Sanofi has agreed to pay $74 a share for Genzyme — totalling a $20.1 billion upfront payment. But the CVR could boost the payments to Genzyme’s stockholders by up to $14 a share, dependent, largely, on Lemtrada becoming an MS blockbuster. Sanofi is backing this outcome — it says the drug has the potential to achieve annual sales of up to $3.5 billion — but the CVR, said CEO Chris Viehbacher in a press conference call announcing the deal, “was an extremely important tool to bridge differences in value.”

Sanofi will pay $1 per CVR if Lemtrada wins US approval, which the company expects will happen in the second half of 2012; increasing amounts of dollars-per-CVR depend on it passing various sales milestones. Lemtrada is currently in Phase III in the US. A Phase II trial of 334 people with early stage, active relapsing remitting MS, conducted over a three-year period in Cambridge, UK, reported in 2008 that the drug led to a 71% reduction in disability progression in participants (compared with those taking beta-interferon) and a 74% reduction in the relapse rate per year. On average, participants also experienced an improvement in disability at six months that was sustained for the three years.

But Lemtrada’s path to ‘blockbusterdom’ is far from certain. The side effects reported in the Cambridge study included a high rate of (mainly respiratory or urinary tract) infections (affecting 66% of participants). Around 30% suffered from thyroid disorders and there were six cases of immune thrombocytopenic purpura (ITP). Speaking to Bloomberg, Howard Weiner, of the Brigham & Women’s Hospital in Boston, said Lemtrada “is a theoretical cure, but to know that you need to follow people for 10 years. It’s a very strong drug and has potential side effects.” Phil Nadeau, an analyst with Cowen & Co.  (New York) added: “We think the side-effect profile is going to relegate [it] to later lines of therapy,” predicting “relatively modest peak sales estimates,” of $500 million to $1 billion.

Although the number of new MS therapies on way is showing that the basic science of innovation is working, the unknown side effect profiles potential in all these drugs show that the transition from bench to actual bedside is harder than ever.

The Multiple Sclerosis Activism Foundation has also expressed concerns about Lemtrada’s role in the Sanofi-Genzyme deal and what it might mean for subsequent pricing, saying that “for it to be used as a possible treatment for MS, and for Genzyme to be using this as leverage for a higher asking price, is… in our opinion, shameful considering the price of Campath, aka Lemtrada.” Campath, MS Activism goes on, “now sells for $30,000 for leukaemia treatment. But MS patients need only a fraction of the dose used in cancer patients. At the current price, MS patients could get Campath for $7,000 or so. That’s far less than other MS treatments.” But what would stop doctors from using the cancer-priced vials rather than the far more expensive MS priced vials, the group asks — could this have anything to do with rebranding Lemtrada “to make us think it isn’t a cheaper drug?”

The CVR aspect of the Sanofi-Genzyme deal, of course, reflects some of these uncertainties, despite Sanofi’s optimistic pronouncements of Lemtrada’s sales potential. But with both companies putting most of their eggs into the Lemtrada basket, there is a danger some of it could end up on their faces.

“This is a critical milestone on the path to potential approval for short-course therapy with Cladribine tablets, moving us one step closer to meeting an unmet need as an oral, disease-modifying drug available for relapsing MS,” stated Fereydoun Firouz, president and CEO of Merck’s US affiliate, EMD Serono, in a release.

FDA originally rejected Merck’s application for any kind of approval in November 2009, prior to the release of CLARITY trial data. It’s possible that FDA reconsidered the application after reviewing the positive results from the two-year global study of 1,326 patients suffering from relapsing-remitting MS.

According to Merck KGaA, patients taking the short-course tablet treatment experienced “rapid and sustained improvements in clinical and magnetic resonance imaging outcomes, which were accompanied by rapid and sustained effects on blood-cell subtypes implicated in the pathogenesis of multiple sclerosis.”

Gavin Giovannoni, principal investigator of the study, told ThePharmaLetter, “The introduction of an oral therapy, particularly one that has no short-term side effects and is as easy to use as oral Cladribine, will have a major impact on the treatment of MS. However, the use of this drug as a first-line therapy will have to be weighed up against the potential long-term risks which have yet to be defined.”

Side effects included headaches, upper respiratory tract infections and nausea—similar to adverse reactions experienced by patients taking the placebo.

Merck is neck-and-neck with Novartis, which received priority review for its own MS tablet-based treatment, Gilenia, in February. There are currently no non-injectable MS treatments on the market, so an early approval is going to be a big win for patients and a financial windfall for whichever company is first to market.

Acorda filed a New Drug Application for fampridine on January 30, and FDA approval is expected in about 10 months. If green-lighted, fampridine will be the first drug approved with the indication to improve walking ability in people with MS, and Acorda’s second commercialized product. It currently markets Zanaflex (tizanidine) for the management of spasticity.

This is the second round of late-stage clinical trials for fampridine. In 2004, the drug completed Phase III trials for reducing spasticity in patients with spinal cord injuries, but the studies did not achieve statistical significance in their primary endpoints.

New data from the recent randomized, double-blind, placebo-controlled trial showed an average 25 percent increase in walking speed for MS patients treated with fampridine, compared to a 5 percent increase in the placebo group.

“We focused particularly on walking because walking is by far, along with general energy loss and fatigability, the most pervasive, common, and the most dreaded part of MS,” said Acorda CEO Ron Cohen, MD. “You can probably live with one hand being weak if the other hand’s OK, but if you can’t walk you’re stuck—you’re utterly dependent.”

MS is a progressive condition where the immune system attacks the nervous system, destroying myelin and interrupting communication signals between the brain and the spinal cord. Nervous system damage may cause muscle weakness, imbalance, and loss of coordination, which can eventually lead to decreased mobility or paralysis.

According to the National Multiple Sclerosis Society, about 400,000 Americans and 2.5 million people worldwide are diagnosed with MS. Between 64 and 85 percent of those patients have trouble walking.

Used in tandem with first-line medications, fampridine works by blocking the open potassium channels exposed after demyelination, which interrupts message transmission between axons. By sealing the leaks, fampridine allows impulses to flow with reduced interference and restores mobility.

In the early days of MS treatment development (mid-90s) the options were few. As Cohen put it, “It was diagnose and adios.” But with the biotech revolution came giant leaps towards effective MS disease management, and the first line treatments—Avonex (interferon beta-1a), Copaxone (glatiramer acetate), Tysabri (natalizumab)—were born. Now the next generation of therapy is using the platform built by these veteran drugs as a stage to showcase their new, more targeted approaches. Instead of attempting to slow its progression like older treatments, new drugs take aim at the disease and the debilitating symptoms and side effects that come along with it.

The latest Phase III data translates clinical trial numbers into tangible results for patients. Already, Acorda has solicited the responses of study participants to a 12-Item survey meant to measure fampridine’s perceived impact on mobility improvement.

“We showed that this average 25 percent improvement in walking speed on this test correlates very strongly with improvements in any number of activities in daily life that are related to walking,” said Cohen. “It was the first time that anyone had ever shown that a drug could improve neurological function and real functionality in people with MS.”