Thursday January 21 2010
People taking the drug showed fewer brain lesions
“The first tablets to fight multiple sclerosis dramatically reduce the chances of symptoms returning,” The Daily Telegraph has reported.
The news is based on clinical trials of two new drugs, fingolimod and cladribine, which cut the likelihood of relapses in people with the most common form of MS. The pills also reduce the chances of the disease progressing, and may be more convenient to take than current MS treatments. The drugs are going through the licensing process, and it is hoped that they will be available by the end of 2011. Their costs have not been announced.
Overall this is exciting new research. However, based on this study, it is too soon to say whether either pill will “go on sale in the next few months” as the Daily Mirror claims. While these drugs are close to clearing the final few hurdles of licensing, regulators may still require more data, particularly regarding their long-term safety.
Where did the story come from?
This news story is based on two pieces of research. The first piece of research, the CLARITY study, focused on the drug cladribine. It was carried out by Professor Gavin Giovannoni and international colleagues from Queen Mary University London, the Blizard Institute of Cell and Molecular Science and other institutions. The study was supported by the pharmaceutical company Merck Serono, which also funded editorial assistance provided by Acumed.
The second study, the FREEDOMS study, focused on fingolimod. It was carried out by Dr Ludwig Kappos and colleagues from the University of Basel, Novartis Pharma, and other international research institutions. The FREEDOMS study was funded by Novartis Pharma.
Both studies were published in the peer-reviewed The New England Journal of Medicine.
The newspapers provide balanced reporting of this drug research and its importance to people living with multiple sclerosis (MS). Some questions still remain over which new drug is better and these current studies do not tell us whether either is better than the current treatments. The Telegraph quotes a consultant neurologist on the matter: “Fingolimod is the only oral MS treatment to have published head-to-head data that demonstrates superiority versus a current standard of care, providing compelling evidence for this promising new drug.” This suggests there may be better evidence for this drug. This Behind the Headlines appraisal has not assessed this head-to-head comparison research.
What kind of research was this?
Two oral drugs, cladribine and fingolimod, have been tested for the treatment of relapsing-remitting multiple sclerosis (MS) using separate phase three, placebo-controlled randomised trials. Relapsing-remitting multiple sclerosis is one of four types of MS, where patients show unpredictable relapses followed by periods of months, or even years, of relative quiet (remission) with no new signs of disease activity. The aims of these studies were to test the efficacy (how well the drug works in trials), and the safety of two doses of each drug.
Phase three, drug company-sponsored trials are often the last step before an application for licensing of a new medicine is made. These trials appear to have been well conducted. Other important factors that were not addressed by these trials, however, are how well the drugs compare in the long term to other drugs used to treat the same group of patients, and how much these drugs will cost.
What did the research involve?
The CLARITY trial
In this trial, the researchers recruited 1,326 patients in 32 countries with relapsing-remitting multiple sclerosis and randomly allocated them to three treatment groups:
- A lower-dose group taking 3.5mg of cladribine per kilogram of body weight.
- A higher-dose group taking 5.25mg of cladribine per kilogram of body weight.
- A group taking matching placebo pills.
Doses were given over two or four short courses during the first 48 weeks, then in two short courses starting at week 48 and week 52. Each course consists of one or two tablets per day for four or five days, adding up to just eight to 20 days of treatment each year. In total, the trial ran for around 22 months.
Cladribine suppresses the production of certain cells of the immune system, so rather than taking the drug continuously, the participants took the drug in short courses of eight to 20 days per year. This pattern of use was designed to allow the participants’ white blood cells time to recover between courses.
The researchers excluded patients from the study if two or more previous disease-modifying therapies had failed. Patients were also excluded if they had received immunosuppressive therapy at any time before study entry, or if they had taken other MS therapies (cytokine-based therapy, intravenous immune globulin therapy, or plasmapheresis) within three months of study entry. The researchers did this to ensure that they were only testing the efficacy of cladribine.
The patients were assessed by a physician for diagnosis, and they had MRI scans. They had regular neurologic examinations, about every 12 weeks, including an evaluation called the Expanded Disability Status Scale (EDSS). This EDSS administered by neurologists is a method of quantifying disability in multiple sclerosis. The scale runs from 0 to 10 and summarises eight different aspects of function. For example, a score from 1.0 to 4.5 indicates a person can walk fully. An EDSS score of 5.0 to 9.5 would indicate impairment in walking.
The FREEDOMS trial
In the FREEDOMS trial, the researchers recruited 1,272 patients in 22 countries with relapsing-remitting multiple sclerosis, and randomly allocated them to three groups:
- 0.5mg fingolimod once daily as capsules.
- 1.25mg fingolimod once daily as capsules.
- A matching placebo.
Treatment continued for 24 months.
The drug fingolimod is thought to act by preventing specific types of white blood cells called lymphocytes from leaving the lymph nodes. It also uses other mechanisms involving nerve cells.
The researchers included patients who had had one or more relapses in the previous year, or two or more in the previous two years. They excluded patients if they had relapsed or taken corticosteroids in the 30 days prior to randomisation, had an active infection, immune suppression caused by drugs or disease, or certain other illnesses.
The patients were assessed by a physician for diagnosis, and had MRI scans. They had regular neurologic examinations every month initially, then every three months. This included an evaluation of their MS symptoms with EDSS tests.
What were the basic results?
The CLARITY trial
The 1,326 patients were generally similar across the three study groups, although patients receiving 3.5mg of cladribine per kilogram (the lower-dose group) had, on average, suffered with MS for a shorter period of time. Almost one third of patients had previously received disease-modifying therapy. In total, 1,184 patients (89.3%) completed the study.
There was a significantly lower rate of relapse among patients who received either dose of cladribine tablets than in the placebo group: there was a 14% relapse rate in the lower-dose group, a 15% relapse rate in the higher-dose group and a 33% rate of relapse in the placebo group. There were also more relapse-free people in the treated groups, a lower risk of progression of disability, and significant reductions in the brain lesion count on magnetic resonance imaging (MRI).
Adverse events that were more frequent in the cladribine groups included low white blood cell count, which occurred in 21.6% of people in the lower-dose group and 31.5% in the higher-dose group, compared to 1.8% in the placebo group. Shingles occurred in 20 patients in the treated groups, but not at all in the placebo group.
The FREEDOMS trial
Just over four-fifths of the participants completed the study (1,033 out of 1,272 patients; 81.2%). Study discontinuation was less common with the lower dose of fingolimod (18.8%) than with the higher dose (30.5%) or with placebo (27.5%).
The annual relapse rate was 18% with 0.5 mg of fingolimod, 16% with 1.25mg of fingolimod, and 40% with placebo. At 24 months, the risk of disease progression was significantly lower with both doses of fingolimod, and both doses were better than placebo on the MRI-related measures, such as number of new or enlarged lesions. There were no significant differences between the two doses in the efficacy measures.
Causes of study discontinuation and adverse events related to fingolimod included slow heart rate and conduction problems between the upper and lower chambers of the heart at the time patients started taking the drug. Other problems were macular oedema, elevated liver-enzyme levels, and mild hypertension.
Lower respiratory tract infections (including bronchitis and pneumonia) were more common with fingolimod than with placebo: 9.6% of patients receiving 0.5mg of fingolimod, 11.4% receiving 1.25mg of fingolimod, and 6.0% receiving placebo.
How did the researchers interpret the results?
The CLARITY trial
The researchers say that treatment with cladribine “significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks”. They say that the benefits need to be weighed against the risks, and that both regimens appear to work equally well.
The FREEDOMS trial
The researchers say that, when compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. They also stated that these benefits need to be weighed against any possible long-term risks.
These studies have shown that, when compared to placebo treatment, these new oral medications resulted in reductions in the rates of clinical relapse and the risk of disability progression. Treatment with the drugs also resulted in improvements in brain lesions, as visualised on MRI.
The possibility of taking tablets with relatively few side effects will be of interest to the many patients with relapsing-remitting MS who are currently treated using courses of injections. While these were well-conducted studies, some care is needed in suggesting that these drugs will be available in a few months:
- More data on the long-term risks of these drugs may well be required by regulators.
- The cost of these drugs has not yet been published. In England and Wales, the availability of these drugs and their funding by the NHS will be determined by their cost-effectiveness compared to alternatives. This has not yet been determined.
- The drug cladribine has not been compared against current standards of treatments. Fingolimod has only been compared to an existing treatment in the short-term (one year). Based on the research currently available, it is not possible to say whether these drugs will be better at treating the problems of MS for longer periods, which may be necessary with this lifelong condition.
Overall, this is exciting new research that will offer hope to MS patients. But based on these studies, it is too soon to say whether either cladribine or fingolimod will “go on sale in the next few months” as one newspaper has speculated. While the drugs appear to have performed well in these studies, licensing authorities will need to be convinced about the safety and efficacy of these drugs and may still require more data. It should also be noted that this research did not test the drugs on people with the more severe, progressive forms of MS.