Wednesday, September 03, 2008

Pfizer Snaps Up Dimebon

This morning, Pfizer announced that it’s paying $225 million in cash upfront and up to $500 million in development milestones, plus assuming 60% of the development costs and commercialization expenses, in exchange for a 60% share of the profits of Medivation’s dimebon, a potential treatment for Alzheimer’s Disease and Huntington’s Disease. Medivation, in addition to retaining a 40% share of the reward and the risk, also gets a US co-promote and a royalty ex-US.

The deal is not surprising given Pfizer’s recent Alzheimer’s forays. The pharma bought Rinat Neuroscience in 2006 mostly to have a large-molecule play that would round out its AD portfolio--an antibody in early-stage development now known as PFE360365 that binds Abeta peptide, one of the hallmarks of the disease. Around the same time, Pfizer also inked a deal with TransTech Pharma on a dual-mechanism antagonist of RAGE (receptor for advanced glycosylation products), a molecule that both binds Abeta peptide and may also reduce the neuro-inflammation seen in AD.

Dimebon is significantly more advanced that the Rinat and TransTech compounds, but the collaboration with Medivation isn't all that expensive in comparison with the price tag of other Pfizer late-stage partnering deals, including that apixaban deal we've talked so much about lately. It also tops the numbers on the other recent deal for one of the few late-stage AD drugs—Lundbeck’s ill-fated spend on Myriad’s Flurizan in May 2008, which included $100 million upfront. Flurizan’s development was discontinued in June after its Phase III trial failed to show any difference between treated patients and the placebo group.

Dimebon also fits the Pfizer portfolio because it differs from most of the late-stage approaches to AD, which are based on modulating the so-called amyloid cascade. The amyloid hypothesis posits that deposition of amyloid beta (Abeta) peptides and the formation of amyloid plaques in the brain are early events that trigger subsequent ones such as neurodegeneration and the formation of the neurofibrillary tangles that can destroy nerve cells and neurons.

Abeta-targeting drugs include Flurizan, the Wyeth Phase III antibody bapineuzumab, and Lilly’s two late-stage AD candidates, the gamma-secretase inhibitor LY450139 and the Abeta antibody LY2062430, whose ultimate development Lilly recently decided to share with TPG-Axon and NovaQuest (the partnering arm of CRO Quintiles), in order to hedge the clinical risk.

The data on a completed Phase II/III trial of dimebon in Russia, which got considerable play at this year’s International Conference on Alzheimer’s Disease (ICAD) in late July, had been previously reported. But the context of Flurizan, disappointing Phase II data on bapineuzumab reported in June and further discussed at ICAD (a highly anticipated explanatory presentation that did nothing to assuage doubters), and even Lilly’s seeming bail-out on its candidates (the antibody data, less noticed than bapineuzumab certainly, remain tantalizing) could only have bolstered Medivation’s bargaining position.

Dimebon also appears to be the only late-stage AD drug candidate with a shot at potentially improving disease symptoms, as opposed to delaying progression of the disease, as is the hope with other putative disease modifying AD agents in development including the Abeta targeting compounds.

The completed Phase II/III study of dimebon was a 26-week trial, with an added blinded open-label six-month extension. More than 80% of the patients decided to stay on, giving the investigators an extended look at both the drug and placebo groups.

They determined that patients given dimebon were significantly improved compared with baseline and compared to those taking placebo, for all five of the designated outcome measures including assessments of cognition, function, and behavior. The primary analysis showed a significant drug-placebo difference in change from baseline on the ADAS-cog (a cognition scale), which was similar to the difference seen in the fully evaluable population at week 26. The improvements “were evident to clinicians assessing global function (CIBIC-plus), which supports the relevance of the treatment effect,” the investigators wrote in the report on the trial in the July 19, 2008, issue of The Lancet.

Moreover, they concluded that the drug-placebo differences were not just driven by worsening of the placebo group: there was actual improvement, which also increased substantially at week 52 compared with week 26, “suggesting that benefits continue to increase with time,” they said. “The continued and increasing benefit of dimebon over the course of the study is especially important because at present no approved therapies for mild-to-moderate Alzheimer’s disease have shown increasing improvement over 12 months,” they added.

At a time when many AD drug developers are content with running Phase II trials focused more on confirming mechanism than on showing efficacy, dimebon stands out. Despite the fact that it was done on a shoestring budget, the Phase II Russia trial was designed to be potentially pivotal, according to Rachelle Doody of Baylor School of Medicine, a consultant to Medivation who was instrumental in its planning. (Doody was also the lead clinical investigator in the development of Aricept, the AD drug marketed by Pfizer and Eisai.)

If an ongoing dimebon Phase III study, set for completion in 2010, meets its endpoints, Medivation (and now Pfizer) may even be able to piggyback the Phase II study as a second pivotal trial. The investigators did the study with English reports forms and “all the things that would be required for FDA audit,” she says. “We are fully prepared to have FDA audit it. [We were] never expecting we would get it, but were being ready just in case.”

The theme of ‘what can you know and how can you know it’ in Phase II is critical in AD drug development, and is the focus of a feature article set for the upcoming issue of IN VIVO (out next week!), based largely on discussions at ICAD about the perils of late-stage clinical trial design in AD. For purely selfish reasons, we wish Pfizer had waited to announce the deal. It’s already too late to amend it in the context of the Pfizer deal. (Woe is us.) And since the article didn’t make it to print before the deal, it’s also too late for us to sound all that prescient. But for what it’s worth, the piece touches on dimebon in its conclusion, as follows:

Perhaps the greatest cause of excitement at this year’s ICAD centered on Medivation’s dimebon, which in a Phase II study conducted in Russia was safe and appeared to improve the clinical course of patients with mild to moderate AD. The drug’s potential in AD was first identified by screening known compounds for dual activity against the cholinesterase and NMDA receptors—its mechanism of action is still being debated--and dimebon is now lined up to begin a pivotal Phase III study. If the new study meets certain endpoints, the FDA has said it would accept an application for approval with the completed Phase II as a second pivotal study—a testament to that study’s design and conduct.

That’s encouraging news for the field... But at the same time, the serendipitous nature of dimebon’s discovery as an AD drug has led some to lament that, in terms of discovery approaches, it may be the best they can do. No wonder Pharma is hedging its bets.

The theme of serendipity is worth reprising here—it goes a long way to explain Pfizer’s portfolio strategy in AD and the price it needed to pay for a competitive asset like dimebon. In fact, there’s no consensus on the mechanism underlying AD: it could be Abeta, aggregation of the Tau protein that causes neurofibrillary tangles, and/or some co-factor such as oxidative stress or the consequences of a build-up of calcium in the brain. In the words of one company’s clinical director, “If there was one mechanism we were sure would work, everybody would be working on it.”

Oh, and congratulations to Medivation's president David Hung, who purchased the patent on dimebon, an antihistamine that was put on the shelf after Claritin hit the market.

No comments: