Pediatric Exclusivity for Viagra?! It's No Joke

You can be forgiven for skipping yesterday's Cardiovascular and Renal Drugs Advisory Committee. After an incredible series of important committee topics (Avandia! Qnexa! Opioid REMS! Avastin! Brilinta!), a day long session focused on pediatric study endpoints for pulmonary arterial hypertension drugs doesn't exactly cry out for attention.

But it was a doozy. Not so much for what the committee decided...or maybe failed to decide. Heck, this was a mess of a meeting, and our colleagues did an amazing job to make sense of the outcome in "The Pink Sheet" DAILY.

No, this was a doozy of a meeting because it is laying the groundwork for what could be a very interesting regulatory decision by FDA: granting a six-month pediatric exclusivity extension for sildenafil, the active ingredient in Pfizer's PAH drug Revatio and another product you might have heard of called Viagra.

Yes, it is true: Pfizer is (we think) going to get a six month pediatric exclusivity extension for an erectile dysfunction product. In fact, we would go so far as to say after the meeting, by any fair interpretation of how the program works, Pfizer should get an extension.

Viagra? Viagra has no role in the pediatric population--except to increase the numbers of children in the US. (Badda Bing!)


Okay, okay: the pediatric extension won't be for Viagra; it will be for Revatio--a truly important therapy for the rare but debilitating condition of PAH. And all indications are that the Pfizer product does have an important role in treating the 500-600 children in the US who suffer from the disease. Pfizer has done extensive research on that population, despite significant challenges finding a viable endpoint given that no one wants to run long-term placebo controlled trials in this setting.


The pediatric exclusivity program was created in 2002 to encourage sponsors to conduct studies in children, by granting them an extra half-year of patent life/exclusivity for completing studies pursuant to a written request by FDA. Pediatric research, everyone agrees, is a very challenging and neglected field, and the law has clearly worked to encourage many more studies than would have occured without it. The Revatio program looks exactly what the law was supposed to deliver.

But the law (as implemented by FDA) is clear: the extension applies to the active ingredient, and so--if Pfizer gets a reward--the basic sildenafil patent will be extended from March 27, 2012 until September, 2012.


That is obviously a big deal for Pfizer. Revatio sales in the US were $300 million last year, so an extra six months is nothing to sneeze at. But Viagra is almost $1 billion, so that's where all the action is. (Badda Bing!, again.)

Now, Pfizer claims Viagra will be protected from generic competition until 2019, thanks to a use patent covering the ED claim. However, use patents tend not to hold up against generic challenges, and Pfizer is already facing a challenge from Teva. On the other hand, given the unusual circumstances of Viagra's development, the use patent on ED may be more robust than most.

Nevertheless, the patent extension will still matter. Obviously it delays the earliest possible date for a generic Viagra in the event Pfizer loses the case. In the more likely event that litigation is still pending, it will delay by six months the earliest possible date that Teva could consider an "at risk" generic launch. That in turn would affect the terms of any possible settlement of the litigation (assuming pending "pay for delay" legislation in Congress doesn't put the kibosh on settlements altogether.)

The extension will also put off the date on which Pfizer will have to wrestle with the possiblity that generic versions of Revatio will start eating into the Viagra market. Revatio is marketed as a 20 mg pill, while Viagra is available as 25, 50 and 100 mg pills. As brands, Revatio retails for slightly less per pill than Viagra ($15.60 vs. $17 on drugstore.com), but it certainly doesn't make economic sense to take two Revatios instead of one Viagra. If Revatio generics are widely available, those economics could change.

So, no matter how you look at it, Viagra will benefit from the pediatric exclusivity award.

Here's the thing: the pediatric exclusivity program has strong support, but it isn't without its critics. When the program came up for reauthorization in 2007, some members of Congress wondered why a sponsor might be given an extra six months of sales for a multi-billion brand in exchange for conducting a relatively small, inexpensive study in children.

It is fair to say those arguments will come up again in 2012--especially if FDA grants an extension to Viagra, every politician's favorite target for criticizing Big Pharma.

Look for more coverage of how the advisory committee wrestled with this issue in an upcoming issue of The RPM Report.

The Medicines Co: No Non-Sinister Deed Goes Unpunished

The Medicines Company’s years-long effort to alter federal patent rules to allow certain filings to be approved even if they are late is neither an example of corporate altruism nor of corporate greed. More specifically, it’s a rather logical response to an unfortunate series of events that began in 2001 when TMC’s attorneys filed a patent extension for intravenous blood thinner drug Angiomax one day late, and the application was rejected by the U.S. Patent & Trademark Office. (See this March 2007 article from IN VIVO for a fuller understanding of the events then and since.)

Enter the national media and the omnipresent front-page stories about health care reform and town hall meetings being disrupted with angry rhetoric, sometimes verging on violence.

Earlier this month, New York Times columnist Frank Rich and MSNBC talk host Rachel Maddow reached the same conclusion when connecting three undeniable facts. 1) Former House Majority Leader Richard Armey (R-TX) up until very recently worked for DC law firm DLA Piper. 2) Armey’s lobbying group Freedom Works has played a role in fomenting the angry dissent occurring at various members of Congress’ town hall meetings. 3) The Medicines Company has employed DLA Piper in the past to lobby for patent law changes that would enable Angiomax to receive an additional four and a half years of patent protection, and Armey at times played a role in those efforts.

Those facts led to the following tautology on the part of both Rich and Maddow: The Medicines Company is helping to finance opposition to federal health care reform. TMC even had the pleasure of seeing its corporate logo displayed on Maddow’s MSNBC program Aug. 6 as she described how these events might connect.

There’s just one problem. TMC, in fact, favors health care reform, at least partially because adding more people to the health insurance rolls would be good for its business. The connections Maddow and Rich alluded to may have seemed to make sense, but in the end, they didn’t add up.

Talking with IN VIVO Blog Aug. 19, TMC CEO Clive Meanwell noted that his company had never retained Armey’s services directly and never given a penny to Freedom Works. TMC continues to retain the services of DLA Piper, he added, which is a matter of public record. Armey recently left DLA Piper so that its work would not be confused with the efforts of Freedom Works.

“I wonder if the media have noticed that the Democrats are in control at the moment,” Meanwell asked, saying that Armey, once one of the two or three most powerful Republicans in the country, has played a de minimis role at most in recent efforts to win patent law changes. “We certainly intend to continue working with DLA Piper,” Meanwell added. TMC will continue to advocate “openly and enthusiastically” for patent law changes that would benefit Angiomax, he said.

Presumably, these efforts will not include dubious tactics such as shouting down Sen. Arlen Specter (D-PA) or hanging in effigy a cardboard cutout of Rep. Frank Kratovil (D-MD).

Our sister publication “The Pink Sheet” DAILY today begins a three-part interview with Meanwell that took place before the current controversy over health care reform erupted. It focuses on TMC’s efforts to protect Angiomax and to expand the drug’s label, as well as the specialty pharma’s other efforts to plan for a post-Angiomax future.

In talking with IVB, Meanwell noted that TMC really would prefer not to be part of the health care reform news cycle – to the extent that this post extends the life of this story, we offer it only in the hope of clarifying the company’s non-role in the heated rhetoric surrounding the health care reform debate.—Joseph Haas

image from flickr user katkreig used under a creative commons license.

GSK Option Deal With Concert Is Just Like Lots of Other GSK Option Deals, Only Heavier

a hydrogen isotope AND a Canadian death-metal band? you betcha.

It seemed a few weeks back when Concert Pharmaceuticals announced they'd been granted patents by the USPTO on deuterated versions of rimonabant and mosapride that one kind of validation could quickly lead to another.

As Derek Lowe has pointed out, the molecules crossed a major threshhold: if one could be patented, why not the rest? Today the other shoe dropped: GSK has entered the fray with another one of its many option-alliances, and Concert's technology has passed yet another test.

GSK paid the biotech $35 million up-front (which includes $16.7 million for equity priced consistent with the price of the shares sold in its $37 million 2008 Series C) in exchange for options on three Concert projects: CTP-518 (a deuterated version of BMS's atazanavir HIV protease inhibitor that is scheduled to enter Phase I this year), a preclinical compound in chronic kidney disease, and a third undetermined compound. Like most of GSK's option-deals, the Big Pharma can choose to opt into a program at clinical proof-of-concept (generally post Phase IIa but in the case of '518 post Phase I).

Concert will also create deuterated versions of three additional molecules for GSK, and hand those off after lead optimization. The deal's milestones total more than $1 billion and are heavily weighted to the three option candidates, says Concert's chief business officer Steve Bernitz. What's more the majority of the payments are for clinical and regulatory accomplishment, as opposed to sales-based payments. Concert will get a double digit royalty on compounds from its pipeline and an undisclosed royalty on deuterium-containing molecules from GSK's pipeline.

Replacing hydrogen atoms with deuterium atoms (hydrogen atoms saddled with a neutron) essentially creates new NCEs, getting Concert around existing composition-of-matter IP. But "it does not change the physical characteristics of a drug," president and CEO Roger Tung, PhD, told us today. After leaving Vertex where he led that company's drug discovery efforts (and co-invented the successful HIV PIs Lexiva and Agenerase) Tung co-founded Concert with Richard Aldrich and Christoph Westphal in 2006, and has largely kept things under wraps until recently (though we were sufficiently intrigued back then to include them in our inaugural A-List of that year's top Series A financings). "So we're retaining the way a drug interacts with receptors and the pharmacology of a drug, with respect to its positive effects and selectivity profile, is unchanged."

But, says Tung, deuterium forms stronger bonds with other atoms in comparison with hydrogen, because of its greater mass. And that increase in bond strength can change the rate of a drug's metabolism and the relative ratio of its metabolites, which in turn can affect the safety and tolerability and even efficacy of certain drugs, he says.

All this remains to be seen in the clinic, but if it works out, Concert's deuteration approach (also embraced by biotechs like Auspex and Protia) seems to be the ultimate in life-cycle management. In an interview both Tung and Bernitz kept returning to the low-risk nature of the company's approach. "Generally we've been able to move from concept to the clinic in about two years," says Bernitz. And Concert doesn't take on "the risk of new biology" that many pharmaceutical companies are now embracing. "That lower risk-approach to drug discovery and development is recognized in this deal," given the substantial terms Concert has garnered for its preclinical programs, he says.

It seems logical that Concert's window for patenting deuterated versions of existing molecules is finite, perhaps now even closed since industry should be wise to deuterated drugs by now, though Tung doesn't see it that way. "Industry will take this up in the coming years, but we believe we have the poll position now and are the leaders in the use of deuterium."

And beyond deuterated versions of marketed drugs there are "tens of thousands" of compounds available that showed promise but for one reason or another did not become marketed therapies, he says. "I think we're going to be very busy for quite some time."

And so for now, what about Bristol-Myers? The company's Reyataz (atazanavir) remains on-patent and according to Tung will likely still be on-patent by the time '518 should be hitting the market. Though Tung says Concert talked to BMS prior to the GSK deal it's unclear whether BMS was in the running for the compound. For Concert, finding a partner with strength in HIV was important.

A bonus? "The deal validates that [the originator] isn't the only company we can work with" when dealing deuterated compounds, says Bernitz.

RNAi IP: Glover Goes Down

"Man I'm gettin' too old for this sh!t."

Alnylam's "Glover" patent has been overturned in Europe. Alnylam has their say here, Silence Therapeutics' slant is here.

We've often noted that with no RNAi therapies on the market and companies effectively operating under the research exemption granted via the 2005 Merck v Integra Supreme Court decision that it's difficult to weigh in on RNAi IP (we do however acknowledge that a good proxy for determining the eventual IP winner is watching where deal dollars wind up, and by that measure Alnylam is lightyears ahead).

So do we know what the European Patent Office decision means in the long run? No. Does it give us an opportunity to entertain you on a sunny summer Friday with Lethal Weapon references? Yes.

Who Needs VCs?

Apparently not Neurimmune Therapeutics, a University of Zurich spin out that began operations in April this year. This antibody-focused start up plans to go direct from seed- to deal-funding, according to CEO Ed Stuart, skipping the VCs entirely. “It’s a new business model,” says Stuart, former managing director and CBO at Munich biotech firm U3 Pharma.

So far, so good. The company started out with $5 million of seed money, most of which came from chairman and lead investor Karsten Henco, a former CEO of Evotec and founder of various other biotechs including Qiagen. Yesterday it upped the ante somewhat, and signed a deal with Biogen Idec that could be worth up to $390 million.

Ok, so we’re skeptical about biodollars. But Stuart assured the IN VIVO Blog that it “wasn’t all post-approval milestones,” and that there was a good chunk of up front money too. Those funds, along with the seed finance, “will fund the company for a number of years,” he said.

For now, Neurimmune’s only got about 10 employees, so it’s not a big burn. But this is nevertheless a rich and validating deal for the young firm that’s hardly out of the blocks. So what’s it doing? Something rather simple, actually. It seeks out antibodies among healthy individuals and uses a range of assays and other selection techniques to identify those that might be useful in fighting certain diseases—particularly CNS diseases.

So in the Biogen deal, Neurimmune will identify antibodies that bind to amyloid beta, thought to be the main culprit behind the neuro-degeneration and loss of cognitive function among Alzheimer’s patients. “We have already found a number of antibodies among healthy patients that recognize amyloid-beta,” explains Stuart. And since Biogen now has access to that entire program, it will receive several amyloid-beta-relevant antibodies over the next couple of years that it will go on to develop and commercialize.

Neurimmune calls its platform Reverse Translational Medicine, since “we’re starting not with disease, but with healthy people,” explains Stuart. It’s a logical approach—if someone at risk doesn’t have Alzheimer’s, what’s protecting them? Importantly, it also skirts the IP roadblocks that prevent many new antibody companies from using conventional techniques such as phage display or transgenic mice to create antibodies against certain well-validated targets. “We don’t face the normal IP issues,” notes Stuart, “since we’re not tampering with antibodies in any way at all. We’re getting out of people something that has already been optimized—by Nature.”

Mother Nature’s never that simple. It’s likely that several antibodies are required to protect people against certain diseases, and this range probably varies among different sets of individuals. As with many small molecule drugs, several moieties might be required to interact with several receptors. “It’s too early to tell,” says Stuart. And if Neurimmune's scientists aren't tampering with antibodies, just finding them, what’s to stop others doing the same? It’s all in the selection assays and the clinically-relevant questions asked of those individuals supplying the antibodies, says Stuart.

Anyway, Biogen Idec is apparently sufficiently convinced to have signed what is, in Henco’s words, “among the largest pre-clinical deals,”—and to have done so while much of its management’s attention is on selling the company. So does Neurimmune have a robust change-of-control clause in place? “We’re smart people,” said Stuart.

Maybe that’s why they’re avoiding VCs, too.