Ocrevus

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies, ATC code: L04AG08. Mechanism of action Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B cells. CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells. The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in MS is not fully elucidated but is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. The capacity of B-cell reconstitution and pre-existing humoral immunity are preserved. In addition, innate immunity and total T-cell numbers are not affected. Pharmacodynamic effects Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 14 days post treatment (first time-point of assessment) as an expected pharmacologic effect. This was sustained throughout the treatment period. For the B-cell counts, CD19 is used, as the presence of ocrelizumab interferes with the recognition of CD20 by the assay. In the Phase III studies, between each dose of ocrelizumab, up to 5% of patients showed B-cell repletion (> LLN or baseline) at least at one time point. The extent and duration of B-cell depletion was consistent in the PPMS and RMS trials. The longest follow up time after the last infusion (Phase II study WA21493, N=51) indicates that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 72 weeks (range 27 - 175 weeks). 90% of all patients had their B-cells repleted to LLN or baseline by approximately two and a half years after the last infusion. Clinical efficacy and safety Relapsing forms of multiple sclerosis (RMS) Efficacy and safety of ocrelizumab were evaluated in two randomised, double-blind, double-dummy, active comparator-controlled clinical trials (WA21092 and WA21093), with identical design, in patients with relapsing forms of MS (in accordance with McDonald criteria 2010) and evidence of disease activity (as defined by clinical or imaging features) within the previous two years. Study design and baseline characteristics of the study population are summarised in Table 3. Demographic and baseline characteristics were well balanced across the two treatment groups. Patients receiving ocrelizumab (Group A) were given 600 mg every 6 months (Dose 1 as 2 x 300 mg intravenous infusions, administered 2 weeks apart, and subsequent doses were administered as a single 600 mg intravenous infusion). Patients in Group B were administered Interferon beta-1a 44 mcg via subcutaneous injection 3 times per week. Table 3 Study design, demographic and baseline characteristics Study name Study 1 Study 2 WA21092 (OPERA I) (n=821) WA21093 (OPERA II) (n=835) Study design Study population Patients with relapsing forms of MS Disease history at screening At least two relapses within the prior two years or one relapse within the prior year; EDSS* between 0 and 5.5, inclusive Study duration 2 years Treatment groups Group A: Ocrelizumab 600 mg Group B: interferon beta-1a 44 mcg S.C. (IFN) Baseline characteristics Ocrelizumab 600 mg (n=410) IFN 44 mcg (n=411) Ocrelizumab 600 mg (n=417) IFN 44 mcg (n=418) Mean age (years) 37.1 36.9 37.2 37.4 Age range (years) at inclusion 18 - 56 18 - 55 18 - 55 18 - 55 Gender distribution (% male/% female) 34.1/65.9 33.8/66.2 35.0/65.0 33.0/67.0 Mean/Median disease duration since diagnosis (years) 3.82/1.53 3.71/1.57 4.15/2.10 4.13/1.84 Patients naive to previous DMT (%)** 73.4 71.0 72.7 74.9 Mean number of relapses in the last year 1.31 1.33 1.32 1.34 Proportion of patients with Gd enhancing T1 lesions 42.5 38.1 39.0 41.4 Mean EDSS* 2.82 2.71 2.73 2.79 * Expanded Disability Status Scale ** Patients who had not been treated with a disease-modifying therapy (DMT) in the 2 years prior to randomisation. Key clinical and MRI efficacy results are presented in Table 4 and Figure 1. The results of these studies show that ocrelizumab significantly suppressed relapses, sub-clinical disease activity measured by MRI, and disease progression compared with interferon beta-1a 44 mcg subcutaneous. Table 4 Key clinical and MRI endpoints from Studies WA21092 and WA21093 (RMS) Endpoints Study 1: WA21092 (OPERA I) Study 2: WA21093 (OPERA II) Ocrelizumab 600 mg (n=410) IFN 44 mcg (n=411) Ocrelizumab 600 mg (n=417) IFN 44 mcg (n=418) Clinical Endpoints Annualised Relapse Rate (ARR) (primary endpoint) 8 0.156 0.292 0.155 0.290 Relative Reduction 46 % (p<0.0001) 47 % (p<0.0001) Proportion of patients with 12 week Confirmed Disability Progression 3 Risk Reduction (Pooled Analysis 1 ) Risk Reduction (Individual Studies 2 ) 9.8% Ocrelizumab vs 15.2% IFN 40% (p=0.0006) 7 43 % (p=0.0139) 7 37 % (p=0.0169) 7 Proportion of patients with 24 week Confirmed Disability Progression (CDP) 3 Risk Reduction (Pooled Analysis 1 ) Risk Reduction (Individual Studies 2 ) 7.6% Ocrelizumab vs 12.0% IFN 40% (p=0.0025) 7 43 % (p=0.0278) 7 37 % (p=0.0370) 7 Proportion of patients with at least 12 weeks Confirmed Disability Improvement 4 20.7% Ocrelizumab vs 15.6% IFN Relative Increase (Pooled Analysis 1 ) Relative Increase (Individual Studies 2 ) 33% (p=0.0194) 61% (p=0.0106) 14% (p=0.4019) Proportion of patients Relapse free at 96 weeks 2 80.4% 66.7% 78.9% 64.3% (p<0.0001) (p<0.0001) Proportion of patients with No Evidence of Disease Activity (NEDA) 5 48% 29% 48% 25% Relative Increase 2 64% (p<0.0001) 89% (p<0.0001) MRI Endpoints Mean number of T1 Gd-enhancing lesions per MRI scan 0.016 0.286 0.021 0.416 Relative reduction 94% (p<0.0001) 95% (p<0.0001) Mean number of new and/or enlarging T2 hyperintense lesions per MRI scan 0.323 1.413 0.325 1.904 Relative reduction 77% (p<0.0001) 83% (p<0.0001) Percentage change in brain volume from Week 24 to week 96 -0.572 -0.741 -0.638 -0.750 Relative reduction in brain volume loss 22.8% (p=0.0042) 6 14.9% (p=0.0900) 1 Data prospectively pooled from Study 1 and 2 2 Non-confirmatory p-value analysis; not part of the pre-specified testing hierarchy 3 CDP defined as an increase of ≥ 1.0 point from the baseline Expanded Disability Status Scale (EDSS) score for patients with baseline score of 5.5 or less, or ≥ 0.5 when the baseline score is > 5.5, Kaplan-Meier estimates at Week 96 4 Defined as decrease of ≥ 1.0 point from the baseline EDSS score for patients with baseline EDSS score ≥ 2 and ≤ 5.5, or ≥0.5 when the baseline score is > 5.5. Patients with baseline score < 2 were not included in analysis. 5 NEDA defined as absence of protocol defined relapses, 12-week CDP, and any MRI activity (either Gd-enhancing T1 lesions, or new or enlarging T2 lesions) during the whole 96-week treatment. Exploratory result based on complete ITT population. 6 Non-confirmatory p-value; hierarchical testing procedure terminated before reaching endpoint. 7 Log-rank test 8 Confirmed relapses (accompanied by a clinically relevant change in EDSS). Figure 1: Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring during the Double-blind Treatment Period (Pooled WA21092 and WA21093 ITT Population)* * Pre-specified pooled analysis of WA21092 and WA21093. Results of the pre-specified pooled analyses of time to CDP sustained for at least 12 weeks (40% risk reduction for ocrelizumab compared to interferon beta-1a (p=0.0006) were highly consistent with the results sustained for at least 24 weeks (40% risk reduction for ocrelizumab compared to interferon beta-1a, p=0.0025). The studies enrolled patients with active disease. These included both active treatment naive and previously treated inadequate responders, as defined by clinical or imaging features. Analysis of patient populations with differing baseline levels of disease activity, including active and highly active disease, showed that the efficacy of ocrelizumab on ARR and 12 week CDP was consistent with the overall population. Primary progressive multiple sclerosis (PPMS) Efficacy and safety of ocrelizumab were also evaluated in a randomised, double-blind, placebo-controlled clinical trial in patients with primary progressive MS (Study WA25046) who were early in their disease course according to the main inclusion criteria, i.e.: ages 18-55 years, inclusive; EDSS at screening from 3.0 to 6.5 points; disease duration from the onset of MS symptoms less than 10 years in patients with an EDSS at screening ≤5.0 or less than 15 years in patients with an EDSS at screening >5.0. With regard to disease activity, features characteristic of inflammatory activity, even in progressive MS, can be imaging-related, (i.e. T1 Gd-enhancing lesions and/or active [new or enlarging] T2 lesions). MRI evidence should be used to confirm inflammatory activity in all patients. Patients over 55 years of age were not studied. Study design and baseline characteristics of the study population are presented in Table 5. Demographic and baseline characteristics were well balanced across the two treatment groups. Cranial MRI showed imaging features characteristic of inflammatory activity either by T1 Gd enhancing lesions or T2 lesions. During the Phase III PPMS study, patients received 600 mg ocrelizumab every 6 months as two 300 mg infusions, given two weeks apart, throughout the treatment period. The 600 mg infusions in RMS and the 2 x 300 mg infusions in PPMS demonstrated consistent PK/PD profiles. IRR profiles per infusion were also similar, independent of whether the 600 mg dose was administered as a single 600 mg infusion or as two 300 mg infusions separated by two weeks (see sections 4.8 and 5.2), but due to overall more infusions with the 2 x 300 mg regimen, the total number of IRRs were higher. Therefore, after Dose 1 it is recommended to administer ocrelizumab in a 600 mg single infusion (see section 4.2) to reduce the total number of infusions (with concurrent exposure to prophylactic methylprednisolone and an antihistamine) and the related infusion reactions. Table 5 Study design, demographics and baseline characteristics for Study WA25046 Study name Study WA25046 ORATORIO (n=732) Study design Study population Patients with primary progressive form of MS Study duration Event-driven ( Minimum 120 weeks and 253 confirmed disability progression events) (Median follow-up time: Ocrelizumab 3.0 years, Placebo 2.8 years Disease history at screening Age 18-55 years, EDSS of 3.0 to 6.5 Treatment groups Group A: Ocrelizumab 600 mg Group B: Placebo, in 2:1 randomisation Baseline characteristics Ocrelizumab 600 mg (n=488) Placebo (n=244) Mean age (years) 44.7 44.4 Age range (years) at inclusion 20 - 56 18 - 56 Gender distribution (% male/% female) 51.4/48.6 49.2/50.8 Mean/Median disease duration since PPMS diagnosis (years) 2.9/1.6 2.8/1.3 Mean EDSS 4.7 4.7 Key clinical and MRI efficacy results are presented in Table 6 and Figure 2. The results of this study show that ocrelizumab significantly delays disease progression and reduces deterioration in walking speed compared with placebo. Table 6 Key clinical and MRI endpoints from Study WA25046 (PPMS) Endpoints Study 3 WA25046 (Oratorio) Ocrelizumab 600 mg (n=488) Placebo (n=244) Clinical Endpoints Primary efficacy endpoint Proportion of patients with 12 weeks - Confirmed Disability Progression 1 (primary endpoint) Risk reduction 30.2% 34.0% 24% (p=0.0321) Proportion of patients with 24 weeks - Confirmed Disability Progression 1 28.3% 32.7% Risk reduction 25% (p=0.0365) Percentage change in Timed 25-Foot Walk from baseline to Week 120 38.9 55.1 Relative reduction in progression rate of walking time 29.4% (p=0.0404) MRI Endpoints Percentage change in T2 hyperintense lesion volume, from baseline to Week 120 -3.4 7.4 (p<0.0001) Percentage change in brain volume from Week 24 to Week 120 -0.902 -1.093 Relative reduction in rate of brain volume loss 17.5% (p=0.0206) 1 Defined as an increase of ≥ 1.0 point from the baseline EDSS score for patients with baseline score of 5.5 or less, or ≥ 0.5 when the baseline score is > 5.5, Kaplan-Meier estimates at Week 120. Figure 2: Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring during the Double-blind Treatment Period (WA25046 ITT Population)* * All patients in this analysis had a minimum of 120 weeks of follow-up. The primary analysis is based on all events accrued. Pre-specified non-powered subgroup analysis of the primary endpoint suggests that patients who are younger or those with T1 Gd-enhancing lesions at baseline receive a greater treatment benefit than patients who are older or without T1 Gd-enhancing lesions (≤ 45 years: HR 0.64 [0.45, 0.92], >45 years: HR 0.88 [0.62, 1.26]; with T1 Gd-enhancing lesions at baseline: HR 0.65 [0.40-1.06], without T1 Gd-enhancing lesions at baseline: HR 0.84 [0.62-1.13]). Moreover, post-hoc analyses suggested that younger patients with T1 Gd-enhancing lesions at baseline have the better treatment effect (≤ 45 years: HR 0.52 [0.27-1.00]; ≤ 46 years [median age of the WA25046 study]; HR 0.48 [0.25-0.92]; <51 years: HR 0.53 [0.31-0.89]). Post-hoc analyses were performed in the Extended Controlled Period (ECP), which includes double-blinded treatment and approximately 9 additional months of controlled follow-up before continuing into the Open-Label Extension (OLE) or until withdrawal from study treatment. The proportion of patients with 24 week Confirmed Disability Progression of EDSS≥7.0 (24W-CDP of EDSS≥7.0, time to wheelchair) was 9.1% in the placebo group compared to 4.8% in the ocrelizumab group at Week 144, resulting in a 47% risk reduction of the time to wheelchair (HR 0.53, [0.31, 0.92]) during the ECP. As these results were exploratory in nature and included data after unblinding, the results should be interpreted with caution. Shorter infusion substudy The safety of the shorter (2-hour) ocrelizumab infusion was evaluated in a prospective, multicenter, randomised, double-blind, controlled, parallel arm substudy to Study MA30143 (Ensemble) in patients with Relapsing-Remitting Multiple Sclerosis that were naïve to other disease modifying treatments. The first dose was administered as two 300 mg infusions (600 mg total) separated by 14 days. Patients were randomised from their second dose onwards (Dose 2 to 6) in a 1:1 ratio to either the conventional infusion group with ocrelizumab infused over approximately 3.5 hours every 24 weeks, or the shorter infusion group with ocrelizumab infused over approximately 2 hours every 24 weeks. The randomisation was stratified by region and the dose at which patients were first randomised. The primary endpoint was the proportion of patients with IRRs occurring during or within 24 hours following the first randomised infusion. The primary analysis was performed when 580 patients were randomised. The proportion of patients with IRRs occurring during or within 24 hours following the first randomised infusion was 24.6% in the shorter infusion compared to 23.1% in the conventional infusion group. The stratified group difference was similar. Overall, in all randomised doses, the majority of the IRRs were mild or moderate and only two IRRs were severe in intensity, with one severe IRR in each group. There were no life-threatening, fatal, or serious IRRs. Immunogenicity Patients in MS trials (WA21092, WA21093 and WA25046) were tested at multiple time points (baseline and every 6 months post treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1,311 patients treated with ocrelizumab, 12 (~1%) tested positive for treatment-emergent ADAs, of which 2 patients tested positive for neutralising antibodies. The impact of treatment-emergent ADAs on safety and efficacy cannot be assessed given the low incidence of ADA associated with ocrelizumab. Immunisations In a randomised open-label study in RMS patients (N=102), the percentage of patients with a positive response to tetanus vaccine at 8 weeks after vaccination was 23.9% in the ocrelizumab group compared to 54.5% in the control group (no disease-modifying therapy except interferon-beta). Geometric mean anti-tetanus toxoid specific antibody titres at 8 weeks were 3.74 and 9.81 IU/ml, respectively. Positive response to ≥5 serotypes in 23-PPV at 4 weeks after vaccination was 71.6% in the ocrelizumab group and 100% in the control group. In patients treated with ocrelizumab a booster vaccine (13-PCV) given 4 weeks after 23-PPV did not markedly enhance the response to 12 serotypes in common with 23-PPV. The percentage of patients with seroprotective titres against five influenza strains ranged from 20.0-60.0% and 16.7-43.8% pre-vaccination and at 4 weeks post vaccination from 55.6-80.0% in patients treated with ocrelizumab and 75.0-97.0% in the control group, respectively. See sections 4.4 and 4.5. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Ocrevus in one or more subsets of the paediatric population in the treatment of multiple sclerosis. See section 4.2 for information on paediatric use.