Extensive coverage was given today to news that there has been a “major step towards treating multiple sclerosis” (as reported by The Guardian ). The newspapers said that a trial of a drug in over 300 people with early symptoms of MS found that it halted and reversed the effects of the disease. The drug is already licensed to treat leukaemia, and reports say that if the next phase of trials is successful, it could be licensed for use in MS by 2010. However, there were some serious side effects in a few patients (2.8%), one of whom died after developing an immune disorder that affected platelets in their bloodstream.
This is the first trial to test the effectiveness of alemtuzumab in treating MS and compare its actions with that of beta interferon, another drug used for the condition. The drug was tested in an early type of MS in which symptoms come and go (relapse and remit). It is unknown what benefit the drug would have for more advanced MS. Regarding the reported side effects, the researchers say that strict control of prescribers and efficient monitoring procedures would be needed to reduce the risk and detect any complications early. The drug's success and the fact that scans appeared to show restoration of brain tissue will need confirmation in larger phase 3 trials, which have reportedly already begun.
Where did the story come from?
A large group of international researchers known as the CAMMS223 Trial Investigators, based in the UK (Cambridge), US and Poland, carried out this research. The study was supported by the pharmaceutical companies Genzyme and Bayer Schering Pharma, and published in the peer-reviewed medical journal, The New England Journal of Medicine.
What kind of scientific study was this?
In this phase 2 randomised controlled trial, the researchers compared alemtuzumab in treating multiple sclerosis (MS) with interferon beta-1a, a drug that is already used to treat the condition. Aletuzumab is a synthetic antibody which was first developed to treat leukaemias or blood cell cancers. Because it affects the immune system, the researchers thought that it might be beneficial in patients with MS, a condition in which the body’s immune system attacks the central nervous system.
As this was a phase 2 trial, the drug was tested in a small number of patients for the first time, and the overall safety and effectiveness of the drug was tested. The drug was given in two doses, either 12mg a day or 24mg a day. Suitable patients were recruited from 49 centres across Europe and the US between December 2002 and July 2004. Patients had to have confirmed MS of a relapsing and remitting type according to recognised criteria, and to have had the disease for less than three years (early disease). The patients also could not have had previous disease-modifying treatments, or a history of autoimmunity such as some thyroid gland diseases.
In total, 334 patients were recruited with scores of 3.0 or less on the 10-point Expanded Disability Status Scale (EDSS), a measure of disability. Equal amounts of patients were randomly assigned to three groups. One group received an injection of interferon beta-1a (44 μg three times a week under the skin); the other two groups received an injection of intravenous alemtuzumab at a dose of either 12mg or 24mg per day for five consecutive days in cycle one (after enrolment) and in two further annual cycles at 12 and 24 months. The monitoring committee stopped the alemtuzumab arm of the trial early in September 2005 after three of the patients developed immune thrombocytopenic purpura. This is a serious condition where the platelet cells involved in blood clotting are reduced in number to the extent that bleeding under the skin occurs. One of these patients died from the condition. The patients who were treated with interferon beta-1a continued to take the drug throughout the study.
The researchers measured the time it took for the patients to reach a steady state of disability, and the rate at which they relapsed. Disability was assessed according to the EDSS score. A steady state (sustained accumulation) of disability was defined as an increase of at least 1.5 points for patients with a score of 0 when they began the study, and of at least 1.0 point for patients with a score of 1.0 or more when they began. All scores were confirmed twice during a six-month period. A relapse was defined as a period longer than two days in which there were new or worsening symptoms with an objective change in nerve signs. The patients were checked annually by radiologists for brain volume and the number of lesions (MS scars). The radiologists did not know which group the patients were assigned to.
What were the results of the study?
Of 334 randomised patients, 111 received interferon beta-1a three times weekly, 113 received the annual cycles of alemtuzumab 12mg per day, and 110 received the 24mg per day dose in an annual cycle. One patient was incorrectly diagnosed, and although they were included in the drug safety analysis, they were removed from the analysis of positive effects.
The sustained accumulation of disability as described above was 9.0% with alemtuzumab, compared with 26.2% in the interferon beta-1a group. This was a statistically significant difference with a hazard ratio (HR) of 0.29 (95% confidence interval, 0.16 to 0.54). The rate of relapse adjusted to an annual rate was also significantly better for the alemtuzumab group. The mean disability score on the EDSS scale (a 10-point scale) improved by 0.39 point in the alemtuzumab group, and worsened by 0.38 point in the interferon beta-1a group.
The lesion burden (as seen on the MRI scan) was reduced in the alemtuzumab group compared with that in the interferon beta-1a group, but this was not significant at three years. The scans also showed that brain volume increased in the alemtuzumab group and decreased in the interferon beta-1a group (P = 0.02).
The adverse events in the alemtuzumab group, as compared with the interferon beta-1a group, included autoimmune thyroid disorders (23% versus 3%] and immune thrombocytopenic purpura (3% versus 1%). Infections were also more common in the alemtuzumab group (66% versus 47%). There were no significant differences in outcomes between the 12mg dose and the 24mg dose of alemtuzumab.
What interpretations did the researchers draw from these results?
The researchers say that in patients with early, relapsing–remitting multiple sclerosis, alemtuzumab was more effective than interferon beta-1a. They note that it was associated with autoimmunity, and this showed itself, most seriously, as immune thrombocytopenic purpura.
What does the NHS Knowledge Service make of this study?
This is a reliable study with several implications for patients and researchers. The extent of the reduction in disability (71%) and the reduction in the risk of relapse (74%) is impressive. No doubt this drug will be studied further and attempts will be made to reduce the autoimmune problems that were identified. The researchers note a few limitations to their study:
- Due to safety concerns, 72% of the patients treated with alemtuzumab did not receive their third cycle of therapy at 24 months.
- The comparison of MRI data was limited by the fact that there was missing data, and that a high rate of people in the interferon group stopped their treatment early.
- It was not possible to ensure that both researchers and patients were blind (unaware of which treatment they were on) because of the different ways that the drugs were administered. The interferon beta-1a was given by injection under the skin, while alemtuzumab was given by infusion directly into the vein in a cycle once a year.
- The trial did not recruit sufficient numbers of patients to detect uncommon side effects or run for long enough to assess the drug’s long-term safety.
Despite these minor problems, this trial will be exciting for patients and researchers. The success of the drug, and the fact that scans appeared to show restoration of brain tissue, will need confirmation in larger phase 3 trials in which patients are carefully monitored for the adverse effects of the drug. The researchers say that these phase 3 trials have already started.