Thursday December 22 2016
Multiple sclerosis affects the brain and spinal cord
"A drug that alters the immune system has been described as 'big news' and a 'landmark' in treating multiple sclerosis," BBC News reports. The drug, ocrelizumab, proved effective in two related studies, for treating both the primary progressive and the relapsing remitting types of multiple sclerosis (MS).
We have focused our analysis on the second study, as relapsing remitting MS is the most common type, accounting for around 80% of cases.
MS happens when the body's immune system mistakenly attacks the brain and spinal cord. For the relapsing remitting type of MS, people have periods of worsening symptoms (relapses) and periods without symptoms, or with only mild symptoms (remissions). Over time, symptoms tend to get worse.
Ocrelizumab works by suppressing B cells, which are part of the immune system. In this 96-week study, people who took ocrelizumab had fewer relapses each year and their symptoms were less likely to worsen. Also, brain scans showed less inflammation or damage to the brain, compared to standard treatment.
However, people who took ocrelizumab were more likely to have adverse reactions, including infections, some of which were serious. People taking ocrelizumab were also more likely to get cancers during the study period.
It is unclear whether steps could be taken to reduce the possibility of adverse reactions.
Another issue is that of price. Ocrelizumab is what is known as a monoclonal antibody and this class of drugs tends to be very expensive.
The BBC reported that "patients in the UK may be disappointed" as the NHS may not be able to provide the drug to all people with MS.
Where did the story come from?
The study was carried out by researchers from 16 universities, hospitals and research centres in the US, Canada, Italy, the UK, Germany, Spain, Poland and Switzerland. It was funded by F Hoffman-La Roche, the company that makes ocrelizumab. Many of the researchers involved in the study are employees and /or shareholders in F Hoffman-La Roche.
The study was published in the peer-reviewed journal New England Journal of Medicine.
BBC News gave a fair summary of the studies and included some useful quotes from researchers involved, as well as independent experts.
What kind of research was this?
Researchers carried out two identical double-blinded, randomised controlled trials (RCTs) of ocrelizumab for relapsing remitting MS. Randomised controlled trials are usually the best way to see whether one treatment works better than a placebo or (as in this case) a different treatment.
What did the research involve?
Researchers recruited patients aged 18 to 55 with relapsing remitting MS, who they randomly assigned to either ocrelizumab or interferon beta, the standard treatment for the disease. They followed their progress for 96 weeks and compared the results.
The patients were recruited separately into the two trials of 821 and 835 participants, which were run independently. Patients came from more than 300 trial centres, across at least 32 countries. Ocrelizumab was given through an infusion every 24 weeks, and interferon beta through injections three times a week. Interferon beta is a widely used treatment for relapsing remitting MS and also works by suppressing immune cells.
To ensure no-one knew which treatment each patient got while the trial was underway, patients had dummy infusions or injections of the treatment they were not assigned to.
In their analysis, the researchers looked at how many relapses patients had on average each year. They then looked at other indicators such as symptom scores over time, and scans.
The brain and spinal cord of people with MS get areas of inflammation and lesions, where the immune system has attacked the coating of the nerve cells. These show up on magnetic resonance imaging (MRI) scans.
Researchers looked at the data separately for the numbers of relapses, then pooled the data for some of the other markers, as the trials were run identically.
What were the basic results?
The average number of relapses per year was lower for people who took ocrelizumab:
- 0.16 per year for ocrelizumab compared to 0.29 per year for interferon beta, in both trials.
- This represents a reduction in relapses of 54% (rate ratio (RR) 0.54, 95% confidence interval (CI) 0.40 to 0.72) for trial one and 53% for trial two (RR 0.53, 95% CI 0.4 to 0.71). The slight difference may be because the two trials did not have identical numbers of participants or may have been a chance finding.
People who took ocrelizumab were less likely to have permanently worsened symptoms after 12 weeks. Looking at the pooled data, 9.1% of people had permanently worse symptoms if they'd taken ocrelizumab, compared to 13.6% who'd taken interferon beta.
People who took ocrelizumab were less likely to have new signs of damage to their brain. The numbers of new lesions seen per scan was:
- 0.02 for people taking ocrelizumab (both trials)
- 0.29 (trial 1) and 0.42 (trial 2) for people taking interferon beta
However, the treatment has side effects, caused by suppression of the immune system. There were four cancers in the ocrelizumab group and two in the interferon beta group.
Another five cases of cancer occurred during a year-long extension to the study, during which everyone took ocrelizumab.
We don't know for sure that the cancers were caused by the treatment, but part of the immune system's job is to keep cancer under control.
One third (34%) of people who had ocrelizumab had a reaction to the infusion. This was most often itchiness, rash, throat irritation and flushing, but one patient had a life-threatening reaction, although they recovered with treatment.
Infections were also more common among patients who took ocrelizumab than among those on beta interferon.
How did the researchers interpret the results?
The researchers say their results show that B cells play a role in the development of MS, which had previously been seen as primarily caused by T cells (another type of immune system cell).
They say that "Additional and extended studies will be required in order to determine whether the outcomes observed in these 96-week trials … translate into enhanced protection against accrual of disability over the long term."
This study shows promising results for a new approach to treating MS. However, the study period is relatively short (96 weeks is about 20 months, so less than two years) and MS is a long-term disease. If this drug is approved for use, longer studies will be needed to be sure that this treatment lives up to its early promise over many years and to monitor for adverse reactions in real life, particularly cancers.
Some people with relapsing remitting MS do well on existing treatments, and have only infrequent relapses of mild symptoms which get worse very slowly.
But for most patients on standard treatment, the damage to their nervous system worsens over time, making it progressively harder to carry on with normal activities. If this drug can lessen the damage to the nervous system, it might help arrest this process.
The numbers of cancers seen in the study gives some cause for concern. While there were also cancers seen in the standard treatment group, it's a reminder that powerful treatments which affect the immune system can also cause harm. Bigger, longer-term studies should give us a clearer picture of how the balance of benefits and harms stacks up for ocrelizumab.
It is expected that these studies should begin in 2017.
If you are interested in taking part in clinical trials for MS, visit the UK Clinical Trails Gateways site for MS research.