OCREVUS 920 mg Solution for injection Ref.[117049] Active ingredients: Ocrelizumab

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.

Subcutaneous ocrelizumab contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-formulated active substances when administered subcutaneously.

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 with intravenous ocrelizumab. 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 intravenous 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 intravenous 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

Subcutaneous formulation

OCARINA II

Study CN42097 (OCARINA II) was a multicenter, randomised, open-label, parallel arm trial conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, immunogenicity, radiological and clinical effects of subcutaneous ocrelizumab compared with intravenous ocrelizumab in patients with either RMS or PPMS. OCARINA II was designed to demonstrate non-inferiority of treatment with subcutaneous ocrelizumab versus intravenous ocrelizumab based on the primary PK endpoint of area under the concentration time curve (AUC) up to week 12 post-injection/infusion (AUC_w1-12).

A total of 236 patients with RMS or PPMS (213 patients with RMS, 23 patients with PPMS) were randomised in a 1:1 ratio to the subcutaneous arm or intravenous arm. During the controlled period (Day 0 to Week 24), patients received either a single 920 mg subcutaneous injection at study Day 1 or two 300 mg intravenous infusions at study Day 1 and 14. After the controlled period, all patients had the opportunity to receive further subcutaneous injections of 920 mg ocrelizumab at Weeks 24 and 48 (Dose 2 and 3, respectively). Patients were excluded if they had previous treatment with anti-CD20 antibodies within the last 24 months, including ocrelizumab.

Patients were aged 18-65 years with an EDSS between 0 to 6.5 at screening. The demographics were similar and baseline characteristics were well balanced across the two treatment groups. The mean age was 39.9 years in the subcutaneous arm and 40.0 years in the intravenous arm. 34.7% of patients were male in the subcutaneous arm and 40.7% of patients were male in the intravenous arm. The mean/median duration since MS diagnosis was 5.70/3.10 years in the subcutaneous arm and 4.78/2.35 years in the intravenous arm.

Non-inferiority of the ocrelizumab exposure after administration of 920 mg subcutaneous ocrelizumab compared to 600 mg intravenous ocrelizumab was demonstrated based on the PK primary endpoint, AUC up to week 12 (AUCw1-12) post-injection (see section 5.2).

Intravenous formulation

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 2.

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 2. Study design, demographic and baseline characteristics:

^* 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 3 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 3. Key Clinical and MRI Endpoints from Studies WA21092 and WA21093 (RMS):

¹ Data prospectively pooled from Study 1 and 2
² Non-confirmatory p-value analysis; not part of the pre-specified testing hierarchy
³ 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 Confirmed Disability Progression (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 4.

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 × 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 × 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 4. Study design, demographics and baseline characteristics for Study WA25046:

Key clinical and MRI efficacy results are presented in Table 5 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 5. Key clinical and MRI endpoints from Study WA25046 (PPMS):

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.

Immunogenicity

Subcutaneous formulation

Across OCARINA I and OCARINA II, no patients had treatment-emergent anti-drug antibodies (ADAs) to ocrelizumab. Patients in OCARINA II were tested at baseline and every 6 months post treatment for the duration of the trial for ADAs. Transient ADAs may therefore not be detected between the assessed time points.

The incidence of treatment-emergent anti-rHuPH20 (hyaluronidase) antibodies in patients treated with subcutaneous ocrelizumab in OCARINA I was 2.3% (3/132). No patients from OCARINA II had treatment-emergent anti-rHuPH20 antibodies.

Intravenous formulation

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 ADAs. Out of 1311 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 intravenous 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 intravenous ocrelizumab group and 100% in the control group. In patients treated with intravenous 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 intravenous 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.