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Ocrelizumab (Ocrevus)

Other names: Ocrevus

Ocrelizumab is a disease modifying drug which is being developed as a treatment for relapsing remitting and primary progressive MS. It is taken as an intravenous infusion every six months.

Summary

Ocrelizumab for relapsing remitting MS: Appraisal

Ocrelizumab for primary progressive MS: Appraisal

Ocrelizumab is a disease modifying drug which is being tested as a treatment for relapsing remitting and primary progressive MS. It is taken as an intravenous infusion every 6 months.
 

  • Ocrelizumab targets a marker (CD20) on the surface of B cells, a type of white blood cell thought to be involved in the abnormal immune response that attacks the myelin coating of nerve cells
  • In relapsing remitting MS, ocrelizumab reduced relapse rates by approximately 50% compared to beta interferon
  • In primary progressive MS, ocrelizumab reduced 12 week disability progression by 24% compared to placebo
  • In clinical trials, infusion-related reactions, chest infections and herpes (oral herpes and shingles) were more frequent in those taking ocrelizumab
  • Neoplasms (abnormal growth of tissues which can be benign or malignant), including several cases of breast cancer, were reported more frequently in those taking ocrelizumab

Licensing and appraisal

Licensing

The European Commission has granted marketing authorization for ocrelizumab (Ocrevus) for the treatment of both active relapsing MS and early active primary progressive multiple sclerosis. This follows a recommendation from the European Medicines Agency in November that a licence should be granted for:

  • Active relapsing MS, meaning people who are having relapses or showing new lesions on MRI scans
  • Early primary progressive MS, defined as people who have had symptoms of MS for 15 years or less, have an EDSS of 3.0 to 6.5 and evidence of MS activity on MRI scans

NHS appraisal

Ocrelizumab is currently being appraised by NICE (National Institute for Health and Care Excellence) and SMC (Scottish Medicines Consortium) to determine NHS availability in the UK for both relapsing remitting and primary progressive MS.

Relapsing remitting MS

NICE has recommended that ocrelizumab can be prescribed for relapsing remitting MS if:

  • you are experiencing relapses or have MRI evidence of new areas of MS activity, and
  • you are unable or unwilling to take Lemtrada (alemtuzumab)

This reverses NICE’s initial decision that it did not intend to recommend ocrelizumab for relapsing MS.  The MS Trust responded to this decision, arguing that ocrelizumab would be a valuable additional treatment for people with relapsing remitting MS and for the NHS.

SMC has rejected ocrelizumab for relapsing remitting MS in Scotland.  

The SMC plans to re-appraise ocrelizumab for relapsing remitting MS in November 2018, with a decision due in mid-December.

​Primary progressive MS

NICE has rejected ocrelizumab as an NHS treatment for primary progressive MS in England and Wales. 

An SMC submission for ocrelizumab for primary progressive MS has been withdrawn for the time being. 

How does ocrelizumab work?

Ocrelizumab is a monoclonal antibody, a type of drug developed to attack specific targets in the immune system. Ocrelizumab has been designed to target a marker (CD20) on the surface of B cells, a type of white blood cell (lymphocyte) which is thought to influence the abnormal immune response that attacks the myelin surrounding nerve cells. Targeted B cells are destroyed.

How is ocrelizumab taken?

Ocrelizumab is taken as an intravenous infusion (drip). The first dose is given as two separate infusions, two weeks apart. Further doses are given as one infusion every six months.

Ocrelizumab research

What are the results so far?

Relapsing remitting MS:

  • In a phase II, 24 week, clinical trial, 218 people were split into groups receiving one of two doses of ocrelizumab (600mg and 2000mg), interferon beta-1a (Avonex) or placebo. After 24 weeks, the number of active lesions as measured by MRI scans was 89% lower in the low dose group and 96% lower in the high dose group compared with the placebo group.

At 24 weeks the annual relapse rate was 0.13 in the low dose group and 0.17 in the high dose group compared to 0.36 for people on interferon beta and 0.64 in the placebo group.

  • Opera I and II - ocrelizumab compared to interferon beta 1a (Rebif)

These phase III studies recruited 1656 participants with relapsing remitting MS who took either ocrelizumab 600mg every 6 months or interferon beta 1a (Rebif) three times per week for approximately two years.

Over the two years of the clinical trials, ocrelizumab reduced the number of relapses by 50% compared to interferon beta 1a, reduced disability progression sustained for 3 and 6 months, and significantly reduced the number of lesions seen on MRI scans compared to beta interferon.  Brain volume loss was reduced and numbers of participants with no evidence of disease progression (NEDA) were increased in the ocrelizumab treatment groups compared to interferon beta 1a. 

Primary progressive MS:

  • Oratorio - ocrelizumab compared to placebo

This phase III study recruited 732 participants with primary progressive MS and EDSS of 3 to 6.5 who took either 600mg ocrelizumab or placebo by iv infusion every 6 months for more than 2 years.

The main measure of the study was the onset of disability progression. This was measured by the number of participants with an increased EDSS which was still evident 3 months later. The study also recorded the number of participants with an increased EDSS still evident after 6 months, walking speed over 25 feet and volume of brain and MS lesions.

Fewer people taking ocrelizumab had an increase in disability, compared to placebo. An increase in disability which lasted 3 months was seen in 32.9% of those taking ocrelizumab and 39.3% of those taking placebo. In addition, increased disability which lasted at least 6 months was seen in 29.6% taking ocrelizumab and 35.7% taking placebo. Comparing the two groups, people taking ocrelizumab were 24% less likely to have an increase in their disability than those taking placebo.

After 120 weeks of treatment, walking speed over 25 feet was 39% slower for ocrelizumab compared to 55% slower for placebo. Brain lesion volume decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo. Loss of brain volume was 0.9% for ocrelizumab and 1.09% for placebo.

What further research is planned?

Relapsing remitting MS:

  • Ocrelizumab for people who have had relapses despite taking another disease modifying drug

This phase III study is recruiting 600 people with relapsing remitting MS who have stopped taking a disease modifying drug because of lack of efficacy.  All participants will take ocrelizumab 600mg every 24 weeks by iv infusion for 96 weeks. The main measure of the study is the percentage of participants with no evidence of disease activity at the end of the study. An identical study is underway in the United States and Canada.
Estimated completion date December 2020. Further details of this study.

  • Ocrelizumab in early stage relapsing remitting MS

This phase III study is recruiting 600 participants who have a diagnosis of relapsing remitting MS and whose first symptoms of MS occurred less than three years ago.  All participants will take ocrelizumab 600mg every 24 weeks by iv infusion for 192 weeks with a follow-up period of at least 48 weeks. The study will monitor a number of measures of MS activity, including disability worsening or improvement, relapses and lesions seen on MRI.
Estimated completion date January 2022. Further details of this study.

Primary progressive MS:

  • Oratorio-Hand - ocrelizumab compared to placebo

This phase III study is designed to evaluate the effect of ocrelizumab on hand and arm function in people with more advanced disability, including those who need a wheelchair. The study will recruit approximately 1000 participants with EDSS between 3 and 8. The main measure of the study will be the nine-hole peg test, a measure of arm, wrist and hand function. A secondary measure will be onset of disability progression, measured by the number of participants with an increased EDSS which persists for 3 months or longer. Detailed planning for the study is still underway but it is anticipated that recruitment will begin at the end of 2018, with study centres worldwide, including the UK.
Press release with further details of this study.

Progressive MS:

  • Consonance - ocrelizumab

This study is recruiting 600 people with either secondary or primary progressive MS. All participants will take ocrelizumab 600mg every 24 weeks for four years. Progression of disability will be assessed using a combination of measures.
Estimated completion date January 2024.
Further details of this study.

Side effects

In the phase II RRMS study, serious side effects were rare and comparable in all four groups. However, one patient in the ocrelizumab 2000mg group died due to brain oedema (swelling), after the occurrence of systemic inflammatory response syndrome with multi-organ failure. The connection of this death to ocrelizumab is unclear.  This dose of ocrelizumab has not been used in subsequent clinical trials.

Across all the clinical trials, infusion-related reactions, chest infections and herpes (oral herpes and shingles) were more frequent in those taking ocrelizumab.

Neoplasms (abnormal growth of tissues which can be benign or malignant), including several cases of breast cancer, were reported more frequently in those taking ocrelizumab. This will need to be monitored closely.

In May 2017, a first case of progressive multifocal leukoencephalopathy (PML) was reported in a person taking ocrelizumab.  The case occurred in someone with relapsing remitting MS who was JC virus-positive, had stopped taking Tysabri in February after three years on the drug and had taken their first dose of ocrelizumab in April. The manufacturer of ocrelizumab is carrying out further investigations. 

Ocrelizumab has previously been investigated as a treatment for rheumatoid arthritis but studies were discontinued because of a high incidence of opportunistic infections in participants. Opportunistic infections are infections that do not normally occur in a healthy person but may occur when the immune system is compromised. To date, opportunistic infections have not been reported in ocrelizumab MS trials.