Two phase 3 trials of a drug for treating multiple sclerosis (MS) that “reboots” the immune system showed it to be effective in patients who had not responded to first-line therapy: it reduced risk of disability and brain shrinkage. Reporting in the 1 November issue of The Lancet, the researchers describe how alemtuzumab (known commercially as Lemtrada), previously used to treat a type of leukaemia, was able to help people with early MS who relapsed on previous treatments as well as patients who had not yet received any treatment.

Alastair Compston, a professor from the University of Cambridge was principal investigator on both trials and also chaired the Steering Committee that supervised them and an earlier trial. He said in a statement from the University:

“Our research shows the transformative effect that alemtuzumab can have for people with MS.”

The findings mark the conclusion of a unique development program for an MS drug that started in Cambridge in 1991. The statement from the University says:

“Never before has an MS drug been tested in clinical outcomes against such a high hurdle, an active first-line drug, in both one phase II trial and two phase III trials; and no drug for MS has been shown to be more effective, in both reducing the risk of disability and reducing the rate of brain atrophy, when compared to another active treatment.”

MS is an autoimmune disease where the patient’s immune system destroys nerve fibers and their protective insulation, the myelin sheath. The resulting damage stops nerves communicating with each other, leading eventually to loss of the nerve fiber, and progressive physical and cognitive disability.

The disease affects millions of people worldwide, including almost 100,000 in the UK, and 400,000 in the US.

The two randomized, controlled phase 3 trials, reported in two separate papers, are called CARE MS I and CARE MS II. They were both funded by Genzyme (Sanofi) and Bayer Schering Pharma.

The developers expect decisions on drug licences for alemtuzumab by the European and US regulatory authorities to be made in 2013.

In another study reported this week, scientists describe how it may be possible to repair the nerve fiber damage caused by MS.

This three-year trial involved 334 patients with active, early relapsing remitting MS (RRMS) who had not received any treatment for the disease (drug-naïve patients). It tested the performance of alemtuzumab against the first-line drug interferon beta-1a (commercially known as Rebif).

The patients were randomly assigned to one of three groups. One group received interferon beta-1a injections three times a week, and the other two groups each received a different daily intravenous dose of alemtuzumab.

The results showed that alemtuzumab reduced the number of attacks by 55% over and above that achieved by the other first-line drug.

Over a 2-year period, 78% of the patients taking alemtuzumab remained relapse free, compared with 59% in the interferon group.

The percentage of patients whose disability got worse during the trial was slightly lower in the alemtuzumab patients than in the interferon patients, but the result was not statistically significant.

The researchers conclude:

“Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis.”

For this 2-year trial, researchers recruited 840 patients agd 18 to 55 with RRMS (from which data from 628 participants was used in the principal analysis), who had received first-line treatment but had recently relapsed during their therapy.

As with the MS I trial, the participants were randomly assigned to received either alemtuzumab or interferon beta-1a. Each patient had their disability assessed every three months by a researcher who did not know which drug they were receiving. They also underwent annual scans to assess lesions and brain shrinkage due to MS.

The results showed that new relapses were reduced by 49% more in the alemtuzumab than the interferon patients.

Over the 2-year period, 65% of patients on alemtuzumab remained relapse free compared with 47% of interferon patients.

Alemtuzumab reduced the risk of acquiring disability by 42% compared to interferon: disability worsened in 20% of interferon patients and 13% of alemtuzumab patients.

Plus, at the end of the study, on average, the patients taking alemtuzumab had less disability than when they started the trial whereas the patients taking interferon had more disability.

The brain scans showed that alemtuzumab not only reduced the number of new lesions, compared to interferon beta-1a, but also reduced the rate of brain shrinkage from the tissue damage caused by MS.

The researchers conclude:

“For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab’s main adverse effect of secondary autoimmunity.”

Compston says:

“Patients who continue to show disease activity while on their initial therapy are especially difficult to treat. Now, we have shown that alemtuzumab works where first-line drugs have already failed.”

The drug “not only reduces the chances of disability associated with MS”, but it “may even result in long-term clinical improvements,” he adds.

In both trials the main side effect from alemtuzumab was the development of other autoimmune diseases.

Additional work by some of the Cambridge researchers on these trials is looking into how to identify people who are susceptible to this side effect, and they are currently recruiting for a trial that is testing alemtuzumab with a new drug aimed at reducing the adverse reaction.

Written by Catharine Paddock PhD