When it was first approved for release in the USA, Australia, Switzerland and by the EMA (European Medicines Agency) in 2017, it was yet another powerful intravenous treatment to combat relapsing-remitting MS (RRMS). More importantly than this, it was also hailed as the first treatment for the primary progressive form of the disease (PPMS), typically associated with worsening disability right from the onset of the condition.
There was much excitement among the global MS community, and whilst questions remained as to which people with PPMS should be offered the treatment, it seemed that it would be made widely available towards the end of 2018. Unfortunately, in the U.K. at least, at the very last moment, ocrelizumab was felt not to be cost-effective in PPMS and therefore would only be offered to people with RRMS. MS charities have been extremely vocal in their opposition to this decision, and we all remain hopeful that it will be overturned.
In the meantime, a new study has been published that offers more evidence on the safety and effectiveness of the drug, as compared to the previously available disease modifying drugs (DMDs). Writing in the journal “Multiple Sclerosis and Related Disorders”, a team of researchers from the UK and Switzerland have performed a systematic review and network meta-analysis of the 13 currently available DMDs. No single randomised control trial has directly compared the DMDs, as most are initially tested against placebo or merely a handful of the pre-existing treatments.
In this study the researchers used very powerful statistical methods and included data from previous trials in such a way as to ‘level the playing field’ of the DMDs and allow fair comparison.
The 4 key outcomes measured were:
Serious adverse events
Discontinuation of treatment due to adverse event
They also assessed;
Proportion of patients remaining relapse free
All cause discontinuation of treatment
After the rigorous selection criteria were applied, 33 studies were included in the analysis.
So how did ocrelizumab compare to the other DMDs and is it worthy of all its hype?
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.
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.
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