Ocrelizumab Effectiveness In Multiple Sclerosis
Overview
Throughout its clinical development program, ocrelizumab has consistently demonstrated efficacy in enhancing clinical outcomes for multiple sclerosis, encompassing annualized relapse rates and confirmed disability progression. Despite these positive findings, the translation of this efficacy into real-world clinical practice remained uncertain. This study aimed to systematically compile published real-world clinical effectiveness data for ocrelizumab in both relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis.
A comprehensive search strategy was devised, utilizing MEDLINE and Embase to identify articles reporting real-world evidence in individuals undergoing ocrelizumab treatment for these multiple sclerosis subtypes. The search encompassed English-language articles without geographical or temporal restrictions. Supplementary manual searches on relevant websites were also conducted, leading to the identification of 52 studies presenting pertinent evidence.
Consistently, the real-world effectiveness data for ocrelizumab proved favorable. Reductions in relapse rates and disease progression rates were akin to those observed in the pivotal OPERA I/OPERA II and ORATORIO clinical trials. Notably, these positive outcomes extended to studies encompassing more diverse patient populations, addressing a gap in representation seen in the original trials. While direct comparisons may be influenced by the absence of treatment randomization, reported outcomes suggest that ocrelizumab exhibits comparable or superior efficacy compared to alternative therapy options.
The initial findings from real-world effectiveness data for ocrelizumab align favorably with results reported in clinical trials. This consistency provides clinicians with confidence in considering ocrelizumab as an effective treatment option for patients grappling with multiple sclerosis.
Introduction
Multiple sclerosis (MS) is a globally prevalent immune-mediated demyelinating neurodegenerative disease, affecting approximately 2.8 million individuals in 2020. Clinical trials have identified four MS phenotypes: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). While existing therapies have significantly impacted RRMS management by reducing or eliminating relapses, disease progression, independent of relapses, persists. Moreover, these treatments exhibit lower efficacy in individuals with PPMS or SPMS.
Ocrelizumab, a humanized monoclonal antibody, functions through the selective depletion of CD20+B-cells. Phase III clinical trials (OPERA I, OPERA II, and ORATORIO) demonstrated its effectiveness. In RRMS patients, ocrelizumab significantly reduced the annualized relapse rate (ARR) compared to interferon beta-1a. Additionally, it lowered the proportion of patients with confirmed disability progression (CDP) at 12 and 24 weeks. In the ORATORIO trial, ocrelizumab exhibited lower rates of confirmed disability progression compared to a placebo in PPMS patients at 12 and 24 weeks.
While randomized controlled trials (RCTs) are considered a robust source of evidence for new treatments, participants in RCTs may not fully represent those in real-world clinical practice. To comprehensively understand ocrelizumab’s impact, it is crucial to consider real-world evidence alongside RCT results. This systematic literature review aims to identify and summarize published literature reporting on the real-world effectiveness of ocrelizumab in both RRMS and PPMS, providing valuable insights beyond controlled trial settings.
Methods
A comprehensive search strategy was employed in MEDLINE and Embase, without time restrictions, to identify articles reporting real-world evidence regarding clinical effectiveness and health-related quality of life (HRQoL) in individuals with relapsing-remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS) undergoing ocrelizumab treatment. The search terms encompassed the health conditions of interest, such as “relapsing-remitting multiple sclerosis,” “RRMS,” “primary progressive multiple sclerosis,” and “PPMS,” as well as terms related to the intervention, including “ocrelizumab” and “Ocrelizumab” (brand name Ocrevus). The search was not restricted by the country of study or the timeframe of the research, and only English language articles were considered. The search covered full peer-reviewed articles and conference abstracts published until March 22, 2022. The full search strategy is detailed in the data supplement.
Study selection was carried out using Covidence software. Two independent reviewers screened articles against the Population, Intervention, Comparison, Outcomes, and Study (PICOS) criteria to assess their relevance to the research questions. For studies where applicability was uncertain, a third reviewer (JLP) conducted additional evaluation, and consensus decisions were reached through reviewer discussion. Additionally, included studies were examined for potential duplication of reported data, such as instances where both abstracts and full texts reported the same data. This rigorous selection process ensures the inclusion of relevant and non-duplicated information in the subsequent analysis.
Results
A comprehensive analysis incorporated 52 relevant studies, meticulously selected for consistency with the study’s scope. The study characteristics are succinctly outlined in the data supplement. Full-text articles were accessible for 23 studies (44%), while the remainder were represented by conference abstracts. The geographic distribution of studies was diverse, with 33 studies reporting real-world outcomes in Europe, seven in the United States, two in the Middle East, three in various regions, and one in South America, while six studies did not specify the country. The predominant study populations comprised combined RRMS, PPMS, and SPMS patients for which data were not stratified by MS type (n=20). Reported mean/median age ranged from 35 to 62, mean/median disease duration ranged from 2.8 to 18.7 years, and baseline EDSS ranged from 2 to 6.5.
Examining clinical relapse, the proportion of patients experiencing relapse following ocrelizumab initiation was consistently low across studies. All studies reported relapse in fewer than 20% of patients at follow-up times ranging from 3 to 30 months, with the majority reporting relapse in fewer than 10% of patients. A specific study conducted statistical analysis on relapse versus baseline, revealing a statistically significant decrease in relapse activity in RRMS patients treated with ocrelizumab for a minimum of 12 months. Two studies performed statistical analyses of relapse data between RRMS patients receiving different DMTs, and both reported significantly fewer relapses in ocrelizumab-treated patients.
Concerning the time to relapse, six studies assessed the time to the first relapse in patients treated with ocrelizumab, with the median time ranging from 52.5 days to 8.7 months, depending on the patient population and treatment history. The study reporting the shortest time to relapse suggested that patients switching from fingolimod to ocrelizumab had relatively longer washout periods, possibly due to prescribers choosing to wait for lymphocyte counts to recover following fingolimod treatment before initiating ocrelizumab.
Moreover, fourteen studies, with patient numbers ranging from 29 to 1104, assessed the change in annualized relapse rate (ARR) compared to baseline, reporting a numerical decrease in ARR following ocrelizumab initiation. Three studies performed statistical analyses comparing follow-up to baseline, all of which found a statistically significant decrease in ARR. Two studies evaluating the effects of ocrelizumab and other DMTs on ARR indicated that ocrelizumab-treated patients experienced significantly greater reductions in ARR compared with fingolimod-treated patients and had a lower risk of ARR compared with patients receiving cladribine.
Additionally, studies reporting magnetic resonance imaging (MRI) activity indicated a statistically significant decrease in the number of RRMS patients with T2 MRI activity following 12 months of ocrelizumab treatment. Fewer ocrelizumab-treated patients had new T2 lesions 3–6 months following treatment initiation compared with fingolimod-treated patients. Expanded disability status scale (EDSS) data were analyzed in five studies, with some reporting no significant change at various time points and others showing significant improvement or progression in PPMS patients.
In terms of disease activity, studies reported a high proportion of patients with no evidence of disease activity (NEDA) following ocrelizumab treatment, while significantly fewer patients exhibited evidence of disease activity (EDA) when switched from natalizumab to ocrelizumab compared with those switched to fingolimod.
Moreover, three studies presented health-related quality of life (HRQoL) outcomes, showing stability in measures like the Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory-II (BDI-II), and EuroQol-5 Dimension Index (EQ-5D) over baseline to 6 months. Another study suggested improvement in MFIS at 1 year, while other HRQoL measures, such as the Multiple Sclerosis Quality of Life-54 (MSQoL-54), remained stable from baseline to 1 year. These findings provide a comprehensive and detailed examination of the real-world effectiveness of ocrelizumab across various clinical parameters.
Conclusion
This systematic literature review analyzes 52 studies on ocrelizumab’s real-world effectiveness in RRMS and PPMS, comparing data to pivotal trials. Most studies align with trial outcomes. Variations in relapse rates and disability progression were noted in a few studies, influenced by baseline characteristics. Studies with different patient groups showed distinct patterns. HRQoL remained stable or improved in several studies. Switching to ocrelizumab from other treatments demonstrated efficacy and safety. Limited comparative studies indicated ocrelizumab’s favorable outcomes, though caution is advised due to potential bias. Overall, this review emphasizes ocrelizumab’s consistent real-world effectiveness and its suitability for diverse patient populations.
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