With the devastating effects of Tysabri and PML in growing numbers of cases and the emergence of CCSVI research around the world, we are beginning to see a new marketing campaign in MS drugs-- the gradual move away from the autoimmune paradigm to potential (yet unproven) mechanisms.
Watch how craftily Novartis and the makers of Gilenya are utilizing the fear of their competitor Tysabri, the new vascular paradigm, and the hope of "altering the disease" to sell their unproven drug----it's all about the mystery mechanism. Here's the complete article--
http://news.bioscholar.com/2010/12/unexpected-mechanism-of-new-multiple-sclerosis-treatment.html
Note how Jerold Chun, M.D., Ph.D., a professor in the Department of Molecular Biology and member of the Dorris Neuroscience Center at Scripps Research, is changing the dialogue on his drug. Chun has been working on this drug, originally called FTY720, for over 15 years. It was created from a Chinese fungus in 1992 to help those receiving organ transplants, but was found to be no better than the current standard of care. No market for the new drug in transplants. So, as with most expensive new drugs without a home, it was repackaged for MS as Gilenya.
Chun is very excited to have discovered a "new" way of looking at Gilenya that isn't related to its immune-modulating properties.
"It’s a surprising result especially considering the purely immunological focus of current MS therapies as well as many under development. That you can alter the course of this disease through S1PR signaling in the CNS points to new ways to treat MS,” says Chun.
Chun comes up with this "disease altering" paradigm after giving Gilenya to MICE WITH EAE. Remember, mice with EAE are not people with MS. Not even close.
Precisely how Gilenya acts in the brain isn't yet clear. But here's their best GUESS:
The researchers have narrowed the drug's key activity to a specific S1P receptor subtype (S1P1) and a kind of nerve cell known as an astrocyte. Other cell types expressing S1P1 or different S1P receptor subtypes may also be involved, however a dominant influence appears to involve S1P1 and the astrocyte. The researchers also found that the knockout mice had lower levels of inflammatory proteins called cytokines that are known to play a role in MS and EAE. "Exactly how all that happens still needs to be understood," says Chun.
(Inflammatory cytokines, found in MS, are also related to hypoxia and hyperperfusion. Here is Dr. Juurlink's hypothesis http://www.direct-ms.org/pdf/CCSVI/Juurlink%20Reduced%20blood%20flow%20MS%2098.pdf
Perhaps correcting this slowed blood flow might be a more efficacious means of ridding the CNS of inflammatory cytokines?)
Here are KNOWN side effects of this drug in human beings, a drug whose mechanism of action is not understood in mice with EAE:
Fingolimod/Gilenya/FTY720 has been associated with potentially fatal infections, macular edema and vision loss, skin cancer and, recently, a case of haemorrhaging focal encephalitis, an inflammation of the brain with bleeding. Two subjects in clinical trials died: one due to brain herpes infection, second one due to zoster. Fingolimod also slows the heart rate (bradycardia or bradyarrhythmia) , sometimes to very dangerous levels, creating heart attacks.
For those interested in more info on this drug, here is a paper on the history of FTY720's evolution as organ transplant immune suppressor to today, as an MS drug. This is called REVERSE PHARMACOLOGY---when the mechanism of a drug is not understood. It is given to test subjects, and then explained. Kind of like throwing spaghetti up to the ceiling to see if it sticks...only with life altering ramifications.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754916/
About fifteen years have passed since FTY720 was first synthesized in 1992. FTY720 showed excellent in vivo immunosuppressive activities in skin and cardiac allograft models and various autoimmune disease models (89) although the molecular mechanism underlying the pharmacological effects was not identified. That stimulated reverse pharmacology to explore FTY720’s molecular mechanism. Since it was elucidated that FTY720’s target is the S1P receptors in 2002, very rapid explorations for understandings of S1P receptors and their signaling have been developed.