Why Merck’s Problems are Also Your Problem

Will Vioxx never go away?

It has been four years since Merck withdrew the COX-2 inhibitor. It is a full year since Congress enacted legislation intended to “fix” the drug safety problems highlighted by Vioxx.

But Vioxx is still in the news. Now, the focus is on how the product was marketed. Academic journals, mining product liability dockets, are highlighting instances of “ghost writing” and “seeding studies” involving the product. The media gleefully piles on.

If you don’t work for Merck, you may be tempted to think none of this much matters. (Except perhaps as an occasion for schadenfreude, if the unrestrained glee of these posts is any indication.)

We’ve written before about the far reaching impact of a damaged reputation, and specifically about the implications of the blemishes on Merck’s once-stellar image as the drug company that does things the “right way.”

But Merck’s problems are not just Merck’s problems. The damage to Merck’s reputation is the whole industry’s problem.

Here’s why: Just as Vioxx was the short-hand explanation for a whole host of drug safety changes—most of which, both Merck and its harshest critics agree—had nothing whatsoever to do with the drug, now it is a short-hand for everything that people object to about industry marketing practices.

And Vioxx’ potency as a weapon against the whole industry is all the greater because it was sold by Merck.

One example came during the Food & Drug Law Institute advertising & promotion conference September 8, when Ann Witt, a former FDA ad division head who is now an advisor to Congressman Henry Waxman, discussed Waxman's opposition to a proposed guidance that would allow companies to disseminate peer-reviewed journal articles on off-label uses:

"There are many many examples, and unfortunately there are more coming to light every day, of company-manipulated data that ends up in peer reviewed reports. I’m sure we’ve all followed the somewhat distressing trail of evidence that is coming out about how Vioxx was promoted. There have now been at least four or five separate articles on the different methods that Merck used to manipulate study results."

"I--who have spent probably 20 years following drug advertising and thought I was pretty cynical about it--I found the stories about Merck personally extremely depressing. I would imagine many of you do. "

"I, like many people at FDA, always thought of Merck as sort of the gold standard in the industry, and to find that this kind of really irresponsible marketing and distortion of the scientific record was so pervasive there is truly troubling."

"I would hope that it would lead all of us to question whether substituting peer review, for FDA review and approval, is really a good way for doctors to learn about new uses of drugs."

In other words, if Merck does it, then everybody must do it.

And consider the context: Witt is citing allegations against Merck to block a guidance on off-label journal reprint distribution. That is an issue that is of far less significance to Merck than to dozens of other companies with more prominent positions in oncology, pain or other markets where off-label uses are essentially standard practice.

That is how it works. Companies that never marketed a COX-2 inhibitor have to live with mandatory post-marketing studies and Risk Evaluation & Mitigation Strategies. They may also have to live with a whole host of new marketing restrictions—whether enacted by Congress or simply created by more aggressive enforcement at FDA.

FDA's Real Risk Communication Challenge

FDA is the first to admit that it hasn’t quite figured out the best way to communicate drug risks to patients—especially how to convey emerging risk information without scaring patients away from a helpful or life-saving treatment.

But it is also clear that FDA hasn’t quite figured out how to communicate within the agency on communicating risk to patients, either.

On Friday, FDA announced a major new policy on risk communication under which it will begin alerting the public to potential safety problems with a drug or biologic at the very beginning of the post-marketing drug safety process. (Check here for our earlier take on that initiative.)

On Monday, FDA’s senior advisor on risk communication in the Office of the Commissioner, Nancy Ostrove, spoke at the Food & Drug Law Institute’s annual meeting on advertising and promotion.

Given that the title of Ostrove’s speech was “FDA’s Initiatives in Communicating Risk Information,” it appeared to be the perfect venue for discussing the new program—so much so that one might have wondered whether the agency timed the announcement to coincide with Ostrove’s FDLI presentation.

Apparently not.

After avoiding mention of the program in her opening remarks, Ostrove gave the following disclaimer before the question and answer session: “I can tell you one thing I am not going to talk about…the press release that went out on Friday concerning the FDAAA provisions on quarterly reports. I didn’t even get it until today. So I can’t talk about it.”

Given the pains that FDA took in announcing the decision—a rare embargoed media call ahead of the official announcement with Office of Drug Safety director Gerald Dal Pan and Safety Policy & Communication associate director Paul Seligman—it was surprising that Ostrove wasn’t on the call herself, or, at the very least, aware that it had taken place.

There may be good reasons for Ostrove not to have been in on that decision. But given FDA’s recent focus on risk communication (check out our coverage in The RPM Report here and here), we can’t help but wonder whether the real communication on risk needs to first take place at FDA.

image from flickr user rubatacchini used under a creative commons license

Parallel Pharma Universe First Side Effect of CERN Collider

Well, the Large Hadron Collider powered up underneath the border of France and Switzerland today. No black holes yet, folks. But we may have entered a parallel universe.

At about the same time the first particle beam zipped through the 27km circular tunnel, French Big Pharma Sanofi-Aventis confirmed the Reuters reports from yesterday, announcing it had indeed hired ex-GSK exec Chris Viehbacher to replace Gerard Le Fur as CEO. The company's release stated rather simply: "the evolution of the worldwide pharmaceutical sector requires the key players to acutely redefine their strategy." No arguments here.

To be fair, since the French company's takeover of Aventis in 2004 Sanofi has lost a modicum of its Francocentrism. But the idea that an outsider, much less a non-Frenchman (and yes, we're aware of his french cred, but still), would become CEO of the French giant seemed a bit far fetched . At least until they turned on the LHC.

Coincidentally, Sanofi's share boost on the news created nearly enough market cap to pay for the CHF 10 billion particle accelerator.

Celgene and FDA’s New Drug Safety List

It’s over for Celgene. That’s it. Revlimid’s done. Investors should evacuate the premises immediately.

After all, a vital cog in Celgene’s cancer portfolio is on FDA’s first quarterly drug safety posting.

Sound too alarmist? Maybe a little extreme? Of course it is. But that’s how a good number of investors reacted to the posting.

Celgene lost about 3% of its value in the two days following the announcement. Not terrible. But if you look at trading the day of the announcement, volume more than tripled and the stock dropped 6% of its value in midday trading with a low of $63.00 per share before edging back up.

We’ve seen that investors and drug companies are finding it challenging to communicate and interpret risk, respectively. To read our take, click here.

FDA threw a new twist into the risk communication equation last week. In response to a specific provision in the FDA Amendments Act, the agency will be posting a list of drugs every three months that officials deem worthy of further risk evaluation following voluntary adverse event reports from patients and health providers. So for all of the FDA critics out there, this is something the agency had to do.

In a September 5 press release announcing the initiative, FDA tried to be as unalarmist as possible. “My message to patients is this: Don’t stop taking your medicine. If your doctor has prescribed a drug that appears on this list, you should continue taking it unless your doctor advises you differently,” said Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research.

The agency was very explicit about what a drug showing up on the list actually means for that drug:

“The appearance of a drug on this list does not mean that FDA has concluded that the drug has the listed risk, or that FDA has identified a causal relationship between the drug and the listed risk. It is on the list only because FDA has identified a potential safety issue.”

In a media briefing prior to the official announcement, Office of Surveillance and Epidemiology director Gerald Dal Pan explained that a listing on quarterly report means FDA has begun an analysis of whether the drug needs further evaluation such as further information, clinical trials, epidemiologic study, need to conduct an epidemiologic study, and possibly the need to conduct a clinical study.

CDER associate director for Safety Policy and Communication Paul Seligman said two things have to happen to get on the quarterly list: first, a provider submits an AER report to FDA’s voluntary AERS reporting system. Second, our FDA staff have judged that further follow up or review is warranted.

Seligman highlighted that the work FDA is doing to support the quarterly list isn’t anything new. “This is work we’ve been doing for decades.” What’s new is, he says, FDA is telling the public what it’s working on in postmarket surveillance at the “earliest stage.”

FDA’s new initiative is not without some irony. The first quarterly report, which is supposed to represent FDA’s work at the “earliest stage” is for January 2008-March 2008, not the just passed April 2008-June 2008 quarter. That is understandable since FDA has a seemingly limitless number of FDAAA provisions to implement and a very limited number of resources to get it done. We’re just pointing it out. There were similar issues with FDA’s “early communication” initiative, which appeared to be anything but early. To read more, click here (also one of our favorite blogs and blog pictures.)

Here’s the first list of 20 drugs on the quarterly post:

Potential Signals of Serious Risks/New Safety Information Identified by the Adverse Event Reporting System (AERS) January - March 2008

Product Name: Active Ingredient (Trade) or Product Class	Potential Signal of Serious Risk/New Safety Information
Arginine Hydrochloride Injection (R-Gene 10)	Pediatric overdose due to labeling / packaging confusion
Desflurane (Suprane)	Cardiac arrest
Duloxetine (Cymbalta)	Urinary retention
Etravirine (Intelence)	Hemarthrosis
Fluorouracil Cream (Carac) and Ketoconazole Cream (Kuric)	Adverse events due to name confusion
Heparin	Anaphylactic-type reactions
Icodextrin (Extraneal)	Hypoglycemia
Insulin U-500 (Humulin R)	Dosing confusion
Ivermectin (Stromectol) and Warfarin	Drug interaction
Lapatinib (Tykerb)	Hepatotoxicity
Lenalidomide (Revlimid)	Stevens Johnson Syndrome
Natalizumab (Tysabri)	Skin melanomas
Nitroglycerin (Nitrostat)	Overdose due to labeling confusion
Octreotide Acetate Depot (Sandostatin LAR)	Ileus
Oxycodone Hydrochloride Controlled-Release (Oxycontin)	Drug misuse, abuse and overdose
Perflutren Lipid Microsphere (Definity)	Cardiopulmonary reactions
Phenytoin Injection (Dilantin)	Purple Glove Syndrome
Quetiapine (Seroquel)	Overdose due to sample pack labeling confusion
Telbivudine (Tyzeka)	Peripheral neuropathy
Tumor Necrosis Factor (TNF) Blockers	Cancers in children and young adults

That’s it. That’s all you get. No numbers of reports and no nature of the seriousness of the adverse events reported.

So back to Revlimid. The drug was associated with reports of the serious skin rash Stevens Johnson Syndrome. As you may recall, SJS was the reason the COX-2 inhibitor Bextra was taken off the market.

We’re not doctors (we don't even play them on TV), but two observations which should quell any investor jitters based on the very little we know so far.

First, if you’re taking Revlimid, a drug used for MDS and multiple myeloma, the potential for SJS is likely the least of your concerns. Second, Revlimid carries one of the most comprehensive, thorough risk management plans (RevAssist) of any drug on the market managed by a company that revolutionized the efficacy of risk management plans for thalidomide, arguably the most dangerous drug ever marketed. If there are more cases, FDA can rest assured RevAssist will catch them.

So what do you think? Is this quarterly list a good idea or a bad one? Are we getting in too deep and too early when it comes to FDA’s postmarket responsibilities? Per usual, we’d love to hear your take.

While You Were Watching Football

You didn't miss anything this weekend. Really, nothing happened, we looked. Oh, but the Eagles destroyed the St. Louis Rams 38-3 and the Phils took the weekend set against the Mets at Shea two games to one. But to dig up anything interesting in the biopharma universe, we had to wait til this morning. So here you go ... while you were driving to work:

• BMS and AstraZeneca released positive data from a study of their DPP-4 inhibitor saxagliptin (Onglyza) at the European Association for the Study of Diabetes meeting in Rome this morning. The companies said that the drug, which was submitted to FDA over the summer, "produced significant reductions across all key measures of glucose control studied."
• Also at EADS, Novo Nordisk said that its liraglutide human GLP-1 analog plus metformin and rosiglitazone led to improved blood glucose lowering, weight loss, blood pressure reduction and improvement in beta cell functioning. For more news out of this diabetes meeting, click here.
  
• Velcade was approved in the EU for combination with melphalan and prednisone for the treatment of patients with previously untreated multiple myeloma (MM) who are not eligible for high-dose chemotherapy with bone marrow transplant.
• Finally, a mini Press Release of (Last) Week: for the PR rep who is sending us pitches to cover the release of "Don't Mess With the Zohan" on DVD, this is for you.

photo of Lincoln Financial field, scene of yesterday's carnage, by flickr user MattP33, used under a creative commons license.

Whoa Nelly: FDA Puts the Brakes on Liraglutide

When FDA knows six months ahead of a user fee deadline that it won’t be able to make an on-time approval decision, it’s not exactly a positive sign of a drug’s future prospects.

But that is exactly what Novo-Nordisk is facing with its once-daily human GLP-1 analogue liraglutide—the company’s much anticipated type 2 diabetes therapy.

FDA isn’t scheduled to make a decision on the approvability of liraglutide until March 23 at the earliest. But despite being six months away from the user fee deadline, the agency has already warned the company not to expect an on-time approval.

The delay, Novo says, will allow time for FDA to absorb feedback from an advisory committee review of liraglutide, which has been scheduled for March 2. The agency told Novo that it doesn’t believe the three weeks between the meeting and the user fee deadline will be enough time to complete the review.

“Since the advisory committee meeting is held shortly before...[the user fee] date, the agency has indicated that it will most likely have to extend the date of completing their assessment by a couple of months,” Novo said in a press release.

While FDA has certainly been able to deliver approvability decisions within three weeks of an advisory committee meeting in the past, there are two reasons why it is different this time around for liraglutide.

First, the agency is simply missing more user fee deadlines—something that we’ve been tracking and writing about in The RPM Report. While FDA is allowed to miss approval deadlines under the Prescription Drug Fee User Act, drug reviewers were given a green light to start missing more than usual earlier this year.

Based on some pretty small numbers, we've found that the longer a drug sits at FDA, the less of a chance of a positive decision. So if the agency is indeed just a "couple of months" late on liraglutide, that seems to bode well for the drug's approvability prospects. That is, of course, barring any other unforeseen (or seen) circumstances.

Which brings us to our second point. FDA is obviously taking it a bit slow on liraglutide given the pancreatitis safety signal seen with another GLP-1: Amylin’s exenatide (Byetta). Novo’s challenge at what will surely be a closely watched advisory committee meeting will be to make a convincing case that its product does not carry the same signal as Byetta.

As the Diabetic Investor points out, we’ve already seen this play out in the diabetes market over the cardiovascular safety issues with GlaxoSmithKline’s rosiglitazone (Avandia). As Avandia was imploding, Lilly/Takeda were asked to defend the safety profile of their thiazolidinedione drug product, pioglitazone (Actos). And in that case, they succeeded.

DotW: Specifics a Surprise; Trends -- Not a Surprise

Your blogger this week did not expect that John McCain would select a nationally obscure, half-term governor of Alaska as his running mate. What wasn’t a surprise was the selection of a pro-life evangelical to shore up the Republican base.

Which leads to our theme in this edition of Deals of the Week. Specifics a surprise. But basic trends: not a surprise.

Take for example the announcement from Zymogenetics and Merck Serono that the two companies were restructuring their deal on the fusion protein atacicept so that Zymo could save up to $260 million in co-development and –commercialization contributions through 2012. (See our Pink Sheet Daily coverage here). Fact is deals which could get biotechs bigger downstream profits also cost them a lot more upfront – and with biotech funding scarce, those obligations are looking pretty scary these days. And particularly scary for Zymo, which was hoping to pay its share mostly out of proceeds from its marketed drug Recothrom. But the recombinant thrombin product hasn’t become the blockbuster Zymo hoped it would be – sales are actually down from the last quarter. In effect, Zymo is now opting to share a lot more of the risk – risk which, following the commercial challenges of Recothrom, looks a lot hairier than it did in 2001, when Recothrom was a great idea about to be a great reality and atacicept the next engine to turbocharge Zymo’s journey to the biotech valuation stratosphere.

And so, on to our surprising but unsurprising...


Medivation/Pfizer: Luckily, little risk sellers have big-company risky buyers to help them out. The late-stage products in other companies’ pipelines look like the only bridges available over the vertiginous patent chasm most Big Pharmas must cross in the next few years -- however shaky those bridges may be. Were it not competing with plenty of other bidders, Pfizer wouldn’t have agreed to pay $225 million upfront, $500 million in development milestones, 60% of the development and commercial costs in order to get 60% of the profits from Medivation’s Alzheimer’s disease drug dimebon (for more of our analysis, see this post). But even Big Pharmas are increasingly unwilling to make these bets on their own. Lilly has taken on financing from TPG-Axon to help it fund Phase III trials of its two late-stage Alzheimer’s drugs. (For a brief idea of what Lilly’s doing, take a look at this posting; for a more significant analysis, see the September issue of IN VIVO – out next week). The economics of the Medivation deal aren’t all that dissimilar from the deal Bristol-Myers Squibb signed last year with Pfizer on apixaban, in which it off-loaded a bunch of the risk that drug might not work out very well. And as we noted last week, that wasn’t a bad move: the drug underperformed Lovenox in its knee-replacement trial and now has lots of people scared that it won’t work in its larger indications, particularly acute coronary syndrome and stroke prevention. Less noted – another big-bet Phase III deal looks smart for the licenser, less so for the licensee: the mid-sized Spanish firm Almirall collected $60 million from Forest Labs plus big help in funding trials, which last week underperformed their sponsors’ and investors’ expectations, with Forest stock dropping 17%.

Shionogi/Sciele: It’s likewise unsurprising, though again the specifics continue to astonish, to see Japanese companies continuing to snap up US properties. We’ve got to believe Shionogi is, years later, still smarting over its decision to out-license Crestor to AstraZeneca. Had it been a bit more self-confident, it could have done what Takeda did with Actos, co-commercializing the drug with a US partner (Lilly, in that case) and then taking the thing over when it could stand on its own two feet. Now Shionogi is paying $1.4 billion, a 37% premium over the pre-announcement 10-day average price (but only an 8% premium to what the company had been trading at last October), to take over spec pharma Sciele Pharma which – probably for all sorts of good reasons – has nonetheless seen declining operating income and prescription volumes in key products. (Check out our PharmAsia News report on the deal.) A comparatively strong yen and a constricting home market are making the US look real good to Japanese companies – which is why you’ve seen them willing to pay up big time for Millennium (Takeda), MGI Pharma and Morphotek (Eisai), and Agensys (Astellas).

Novacea/Transcept: When a company’s major drug fails, and it has plenty of cash left, it’s got basically two choices: distribute the money to shareholders (rarely done) or roll the dice on someone else’s pipeline – usually through reverse mergers (the popular choice). Indeed, since January 2005, we’ve seen 29 such deals announced (not all closed), with privately held Transcept’s reverse-merging into publicly traded Novacea the most recent. Since November of 2007, when it stopped its pivotal trial of its anti-cancer drug Asentar because more people were dying on the drug than in the control arm, the writing was on the wall for the company. With something like $90 million in cash and marketable securities as of its last 10Q, Novacea was more valuable as a bank and a listing than as a company. And although these deals are hardly picnics, they seem a lot easier than going public (two IPOs in the US this year vs. two dozen in 2007). Whether that’s the right thing for investors is another question: analysis from our colleague Chris Morrison shows that the average share price decline for reverse-merged companies was about 40%, worse even than the declines from IPOs or the biotech index in general (we’ll publish a more in-depth analysis in next month’s Start-Up).

Ablynx/Merck-Serono: Apologies for spoiling the theme, but it wasn't all surprises this week. Merck-Serono has been relatively straightforward in its ambitions to assemble rights to a handful of next-generation large molecule technologies around chosen targets (or so said M-S EVP research Dr Bernhard Kirschbaum when we spoke to him for a story about one of their current partners, Archemix, a few months ago). And so its deal with Ablynx announced Thursday fits right in. The two-target deal will see M-S and Ablynx co-discovering and co-developing Ablynx Nanobody-based therapies in the areas of oncology and immunology. Ablynx receives €10 million up-front and the companies will split all costs and profits 50/50. Unless! Unless Ablynx decides to fully opt out (in which case it will receive milestones and a royalty) or partially opt out (in which case it will receive a reduced profit share). Ablynx CBO Eva-Lotta Allan told us today that this was the biotech's first 50/50 deal, a result of being in a solid financial position thanks to last year's healthy IPO proceeds of €85.2 million. --CM

Acucela/Otsuka: On Thursday, Japanese pharma Otsuka and ophthalmology-focused biotech Acucela announced twin licensing deals. In Part One, Otsuka will pay Acucela $5 million upfront plus milestones for co-development rights to Acucela's Phase I dry AMD small molecule compound ACU-4429. The companies will share commercialization expenses and profits 50/50 in North America, Acucela retains all European rights, and Otsuka gets Asia and some rest-of-world territories. The pharma also funds all pre-Phase III development costs. Part Two sees Acucela getting co-dev/co-promo rights to Otsuka's Phase III rebamipide suspension for dry eye in the US. Otsuka will again pay Acucela an (undisclosed) upfront and milestones, plus royalties on sales, and Acucela will take the lead in getting the drug approved. Under certain circumstances, Acucela could co-promote rebamipide as well, but Otsuka will cover all development and commercialization costs. If you are having deja vu, that might be because Otsuka has licensed this drug before (though the first time it probably took money in instead of paying it out). In 2005 Novartis took on worldwide rights to rebamipide (which was in Phase III back then as well), but at some point between now and then killed the project. In a conversation with IN VIVO Blog, Acucela CEO Ryo Kubota, MD, PhD, wouldn't let on what hindered the drug, saying only that the partners hope to run another Phase III and that the drug could be developed "relatively quickly." Acucela was founded in 2002 but only came out of stealth mode earlier this year. The biotech is developing so-called visual cycle modulators and has raised more than $40 million in three rounds of venture funding from Japanese investor SBI Investment Co. Ltd.--CM

Viagra and Mad Men: A Match Made in Heaven...

Forget "wild man." Viagra may have found the perfect marketing tie-in, at least on our local cable provider in DC: as the sponsor of "On Demand" replays of AMC's Mad Men.

If you are not a fan, Mad Men is a show about an advertising firm circa 1960 (Ad men+ Madison Avenue=Mad Men). It revels in depicting the corporate culture of that era: three-martini lunches, chain smoking executives, and sexual harassment as office sport.

What better vehicle to promote the quintessential product of the direct-to-consumer advertising era than a program about the invention of Madison Avenue itself?

The placement of Viagra on the season two premier was even more perfect. The episode in question, entitled "For Those Who Think Young," is set on Valentine's Day. And the ad break came after a pivotal scene. Here is how the episode summary describes the action:

Upstairs in their hotel room, Betty emerges from the bathroom, in heels, stockings, and a bustier. "Wow," says Don (pictured above), although later he can't pull the trigger in the midst of lovemaking. "I wish you'd just tell me what to do," Betty says afterwards. They order room service and watch Jackie Kennedy’s televised White House tour.

Cue "Viva Viagra."

There is one other reason why this sponsorship may be perfect. Mad Men's entertainment relies on the almost over-the-top behavior of its ad men--but it also makes unflinchingly clear that the world was most definitely not a better place in those "good old days."

We can't help but think that one day industry may look back on broadcast TV ads in the same light. It seemed fun at the time, but was it really the right way to do things?

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.

While You Were Saying Goodbye to Summer

going, going, gone.

Outta here like a Ryan Howard shot to deep right field, vanished like Keyser Soze, Summer 2008 is now just a memory. Hey, at least football season has begun, right? Below, our roundup of what you might have missed while enjoying that last BBQ of the season.

• European Society of Cardiology: News came thick and fast out of this annual meeting in Munich. The results of a potentially important study of stents vs scalpels in treating clogged arteries are in, and surgery has come out on top. Lilly and Daiichi's prasugrel got a boost in diabetics prior to its 26th September FDA deadline. An analysis of the previously released Triton-Timi 38 trial showed that prasugrel was more effective than standard-of-care clopidogrel (Plavix) in that patient population, reports Reuters. Pronova/GSK's Omacor (fish oil) met both primary endpoints in a Phase III outcomes study in patients with heart failure, who were 9% less likely to die than patients given placebo. AZ's Crestor didn't fare as well in a similar population. Finally, Bayer said it would speed up development of rivaroxaban--putting a little extra pressure on Pfizer/BMS, whose rival candidate apixaban hit a snag last week, as we wrote about here. For more news out of the meeting, click here.
• Shionogi & Co. is the latest in a pretty long line of Japanese pharmaceutical companies buying up cheaper American firms to help expand into western markets. Shionogi bought Sciele Pharma for $1.1 billion ($31/share, a 61% premium to the stock's previous close) plus the assumption of $325 million in debt, the companies announced on Monday. Atlanta-based Sciele had revenues of more than $382 million in 2007, and specializes in women's health, cardiovascular disease, diabetes, and pediatrics. For more on Japanese Pharma appetites, see here, and look for a feature on these trends in an autumn issue of IN VIVO.
  
• Oncology expert Prof. Karol Sikora of CancerPartnersUK diagnoses the ills of the country's NHS and writes this prescription in The Sunday Times: "Radical structural change to the NHS is vital. Competition and choice drive up quality and access, so leading to greater value, just as we’ve seen in other consumer areas such as mobile phones, budget airlines and the high street. Sensible incentives linked to performance and outcomes are essential. Drastic reform, not more money, is now needed."
• Novacea, which begun a strategic review in May after Schering-Plough canceled an alliance around its entered an agreement to merge with Trancept Pharmaceuticals (nee TransOral Pharmaceuticals, click here for our admittedly old 2003 profile of the firm). The latter company, a privately-held specialty pharma that specializes in tweaking the pharmacokinetics of CNS compounds, has raised more than $70 million in venture funding but--surprise, surprise--has been unable in this climate to tap the public markets. If investors buy into this reverse merger, TransCept backers will hold 60% of the combined company, which, the companies say, will have enough cash to pursue FDA approval for and launch its Intermezzo lozenge formulation of the insomnia drug zolpidem (the now-generic Ambien).
• Lipitor ads are back after six months off the air, but you mean nasty bloggers won't have Dr Jarvik to kick around any more! According to the WSJ, Jarvik's out and heart attack survivor John Erlendson is in. What are the odds that he's a rower?
• In the latest installment of its A1 "The Evidence Gap" series, The New York Times asks why more than three million people still take Vytorin/Zetia every day, and notes that some prominent cardiologists are now calling for it to be taken off the market.
  
• The Guardian adds up the challenges facing Big Pharma and, well, that's pretty much it. Would have been nice to see some answers in there too.
  
• Speaking of The Guardian, Ben Goldacre's Bad Science (the book) is on shelves now (at least in the UK). Go on, buy one. And if you haven't already, click the link to his web site in our blogroll to the right to get a preview.