The first clinical descriptions of multiple sclerosis (MS) were made round 1835, but it was only thirty years later that Jean-Martin Charcot was able to clearly differentiate MS from other neurological disorders.

At the time, the only tool available for scientific research in this area was the microscope. Immunology, molecular biology and neuroradiology did not yet exist. Anatomopathology made it possible to study the lesions caused by the disease in the central nervous system and to match them with clinical observations. However, these observations did not enable researchers to determine the nature of the mechanisms that caused the lesions and, consequently, for almost a century MS remained an insoluble problem for medical science.

The last few decades of the 20th century marked a turning point in the fight against MS. The development of new immunological, neurophysiological and neuroradiological exploration techniques (particularly Magnetic Resonance Imaging - MRI) finally enabled physicians to understand the physiopathological mechanisms involved in MS, this being a prerequisite for the development of new treatments. For the first time in the history of the disease, MRI enabled us to objectively observe the effect of different medications on the progression of the cerebral lesions. Furthermore, methodological improvements have increased the scientific reliability of clinical studies, making it possible to identify beneficial effects, even when they are only very slight.

Over the past few years, research has led to the development of drugs whose effectiveness is acknowledged by the scientific community as well as by public health managers, and it has also enabled significant progress to be made in the treatment of symptoms that can be very distressing for patients, such as spasticity, urinary disorders, pain, etc. All this means that the life expectancy and quality of life of people affected by the onset of MS early in the 21st century will certainly be better than those of patients who were first diagnosed with the disease 50 years ago. In spite of these very significant improvements, however, medicine is still unable to "cure" MS.

As we move further into the 21st century, the short-term objectives of the research supported by the Charcot Foundation are to improve the efficacy of the treatments currently available, to reduce their adverse side effects and to explore the possibilities offered by "therapeutic combinations", which are already being used successfully to combat other immunological disorders. In the longer term, research aims to develop new treatments which will make it possible to stop the progression of the disease as soon as it is diagnosed in a patient.

Of course, much remains to be done, and everyone's help, including substantial financial support, will be needed to enable research to win the battle against MS in the next few decades.

Most are Phase 2 studies, in which the most promising molecules are selected. The most advanced of these concerns fingolimod, the Phase 3 results of which have been published recently and are discussed in Issue 25 of our newsletter.
The Phase 2 studies of three other molecules are encouraging (fumaric acid, cladribine, laquinimod) and will be followed by Phase 3 studies.

Fumaric acid, which is used to treat psoriasis, is an immunomodulator, the mechanisms of which remain elusive, but that possibly stimulates the body's natural defences, in particular by increasing anti-oxidant production. The Phase 2 study was performed on 257 patients divided into four groups: placebo, 120 mg x 2, 120 mg x 3 and 240 mg x 3 per day. As it is increasingly frequent, the placebo group was given the substance after six months, which makes assessment of the effects on progression impossible over such a short period. The best results were achieved by the highest doses, i.e. a 69% decrease in active plaques detected by magnetic resonance (MRI) and a 32% decrease in flare-ups. These results are comparable to those achieved with IFNs. The secondary effects are flashing and gastro-intestinal disturbances. Of greater concern is the fact that 25% of the patients given the high doses left the study due to intolerance.

Cladribine is an immunosuppressant which has long been in use for the treatment of certain blood cancers. Several Phase 2 studies have already been performed for MS. For methodological reasons, the clinical results were difficult to interpret. However, a study of the radiological data showed a definite decrease in active plaques detected by magnetic resonance (MRI). Despite this, the company had abandoned MS potential indications.
Two years ago, a Phase 3 trial on 1327 patients was initiated. The patients were divided into three groups: placebo, 2 immunosuppressive treatments per year (1 tablet a day for 10 days) during 2 consecutive months, and 4 treatments during 4 consecutive months per year. The duration of the study was 2 years. Later, all patients were treated with 2 treatments a year of cladribine. The first results were released in the press, showing a decrease of exacerbations by 58% (higher than with IFNs) at the low dose and 55% at the high dose. Cladribine is an extremely powerful immunosuppressant and its effects can last for over a year. It may be surmised that its effect on active plaques detected by MRI will be considerable. The study included a placebo group for 2 years, which makes it possible to assess the effect of the drug on the progression of the disability, and it is likely that cladribine will slow down this progression. The long-term secondary effects are opportunistic infections and disturbances of the hematopoietic system. This molecule has been fast-tracked by the FD.

Laquinimod is an immunomodulator, the mechanisms of which are at present little-known, but which mainly has an anti-inflammatory effect. Two Phase 2 studies on the mother molecule (linomide/roquinimex) had shown a decrease in active plaques detected by magnetic resonance (MRI) but had had to be stopped due to severe complications. A clinical test on 306 patients has been published recently, which comprised 3 groups: placebo, 0.3 mg/day and 0.6 mg/day. Although the 0.3 mg/day dose had no significant effect on active plaques detected by magnetic resonance (MRI), the 0.6 mg dose caused them to decrease by 55%. The reduction in the number of exacerbations was 33%, i.e. comparable to that achieved with IFN βs. The duration of the test was too short to assess the effect on the progression of the disability. Secondary effects included pains in the joints and chest, flu-like states, viral infections and liver enzyme disturbances. Laquinimod has also been fast-tracked by the FDA.

There are approximately 80 studies concerning 30 molecules which could be administered by mouth. Except fingolimod, some have been used for years in the treatment of immune or cancerous diseases. Although their tolerance is generally well-known, they are usually employed for short periods only. As MS is a chronic disease, the treatment also needs to be "chronic". Long-term tolerance therefore remains a major problem for the assessment of the risk/benefit ratio of such new treatments. With 20 years' hindsight, it is known that long-term tolerance of IFN βs and copraxone is highly acceptable. Although their effectiveness is limited, that of most new molecules (with the exception of the immunosuppressants, which are far less well tolerated) is hardly better.

Dr Richard E. Gonsette
President