Alemtuzumab
Alemtuzumab (Campath®) is a humanised anti-leukocyte monoclonal antibody. In patients with SPMS, it has been shown to induce pronounced effects on the immune system as well as marked suppression of cerebral inflammation, as documented on serial MRIs. In addition, there has been a suppression of relapses. A recently performed clinical trial showed a significant treatment effect of two doses of alemtuzumab compared with a standard treatment of interferon beta-1a (Rebif®) in patients with early, active RRMS. There are concerns with respect to the safety of the compound because in early studies about 30 percent of patients developed Graves’ disease, an autoimmune thyroid condition. The more recent studies were temporarily suspended because of cases of severe immune thrombocytopenic purpura. The first patient to present with this disease died from it.

Fingolimod (FTY720)
Fingolimod is an orally administered agent that has an impact on the systemic circulation of immune cells. It deprives these cells of a signal necessary to egress from lymph nodes which reduces recirculation of lymphocytes in the central nervous system. In a proof-of-concept study 281 patients with relapsing MS received oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or a placebo. Fingolimod significantly reduced both the number of lesions detected on MRI and the number of clinical relapses. Short-term treatment is generally well tolerated despite some cardiorespiratory side-effects; long-term safety is yet unknown. Larger studies with fingolimod are currently ongoing, to further evaluate efficacy and safety.

Teriflunamide
Teriflunamide is another immunomodulatory agent with anti-inflammatory activity that has been shown effective in suppressing EAE, an animal model for MS. In a recent study 179 patients with relapsing MS were treated with placebo, or one of two doses of teriflunamide (7 mg/day and 14 mg/day) administered orally. Teriflunamide was effective in reducing MRI activity and showed a trend for reducing the number of relapses. Short-term treatment is well tolerated; long-term safety is unknown. Further studies with teriflunamide are ongoing, to further evaluate efficacy and safety.

Rituximab
Rituximab is a monoclonal antibody that achieves a systemic depletion of B lymphocytes. So far, it has mainly been used in certain haematological malignancies and autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. Recently, some very small studies suggest that rituximab can also effectively suppress disease activity in MS. The compound can cause profound immune suppression, and therefore long-term safety should be studied very carefully. Further studies with rituximab are planned.

Minocycline.
Minocycline is an antibiotic agent that also reduces lymphocyte access to the central nervous system and – according to some reports – also has the potential to have neuroprotective effects. In a recent, very small Canadian study it was shown that orally administered minocycline can suppress MRI activity in relapsing MS. Among potential future therapies for MS, minocyclin is interesting because it is given orally and has a favourable safety record. Further studies are ongoing.

Statins
Statins are orally-administered, lipid-lowering drugs. Statins have already been shown to ameliorate clinical signs in EAE, an animal model for MS. Furthermore, in vitro data demonstrate that these agents have several potentially favourable immunomodulatory actions that make them candidate treatments for MS. In a small study, 30 individuals with RRMS, who had at least one new lesion during a three-month screening period involving monthly MRIs, were treated with a very high dose (80 mg) of simvastatin (Zocor®) daily. Preliminary analysis of the results indicates a significant (43 percent) decrease in the mean number of new lesions on monthly MRI. Among potential future therapies for MS, statins are especially interesting because they are given orally and have an outstanding safety record. The main question is whether effective immunomodulation occurs at the cholesterol-lowering doses currently used clinically. Additional studies are ongoing.

Estriol
Following the observation that MS patients are less likely to have relapses during pregnancy, a small, open-label study of daily high-dose (8 mg/day) estriol was recently published showing an apparent reduction in MRI evidence of disease activity in the six RRMS patients but not in the six SPMS patients. Again, further work is needed in this area. Potential benefits of estriol, when given for long periods, have to be weighed against side-effects and toxicity, including risks for carcinogenesis and thrombosis.

Daclizumab
Daclizumab is a humanised monoclonal antibody against the IL2 Receptor that plays a fundamental role in immune activation; it is an approved drug for the treatment of kidney transplant rejection. Some small studies suggest that daclizumab suppresses disease activity in patients with active RRMS, either as monotherapy or given in combination with interferon beta. Further studies are needed to better understand the potential value of daclizumab in MS.

Other Experimental Treatments
The aim of several experimental therapies is to modulate the specific immune response in some way or another. One way would be to induce antigen-specific tolerance by modifying the method of applying the antigen; for example, via the gut (“oral tolerance”). Unfortunately, however, in MS the oral administration of myelin has been ineffective, despite encouraging results in a small pilot study. A problem for this approach, of course, is that a MS-specific antigen so far has not been identified.

T cell (receptor) vaccination is another method that is being applied in clinical trials. The concept is that injection of disease causing T cells, or their specific T cell receptors, isolated from a recipient and undergoing culturing and inactivation, as a vaccine stimulates regulatory mechanisms. Some promising immunological responses have been observed in small studies, but so far rigorous proof of efficacy is still lacking.

Future studies will also include the administration of neuroprotective agents or molecules that would facilitate axonal regrowth, the administration of growth factors that promote the proliferation and survival of oligodendrocytes, the cells that make myelin, and the transplantation of cells (e.g., neural stem cells or progenitor cells) that are capable of making new myelin.

In the opinion of the Committee, the approaches mentioned in this “Emerging Treatments” section require more research before their role in the treatment of MS can be determined. At this time their use cannot be recommended outside the context of well-designed clinical trials.

Although proof has become available that we have developed the tools to generate intervention strategies that are effective in the treatment of patients with MS, we must be careful that in this atmosphere of optimism we do not too easily adopt new therapeutic approaches based on the results of small studies without phase III trials involving large numbers of patients being performed. There is increasing pressure towards shorter studies to obtain quick answers, even though it has been observed that short-term favourable trends may reverse with prolonged follow-up; for example, an immunomodulatory agent (Linomide®) that had shown promising effects in phase II studies had to be withdrawn from phase III studies because of unexpected serious (cardiovascular) side effects.

In a disease such as MS, in which disability generally accumulates slowly over many years, severe side-effects, even if infrequent, might invalidate a therapeutic approach.

Even with the development of MRI as a more and more powerful tool to study therapeutic interventions, there is a need to obtain meaningful, robust data on long-term clinical efficacy and safety. There is still no substitute for longer-term, carefully monitored, randomised clinical trials. In addition to generating the registration data required for regulatory approval, clinical trials should also be seen as instruments to test research hypotheses on mechanism of action and the type of patients to respond most favourably. As evidence mounts that MS comprises several distinct subforms, the choice of treatment for individual patients, ideally, should be determined by knowledge of the specific underlying pathophysiologic mechanism and the respective profile of available drugs. The ultimate goal is tailor-made therapy.