extend the possible use of this powerful agent in selected patients under the age of 65 years.

Keywords: Efficacy; Multiple sclerosis; Ocrelizumab; Primary progressive multiple sclerosis.

Fig. 1

Patients’ selection flow chart. EDSS, Expanded Disability Status Scale; PPMS, primary progressive multiple sclerosis. The ORATORIO group includes patients fulfilling the ORATORIO eligibility criteria for ocrelizumab treatment (age of 18 to 55 years, EDSS of 3.0 to 6.5, disease duration less than 15 years in patients with an EDSS score of more than 5.0 at screening or less than 10 years in patients with an EDSS score of 5.0 or less [14]); non-ORATORIO includes patients not fulfilling the ORATORIO criteria

Fig. 2

Proportion of patients who reached 1-point CEW at 24 months, stratified according to the presence of disease activity in ORATORIO and non-ORATORIO groups (A), in each non-ORATORIO subgroup (B), and in each age category (C). CEW, confirmed EDSS worsening of at least 1 point at 24 months; EDSS, Expanded Disability Status Scale

Fig. 3

Cox regression analysis of developing confirmed EDSS worsening (CEW) at 24 months. EDSS, Expanded Disability Status Scale; OCR, ocrelizumab.*p value = 0.01

Fig. 4

Kaplan–Meier curves for the time of reaching 1-point CEW at 24 months during treatment with ocrelizumab in the entire cohort (A), and in patients stratified according to EDSS (≤ 6.5 and > 6.5) (B), disease duration (≤ 15 or 10 and > 15 or 10 years) (C), and age (≤ 55, 56–64 and > 65 years) (D). CEW, confirmed EDSS worsening of at least 1 point at 24 months; EDSS, Expanded Disability Status Scale; DD, disease duration