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Posts Tagged → multiple sclerosis

Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12

Biogen Idec made a splash last week when its oral medication for multiple sclerosis (MS), BG-12, was found to reduce relapses in 44-53% of nearly 3,800 patients in two separate Phase 3 clinical trials (CONFIRM and DEFINE, respectively). Continued hopes for an orally available, non-injectable MS treatment have created a race between Biogen Idec and several other firms, as C&EN’s Lisa Jarvis examines in a 2009 MS cover story. In fact, so much has changed in 2 years that two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition.

So what’s the secret sauce behind BG-12? Many pharmaceuticals are small molecules with multiple heteroatoms and aromatic rings, but not BG-12: it’s just dimethyl fumarate! A search for ‘fumarate’ on pubs.acs.org returned >4800 hits, which gives you an idea of its common use in several organic reactions: [3+2] cycloadditions, Diels-Alder reactions, and Michael additions. Interestingly, dimethyl fumarate is the all-E stereoisomer; the Z-configuration, where the two esters are on the same side of the central double bond, goes by the tagline ‘dimethyl maleate’ and does not seem to possess anti-MS effects.

Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects (see Derek Lowe’s 2005 article regarding the FDA “approvability” of several common drugs today). Toss in BG-12’s alkylating behavior to boot (fumarates can interact with nucleophilic amines or sulfides at multiple sites, including enzyme active sites), and you have to wonder how it functions in the body. Well, so do scientists. A 2011 review implicates up to 3 potential biochemical mechanisms – the Nrf2 pathway Lisa mentioned in the 2009 piece, T-helper phenotype 2 interleukin upregulation (IL-4, IL-10, IL-5, which “change gears” for immune system functioning), and CD62E inhibition, which controls adhesion of blood cells to inflammation sites.

Side notes: Flavoring chemists have added fumaric acid, the parent diacid of BG-12, to industrially-prepared foodstuffs such as baking powder and fruit juices since the 1930s. A darker side of dimethyl fumarate emerges when you consider its non-medicinal use: certain furniture companies applied it to new upholstered chairs and sofas to stop mold growth. This unfortunately caused several cases of severe skin irritation, which a 2008 exposé in London’s Daily Mail likened to actual burns.


Novartis’ MS drug Gilenia gets the green light

The path to approval looks clear for Novartis’ Gilenia, which is poised to be the first oral treatment for multiple sclerosis on the market. Today, members of an FDA advisory panel unanimously gave the drug a positive vote, despite worries about its side effects.

Gilenia (also known as fingolimod or FTY720) is a derivative of myriocin, a compound found in a fungus that had been used for thousands of years in Chinese medicine. The drug taps into a concept similar to the one used by Biogen Idec’s Tysabri, both binding to proteins on the surface of immune cells. As we wrote last year:

Once activated in the lymphatic system, T cells and other immune cells travel the busy highway known as the bloodstream to get to their target tissues. Nature has provided them with a built-in GPS: proteins that sit on the surface of the cells and point them to the proper exit ramps during their journey. In the early 1990s, scientists realized they might be able to alter the course of the disease by disabling that GPS.

Biogen’s Tysabri was the first drug approved to block one of those cell surface proteins, alpha-4-beta-1 integrin, which tells the immune cells when to leave the bloodstream and enter the brain and spinal cord.

Gilenia, meanwhile, binds to sphingosine-1-phosphate (S1P) receptor, a cell-surface protein that tells the immune cell to leave the lymph nodes. By doing so, some T cells are kept out of circulation, and preventing them from later reaching the nervous system.

Both drugs are very effective, but there are consequences to tweaking the immune system. Tysabri was temporarily sidelined after its launch after several patients died of a serious brain infection. The company is now working on an assay to predict whether a patient is susceptible to the virus that causes the infection, but in the meantime, the safety worries have limited widespread use of what is otherwise considered the most effective treatment on the market.

Gilenia, meanwhile, has its own set of side effects, including heart problems and weakened lung function. The FDA advisory panel will reportedly suggest that the company study a lower dose of Gilenia than that being proposed in Novartis’ new drug application, but the panel also said that study could be done after the drug was approved.

Assuming Novartis gets the greenlight from FDA, which usually follows the advice of its advisory panels, Gilenia will be the first pill approved to treat MS (it should be noted that Acorda’s pill Ampyra addresses the neurological symptoms of the disease, rather than the underlying inflammation that causes the brain lesions in people with MS.).

The race to get the first oral MS treatment had been neck-and-neck until last fall, when FDA rejected Merck Serono’s application for cladribine. This week, the German firm said it had resubmitted its application in the U.S., and will likely hear from European regulatory authorities in the third quarter of this year.

Cladribine takes more of a brute force method of suppressing lymphocytes. An intraveneous version of the drug, a purine nucleoside discovered at Scripps Clinic in La Jolla, Calif., was initially used to treat a rare form of leukemia. The toxicity issues, particularly cardiovascular effects, associated with a cytotoxic agent had some neurologists we spoke to last year thinking the drug would have a limited audience.

You might look at the side effect profiles of all these options and think: Whoa, kinda harsh. But people with MS are in desperate need for some new drugs. Aside from Tysabri, every other available treatment is elderly and simply an iteration of an interferon, which has proven only weakly effective at keeping the disease at bay.