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Posts Tagged → Biogen

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two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition.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.


Biogen Taps Exelixis’ Scangos–Updated

Reuters and several other news outlets are reporting that Exelixis CEO George Scangos is being tapped as the next leader of Biogen Idec. It’s a curious choice, to say the least. Scangos heads up a small molecule, oncology-focused biotech that has yet to commercialize a product, and Biogen Idec has several biologic drugs on the market and multi-billion dollar sales.

So why Scangos? My only thought is that Biogen has been wanting for years to up its presence in the small molecule space, and Scangos certainly has experience on that front. Only it was a different ball of wax at Exelixis: all those small molecules in the pipeline, successful or not, were home grown. Biogen, on the other hand, has pretty much bought all the small molecules in its pipeline (see its 2006 acquisitions of Conforma Therapeutics, which brought a series of Hsp90 inhibitors for cancer, and Fumapharm, which brought the dimethyl fumarate BG-12, now in Phase III trials in multiple sclerosis). The other small molecule in its pipeline, the Parkinson’s drug vipadenant, was discovered at Vernalis. Do they think Scangos can lead them in the right direction?

It’s also worth noting that rogue investor Carl Icahn had just two months ago been pushing for a plan to split Biogen Idec into two companies: one focused on oncology, and the other on neurology. Most folks thought the idea was nuts; it would mean putting the majority of the big assets in one basket and creating an oncology company with one product on the market and an otherwise sparse pipeline. Bringing in someone who helped to build an oncology company from scratch might help matters.

Well, readers, I leave it to you. Is there any sense in this choice? Or has April Fools’ Day come early? What does it mean for the future of Biogen? Despite a resurgence of sales in its multiple sclerosis drug Tysabri, many believe its pipeline could use some work. Not to mention Exelixis—the company has hit a rough patch, losing two consecutive partners for its lead drug candidate, and laying off 40% of  its staff earlier this year. Can either ship be righted with fresh leadership?

Update: Well, it’s official. Biogen announced the appointment of Scangos, and Exelixis said its former head of R&D Michael Morrissey, a PhD chemist, will become CEO as of July 15. Some small take aways from the brief conference call Scangos held with analysts this afternoon:

Biogen made a point of underscoring Scangos’ experience with biologics at Bayer, where he worked for a decade before his 14 years at Exelixis. The call clearly seemed crafted to quell any concerns that Scangos lacks experience commercializing products, particularly biotech products. And in his own comments, Scangos seemed to focus more on his time at Bayer, which included working on its hemophilia franchise and securing the company’s deal with Onyx Pharmaceuticals, than on his accomplishments at Exelixis.

Scangos emphasized several times the need to “take a hard look” at how R&D is done at Biogen. He said a pipeline review would begin immediately, in tandem with the search for a new head of R&D. I’m wondering what will go, since as it is the pipeline is not looking too beefy.

Is Incubation a Win for Big Pharma?

Johnson & Johnson appears to be the next big pharma company looking to test out the incubator model as one way to spur innovation. According to an article in the San Diego Business Journal, the big pharma company is interested in renting space to entrepreneurs that would have access to J&J’s equipment and technology at its research site in La Jolla, Calif. Diego Miralles, facility head at La Jolla, tells the SDBJ that up to 17 small biotechs could be housed at the site. The first biotechs could be moving in as early as this year.

Many will recall that Pfizer established an incubator, also in La Jolla, in 2007. So far only three companies—Fabrus, Intherix, and RGo Bioscience–occupy the space there, and, as the article points out, no new firms have been signed on since Pfizer’s merger with Wyeth. Biogen Idec seems to have a similarly slow start to its incubator, also launched in 2007. So far, the big biotech’s incubator, bi3, has only invested in two companies, Escoublac and Provasculon.

An incubator can offer some advantages over the traditional VC funding route. In addition to cash, companies get space in often well-appointed digs, infrastructure, scientific support, and access to bigger firms’ business acumen. On the downside, the deals also come with strings attached:  generally the big pharma firm gets a stake in the companies in which they’ve housed in their incubator.

Other companies have taken a different tack. The Novartis Option Fund makes seed investments in companies with early-stage technology in exchange for a stake in the firms and the first crack at any discoveries they make. With much deeper pockets—the fund started out with $200 million—Novartis has made a substantial number of investments, including some “opt-ins” on drug candidates.

The jury is out on whether incubators, internal investment funds, or some other measure will actually be a winning proposition for big pharma. But the slow start for Pfizer and Biogen’s ventures might cause J&J to keep its expectations low for filling its space with those 17 firms.