MULTIPLE SCLEROSIS

What is multiple sclerosis?

Multiple sclerosis is a disorder of the central nervous system in which nerve cells lose their insulating sheath, called myelin. Nerves are able to regenerate their myelin sheath, but its destruction in MS is so rapid that the nerve may die before regeneration can occur. This results in the appearance of plaques (sclera) in the brain and spinal cord, in which nerve cells are replaced by fibrous connective tissue. Clinical symptoms depend on the location of the damage, but can include vision loss or double vision, speech difficulties, muscular weakness, abnormal skin sensations, bladder problems, fatigue, pain and mood alterations. Multiple sclerosis typically shows periods of acute illness (exacerbations) and remissions, although there is often a general worsening over time. Magnetic resonance imaging (MRI) is a sensitive diagnostic technique that can be used to measure its progress.

The cause of multiple sclerosis is unknown and its progress cannot be predicted with certainty. No infectious agent has been definitely linked to MS, but the immune system is thought to be involved in the inflammation that accompanies myelin destruction. Two distinct patterns of MS are generally recognised. At diagnosis, about 15 per cent of those affected have primary chronic progressive MS (CP-MS) and 85 per cent have relapsing-remitting MS (RR-MS). Over time, about half of the RR-MS patients develop a secondary progressive form (SP-MS). In relapsing-remitting MS, problems with the nervous system appear suddenly, followed by slow improvement. About 15-20 per cent of these patients relapse within the first year: the shorter the time to relapse, the poorer the prognosis. In CP-MS, the deterioration is gradual and the intervals of remitted disease are absent.

Who does MS affect and what does it cost?

MS is estimated to affect around 85,000 people in the United Kingdom and typically strikes young adults in their 20s and 30s. It is more common in women than in men by a ratio of 3:2. A recent study of treatment costs in nine European countries estimated that the total average annual cost per patient was £12,300 for someone with mild disease, almost £25,000 for moderate disease and as much as £42,300 for those with severe disease.

Present treatments and shortcomings

Acute exacerbations of MS are usually treated with anti-inflammatory steroids, such as prednisone, methylprednisolone and dexamethasone. These reduce the duration and severity of acute attacks but do not alter the condition's long-term course. Their possible adverse effects (skin reactions, weight gain, osteoporosis, mood alterations) make them unsuitable for prolonged use. In addition, baclofen, tizanidine or benzodiazepines may be given to relax muscular spasms and anticholinergic drugs (oxybutinin, tolterodine, propiverine) can be helpful to treat urinary complications.

Newer treatments for RR-MS include three forms of recombinant beta interferon. These are interferon beta-1b from Schering (Betaferon), interferon beta-1a (Avonex) from Biogen Idec and Serono's interferon beta-1a (Rebif). All are given by injection. These reduce the frequency of relapses in RR-MS by about 30 per cent as well as the severity of attacks, although not everyone responds to them. They are, however, not a cure for the disease and may cause flu-like symptoms in some people. Moreover, neutralising antibodies may develop in some cases, potentially reducing their effectiveness.

Glatiramer acetate (Copaxone, Teva), another treatment for RR-MS, is believed to work in a quite different way from beta interferon. It is thought to mimic the protein component of the nerve's myelin sheath and act as a decoy during acute attacks by immune system cells (T-cells) which would otherwise damage myelin. It reduces the frequency and severity of relapses to a similar extent to beta interferon and is given by daily injection. Ten-year study data show that long-term use of glatiramer can reduce the relapse rate by as much as 80 per cent. Adverse reactions may include redness and pain at the injection site, flushing, chest pain, muscle weakness and nausea.

The most recently introduced medication for RR-MS is natalizumab (Tysabri, Biogen Idec), for use in those with very active RR-MS or those who have not responded to treatment with beta-interferon. Natalizumab is given by intravenous infusion every four weeks and, because its use has been associated with an increased risk of a potentially fatal opportunistic viral infection of the brain, it may not be used in those at increased risk for such infections, including people undergoing immunosuppressive treatment. It may also not be given in combination with beta-interferon or glatiramer acetate. In clinical trials, natalizumab has been shown to be highly effective in reducing disability progression, the rate of relapses and the number of new or enlarging brain lesions detected by MRI. Persistent antibodies against natalizumab developed in about 6 per cent of those exposed to it and may potentially limit its effectiveness.

What's in the development pipeline?

Compounds are in development for all types of MS. Until now, no medication has been indicated for the primary progressive form of MS, but the monoclonal antibody rituximab (Mabthera, Roche), already available for use in non-Hodgkin's lymphoma and rheumatoid arthritis, is now in Phase 2/3 trial for this category of MS, as well as being in Phase 2 trial for the relapsing-remitting form. Secondary progressive MS is also being studied; BioMS Medical is conducting a Phase 2/3 trial in Canada, the UK and Scandinavia with MBP8298, which is given intravenously every six months, to demonstrate delay of progression in this form of the disease. In an earlier Phase 2 study, some patients treated with MBP8298 had a median time to disease progression of 78 months, as compared with 18 months for those given placebo.

Trials are also in progress in seeking new medicines for some of the troublesome symptoms of MS. GW Pharmaceuticals has conducted Phase 3 studies of the ability of the cannabis-based Sativex (taken as a spray in the mouth) to relieve involuntary muscular contractions and is planning to start trials in pain associated with MS. Also, Avanir Pharmaceuticals is conducting a Phase 3 trial of AVP 923 in involuntary emotional expression disorder.

Most research is, however, focused on the relapsing-remitting form of MS. At the Phase 3 stage, Novartis is conducting a trial of the oral compound fingolimod (FTY720), which lowers the number of circulating activated T-cells and has demonstrated a reduction in relapse rate in earlier trials, Serono has cladribine under study, Biogen-Idec has BG-12 and sanofi-aventis is investigating the immunomodulator teriflunomide.

Many compounds are being studied in Phase 2 trials. Abbott has ABT-874 and Biogen Idec is studying the orally active compound CDP323 and the monoclonal antibody daclizumab, which is already available for the prevention of organ rejection in kidney transplantation. Other monoclonal antibodies in trial are alemtuzumab (Mabcampath, Schering), already available for use in chronic lymphocytic leukaemia, and MLN1202, from Millennium Pharmaceuticals. Other agents at this stage include Eisai's E-2007, GSK's GSK 683699, and Medicinova's Ibudilast. The antidiabetic agent pioglitazone (Takeda) is also being evaluated in MS, because of its anti-inflammatory properties.

The longer-term future

More than 25 new compounds are currently in clinical trials for MS and it is not possible to discuss all of them here. There is, however, reason to hope that future therapy for this devastating disease may be more than just palliative and that it may be possible to delay substantially, or even halt, progression of multiple sclerosis.

FOR FURTHER INFORMATION CONTACT:

THE MULTIPLE SCLEROSIS SOCIETY
372 Edgware Road
London, NW2 6ND
Phone: 0808 800 8000 (Helpline)
Website: www.mssociety.org.uk