“A new oral drug for multiple sclerosis has produced promising results in clinical trials,” BBC News reported today. It said the new drug, laquinimod, improved the condition of patients with the relapse-remitting form of multiple sclerosis (MS) with few side-effects. Scans showed that patients taking a high dose of the drug had 40% less damage than those taking a placebo. The BBC explained that an oral drug could be a significant advance as existing MS drugs all need to be injected.
This report is based on a phase II randomised controlled trial of 306 MS patients conducted in eight European countries and Israel. It was designed to investigate the dose and safety of the drug, as well as to give preliminary results on how well it worked. The trial was well-conducted and used MRI scans as an objective measure of the drug’s effectiveness. Further assessment of the benefits of the drug is planned in a larger phase III study.
Where did the story come from?
Doctor G Comi from the Scientific Institute San Raffaele in Milan, Italy and 11 colleagues from the international study group that carried out the research were listed as the authors of the journal article. The study was funded and sponsored by Teva Pharmaceutical Industries, a global pharmaceutical company with headquarters in Israel. The study was published in the peer-reviewed medical journal The Lancet.
What kind of scientific study was this?
This was a phase II randomised clinical trial, which ran for 36 weeks. Phase II studies usually follow phase I studies that have confirmed the initial safety of a drug. Phase II studies are designed to test how well a drug works (efficacy) in a small group of patients. They are sometimes divided into phase IIa studies, which test dosing requirements, and IIb studies, which test how well a drug works at the prescribed doses. This trial is an example of a IIb study, and used two doses of laquinimod, 0•3 and 0•6 mg daily.
The research group explained that laquinimod is a new agent and has been developed as a potential disease-modifying treatment for multiple sclerosis (MS). MS mainly affects the white matter of the nervous system, and is thought to be caused by immune and inflammatory processes. Laquinimod targets these processes, the effects of which can be seen with a magnetic resonance imaging (MRI) scan of the brain. A similar drug had improved clinical outcomes for sufferers of MS, but phase III trials showed it had severe adverse events, and the trials had to be stopped early. The researchers were therefore interested in how well this drug performed in a trial setting.
The study was carried out in 51 centres in nine countries. The researchers initially recruited 720 patients aged 18 to 50 years who could walk and who, according to a disability status score, were rated between being normal and having a disability severe enough to impair their full daily activities. To be eligible they also had to have had one or more relapses in the year before entry, and have shown at least one lesion on a MRI-scan. They could not be taking steroids and had to be in a quiet phase of the disease (in remission). The researchers excluded patients who were taking other conventional treatments for this relapsing form of MS, including the injectable immunomodulators, glatiramer acetate, interferons or immunoglobulins.
This process left 306 people with MS, 102 of whom were randomly assigned the inactive placebo pill, and roughly equal amounts of the rest assigned one of two doses of the active drug. Repeat brain MRI scans and clinical assessments were performed prior to enrolment, and also at the beginning of the study, after four weeks and then monthly from week 12 to week 36. Twenty-three patients withdrew from the study for a variety of reasons.
The researchers counted how many gadolinium enhancing (GdE) lesions the patients had on their scans. GdE lesions are sites of damage in the brain and spinal cord that provide a marker of inflammatory activity in MS.
What were the results of the study?
Compared with placebo and after adjustment, the treatment with the higher dose of laquinimod (0•6 mg per day) showed a statistically significant 40•4% reduction in the number of GdE lesions per scan on the last four scans. Treatment with the lower dose (0•3 mg per day) showed no significant effects.
The researchers also reported that “both doses of laquinimod were well-tolerated” with some transient (temporary) increases in liver enzymes, which were more pronounced in the higher dose group. They also reported that one patient developed a clot in the veins within the liver after the first month of treatment with the 0•6 mg daily dose of laquinimod. This person, who had a predisposition to clotting, was successfully treated with anticoagulant (clot busting) treatment.
The researchers were interested in the complications that occurred in previous trials of similar drugs, and reported that no cases of heart attack, inflammation of the lungs or lining of the heart had occurred in their study.
What interpretations did the researchers draw from these results?
The researchers concluded that “in patients with relapsing-remitting multiple sclerosis, 0•6 mg per day of laquinimod significantly reduced MRI-measured disease activity, and was well tolerated.”
What does the NHS Knowledge Service make of this study?
This is a reliable study that was conducted across a wide number of international settings. It has shown an important effect of the drug on an objective measure of disease activity - the MRI scan - with a reasonable number of randomised patients (283 out of 306) completing the study. The authors mention a few limitations, such as:
- The short duration of the trial means that the changes in clinical measures, such as relapse rate, should be interpreted with caution. There were non-significant improvements in the relapse rate and in the number of patients who were free of relapses in the 0.6 mg treatment group compared to the placebo.
- The absence of significant effects in the low dose 0.3mg dose group surprised the researchers, because a previous trial had shown a significant effect at this dose. They attribute this to differences in the way that the MRI scans were performed between the trials, and speculate that either smaller lesions were not detected, or that the lower dose of the drug might have taken longer to begin reducing the number of lesions.
- Two serious adverse events were reported: a case of clotting within liver veins known as Budd-Chiari syndrome, and a case of abnormal liver enzymes.
The authors confirm that they will proceed with plans for a larger phase III study. Some safety issues only become known once larger studies are conducted, and even then, some drugs may appear safe in trials only to have unacceptable risks when used in real clinical situations. For this reason, the researchers and newspapers have been suitably cautious in their interpretations of the study.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
Channel 4 News, 20 June 2008
BBC News, 20 June 2008
Links to the science
Cochrane Database Syst Rev 2003, Issue 4
Cochrane Database Syst Rev 2001, Issue 1
The Lancet 2008; 371: 2085-2092