An investigational oral medication for the treatment of multiple sclerosis is continuing to show promise, based on results of a Phase 2 clinical trial. The drug, known currently by its code name, FTY720, may move into Phase 3 testing with patients in North America and Europe beginning later this year. Manufacturer Novartis AG says it is currently discussing the initiation of these final phase trials with regulatory authorities.
"FTY720 differs from currently approved treatments because it is the only medication that binds the receptors of S1P [sphingosine-1-phosphate], present on the surface of lymphocytes, which are a subpopulation of white blood cells," explained Ludwig Kappos, MD, a neurologist at University Hospital in Basel, Switzerland, who released the results of the Phase 2 trial at the European Neurological Society Meeting in Vienna, Austria this month.1
It is the lymphocytes, among other immune cells, that attack myelin as part of the pathology of MS. "As a consequence of receptor binding, the lymphocytes can no longer respond to the molecule that signals them to circulate to sites of inflammation in the body, and they stay in the lymph nodes," Kappos told Priority Healthcare.
Relapse Reduction
A large double-blind, placebo-controlled Phase 2 study of FTY720 was performed at 32 centers in Europe and Canada. Nearly 300 patients diagnosed with relapsing-remitting multiple sclerosis were involved. Doctors evaluated the effectiveness of the drug on MS disease activity based on magnetic resonance imaging (MRI) scans and relapse incidents reported by patients over a 6-month period. The patients had been assigned at random to a group receiving 1.25-mg doses, 5-mg doses, or a group given only a placebo—a non-therapeutic intervention used in studies as a comparison to the intervention being tested.
The study investigators reported a reduction in the number of relapses by 55% in the group given the 1.25 mg dose of the drug and by 53% in the group given the 5 mg dose, compared to those taking the placebo. Additionally, the amount of time to the first confirmed relapse following therapy initiation was significantly extended in both medication groups. Nearly 90 percent of the patients in the treatment groups remained relapse-free throughout the 6-month study, compared to about 70 percent of those on the placebo.
Inflammation, measured by the number of brain lesions seen on an MRI scan, was also significantly reduced in both groups of patients taking FTY720 in the trial, Kappos and his team reported. Additionally, new disease activity measured as the number of new lesions in the brain was reduced by more than two-thirds in the patients taking both doses of the medication, compared to those given the placebo, the researchers reported.
Nearly all of the patients completed the 6-month study, indicating the medication had been well tolerated, and 98 percent volunteered to enroll in an extension phase, which is still ongoing. The most frequently reported side effects included colds, diarrhea, nausea, headaches, shortness of breath, and cough. Those taking the higher dose of FTY720 experienced more side effects compared to those in the group given the 1.25 mg dose.
So far, it's too early to determine the optimal dose, Kappos stated.
Moving to the Next Phase
Prompted by the positive findings, Novartis plans to initiate an upcoming Phase 3 trial, which will involve larger numbers of patients tested over a longer period. The trial's objectives will include confirming the safety and efficacy of the drug seen in earlier trials, and evaluating the effect of the medication on patients' disability progression after two years.
Kappos added that the drug may hold promise for other, more progressive diseases, as well as later stages of MS. But these will have to be tested in future studies. "There may also be additional effects directly in the central nervous system that co-determine the therapeutic potential of FTY720, but are not yet fully understood," he said.
FTY720 is being investigated elsewhere as a possible immunosuppressant to prevent rejection after kidney transplant procedures.2
Underlying Origins of MS
When MS strikes, it is primarily myelin that is the target of an immune system attack. Myelin is a fatty sheath surrounding vulnerable nerve fibers in the central nervous system. When it is destroyed by immune system cells, the sensitive nerve fibers also get damaged, resulting in the symptoms seen in MS.3 While it's not known what causes the immune system to incorrectly target the body, it's believed several factors predispose certain people to the disease:
• Genetics
• Gender (more women than men contract MS)
• Environmental Triggers (viruses, trauma, heavy metals)4
Most people between the ages of 20 and 50 are diagnosed with MS. It's estimated some 400,000 Americans have the disease, with an additional 200 being diagnosed each week.5
1. Kappos L, Radue EW, Antel J et al. FTY720 in relapsing MS: results of a double-blind placebo-controlled trial with a novel oral immunomodulator. 15th Meeting of the European Neurological Society. 2005 Jun 18-22. Vienna, Austria.
2. Brinkman V, Cyster JG, Hla T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 2004 Jul;4(7):1019-25.
3. National Multiple Sclerosis Society. What is Multiple Sclerosis? Available at: http://www.nationalmssociety.org/What%20is%20MS.asp. Accessed June 24, 2005.
4. National Multiple Sclerosis Society. What Causes MS? Available at: http://www.nationalmssociety.org/What%20causes%20MS.asp. Accessed June 24, 2005.
5. National Multiple Sclerosis Society. Who Gets MS? Available at: http://www.nationalmssociety.org/Who%20gets%20MS.asp. Accessed June 24, 2005.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
