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Ocrelizumab (Ocrevus) for MS

Natalizumab (also called Tysabri) is a potent therapy for treating very active relapsing remitting MS. Treatment is given through an intravenous infusion every four weeks.

Ocrelizumab is the first treatment to be licensed for Primary Progressive MS (PPMS), and also can be used to treat relapsing remitting MS (RRMS).  It acts by targeting a marker (CD20) on a type of white blood cell (B cell) thought to be involved in the abnormal immune response that attacks the myelin coating of nerve cells.  

 

In both forms of the disease, it is given as an intravenous infusion, initially split over 2 weeks, and then every 6 months.

Ocrelizumab infographic

Ocrelizumab in clinical trials

In clinical trials for PPMS, the group taking Ocrelizumab reduced the chance of worsening disability after 12 weeks by approximately one quarter (24%), compared with those taking a placebo.  Whilst this may not sound like a huge difference, it is the first medication ever to show a statistically significant improvement in PPMS outcomes, and it would be very interesting to see how these improvements will be borne out over the longer-term.

After 2 years of treatment, walking speed had slowed less in the treatment group than the placebo group.  There were also less brain lesions and brain shrinkage in the treatment group.

Ocrelizumab prescribing in PPMS is very dependent on location, and in the U.K. is not currently approved, due to early cost-benefit analysis.  The European Medicines Agency (EMA) has mandated it use in “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​”.

When used to treat RRMS, Ocrelizumab reduced the number of relapses by 50% compared to beta-interferon and 70% compared to placebo, 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 there were more people with no evidence of disease activity (NEDA) in the ocrelizumab treatment groups compared to beta-interferon.  

Side effects:

It is generally very well-tolerated and no unexpected side effects were reported in the phase III trials.

That said, it is not without risks, and these typically include:

  • Infusion site reactions

  • Chest infections

  • Cold sores and shingles (herpes infections)

  • Opportunistic infections (caused by bacteria or viruses normally kept under control by the immune system)

  • Potentially increased risks of some cancers, as yet not confirmed and being closely monitored

All of these side effects will be monitored closely as the use of Ocrelizumab becomes more wide-spread.  

Our website also has some information on a recent piece of research comparing Ocrevus to the other disease modifying drugs (DMDs) in terms of effectiveness and side effects.

Can Ocrelizumab affect conception and pregnancy?

Pregnancy is not recommended during treatment with Ocrevus.  If you are planning to start a family you should discuss this with your MS team.  Women of child-bearing age should use an effective method of contraception during treatment and for 12 months after stopping Ocrevus.  Breastfeeding is currently not recommended.

References

  1. JAMA Neurol. 2019 Feb 18. doi: 10.1001/jamaneurol.2018.4905.
  2. https://doi.org/10.1016/j.msard.2018.12.040
  3. https://www.mstrust.org.uk/a-z/ocrelizumab-ocrevus

How does Ocrelizumab compare to other DMD's?

Well in terms of disability progression, ocrelizumab fared very well, found to be superior to 10 other treatments in delaying progression, including placebo. There was a greater than 50% probability that it was superior to the 6 remaining treatments, and no treatment was found to be more effective in slowing disability progression.

With regards to reducing relapse rate, ocrelizumab was more effective than 12 treatments, including placebo, had a greater than 50% probability that it was more effective than 2 of the 4 other treatments, and there was no evidence suggesting that any treatment was more effective than ocrelizumab in reducing relapses.

Ocrelizumab side effects

The serious adverse events (SAE) data was especially interesting. This is one of the most important safety measures in determining if a drug is released to market, and includes key components such as whether the treatment resulted in death, was life-threatening or if the patient required hospitalisation. In this regard, ocrelizumab was no more likely to cause an SAE than any other treatment, including placebo. In a related test, there was no difference found between Ocrelizumab and any other treatment in the chances of stopping treatment due to side effects (adverse events).

Next the authors combined the 4 key outcomes to give an overview of how ocrelizumab might fit in to the bigger DMD picture. They found that it “demonstrated a consistently high probability of being ranked as the most effective or tolerable treatment”.

A really important “real-world” measure is the proportion of patients remaining relapse-free. In this regard, Ocrelizumab proved superior to 14 of 18 other treatments.

Another important aspect is how likely it is that a patient will stop taking their treatment (all-cause discontinuation), often because they either feel it doesn’t work, or that the side effects are too severe. People with MS who received ocrelizumab were less likely to stop their treatment than those given interferons, but more likely to stop than those using natalizumab (Tysabri) or alemtuzumab (Lemtrada). A word of caution however, once someone has been given an induction treatment such as Lemtrada, they cannot “undo” it by stopping, but also in some of the trials, people knew which treatment they were taking (open-label trials), introducing the potential for bias. In real-terms, I think it is safe to infer that ocrelizumab performs very well in terms of tolerability for pwMS.

Conclusions about Ocrelizumab

So what’s the take home message? Well from the evidence available here, it appears that ocrelizumab is at least as safe and effective as any other DMD. In fact, it appears to be more effective than any of the previously available treatments in slowing disability progression and reducing relapses, and appears to be very safe. It really is significant that a highly effective MS treatment has a safety profile comparable to placebo (i.e. no active treatment). In the past, there was a very delicate balance to be struck between the benefits of the more powerful medications (Tysabri and Lemtrada) and the very real potential for serious and sometimes life-threatening side effects.

One note of caution however. Clinical trials by their nature are too small to detect uncommon side effects. So we don’t expect to see a significant difference between the tested drug and placebo in terms of occurrence of the less common side effects, like rare infections for example, simply because of too few numbers of participants. It is important to note that the original study of ocrelizumab in primary progressive MS by Montalban and colleagues showed that the treated group had approximately three times the rate of cancers compared to the placebo group; those researchers noted in that paper that across all studies to date at that time (December 2016), people with MS treated with ocrelizumab had developed cancer at twice the rate of those in the placebo groups. So we have to await longer term real-world data to see if this difference persists in larger populations and if so, whether ocrelizumab remains as safe a choice as is being suggested.

This latest meta-analysis though should be reassuring for those considering or already taking ocrelizumab, that it is a highly effective treatment, and further incentive to those MS charities, drug companies and researchers to try and replicate this evidence in PPMS, so that a treatment can finally be made available for those people with MS who could quite rightly feel let down and left behind.

Dr Jonathan White MBChB MRCOG