RECORD STATUS:

This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality of this assessment has been made for the HTA database.

CITATION:

NIHR HSC. Ocrelizumab for relapsing-remitting multiple sclerosis. Birmingham: NIHR Horizon Scanning Centre (NIHR HSC). Horizon Scanning Review. 2014

RECORD STATUS:

This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality of this assessment has been made for the HTA database.

CITATION:

NIHR HSC. Ocrelizumab for primary progressive multiple sclerosis. Birmingham: NIHR Horizon Scanning Centre (NIHR HSC). Horizon Scanning Review. 2014

BACKGROUND:

B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis.

METHODS:

We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 μg) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00676715.

FINDINGS:

218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68-97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89-99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0-4·4) patients in the placebo group, one of 55 (2%; 1·3-2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6-6·3) in the 2000 mg group, and two of 54 (4%; 3·0-4·4) in the interferon beta-1a group.

INTERPRETATION:

The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials.

FUNDING:

F Hoffmann-La Roche Ltd, Biogen Idec Inc.

We conducted this systematic reviews and meta-analysis to investigate the safety and efficacy of ocrelizumab in patients with active rheumatoid arthritis (RA) who exhibited resistance or intolerance to methotrexate or biological therapy. We performed a web-based literature search of PubMed, Google Scholar, EBSCO, Scopus, Embase, and Web of science for studies that compared ocrelizumab plus methotrexate versus methotrexate plus placebo in RA patients. Data were extracted from eligible studies and pooled as risk ratios (RR), using RevMan software. Pooling data from four RCTs (2230 patients) showed that ocrelizumab plus methotrexate were superior to methotrexate plus placebo at 24 weeks in terms of improvement on the American college of rheumatology (ACR20, ACR50, and ACR70) criteria (p < 0.00001), disease activity score 28-ESR (RR = 3.77, 95% CI [2.47, 5.74], p < 0.00001), and Sharp/van der Heijde radiological score (RR = 1.63, 95% CI [1.43, 1.85], p < 0.00001). These effects were consistent among all ocrelizumab doses. The rates of serious adverse events were comparable between the ocrelizumab and placebo containing groups (RR = 1, 95% CI [0.78, 1.28], p = 0.98). However, infusion related reactions were significantly higher in ocrelizumab group (RR = 2.13, 95% CI [1.69, 2.68], p < 0.00001), compared to placebo group. The combination of ocrelizumab plus methotrexate was superior to methotrexate plus placebo on all clinical and radiographic improvement scales. The incidence of adverse events, including serious adverse events, was comparable between both groups. Future trials should investigate the efficacy of ocrelizumab alone and develop strategies to alleviate its related infusion reactions.

BACKGROUND:

Ocrelizumab is a humanised anti-CD20 monoclonal antibody developed for the treatment of multiple sclerosis (MS). It was approved by the Food and Drug Administration (FDA) in March 2017 for using in adults with relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only disease-modifying therapy (DMT) approved for PPMS. In November 2017, the European Medicines Agency (EMA) also approved ocrelizumab as the first drug for people with early PPMS. Therefore, it is important to evaluate the benefits, harms, and tolerability of ocrelizumab in people with MS.

OBJECTIVES:

To assess the benefits, harms, and tolerability of ocrelizumab in people with RRMS and PPMS.

SEARCH METHODS:

We searched MEDLINE, Embase, CENTRAL, and two trials registers on 8 October 2021. We screened reference lists, contacted experts, and contacted the main authors of studies.

SELECTION CRITERIA:

All randomised controlled trials (RCTs) involving adults diagnosed with RRMS or PPMS according to the McDonald criteria, comparing ocrelizumab alone or associated with other medications, at the approved dose of 600 mg every 24 weeks for any duration, versus placebo or any other active drug therapy.

DATA COLLECTION AND ANALYSIS:

We used standard methodological procedures expected by Cochrane.

MAIN RESULTS:

Four RCTs met our selection criteria. The overall population included 2551 participants; 1370 treated with ocrelizumab 600 mg and 1181 controls. Among the controls, 298 participants received placebo and 883 received interferon beta-1a. The treatment duration was 24 weeks in one study, 96 weeks in two studies, and at least 120 weeks in one study. One study was at high risk of allocation concealment and blinding of participants and personnel; all four studies were at high risk of bias for incomplete outcome data. For RRMS, compared with interferon beta-1a, ocrelizumab was associated with: 1. lower relapse rate (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.52 to 0.73; 2 studies, 1656 participants; moderate-certainty evidence); 2. a lower number of participants with disability progression (hazard ratio (HR) 0.60, 95% CI 0.43 to 0.84; 2 studies, 1656 participants; low-certainty evidence); 3. little to no difference in the number of participants with any adverse event (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 1651 participants; moderate-certainty evidence); 4. little to no difference in the number of participants with any serious adverse event (RR 0.79, 95% CI 0.57 to 1.11; 2 studies, 1651 participants; low-certainty evidence); 5. a lower number of participants experiencing treatment discontinuation caused by adverse events (RR 0.58, 95% CI 0.37 to 0.91; 2 studies, 1651 participants; low-certainty evidence); 6. a lower number of participants with gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) (RR 0.27, 95% CI 0.22 to 0.35; 2 studies, 1656 participants; low-certainty evidence); 7. a lower number of participants with new or enlarging T2-hyperintense lesions on MRI (RR 0.63, 95% CI 0.57 to 0.69; 2 studies, 1656 participants; low-certainty evidence) at 96 weeks. For PPMS, compared with placebo, ocrelizumab was associated with: 1. a lower number of participants with disability progression (HR 0.75, 95% CI 0.58 to 0.98; 1 study, 731 participants; low-certainty evidence); 2. a higher number of participants with any adverse events (RR 1.06, 95% CI 1.01 to 1.11; 1 study, 725 participants; moderate-certainty evidence); 3. little to no difference in the number of participants with any serious adverse event (RR 0.92, 95% CI 0.68 to 1.23; 1 study, 725 participants; low-certainty evidence); 4. little to no difference in the number of participants experiencing treatment discontinuation caused by adverse events (RR 1.23, 95% CI 0.55 to 2.75; 1 study, 725 participants; low-certainty evidence) for at least 120 weeks. There were no data for number of participants with gadolinium-enhancing T1 lesions on MRI and number of participants with new or enlarging T2-hyperintense lesions on MRI.

AUTHORS' CONCLUSIONS:

For people with RRMS, ocrelizumab probably results in a large reduction in relapse rate and little to no difference in adverse events when compared with interferon beta-1a at 96 weeks (moderate-certainty evidence). Ocrelizumab may result in a large reduction in disability progression, treatment discontinuation caused by adverse events, number of participants with gadolinium-enhancing T1 lesions on MRI, and number of participants with new or enlarging T2-hyperintense lesions on MRI, and may result in little to no difference in serious adverse events (low-certainty evidence). For people with PPMS, ocrelizumab probably results in a higher rate of adverse events when compared with placebo for at least 120 weeks (moderate-certainty evidence). Ocrelizumab may result in a reduction in disability progression and little to no difference in serious adverse events and treatment discontinuation caused by adverse events (low-certainty evidence). Ocrelizumab was well tolerated clinically; the most common adverse events were infusion-related reactions and nasopharyngitis, and urinary tract and upper respiratory tract infections.

The goal of the current project is to measure the levels of ocrelizumab in the breastmilk of women with multiple sclerosis (MS) and clinically isolated syndrome (CIS) who are postpartum, and to collect information on 12-month infant development outcomes (length, weight, head circumference, infections) in their offspring.

This study will fill a significant unmet need as many women with MS at high risk for postpartum relapses are not effectively treated for their MS in the postpartum period due to lack of information about the presence, concentration and effects of medications in breastmilk.

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Some people who have what doctors currently call schizophrenia or bipolar disease may actually have a brain disease caused by auto-antibodies. Auto-antibodies are produced when the normal defense mechanism of the body goes wrong and begins to attack the body, similar to \"friendly fire.\" Auto-antibodies attack brain receptors and then the person who has this problem begins to have hallucinations and other manifestations of schizophrenia, like feeling that people can see what they are thinking and also feeling that other people do not like them. If this disease is caused by auto-antibodies, typically the person is well until they are 15 years of age or older, but seldom older than 35 years. Then, in a matter of a few months they begin to have hallucinations and the other symptoms. Doctors still do not know whether some people with schizophrenia or bipolar disease have auto-antibodies attacking their brain. For this reason, in this study some of these patients will receive a treatment that suppresses the auto-antibodies and their symptoms after treatment will be compared with the symptoms of a group of similar patients who are given a preparation that looks like the real treatment, but it is not.

BACKGROUND AND PURPOSE:

We know that treatment algorithms have changed in Multiple Sclerosis (MS) practice during the pandemic. In this study, we aimed to investigate whether there was a change in the patient population for ocrelizumab (OCR) treatment during the pandemic period, the treatment compliance of the patients, and the course of the Coronavirus Disease-19 (COVID-19) disease in the patients who received OCR.

METHODS:

Our study was designed as a survey study. A questionnaire was sent to the patients assessing whether they had COVID-19 infection, whether they received treatments regularly before and after the pandemic, vaccination status and duration of OCR treatment. Demographic characteristics of the patients, treatments they used before, MS type, Expanded Disability Status Scale (EDSS) scores were determined from the database. Each group of OCR started before pandemic and OCR started after pandemic were compared.

RESULTS:

We included into the study 86 patients who started OCR before pandemic period and 75 patients who started OCR after the pandemic. Demographic features were similar. EDSS scores were higher in the group that started OCR treatment before the pandemic (p<0.0001). The patients who started OCR treatment before the pandemic had more disruptions than which started during the pandemic (p<0.0001). No correlation was found between the duration of OCR treatment and COVID-19 infection (p=0.940). We observed that the patients who had severe COVID-19 infection had received OCR therapy for a longer period.

CONCLUSION:

This retrospective study concluded that the OCR treatment approach in our center had changed during the pandemic period. OCR therapy was started in patients with less disability. The possible reasons for this situation include the proven relationship between high EDSS and serious COVID-19 infection, and that the patients who have higher EDSS score had troubles in reaching health institutions during the pandemic. The result that patients with severe COVID-19 infection received OCR treatment for a longer period necessitates more evidence-based research to investigate the relationship between treatment duration and disease severity.

Rationale: B-cell depleting therapies like ocrelizumab are very effective in the treatment of relapsing remitting multiple sclerosis (RRMS). As B cell repopulation varies extensively between individuals (ranging from 27-175 weeks), using a treatment scheme with a fixed infusion interval may be suboptimal. So far personalized adapted treatment of ocrelizumab in RRMS has not been studied in a prospective setting.

Objective: Evaluating the efficacy, safety and cost-effectiveness of ocrelizumab when administered in personalized B cell tailored intervals in RRMS patients.

Study design: This is a national multicenter randomized controlled trial with 96 week follow-up.

Study population: The study population consists of 296 adult RRMS patients who have received ocrelizumab treatment for a minimum of 12 months (2x 300 mg infusion and 1x 600mg infusion).

Intervention: Patients will be randomized into the standard interval group (600 mg infusions every 24 weeks) or the personalized interval group in which the infusions will be extended as long as the serum CD19 B cell count is below 10 CD19 cells/µL, determined every 4 weeks.

Main study parameters: To conclude non-inferiority of personalized B cell tailored ocrelizumab there will be two co-primary endpoints: 1. the difference of percentage of confirmed relapse-free patients between the two groups after 96 weeks and 2. the difference of percentage of patients free from new/enlarging T2 lesions on MRI between the two groups after 96 weeks. Secondary study parameters are number of confirmed relapses, annualized relapse rate, number of new T2 lesions and brain atrophy on MRI, disability progression, no evidence of disease activity (NEDA), MS disease biomarkers (serum neurofilament light), quality of life, burden of treatment, immunoglobulin levels and (serious) adverse events including occurrence of infections and COVID-19. Furthermore, various immune cell subsets will be studied in relation to ocrelizumab concentration in a subgroup.

Nature and extent of the burden and risks: All patients will be subjected to visits every 24 weeks including clinical scoring and questionnaires. Blood samples and MRI scans will be taken and performed every 48 weeks. Continuous assessment of key stroke dynamics on the patients smartphone and monthly digital cognitive test and walk test will be performed in most patients. As CD19 B cells are kept near complete depletion, the estimated risk of recurrence of disease activity is very low.