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OCREVUS

OCREVUS is a monoclonal antibody that selectively targets CD20-expressing B-cells in Multiple Sclerosis

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Please review the Data Sheet before prescribing.

OCREVUS® (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.1

B Cells in MS

OCREVUS is administered by intravenous infusion every six months. The first dose is given as two 300 mg infusions given two weeks apart. Subsequent doses are given as a single 600mg infusion.1

The Medsafe registered indications are:

  • OCREVUS is indicated for the treatment of patients with relapsing forms of multiple sclerosis (RMS) to suppress relapses and disease progression (clinical and subclinical disease activity).
  • OCREVUS is indicated for the treatment of patients with primary progressive multiple sclerosis (PPMS) to delay disease progression and reduce deterioration in walking speed.

For more information on OCREVUS, please refer to the data sheet on the Medsafe website here.

OCREVUS funding status

OCREVUS is not funded by PHARMAC. For more information on how to access OCREVUS privately, please contact Roche Medical Information on 0800 276 243.

OCREVUS in RMS2

Study design

OPERA I and OPERA II are Phase III, randomized, double-blind, double-dummy, parallel-group studies evaluating the efficacy and safety of OCREVUS (600mg administered by intravenous infusion every six months) compared with IFN beta-1a (44µ administered by subcutaneous injection three times per week) in 1,656 patients with relapsing forms of multiple sclerosis. In these studies, relapsing MS (RMS) was defined as relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) with relapses.2

Patients 18-55 years of age with ≥2 documented clinical attacks within the last 2 years or 1 clinical attack in the year prior to screening (but not within 30 days), and an EDSS score of 0-5.5 were eligible for inclusion. Patients with a disease duration ≥10 years and an EDSS ≤2 were excluded.

A total of 821 and 835 patients were randomised in OPERA I and II, respectively to receive OCREVUS 600mg IV (given as two 300mg infusions on days 1 and 15, of dose 1, followed by a single infusion of 600mg for each subsequent dose) every 24 weeks or IFN beta-1a 44µ SC 3 times weekly, for 96 weeks.

In OPERA I and II, the primary endpoint was the ARR at 96 weeks. The ARR reflects the number of observed relapses that met the pre-defined criteria per person-year of follow up.

Secondary endpoints included:

  • Time to onset of 12-week CDP in a pre-specified pooled analysis of OPERA I and II during the 96 weeks
  • Total mean number of T1 Gd-enhancing lesions at weeks 24, 48, and 96
  • Total number of new/enlarging T2 hyperintense lesions at weeks 24, 48 and 96
  • Pooled analysis of time to onset of 24-week CDP during the 96 weeks
  • Total number of new T1 hypointense lesions at weeks 24, 48 and 96
  • The safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of OCREVUS

Baseline characteristics were similar between the 2 treatment groups.

Results

OCREVUS met the primary and major secondary endpoints.

  • Treatment with OCREVUS significantly reduced the protocol-defined ARR at 96 weeks vs interferon beta-1a by 46% in OPERA 1 (p<0.001) and by 47% in OPERA II (p<0.001).
  • In a pre-specified pooled analysis in OPERA I and II, OCREVUS treatment also significantly reduced the time to onset of both 12-week and 24-week CDP versus IFN beta-1a by 40% for both time points (p <0.001 and P=0.003 respectively).

MRI results

  • A 94% and 95% relative reduction in the total number of T1 gd-enhancing lesions compared with IFN beta-1a in OPERA I and OPERA II, respectively (p <0.001 and p <0.001).
  • A 77% and 83% relative reduction in the total number of new and/or enlarging T2 lesions compared with IFN beta-1a in OPERA I and OPERA II, respectively (p <0.001 and p <0.001).

Safety results

Adverse events were reported by 80.1% and 80.9% of patients in the OCREVUS and IFN beta-1a groups respectively. The incidence of serious adverse events, including serious infections was similar between OCREVUS and IFN beta-1a in both studies. The most common serious side effect was the infusion-related reaction which occurred in 34.4% of OCREVUS patients compared to 9.7% in the IFN beta-1a arm.

To read the summary of adverse events, click here

To read the full OPERA I and II trial results, click here

OCREVUS in PPMS3

Study Design

ORATORIO is a Phase III, randomized, double-blind, global multi-centre study evaluating the efficacy and safety of OCREVUS (600mg administered by intravenous infusion every six months; given as two 300mg infusions two weeks apart) compared with placebo in 732 patients with PPMS.

The blinded treatment period of the ORATORIO study continued until all patients had received at least 120 weeks of either OCREVUS or placebo and a pre-specified number of confirmed disability progression (CDP) events was reached overall in the study.

The primary endpoint was the percentage of patients with disability progression (as defined by increase in EDSS score) confirmed at 12 weeks in a time-to-event analysis.

Secondary endpoints were tested in the following order if the primary endpoint and each preceding endpoint reached a significance level of p=0.05

  • Time to onset of 24-week CDP
  • Change from baseline to week 120 in the timed 25-foot walk (T25FW)
  • Change from baseline to week 120 in total volume of T2 lesions
  • Percentage change in total brain volume from week 24 to week 120
  • Change from baseline to week 120 in quality of life as measured by the SF-36 (physical component)

Baseline characteristics were similar between the treatment groups.

Results

ORATORIO met its primary endpoint, showing that treatment with OCREVUS significantly reduced the risk of 12-week CDP as measured by EDSS by 24% compared with placebo (p =0.03).

Key secondary and exploratory endpoint results

  • OCREVUS significantly reduced the risk of 24-week confirmed disability progression by 25% vs placebo
  • Compared to placebo, treatment with COREVUS resulted in a 25% relative risk reduction in the proportion of patients with 20% worsening of the timed 25-foot walk confirmed at 12 weeks (p=0.04)
  • The total volume of hyperintense lesion on T2 weighted images from baseline to week 120 decreased with OCREVUS and increased with placebo (mean % change, -3.4 vs. 7.4; p<0.001)
  • The adjusted mean % change in brain volume from week 24 to week 120 was lower with OCREVUS vs placebo (-0.90 vs. -1.09, p=0.02)
  • There was no significant difference in the change in the Physical Component Summary score of the 36-item Short-Form Health Survey between treatment groups
  • OCREVUS resulted in a significant reduction in both 12 and 24 week confirmed ≥20% progression in 9HPT by 44 and 45% respectively compared with placebo (p.0.001)

Safety results

A similar proportion of patients in the OCREVUS group experienced adverse events and a low rate of serious adverse events compared to the placebo group. The most frequently reported adverse event among the OCREVUS treated patients was infusion-related reaction (39.9% vs. 25.5% in the placebo group). Two patients withdrew from OCREVUS treatment because of infusion-related reactions. IRRs decreased in rate and severity with subsequent administration. The overall rates of infection were 71.7/100 patient-years for OCREVUS and 73.8/100 patient-years for placebo. The incidence of serious infection was similar between the OCREVUS and placebo groups. No opportunistic infections were reported in the study.

Safety of OCREVUS in the PPMS population will continue to be assessed throughout the open-label extension phase.

To read the ORATORIO trial results, click here

Safety

The most common side effects associated with OCREVUS in all Phase III studies were infusion reactions and upper respiratory tract infections, which were mostly mild to moderate in severity.1-3

Summary of adverse drug reactions associated with OCREVUS (RMS or PPMS) with an incidence of ≥2% and higher than the comparator1

Table 1 Adapted from OCREVUS Data Sheet1

1. Interferon beta-1a 44mcg s.c. or placebo

2.PPMS patients were randomised 2:1 (OCREVUS:placebo)

3.Symptoms reported as IRRS within 24 hours of infusion are described in the Data Sheet under Infusion Related Reactions

Progressive Multifocal Leukoencephalopathy (PML)

No cases of PML have been identified in the OCREVUS clinical trials. John Cunningham (JC) virus infection resulting in PML has been observed in patients treatment with anti-CD20 antibodies and other MS therapies, and is associated with risk factors (e.g. patient population, polytherapy with immunosuppressants). However, as a risk of PML cannot be excluded patients should be monitored for early signs and symptoms of PML, which can include any new onset, or worsening of neurological signs or symptoms as these can be similar to a MS relapse1.

References

  1. OCREVUS® (ocrelizumab) Data Sheet December 2017 available here
  2. Hauser SL, Bar-Or, A, Comi, G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376:221-234.
  3. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376:209-220.

Abbreviations

MS = multiple sclerosis

RRMS = relapsing-remitting multiple sclerosis

PPMS = primary progression multiple sclerosis

EDSS = Expanded Disability Status Scale

CDI = confirmed disability improvement

CDP = confirmed disability progression

ARR = annualized relapse rates

IFN = interferon

Gd = gadolinium

SF-36 = Short-Form 36

PML = Progressive Multifocal Leukoencephalopathy

IRR = infusion-related reaction

T25FW = timed 25-foot walk

9HPT = 9-Hole Peg Test