A new treatment for multiple sclerosis - is this new Cure?

By Kath Ibbetson
On September 22nd 2010,the US Food and Drug Administration (FDA) announced approval of fingolimod (Gilenya, Novartis), the first of the long-anticipated oral treatments for multiple sclerosis (MS). Multiple sclerosis is a chronic, debilitating autoimmune disease that affects the brain and spinal cord of 2.5 million people worldwide.

Fingolimod (also known as FTY720, brand name Gilenya) is a new oral treatment currently being tested in phase III clinical trials for relapsing remitting and primary progressive multiple sclerosis (MS). It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. Other phase 3 clinical trials of fingolimod/Gilenya, including one involving people with primary progressive MS, are still under way, as are extension studies involving those who've completed other fingolimod trials.

In these clinical trials the end points included the annualized relapse rate (ARR) and the time to disability progression. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20-0.21, and 68-73% remained relapse-free at 36 months. Patients on Gilenya 0.5mg for two years had a ARR at year one of 0.16 and at year two of 0.18. These patients also retained a significant reduction in relapses and MRI brain lesions over 2 years As a result, fingolimod/Gilenya is approved to reduce relapses and delay disability progression in patients with relapsing forms of MS but at this stage long-term safety is unknown. Post marketing studies (phase IV clinical trials) should provide additional data on its safety and efficacy.

How does fingolimod work?

MS causes the body to direct antibodies and white blood cells against proteins in the myelin sheath that surrounds the nerves in the brain and spinal cord thus causing the breakdown of myelin and interruption to nerve signals. Fingolimod acts on certain types of white blood cells (lymphocytes) which are involved in this immune attack. It attaches to special locations (or receptors) on the surface of lymphocytes, called sphingosine-1-phosphate receptors (S1P-R). This causes a large proportion of the lymphocytes to be retained in the lymph nodes (part of the body's immune system) and so reduces the number of lymphocytes circulating in the blood. As the lymphocytes are held in the lymph nodes then less reach the central nervous system so there is less immune attack on nerve cells in the brain and spinal cord.[1] There is also evidence that fingolimod may have a direct effect on nerve cell damage and enhance remyelination by acting on sphingosine receptors in the central nervous system.[2, 3]

How is fingolimod given?

Fingolimod is administered in the form of a 0.5 mg oral capsule. Patients usually take 0.5 mg once per day although in trials many were given 1.25mg per day. However, Fingolimod doses higher than 0.5 mg are associated with a greater incidence of side effects without additional benefit.

Side effects and contraindications

Generally fingolimod is well tolerated but the side effects that have occurred include: • headache • shortness of breath • upper respiratory tract infection • diarrhea and nausea. Increased levels of liver enzymes and raised blood pressure have also been observed although these are generally mild. In one of the clinical trial, two deaths resulting from herpes virus infections occurred in patients taking the higher dose of fingolimod. Other aspects of the treatments these two patients received may have contributed but, given its immunomodulatory action, a role for fingolimod cannot be ruled out. Macular oedema (swelling in the back of the eye) also occurred more frequently in the fingolimod-treated participants. In more than one trial there were cases of localised skin cancer in the fingolimod groups but these were successfully removed.

Other drugs in the pipeline

Cladribine (Merck KGaA) was also in the race for first oral agent for the treatment of MS in the United States. In August 2010, the FDA accepted the company's application and granted it priority review. Cladribine was recently approved in Russia and Australia and is under review by the European Commission and other regulatory agencies. Other oral MS treatments in development include laquinimod (Teva), teriflunomide (Sanofi-Aventis), and BG-12 (Biogen).

1 Brinkmann V, et al. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. American Journal of Transplantation 2004;4:1019-1025.

2 Miron VE, et al. Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod. American Journal of Pathology 2008;173:1143- 1152

3 Miron VE, et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. American Journal Pathology 2010;176:2682-2694.



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