First use of Campath-1H in relapsing-remitting multiple sclerosis: 1998-2002

At that stage, we speculated that, in order to prevent the progressive phase of multiple sclerosis, we needed not only to suppress relapses, but also we needed to do it early on in the disease course. This raised the dilemma of exposing people who were young and relatively non-disabled to a potentially toxic drug. So we chose our second group of “guinea pigs” very carefully. Eventually we treated 22 people with early relapsing-remitting multiple sclerosis and reported our results in 2006 (4). Once again, Campath-1H reduced the relapse rate very dramatically: see figure 1. But this time, the patients’ disability did not progress; instead there was a hint that their disability may even have improved. Figure 2 shows the different effect of the same dose of Campath-1H on disability, depending upon what stage in the disease process we treat.

So far, so good. Alongside this encouraging news, we had also noticed some troubling side-effects of Campath-1H. The first dose of the drug may cause a headache, rash, fever and malaise, as well as transiently worsen peoples' multiple sclerosis symptoms (David's story ). The main problem was that, months or years after Campath-1H, people developed “autoimmune diseases”, where the immune system attacked part of the body. The most common, which occurred in 30% of people treated using Campath-1H, was an overactive thyroid gland (Graves’ disease) (3). This is relatively easy to treated using pills. But there was an altogether much more worrying forms of autoimmunity: one person developed an autoimmune disease which damaged her kidneys, who needed dialysis and then a kidney transplant.
 

The CAMMS223 Trial 2003-7

On balance, we felt that the dramatic effects on controlling multiple sclerosis justified further exploration of Campath-1H, even though it causes significant side-effects. So, with a company called Ilex Oncology (which then was taken over by Genzyme) we set up a formal study of Campath-1H in early relapsing-remitting multiple sclerosis: the CAMMS223 trial. This took place in many different countries in US and Europe and involved over 300 people with multiple sclerosis. This was a head-to-head trial comparing Campath-1H against interferon-beta. Each person will be followed-up for three years followed by a further assessment after another two years. Monitoring was done by clinical examinations every three months (using the famous Kurtzke score among others). In addition everyone had an annual MRI scan looking for signs of demyelination and nerve damage. (Research trials recruitment ; Controlled trials ). This trial is due to finish in the Autumn of 2007.

In June 2005, tragically, one of the patients on this trial died due to a bleed in the brain. This occurred because the persons’ blood did not clot because he had a lack of platelets in the blood. The underlying cause was immune thrombocytopenic purpura often just called “ITP”). This is an autoimmune disease, rather like Graves’ disease. We had never seen it after Campath-1H prior to this. The death was doubly tragic because ITP is a treatable condition, if picked up early.

The company behind the CAMMS223 trial, Genzyme, immediately set about warning all the teams running the CAMMS223 trial all over the world about ITP. In the next few months, two more cases were found. Both of these were picked up early and responded to treatment. Now, with three people affected by ITP, the company very responsibly decided to stop giving Campath-1H to people on the trial. In fact, by this stage, all but two patients had received their second dose of Campath-1H. An intensive monitoring program was put in place and, as a result, a further three cases of ITP were identified in the early stages of ITP. This means that a total of 6 people have been affected by ITP out of the 216 people who received Campath-1H on the trial. Since we have been on the look-out for ITP, all the cases have been picked up early, have responded to treatment rapidly and are completely well.

The good news of the CAMMS223 trial was the fantastic results on controlling multiple sclerosis. We have announced the results at the two-year point. At this stage, people taking interferon-beta had an average of 0.3 relapses per year; the figure for the two doses of Campath-1H were 0.11 and 0.05. Campath-1H reduced the chance of having a relapse, compared to interferon-beta, by 72% and 87%. The most remarkable effect, though, was on disability: Campath-1H reduced the chance of getting more disabled on the trial by 66% or 88% compared to interferon. On average, the disability of people taking interferon got a bit worse by the end of two years (by 0.2 EDSS points), whereas the disability of patients on Campath-1H actually improved (by about half an EDSS point). This has not been seen in a clinical trial in multiple sclerosis before.
 

The future for Campath-1H as a treatment for multiple sclerosis

Campath-1H is clearly a powerful treatment. It has delivered unprecedented benefits to people with multiple sclerosis in a clinical trial over two years, but it has serious treatable side-effects. The effort now must be to maximise the benefit and minimise the risks of Campath-1H. So, the next step is to do further controlled trials, in which we can carefully monitor patients for possible side-effects. We are hoping to do two phase 3 trials: one for people which have never taken disease-modifying treatments for multiple sclerosis and another for those whose multiple sclerosis seems to be active despite being on interferon. Even if these trials are very positive, the earliest that Campath-1H could be licensed would be 2011 or so. We strongly discourage people from receiving Campath-1H outside of clinical trials.

The benefits and side-effects of Campath-1H, and some other drugs in multiple sclerosis, raise important questions about risk. How risky a drug is justifiable in the treatment of multiple sclerosis? How risky is multiple sclerosis? Who should decide what risks are acceptable? These are questions we will all have to grapple with, as the next generation of treatment for multiple sclerosis become available.

Alasdair Coles, May 2007

References
1: Compston A, Coles A. Presented at the 2003 meeting of the Association of American Neurologists.

2: Moreau T, Coles A, Wing M, Isaacs J, Hale G, Waldmann H, Compston A. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain. 1996 Feb;119 ( Pt 1):225-37.

3. Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, Weetman A, Hale G,Chatterjee VK, Waldmann H, Compston A. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 1999 Nov 13;354(9191):1691-5

4. Coles AJ et al, The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108.