Best of the Blog: IN VIVO, September 2008

Highlights of our blog coverage for September 2008 included ongoing coverage of the financial crisis and how the broader financial woes may manifest in the world of healthcare financing.

Best of the Blog is a monthly column highlighting the best of our free online content at www.windhover.com/blog. In September, Windhover’s editorial staff posted 35 articles to the site, covering biopharma, device and diagnostics R&D, business development, regulatory and commercial news. Highlights included our ongoing coverage of the financial crisis and how the broader financial woes may manifest in the world of health care financing. Here are a few of our favorite blog posts and excerpts for stories not covered elsewhere in this month’s IN VIVO.

Pfizer Snaps Up Dimebon

(September 3rd.) This morning, Pfizer Inc. 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 Inc.’s Dimebon, a potential treatment for Alzheimer’s disease and Huntington’s disease. [See Deal] 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 Corp. 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. [See Deal] Around the same time, Pfizer also inked a deal with vTv Therapeutics Inc. 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. [See Deal]

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—H. Lundbeck AS’s ill-fated spend on Myriad Genetics Inc.’s Flurizan in May 2008, which included $100 million upfront. [See Deal] 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 Eli Lilly & Co.’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 Transnational Holdings Inc.), in order to hedge the clinical risk [See Deal]. (See "Alzheimer’s Development Financing: Risky Therapies Call for Innovative Deals," IN VIVO, September 2008 (Also see "Alzheimer's Development Financing: Risky Therapies Call for Innovative Deals" - In Vivo, 1 Sep, 2008.).)

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 College of Medicine, a consultant to Medivation who was instrumental in its planning. (Doody was also the lead clinical investigator in the development of Aricept (donepezil), 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."

—Mark L. Ratner

New CMO Means Business for GSK

(September 11th.) No new CEO in our industry has done more to shake up his organization than GlaxoSmithKline PLC's Andrew Witty (except perhaps Severin Schwan of Roche with his bid for Genentech Inc.--but that's another story).

Earlier this spring he created high level positions devoted to corporate strategy and emerging markets and the formation of a new $500 million corporate venture fund. Just days after rumors concerning also-ran Chris Viehbacher's departure were confirmed comes news that Witty's lured Ellen Strahlman, MD, away from Pfizer, where she served as VP of licensing and worldwide business development, to the role as GSK's chief medical officer.

As the press release announcing Strahlman's appointment helpfully points out: "the chief medical officer is the most senior physician leader of the company with primary responsibility for matters of patient safety, general medical governance, ethics and integrity, medical information, and investigation involving human subjects relating to any GSK products in development or on the market."

Which is what makes Strahlman's appointment so interesting. Yes, she's a well respected physician--an ophthalmologist by training. And since she once served as CMO and global head of R&D for Bausch & Lomb Inc., so she's no stranger to the duties a CMO title brings with it. But her most recent stint at Pfizer, where she was at least partly responsible for spin-outs and outlicensing, means she comes with a business focus that's atypical of most of the industry's CMOs.

And Strahlman's background is by no means unique in the boardroom at GSK. When you look at who occupies the top spots at this pharma, a number of them have deep biz dev experience. Among them: Russell Greig, head of the new GSK Venture Fund, who was GSK's senior VP of worldwide business development before becoming president of pharmaceuticals, international; David Redfern, the company's new strategy guru, who has held stints at GSK as SVP corporate strategy and development and SVP of Northern Europe; and Moncef Slaoui, who was SVP worldwide business development for GSK before becoming chairman of the R&D program.

And that leads this IN VIVO Blogger to wonder...With so many top brass at GSK--including now the CMO--trained to look for products outside GSK's own pharm system, what's the importance of internal R&D to GSK?

It's a fair question. GSK has never shied from inking big deals to fill its late stage pipeline drought. In recent months that's meant tie-ups with Valeant Pharmaceuticals International Inc. for their Phase III anticonvulsant, Actelion Pharmaceuticals Ltd. for their Phase III insomnia drug, and Cellzome AG for their Kinobead technology and kinase inhibitor discovery/early development. [See Deal] [See Deal] [See Deal] And in attempt to spur innovation within GSK's walls, Witty announced in July a reorganization of the CEDDs into discovery performance units that will compete for internal financial resources much the way biotech start-ups vie for VC funding.

"Externalising R&D enables GSK to capture scientific diversity and balance expenditure and risk in drug development. In the future, we believe that up to 50% of GSK’s drug discovery could be sourced from outside the company," Witty said in a press release announcing the new strategic priorities.

No one is suggesting that Witty wants to jettison GSK's internal R&D--at least for now. But the structural changes that have already been announced and this most recent appointment of Strahlman to CMO suggest that more and more business as usual at GSK will also come with an external focus.—Ellen Foster Licking

Waiting on Prasugrel: No News is Good News

(September 29th.) Another NDA, another missed deadline.

This time around, it’s a product upon which Lilly has hung much of its future, the anti-clotting drug prasugrel (Effient).

Lilly has already been on a rollercoaster ride on Wall Street over prasugrel once the risks associated with the drug surfaced (32% increased chance of bleeding). And time is not on Lilly’s side: the company is racing to establish the drug on the market before 2011, when Plavix generics will complicate the anti-clotting landscape.

Prasugrel has also been closely watched as another sign of how FDA will use its new risk management authorities under the FDA Amendments Act. The billion-dollar questions: would FDA agree that the bleeding risk associated with prasugrel could be appropriately managed by a REMS, or is more needed for approval? And is there any chance for a relatively clean label?

All that makes prasugrel the closest-watched drug approval this year. Indeed, between the September 26 prasugrel user fee deadline and the Wall Street bailout agreement, there were more than a few investors who were constantly refreshing their computer screens as Friday wore on.

While a bailout deal may be at hand, we’ll have to wait a little longer to find out about the fate of prasugrel. For now, Lilly’s not talking, except to say—in a press release that crossed the wires at 5 pm on Friday—that FDA would miss the deadline, that the review is "very far along," and that Lilly "remains optimistic" that an approval is imminent.

Wall Street’s immediate reaction was not positive—the announcement drove Lilly shares down 3.9% to $45.01 in after-hours trading, and shares opened lower this morning. Les Funtleyder at Miller Tabak expressed his frustration in a research note: "This has become a bit of an unsettling trend at the FDA. The decision tree used to be pass or fail, now there is a third column, the ‘I don't know.’" (Hat tip to CNBC).

We think that pessimism is misplaced.

We told you three months ago why we think FDA will approve prasugrel, and that reasoning hasn’t changed. (See "Prasugrel: Signs Point to FDA Approval," The IN VIVO Blog, June 23, 2008.) Indeed, the fact that the agency missed the user fee deadline bodes even better for the drug’s prospects, because it indicates—barring any last-minute surprises—that an approval is close at hand.

Here’s why: Since FDA’s drug review divisions were given the green light to start missing deadlines, most of the applications delayed by workload issues were eventually approved within weeks, based on a recent analysis in The RPM Report. (See "Running Late: FDA Review Timelines Lengthen For New Product Applications," The RPM Report, September 2008 (Also see "Running Late: FDA Review Timelines Lengthen For New Product Applications" - Pink Sheet, 1 Sep, 2008.).)

For one recent example, look no further than Amgen Inc.’s Nplate (romiplostim), which cleared FDA a little over two months after the user fee deadline. GlaxoSmithKline’s Entereg (alvimopan) was approved 10 days late. UCB Pharma’s Cimzia (certolizumab) was three weeks late. And there are other examples of how small allowances for heavier workloads at FDA have led to product approvals.

There are many reasons for a missed deadline, and some (like finding enough members to staff an advisory committee) have led to months-long delays for new products. But that’s doesn’t appear to be the case with prasugrel: "This is a very large, complex submission, and it should not be surprising that delays occur," Lilly said.

Given the much-ballyhooed size of that NDA package, perhaps it’s not surprising that it would take FDA extra (and then some more) time to read through it. (See "The REMS Pioneers: Amgen’s NPlate Sets Another New Standard," The IN VIVO Blog, September 24, 2008.) The absence of an advisory committee meeting for prasugrel is also a positive sign, given that drugs without one have a greater chance for a first cycle reviews.

Sanford Bernstein analyst Tim Anderson agrees that no news is good news: "Our best guess at this point is that while the Effient review is not yet complete, a final decision by FDA is not likely to require that Lilly/Daiichi-Sankyo generate new clinical data; the issue may be a smaller one like finessing the label, the risk management plan, etc."

We couldn’t agree more.

—Kate Rawson