XenoPort Experiences Restless Investor Syndrome

File this one under Regulatory Setback Syndrome. The FDA decision to issue a complete response letter to XenoPort and GlaxoSmithKline for their Horizant drug to treat Restless Leg Syndrome appears to have stunned the drugmakers. In a conference call this morning with analysts, XenoPort chief executive Ron Barrett confessed he didn't see it coming until the FDA missive arrived yesterday.

"It certainly did surprise us," he told the listeners, insisting the issue was never raised in any discussions with the agency during the entire pre-approval processs. "Many of the activities that you would expect to happen going into a PDUFA date had and were happening, including the REMS, and this one came out of left field."

What went wrong? The FDA bounced the drug because a trial showed a cancer risk in rats, specifically a prevalence of pancreatic acinar cell tumors in male rats. Interestingly, a similar finding showed up in Pfizer's Neurontin (gabapentin), which is approved to treat refractory epilepsy, and Barrett said the strength of the signal was no worse than what was seen with the Pfizer drug.

The FDA acknowledged that findings in lab animals don't necessarily translate into risk in humans, Barrett continued, adding that the agency "noted that gabapentin products have been available for over 15 years, and they do not appear to be associated with a clinical signal for pancreatic cancer based on analysis of spontaneous reports in the adverse event reporting system."

The issue for the FDA, though, is that treating epilepsy is a more serious matter than Restless Leg Syndrome, a line of thinking that may bolster those who have criticized the marketing surrounding the condition, even though it is deemed to be kosher by the National Institute of Neurological Disorders and Stroke (take a look).

For now, the implications for XenoPort are more immediate and severe than any marketing debate. Glaxo already announced plans to exit research into pain, and Barrett concedes their deal for the drug may be up in the air, possibly threatening further development of Horizant to treat neurothropic pain, where a Phase II trial failed last year, and migraines. Barrett, however, refused to offer any definitive insights on this particular topic. "The question of risk-benefit is something that is going to have to be probed for each indication."

In response to a question about Glaxo's ability to end the deal based on development setbacks, Bennett offered this sobering reply: "I think it's fair to say that any license agreement of this type is going to have termination provisions. And without speaking to language that might be redacted, I think it is reasonable to expect that this agreement is no different than that GSK would have the ability to terminate for reasons that include what you have articulated, among others. So I think people should understand that a termination by GSK is possible in the wake of this news, as well as in the wake of other developments."

Consequently, XenoPort is now suffering from Restless Investor Syndrome - its shares are down a whopping 67% in midday trading to about $6.54 on nearly 10 times normal trading volume. Given these events, Bennett has to be sorry Horizant isn't already available to treat migraines.

arrow thx to austinsdkeys on Flickr Creative Commons

Deals of the Week: Holiday Shopping

Having trouble this holiday season deciding what to get for the Big Biotech CEO in Your Life Who Has Everything? Join the bidding for Facet Biotech! The reserve may be quite high--higher than $17.50 per share, anyway--and it's not technically an auction (because Facet isn't necessarily going to sell, which would be sure to garner it some negative feedback on eBay). But is money really a problem when it comes to that special someone?

And don't worry about losing any of Facet's drug candidates if you're the winning bidder. "The Pink Sheet" DAILY noted this morning that while Facet's top compounds are tied up in partnerships, including Biogen Idec's co-ownership of its most advanced drug, daclizumab for rheumatoid arthritis, none of the agreements will be affected by a change-of-control.

"In each of our three collaborations, the non-acquired entity would not have a right to terminate the collaboration," Facet CEO Faheem Hasnain told "The Pink Sheet" DAILY. "In fact, the acquiring entity would step right into Facet's shoes."

Whatever you do, though, just don't materially undervalue those shoes while overstating their liabilities. That approach has gotten Biogen Idec nowhere. Respect the shoes!

Meanwhile the rest of you biopharma dealmakers have had a busy week (makin' AND breakin' deals), so we oughta get to it. The following companies won't be trawling the malls on Christmas Eve, they're ...



GSK/Intercell: Not even Santa Claus himself could earn this much for delivery. This morning Austrian vaccines company Intercell said it licensed to GSK its patch vaccine delivery technology in a deal worth €33.6 million ($49.4 million) in up front cash. GSK also agreed to purchase up to €84 million worth of Intercell shares in a "staggered shareholding purchase option" that could reach a 5% holding in the biotech (€28 million u/f for 0.9mm shares at an 18% premium, other investments milestone-based). The development and commercialization deal will include Intercell's Phase III travelers' diarrhea vaccine, a Phase II pandemic flu vaccine, and future patch vaccines. Intercell will be eligible for a slew of milestone payments and profit sharing on the projects already in development, as well as milestones and royalties for future products that include its patch technology. GSK is now Intercell's second strategic investor--Novartis owns about 16% of the company through a 2006 deal for a Japanese encephalitis vaccine and a monster 2007 deal for the biotech's vaccines for bacterial infections. Intercell has a variety of other partners, including Merck, Sanofi-Pasteur, and Kyowa Hakko Kirin. For more on Intercell and the market for adult vaccines, check out this recent IN VIVO feature.--CM

Novo Nordisk/ZymoGenetics: This is Novo/Zymo IL-21, the Sequel. In a second deal around the IL-21 cytokine, these two companies' long, entwined history continued this week when Novo Nordisk licensed from ZymoGenetics a preclinical anti-IL21 antibody for auto-immune and inflammatory diseases. The terms look good for Zymo: $24 million up-front, reflecting the value of IP around the target that was included in the deal. As Novo EVP and CSO Mads Krogsgaard Thomsen told "The Pink Sheet" DAILY: "we're buying all IP surrounding [the blocking of] IL-21 as a concept, and its utility in different disease areas." That move should provide the Danish firm with "a good degree of exclusivity on this target," he says. "We now have global patent rights to block cytokine IL-21; no one else can do that." (Competitors could block the IL-21 receptor, however, just not the molecule itself.) ZymoGenetics is eligible to receive $157.5 million in potential milestones, up to and including the antibody's regulatory approval in major global markets, and royalties on net sales. ZymoGenetics may opt to co-promote the biologic in the U.S., for a $10 million fee and a 15% contribution to Phase III trial costs. In this scenario, US royalty payments would increase from single to double digits. Novo is familiar with ZymoGenetics efforts in the IL-21 space; until last year when it retrenched into diabetes and opted out of the alliance, it was the biotech's partner on its recombinant IL-21 cancer project. Novo is confident that blocking the cytokine has broad applicability in immune disorders. Hence why it's snapping up that IL-21 IP. --CM/Melanie Senior

Celgene/Gloucester Pharmaceuticals: In a move that adds to its hematological cancer franchise, Celgene purchased privately held Gloucester Pharmaceuticals and its recently approved Istodax (romedepsin) for $340 million in upfront payments, plus potential milestones that could total another $300 million. The deal secures a nice exit for Gloucester’s five venture capital investors – Novo A/S, Apple Tree Partners, ProQuest Investments, Prospect Venture Partners and Rho Ventures – who backed the biotech with a $29 million Series D round in August. Over Gloucester’s six years of operations, the investors kicked in a total of roughly $100 million. Celgene predicts the Gloucester purchase will be accretive to earnings by 2011, in part because it would not need to add to its marketing and sales infrastructure since it already sells hematological cancer drugs Revlimid, Thalomid and Vidaza.--Joseph Haas

BMS/Tranzyme: In its first alliance with a Big Pharma company, Tranzyme Pharma will receive $10 million upfront plus two years of research funding from Bristol-Myers Squibb in a collaboration to discover potential new macrocyclic compounds, which have potential in a wide range of therapeutic areas, including oncology and metabolic disease. Announced Dec. 7, the deal is not Bristol’s first foray into the macrocyclic space – in April, it paid $5 million upfront plus $7.5 million in research and development funding to Ensemble Discovery to develop macrocyclic compounds called Ensemblins against eight undisclosed targets. It’s likely Bristol is trying to get ahead of the curve on what Tranzyme calls an underdiscovered area – no other Big Pharma companies are doing deals in the space and Tranzyme has thus far not partnered any of its clinical or preclinical assets. The new deal centers on Tranzyme’s MATCH (Macrocyclic Template Chemistry) drug-discovery platform. The biotech will perform early lead discovery against a range of undisclosed targets specified by Bristol, which will then be responsible for lead-optimization, preclinical and clinical development, and commercialization. Tranzyme will receive two years of research funding ranging between $3 million and $6 million and could earn regulatory milestones up to $80 million for each target program, as well as sales milestones and royalties.--JH

Mylan/Pfizer: Details are scant on the authorized generic agreement around the Wyeth antidepressant Effexor XR. But Mylan said early this week it had reached an agreement with Pfizer to sell the long-acting capsule formulation as early as June 1, 2011. Doses equivalent to Mylan's planned generic venlafaxine capsules racked up $2.9 billion in sales in the year to September 30, the company said in its release. Legislation that would curtail or even ban brand/generic settlements is winding its way through Congress these days (it may even catch a ride on the behemoth of health care reform) and we know where the FTC stands on these deals.--CM


Lilly/Isis: Lilly and Isis called it quits this week on their 5-year collaboration on LY2275796, a second-gen antisense compound targeting eukaryotic initiation factor-4E that recently completed Phase I trials in oncology. Isis is paying an undisclosed amount to take back the product, arguing that ‘5796 got lost in the shuffle after the big drugmaker’s 2008 ImClone acquisition. Is this spin control or honest truth? Data related to ‘5796 are sparse, with Isis failing to provide an update at its recent R&D day, leading Joseph Schwartz, an analyst at Leerink, to write in an investor note: “it’s logical to conclude that lack of anticancer activity and/or toxicity may be the reason why LLY [Lilly] is not pursuing it.” As Isis CEO Stanley Crooke points out in “The Pink Sheet” DAILY, Lilly has right of first negotiation to opt back in to the molecule’s development when—or if—it enters Phase III studies. (The two companies are also still partners on a Phase II antisense prostate cancer drug.) So, maybe for Lilly this is about curbing risk: with critical drugs coming off patent near-term (including Zyprexa and Cymbalta), Lilly needs late-stage assets to bolster its flagging pipeline, not early stage, highly risky products that are going to be a drain on resources. Better to let Isis carry the risk—and cost—but keep a just-in-case door open. The central question for many investors becomes will another partner, Genzyme, reach the same conclusion? Recall Genzyme and Isis announced a lucrative tie-up in January ‘08 on the CV medicine mipomersen, with Isis garnering $175 million in upfront cash and another $150 million in equity. Six months later, the two revised the deal terms, with Isis having to pony up more development money after data from a competing trial highlighted the regulatory risks associated with cardiovascular studies. Mipomersen is much further along than the Lilly cancer drug, and recently scored good data at the American Heart Association meeting, giving partner Genzyme some positive news to tout after a string of manufacturing and regulatory gaffes. But the Phase III medicine has also been the subject of questions, especially related to adverse liver side-effects and high clinical trial drop-out rate.--Ellen Foster Licking

GSK/Cytokinetics: Cytokinetics continues to phase out its oncology R&D and on Thursday announced it had scrapped a third and final cancer program with GSK (GSK decided not to opt into two others late last year). GSK will complete an ongoing Phase I trial of the compound, GSK-923295, in advanced, refractory solid-tumor patients. Then rights will revert to Cytokinetics, which says it is de-emphasizing its oncology work in favor of its core muscle-related R&D (which includes the Amgen-partnered cardiac contractility program discussed here). The three GSK-partnered programs were the company's entire clinical oncology portfolio.--CM

Genentech A Wholly Owned Member of the Roche Group/Seattle Genetics: As the Roche Pipeline Purge rolls on, the latest casualty is SeaGen. Genentech paid $60 million up-front for access to SGN-40 (dacetuzumab) in 2007 and at least $8 million more in milestones since then. But this morning the companies said that Roche was giving back rights to the anti-CD40 antibody in development for non-Hodgkin's lymphoma and multiple myeloma. The end of the SeaGen alliance follows Roche's decision this past week to drop partnerships with Actelion and GenMab. But you can't just blame Roche's re-org. Earlier this year a trial of SGN-40 in diffuse large B-cell lymphoma was halted when an interim analysis suggested the trial would not reach its goals. In any case, hold onto your hats, Genentech partners! --CM

2009 M&A/Alliances DOTY Nominee: GSK/UCB

It's time for the IN VIVO Blog's Second Annual Deal of the Year! competition. This year we're presenting awards in three categories--that's 300% more fake prizes than last year!--to highlight the most interesting and creative deal making solutions of the year. The categories are: Big Pharma Deal of the Year, M&A/Alliance Deal of the Year, and Exit/Financing Deal of the Year. We'll supply the nominations (roughly half a dozen in each category throughout December) and you, the voting public, will decide the winners (by voting early and often, commencing once we've announced all the nominees). Strap yourselves in, it's The Race for the Roger™.


OK, it involves some far away places we never think of – even beyond the fabled BRIC countries. But the January deal in which GSK paid UCB $670 million for commercial operations in more than 50 non-core countries, as well as rights to sell some primary care drugs in those territories, could be the IT deal of 2009.

After all, it captures so many of 2009's biggest trends: the land grab in emerging markets, the tug of regionalization versus globalization, the ongoing shake up in primary care, and diversification--the bluster of the big versus the commitment of the focused.

On one level, the deal shows how two companies with very different strategies are reacting to the mania about emerging markets. GSK is looking to be a geographically diversified global provider of medicines at all price points to as many countries as possible—and says its far-flung infrastructure, deep pockets, and global expertise make it the go-to company for late-stage deal-making in emerging markets. In other words, it can be a Big Brother.

UCB, on the other hand, is concentrating on what it does best: it is in effect taking a "master craftsman" approach. At a fraction of the size of GSK or other Big Pharma, it can't be everywhere selling everything. And so, it is joining a small, but important group of biopharma—including the much bigger Bristol-Myers Squibb and Lilly—that has chosen to intensify its focus rather than diversify. It recently repositioned itself as a spec pharma focused on CNS and inflammatory diseases and is extending that idea globally.

GSK's funds enable UCB to pay down its burdensome debt by shedding non-core assets—which were attractive enough for GSK to pay nearly 4X sales. UCB is not giving up on emerging markets, by any means, and still plans to sell specialty drugs in the BRIC countries, along with Mexico, Canada and South Korea. But it won't be stuck with infrastructure or products it can't afford.

GSK is another matter. Even as it cuts expenses in its Western markets, it is bulking up in emerging markets, where antiquated Western terms like "sales force arms race" and "shortage of human capital" –are real business concerns, not just pleasant reminders of the now-gone good old days in the West.

And that strategy is based on fortifying its product portfolio with a series of deals in the mature products and primary care sectors of the pharma industry; the assets UCB sold to GSK include rights to the anti-epileptic Keppra and the allergy drugs Zyrec and Xyzal in certain countries in Africa, the Middle East, the Asia Pacific region and Latin America.

GSK is being ultra-aggressive: along with Sanofi it's been a high-profile deal maker in emerging markets in 2009. Pre -2009, GSK was a player in four of the 10 fastest-growing therapeutic areas in the Middle East and North Africa. Now, the company is in nine of the top 10 therapeutic areas in those countries—a stat it's been communicating as it circles the globe for partners.

Eventually, it expects doors in emerging countries to open for its novel, proprietary specialty drugs. Meanwhile, it, like others, is making hits of some of primary care drugs that are flailing back home, for in emerging markets, primary care drugs still have good value. Hard to believe, but GSK's second largest product in emerging markets is the antibiotic Augmentin, which is growing 30% a year, even as it faces competition from 15-20 generics--people there are so eager for quality, they're willing to pay more out of pocket for branded, proprietary drugs, despite generic alternatives. Now that's a market worthy of a land-grab, and a deal worthy of IVB's Deal of the Year.

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

2009 M&A/Alliances DOTY Nominee: GSK/Concert and the Option-Based Orchestra

It's time for the IN VIVO Blog's Second Annual Deal of the Year! competition. This year we're presenting awards in three categories--that's 300% more fake prizes than last year!--to highlight the most interesting and creative deal making solutions of the year. The categories are: Big Pharma Deal of the Year, M&A/Alliance Deal of the Year, and Exit/Financing Deal of the Year. We'll supply the nominations (roughly half a dozen in each category throughout December) and you, the voting public, will decide the winners (by voting early and often, commencing once we've announced all the nominees). Strap yourselves in, it's The Race for the Roger™.
We’re cheating a bit on this one. For even though the nomination goes to GSK’s deal with Concert—a harmonious June deal indeed—it’s also a nomination that represents the Big Pharma’s entire 2009 listing of option-based deals. Why do they deserve your vote? Because they’re flexible, low-cost, risk-mitigating, pay-for-performance-oriented and, frankly, we think just rather clever. They’re also a very definite sign of the times.

In brief: GSK (or whomever; they’re not the only ones doing these deals, but they’re among the most prominent) pays a small fee up-front in order to take an option, or several options, on one or more partner compounds (typically pre-clinical). This secures for GSK a pre-defined licensing deal down the line—but only if it wants it, i.e. if the data look good. If they don’t, GSK has only lost relatively small change. If they do, GSK not only secures an asset that would otherwise very likely attract other interest, but does so at a pre-agreed price, which would arguably otherwise be higher. And the partner runs (& funds) the R&D program in the interim.

The Concert deal’s on the rich side, but typical in structure (and that’s why it’s such a perfect template): GSK paid $35 million up front (including $16.7 million in equity, another way to spread risk) for options on three projects, the most advanced of which started Phase Ib in November this year, the least advanced of which hadn’t even been selected at the time of the deal. GSK can opt into these programs at clinical proof-of-concept (or slightly earlier, at Phase I, for the lead). If it does, Concert begins to access various slugs of milestone money, mostly tied to clinical and regulatory achievements. So the biotech got $12 million a month or so ago for starting Phase Ib on the lead; its total milestones may reach over $1 billion.

This isn’t just a risk-sharing deal structure, it’s risk-sharing deal content, too: Concert’s compounds are mostly deuterated versions of existing molecules (the lead is a version of Bristol’s HIV drug atazanavir, for instance)—meaning it has replaced hydrogen atoms with deuterium atoms, creating new, patentable chemical entities that skirt existing IP and that may even be safer and/or more effective than the originals.

Beyond the Concert deal GSK has an orchestra of others: Chroma (Jun 09), Protea Vaccine Technologies (Jun 09), Vernalis (Aug 09) or SuperGen (Oct 09) for example. And don't overlook the dual-melody rare disease pact with Prosensa (Oct 09), which comprised a straightforward licensing deal and an option component. For a recent addition to the group, check out the November GSK/Nabi deal, which includes $40 million up-front for the option to license smoking cessation vaccine NicVAX, currently in Phase III.

image from flickr user greenbloodman 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.

GSK and Pfizer's HIV Joint Venture: Why It’s a Path Forward

Real innovation in dealmaking, like pharma R&D, is a rare commodity. As with R&D, dealmaking innovation often gets blocked by entrenched interests or misunderstanding or simple inertia. There are lots of reasons not to repeat the single most innovative and successful transaction of all time – Genentech/Roche – but none of them outweigh the spectacular opportunity that deal created.

We’re not going to say that the GlaxoSmithKline/Pfizer joint venture in HIV is, itself, comparable to Genentech/Roche. (See some short reports with some additional transaction details on the JV here and here and a more in-depth analysis here). But it could solve a set of knotty problems that by and large companies have, for whatever reason, failed to address.

First, earnings-pressured pharmas need help financing their pipelines. One option seems to be disappearing – getting investors to directly fund development (like the Lilly/TPG/Novaquest arrangement on a group of Alzheimer’s projects). Besides the market meltdown, which has taken cash away from speculative, illiquid investments, the parties’ goals were, in the dealmaker’s parlance, unaligned. Investors want to cherry pick the pieces of the pipeline they’d most like to fund, Pfizer EVP and chief strategy officer Bill Ringo told us the other day, almost as if they wanted to guarantee themselves a return (which, in the good old days, was something they could pretty much get just by investing in Pharma). The more risk they run, of course, the more upside they want (ideally, to be able to sell successes to the highest bidder) – which naturally limits the upside, and strategic value of the asset, for the pharma partner.

Here’s another problem. Most Big Pharmas want to be big and diverse enough to balance out the risks of development – but also want to be small enough to encourage biotech-ish entrepreneurialism. Various companies are trying to have their cake and eat it too by splitting into divisional enterprises (specialty pharma, or primary care, or oncology) with their own CEOs and CSOs and P&Ls. But we remain firmly Missourian about the whole idea. Will the commercial groups be able to buy research wherever they want – or remain saddled with what’s provided internally? Will research be able to sell its best fruits to the highest bidder in order to maximize their value? And for all their divisionality, how much of the corporate infrastructure – IT, manufacturing, finance – will these divisions have to absorb?

The GSK/Pfizer HIV joint venture is an interesting solution to both problems – the big/small paradox and the funding troubles. The new company is relatively small (first year projected sales: $2.4 billion); it’s got its own managers; it makes its own R&D decisions. The research stays within the parent companies and the JV pays its expenses – but if the pipeline projects don’t work out, and the JV doesn’t like what GSK and Pfizer are producing, the JV can buy their research from wherever they want. “It puts pressure and accountability onto the scientists,” GSK’s chief strategy officer David Redfern told us, echoing a favorite theme of GSK’s R&D boss, Moncef Slaoui.

Meanwhile, Pfizer doesn’t have to pay for a new worldwide commercial HIV organization on the basis of its underperforming HIV assets (maybe underperforming because it doesn’t have the commercial group it needs); GSK gets the near-term HIV pipeline it had otherwise failed to deliver. Far as we can see, no cash changes hands.

The biggest negotiating obstacle, apparently, was the equity split (right now, 85% GSK, 15% Pfizer) – but according to Redfern, once they’d abandoned the attempt to price the pipelines, and instead started to adjust ownership based on cash flows, “the heat went out of the valuation debate.”

And then there’s the optionality of the thing – one of its main advantages, believes Redfern. The JV could fund its business development with its own equity rather than dipping into cash. When the financial markets get friendlier, the whole thing could be spun off. And presuming success even close to what Gilead has achieved, the JV owners would get big stakes in a growth company that would theoretically trade at a significantly higher PE.

And that same equity would reward the JV’s employees in a way Pfizer and GSK stock simply can’t. Not to mention the fact that it’s a lot easier for an employee to see his personal contribution to growing a company 1/29th the size of Pfizer.

And one other aspect of optionality, notes Bill Ringo: if this works, “it provides us a model we can duplicate elsewhere.” He hasn’t apparently talked to GSK yet about repeating the idea in another therapeutic area, “but if there were another opportunity to do the same thing again with GSK, we’d do it.”

We recognize that plenty can go wrong with this deal. GSK’s firmly in the driver’s seat, with seven members of the nine-person board. And Pfizer could get tired of that. We also sense that Pfizer and GSK are not on the same page when it comes to R&D accountability (we think GSK is going to be tougher on its researchers than Pfizer will –rewarding more and firing more).

But whether it works or not, the drug industry should be paying close attention to this deal. Even more attention than to the big mergers. All of those are one-time events; it’s hard to see that they’ll be in any significant way transformational. Mostly, they’re stop-gap measures. (OK, we did argue the opposite way around about Pfizer/Wyeth – though most of the reader response was pretty skeptical).

But the GSK/Pfizer JV is repeatable. And scalable. It moves the industry in the direction it needs to go: smaller, customer-focused, financeable. And it gets our vote for the most innovative deal we’ve seen so far this year.

Image from flickr user joefutrelle used under a creative commons license.

GSK’s Tempero: Pushing Entrepreneurialism to the Limit?

We’re not sure why they didn’t shout about it, but GlaxoSmithKline has, according to a report in Xconomy last week, stealthily launched Tempero Pharmaceuticals, a Cambridge, MA-based start-up focused on regulatory T-cells for treatments in auto-immune disease and inflammation.

Jose Carlos Gutierrez-Ramos, head of the Immuno-Inflammation Center of Excellence for Drug Discovery at GSK that has seeded this newco, had flagged up the project to IN VIVO for this February feature. We blogged it here, too, but heard nothing since.

And yet “this is a very exciting project for us,” JC confirmed today to The IN VIVO Blog. Indeed, Tempero—though not technically a spin-out—takes GSK’s ongoing Drug Performance Unit (DPU) R&D experiment a step further. Need a refresher? The Big Pharma is already trying to foster a biotech-like culture internally, through the creation last year of these small, pathway-focused DPUs, each on a three-year funding cycle overseen by an investment board that includes a couple of external CEOs and VCs too.

Tempero, though, is (or will be) a fully external DPU—the plan is to bring VCs in on a later B round. If they come, that would provide the sort of outside validation GSK’s after for what will become GSK assets. Gutierrez-Ramos explained in February that GSK will buy back those investors at a certain return—granted, presumably, clinical milestones are met—thus providing them with a pre-determined exit.

"Pre-determined exit" and "certain return" probably sound rather sweet these days to VC ears. The devil is in the detail---figuring out what return will be enough for the VCs, and worthwhile for GSK. And the timeframe for all this.

GSK isn't commenting on any of those questions, or indeed on Tempero, other than to say that:

".....GSK has created a new Discovery Performance Unit which will be a separate company dedicated to researching and discovering small molecule drug candidates targeted to regulatory T-cells and effector Th 17 cells, which are thought to play a key role in autoimmune diseases. We believe its planned status as a stand alone company will stimulate innovation and provide the flexibility to respond to research leads, thus creating the best chance of success."

Of course, the point for GSK is to share more R&D risk, as it and other Big Pharma are doing as much as they can, including via the increasingly popular option-based deal structure. In this case, though, rather than share risk with an existing biotech partner, GSK has created one itself and gone directly to VCs to unload risk—since it apparently couldn’t find an existing company with the focus it was after.

Gutierrez-Ramos earlier described the Tempero set-up as “pushing entrepreneurialism to the limit,” and “forcing these guys [within the company] to deliver.” Just how much forcing the external VCs will need isn’t clear, but hopefully GSK will have more to say at that point.

image by flickrer su-lin used under a creative commons license

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.
  

DotW: Yes We Can

As the US prepares for its last chance to check out of the office early on Friday, Dems converged this week on the Mile High Stadium in Denver to listen to ordinariness and outstanding oratory. The GOP will be hard pressed to match the rhetoric as they bear down on the Twin Cities for their own back-slapping event.

There was no shortage of rhetoric in our industry either. Amylin and Lilly finally decided to publicly address Byetta's potential role in pancreatitis in a late day conference call Tuesday. Clearly the speechifying--"Yes we can get through what ought to be a non-event"-- didn't convince a majority of investors. The stock prices of both companies continue to suffer.

Also on Tuesday came news from BMS and Pfizer that their eagerly anticipated Phase III clotting drug Apixaban--pitted in a head-to-head against Sanofi-Aventis's Lovenox for the prevention of venous thromboembolism in knee replacement surgery patients--just barely failed to show non-inferiority. The market reacted--but more modestly--with the share price of each company dipping slightly as Wednesday's trading began. For Pfizer it was a "Yes we can weather another round of negative news" moment. For Bristol, it was proof that the company's risk-sharing strategy makes sense.

Then there was Cell Genensys's announcement that it was stopping a Phase III trial of its prostate cancer vaccine GVAX due to potential safety concerns. Many believe the drug's future is in question, though a different pivotal trial of the product is still on-going. At least the Cell Genesys team has this consolation: "Yes we can ink a lucrative deal with a mid-size Pharma on limited data."

And having failed to partner its lead program, faropenem, Replidyne announced it was restructuring, reducing headcount to just 5 employees and taking a charge of $3.1 million. Undoubtedly the remaining staffers will have a "yes we can moment" that involves selling everything not already nailed down, including their investigational drug to treat C. difficile infection and additional anti-infective compounds. With nearly $61 million in cash on hand, they might even say "Yes, we can pull off a reverse merger."

We aren't going to call roll and ask readers to vote for their favorite weekly run-down of news. It's official. By acclamation, we bring you...


GlaxoSmithKline/Valeant: GSK made another valiant--er, we mean Valeant--attempt to add late stage, specialty focused products to its pipeline this week. On Thursday it announced a tie-up with Valeant for the specialty pharma's late stage epilepsy drug retigabine in a co-commercialization deal worth $125 million up-front and more than $500 million in potential milestones. In addition, the deal also involves earlier stage Valeant programs, and gives GSK world-wide rights to both its VRX698 as well as downstream potassium channel opening drugs. Milestones for these candidates could eventually reach $150 million. The two companies expect to file for approval in both the EU and US for retigabine in early 2009. As The Pink Sheet Daily notes, the deal shores up a looming gap in GSK's epilepsy franchise. The pharma's Lamictal, which will go off patent in 2010, posted global sales of $2.2 billion last year. But GSK will have to master the potentially tricky side-effect profile that comes with retigabine's first-in-class mechanism. In one trial of the drug, nearly 27% of patients withdrew due to problems that included dizziness, somnolence, headache, and fatigue. For J. Michael Pearson, Valeant's CEO, the deal validates his turn-around vision for the specialty pharma. Since coming on-board in February, Pearson has made partnering the company's retigabine and Phase II HepC drug taribavirin a priority.

Genzyme/Medicines for Malaria Ventures/Advinus: There’s a certain irony to a company that’s made its fortune finding treatments for rare diseases to go after a mega-disease and eschew all profits from it. But that’s what Genzyme is doing with the not-for-profit MMV – one of a growing number of groups, operating largely through virtual organizations, focused on just one or two diseases that can be attacked via collaborations with academics and companies. It’s likely Genzyme, along with help from MIT’s Broad Institute and Harvard, will do most of the discovery work while the Indian Advinus – a unique combination CRO and biotech firm – will do most of the development. And while Genzyme is doing its work gratis, the Advinus collaboration will also advance its nascent ambitions in India, where it is one of the few major biotechs with an R&D presence--Roger Longman.

Isis/Novosom: So many targets, so little time. As Isis and others grapple with that dilemma a variety of smaller biotechs are maneuvering to gain access to sequence- or target-specific IP from platform players to move from technology purveyors to drug development companies. Germany’s Novosom—which boasts a nucleotide-agnostic, charge-reversible systemic and topical delivery platform called Smarticles—this week exercised its option (which it lined up in an April 2007 deal with the antisense specialist) to develop antisense oligos targeting CD40, a target in B-cell cancers and inflammatory diseases. That deal lands it worldwide rights to Isis’ CD40 related IP and “non-exclusive worldwide and sublicensable access to certain aspects of Isis’ core technology patents.” Isis gets upfront and milestone payments and royalties on sales. Smarticles (animation here) should not to be confused with Nestle’s Smarties, the colorfully coated chocolate candies that taste delicious but are crap at delivering RNAi and antisense molecules to the inside of cells--Chris Morrison.

QLT/Reckitt Benckiser: Canadian biopharma QLT says "yes we can" continue to sell off assets, announcing the licensing of its Atrigel drug delivery technology to Reckitt Benckiser Pharmaceuticals for $25 million plus potential milestones payments of up to $5 million. (This should give Replidyne hope.) As part of the deal, Reckitt took some of QLT's infrastructure off its hands, acquiring 18 employees and a facilty in Fort Collins Co. QLT has been selling off assets since January, when it announced its intention to focus on its macular degeneration treatment Visudyne. The company has already sold its headquarters, cut staff, and offloaded its acne gel, Aczone, to Allergan for $150 million. Next up: the company will sell QLT USA in its entirety.

Photo courtesy of Flickr user davidhanddotnet via a creative commons license.

The REMS Pioneers: GlaxoSmithKline Edition

By our count, the Food & Drug Administration has used its newest regulatory tool--Risk Evaluation & Mitigation Strategies--seven times since the authority took effect at the end of March.

The REMS is the centerpiece of the new drug safety legislation enacted in 2007, giving FDA much greater authority to regulate drugs on the market using tools like consumer medication guides, enhanced communication programs, and restricted distribution. (If you haven't been keeping up, you should be: start here.)

Remarkably, one sponsor--GlaxoSmithKline--has been involved in four of the first seven. GSK (or its partner) has negotiated a REMS as part of the approval process for the migraine combo Treximet (developed by Pozen), a broader indication for Advair, the new drug Entereg (developed by Adolor), and a pharmacogenomic safety screen on Ziagen. (And GSK isn't done: another REMS is in the works for the pending Promacta application.)

The other REMS all involve different sponsors: UCB's new biologic Cimzia, Biovail's new salt formulation of bupropion Aplenzin, and a revised label for Schering-Plough's Intron A.

So GSK's regulatory affairs group sure has been busy lately, since the new REMS authorities involve unchartered territory for both FDA and the sponsors.

But don't feel too bad for GSK. The company has had more than its share of the early work on navigating the REMS process--but it also has benefited in at least two ways.

First, as we wrote here, the intial wave of REMS pioneers have all involved applications stuck at FDA. So GSK has shouldered a greater burden in figuring out how the REMS will work in the regulatory process, but it has been rewarded with the opportunity to sell two new products--Treximet and Entereg--that might not otherwise have been marketed at all. The broader labeling for Advair also helps the company tell a good news story about the drug at a time of ongoing safety concerns for the long-acting bronchodilator class.

The Ziagen REMS may be the most interesting of all--a real world case-study in personalized medicine--but its hard to say it is paying off for the sponsor. (You can read more about that REMS in "The Pink Sheet.")

Here's the second payoff for GSK: the company now knows the most about how the new drug safety regulatory system works. FDA officials have put it better than we can: this is the most important change in the drug approval process in generations, and essentially every new approval sets a precedent. FDA plans to draft guidance to explain the new system to sponsors, but not until it has more experience. So the only way to learn is by doing.

GSK finds itself as the early leader in that learning.

Now, does that pay off in a competitive advantage for the company as it tries to get more drugs to market? We'll see....

DOTW: Short, Sweet, and Not Just Roche

Thanks to some well-timed vacation for a few members of your hard-working blog team here at IVB things might be a little quiet for the next week or so. Not entirely so, but just enough that you'll have a dull ache somewhere in the bottom of your soul. Take an antacid, you'll be fine. Probably.

But what a week it has been, and we're not just talking about the NL East race. Roche has kept us all entertained with its bear-hug of Genentech and--as if to say, hey, its business as usual here in Basel--two further acquisitions: RNAi delivery play Mirus and the antibody screening platform company Arius.

We hope we've entertained you with our coverage here and elsewhere within the broad FDC-Windhover family of fine publications, and we've had a good response to our poll about the wisdom of Roche's $44 billion move: 54% of the nearly 200 responses we've had thus far think that the Roche/Genentech relationship wasn't broke and so Roche is stupid for trying to fix it. If you haven't voted, go ahead, the poll is still open. And don't forget to suggest other ways Roche could spend all that money: we've started a list here.

Of course this week hasn't been all hand-wringing about Roche's moves, other companies have been busy as well. GE bought Vital Signs for $860 million. Summit and Biomarin teamed up to develop Summit's Duchenne muscular dystrophy preclinical candidate. GSK pronounced its tie-up with the South African generics player Aspen a "transformative" deal. Sanofi-Aventis' Sanofi-Pasteur vaccines division today snapped up UK vaccine play Acambis. And Lilly decided to find an alternative way to finance its Alzheimer's pipeline with a deal involving Quintiles' NovaQuest division and the massive investor TPG-Axon (see their earnings release for more details).

We're tired just thinking about all that.

image from flickr user Derek Farr used under a creative commons license.

Deals of the Week: All Star Break

In a week when the AL (again) defeated the NL 4-3 in a marathon 15-inning All-Star game at Yankee Stadium (thanks, Billy Wagner, for blowing the save and losing home field advantage for the World Series-bound Phightin' Phils), there were a few all-stars in the pharmaceutical world as well.

The buzz word this week was diversification, with health-care behemoths Johnson & Johnson and Abbott Labs posting better-than-expected quarterly results. J&J was buoyed by its consumer products business and Abbott had both stents and Humira to thank for its performance. On the other hand Novartis--an increasingly diversified company--grew in spite of its non-branded Rx divisions: its consumer medicines and Sandoz generics business enjoyed only moderate success thanks to tough times in the key US market, but that didn't stop the Swiss company from posting solid second quarter numbers. (We'll have more to say on Big Pharma business models and the yin and yang of focus and diversification in an upcoming IN VIVO piece.)

Keeping with the baseball theme: we're not a blog to steal signs but we couldn't help but pick up on something earlier this week. On Tuesday we gave you all free access to the denosumab record from Elsevier's Inteleos database and noted that Amgen has suggested it would be open to licensing the project, at least for the primary care indication of post-menopausal osteoporosis (PMO).

The challenge? For all of you expert dealmakers out there to add your two cents regarding the value of the project and potential deal strategies for Amgen. We can only assume that the dearth of comments suggests that all of you are in preliminary or even final-stage negotiations with Amgen and therefore recuse yourselves from the prize-less competition. Wink wink, we get it. Slackers.

You know who hasn't been slacking off? Those intrepid dealmakers responsible for ...



GSK/Actelion: The week started off with a bang when on Monday Glaxo fronted CHF 150 million ($148 million) in a worldwide (ex-Japan) co-development and co-promotion pact with Actelion for the Phase III orexin receptor antagonist almorexant. The Big Pharma pledged an additional CHF 415 million in pre-commercial milestones for the drug’s first indication of primary insomnia and an absolutely filthy figure for total milestones in two additional indications. Reactions to this deal were varied, to say the least. One analyst called it "the largest-ever partnering deal in the history of the industry," while others pronounced themselves decidedly "underwhelmed." Certainly you can't please everyone. But allow us to be the voice of reason, the voice of moderation, the voice of baby bear, when we say that GSK's figure was probably "just right." Why's that? Well forgetting the non-insomnia terms and taking into consideration the fact that GSK will help Actelion get its primary care field force off the ground by paying it to promote an undisclosed GSK drug prior to almorexant, the upfront payment may have been low for a Phase III primary care drug circa 2000-2003, but not anymore. The few primary care drugs available for licensing in Phase III, with novel mechanisms of action designed to treat non-life-threatening diseases, come saddled with higher than ever clinical development hurdles and increased regulatory scrutiny. GSK’s ante for almorexant—though large enough to put the deal in the upper echelon when it comes to guaranteed money—might seem small were it not for those circumstances. The fact that the Big Pharma is only chipping in for a minority of almorexant’s pivotal development program (which aside from the ongoing RESTORA 1 study will include at least two more Phase III trials) is further evidence that GSK is hedging its bets here.

Genzyme/PTC: We'll spare you the "London buses" reference but suffice to say it's unusual to see one $100 million+ upfront licensing deal and to see two in a week--well, that's plain crazy. But score another one for the orphan drug seekers. On Thursday, Genzyme paid $100 million to PTC Therapeutics to enter into a global collaboration to develop and commercialize PTC124, PTC's novel oral therapy in late-stage development for the treatment of genetic disorders due to nonsense mutations. The drug is in Phase IIb trials for Duchenne muscular dystrophy and is scheduled to enter a Phase IIb in cystic fibrosis later this year. PTC will cover the cost of 124's remaining Phase II program--which is slated to include four trials--and from there the parties will split development costs 50/50. PTC is eligible for $165 million in development and approval milestones and $172 in sales milestones. PTC will commercialize in the US and Canada (where it is responsible for all commercialization costs) and Genzyme takes responsibility for marketing and associated costs for the RoW. In addition to Genzyme's up-front contribution PTC pulled in up to $25 million from the non-profit Cystic Fibrosis Foundation the day before the deal was announced to support development of '124 in CF.

ViroPharma/Lev: Specialty pharma outfit ViroPharma announced it was entering the hereditary angioedema (HAE) space with its $443 million acquisition of Lev Pharmaceuticals. The linchpin of the deal is Lev's C-1 esterase inhibitor Cinryze, a biologic that has been available in Europe for 35 years to treat this rare and life-threatening condition, which causes inflammation of the larynx, abdomen, face, and extremities. Lev filed a BLA for Cinryze in July 2007, seeking approval for both prophylaxis and acute treatment of HAE. The product faces competition from CSL Behring's C1 inhibitor Berinert and Jerini's Firazyr. Our sister publication Pink Sheet Daily has more on the HAE market and Cinryze's chances of success. For ViroPharma, the deal marks a shift away from the antiviral space, which has long been its focus, into the hospital/ transplant arena. And with the addition of a soon-to-be marketed product, it continues the company's trend of playing to an investor base attracted to fully-baked and largely derisked assets. Recall this is the company that made a tidy profit on Vancocin, a decades old product it inlicensed from Eli Lilly, to treat Clostridium difficile outbreaks. ViroPharma's timing on Vancocin was exquisite. It brought in the product just when very nasty strains of the bacterium were causing large scale hospital outbreaks of the disease; given the market forces, ViroPharma was able to raise prices of the drug considerably. It is currently working on a follow-on to Vancocin, NTCD. Meantime, there's little information available about ViroPharma's hepatitis C program: ViroPharma discontinued its HCV-796 program, partnered with Wyeth, earlier in the year. According to ViroPharma's website, the two companies continue to exlore follow-on molecules to treat the disease.--Ellen Foster Licking

MacroGenics/Raven: Raven Biotechnologies finally found a buyer in MacroGenics. Last November, Raven announced a tie-up with VaxGen worth about $39 million. But VaxGen's shareholders revolted and scuppered the deal this past spring. MacroGenics, in turn, has been working to build a fully integrated biopharmaceutical company (how quaint) around its Fc antibody engineering and dual affinity re-targeting (DART) programs. It has a large deal with Lilly to develop and commercialize its anti-CD3 mAB for use in the treatment of autoimmune diseases, icluding recent onset-type 1 diabetes. On July 17, MacroGenics and Raven announced their tie-up. Financial terms weren't disclosed but it seems unlikely that Raven got more than what VaxGen originally offered. For MacroGenics, the acquisition provides additional preclinical assets, including more than 1300 monoclonal antibodies that Scott Koenig, CEO of MacroGenics, claims can rapidly be developed using their optimization platforms. In addition, the deal gives MacroGenics access to a portfolio of proprietary cancer stem cells from many types of primary tumors that could be an important addition to MacroGenics R&D capabilities. --EFL

Teva/Barr: What's $7.6 billion buy these days? Maybe a top-five starting pitcher, but those are hard to come by. No, this week it was Barr Laboratories. This late-breaking deal of the week is the latest chapter in the ongoing consolidation of the generics sector, but the bigger story here is the combination of Teva and Barr's biologics programs. Teva also noted Barr's legal prowess and at-risk launch capabilities. Under the terms of the deal, each share of Barr common stock will be converted into $39.90 in cash and 0.6272 Teva ADRs and Teva will assume Barr's $1.5 billion in debt, to boot. In other generics news, Czech generics play Zentiva is now telling investors to reject Sanofi-Aventis' attempt to up its stake in the company, saying the $2 billion play is a lowball offer.

photo by flickr user mori claudia used under a creative commons license.

FDA and Drug Safety: It Keeps Getting Worse

How bad is the drug safety climate? Just ask GlaxoSmithKline.

Sure, last Monday was a rough day—nothing like having two FDA officials tell an advisory committee that one of your biggest products ought to be pulled—but we’re not talking about Avandia today.

No, today we are talking about the product formerly known as Trexima, a fixed-dose combination of the GSK’s migraine drug sumatriptan (Imitrex) and the nonsteroidal anti-inflammatory drug naproxen. GSK is developing the combo in partnership with Pozen. On July 31, the Food & Drug Administration issued a second “approvable” letter for Trexima, saying that it is still not convinced the combination is safe enough for marketing. (FDA has already told the companies that it will not approve the Trexima brand name, but the firms are still using it until they settle on a new one.)

In particular, Pozen says, FDA is concerned about a positive genotoxicity test. The agency apparently wants the company to conduct a relatively simple human study to provide reassurance that it is a false signal. This comes after FDA previously declined to approve Trexima because of concerns about the cardiovascular safety profile of the combination.

Keep in mind that this pill combines two ingredients that have been used together countless times in the 15 years that Imitrex has been on the market. If there really is a safety problem here, FDA probably should be doing more than just sending an “approvable” letter to Pozen.

To be fair, Imitrex has well known cardiovascular risks, and naproxen’s cardiovascular safety profile became an issue in the context of the cox-2 inhibitor safety brouhaha. So you can understand why FDA asked for more data. Now, Pozen says, the agency is satisfied on that front (thanks in part to GSK’s willingness to do a post-marketing study on the blood pressure effects of the combo). But the drug is still on hold.

Welcome to the world of new drug reviews in 2007. Trexima is just the latest indication that this may be the worst time ever to try to get a new drug through FDA.

There should be good news soon. Congress is on the verge of enacting historic drug safety legislation—at least, Congress says it will after August vacation. The bill will put new burdens on manufacturers to be sure, but it will also allow Congress to declare the drug safety problem to be fixed. That may lead to increased confidence in FDA as a regulator—and maybe increased confidence within FDA itself to allow the agency to approve drugs even if they do have a safety signal.

SHAMELESS SELF-PROMOTION ALERT: The RPM Report and Ropes & Gray will host a webinar on Aug. 14 to discuss the impact of the pending FDA bill. Two experts from Ropes & Gray’s legal practice will dissect the key provisions of the legislation, and the editors of The RPM Report will tease out the business implications of the law. Registration information is available here.

The Nail in the Coffin on Avandia

It doesn't matter what the committee votes now.

The final blow to GlaxoSmithKline's diabetes drug Avandia was not delivered by FDA whistleblower and director for science and medicine in the office of surveillance and epidemiology David Graham, although he gave the most persuasive presentation during the morning session of today's advisory committee meeting on the troubled product. It was his boss, drug safety director Gerald Dal Pan.

Graham gave the last presentation before lunch and predictably came to the conclusion that Avandia should be pulled from the market. He went through a detailed, half-hour talk explaining why he came to his conclusion, using a combination of results from long-term, placebo controlled studies, and meta-analyses to show rosiglitazone's benefits did not outweigh its cardiovascular risks.

"There is no evidence, none whatsoever, to support the benefits of rosiglitazone with these outcomes," Graham said refering to a host of cardiovascular adverse events including heart attack. He paralleled the Avandia situation to Warner-Lambert's Rezulin, saying it had cardiovascular risks other drugs (read Takeda's Actos) in the class did not have. Rezulin was pulled for showing fatal liver toxicities other drugs in the class did not have (read our earlier post).

Everyone expected that from Graham. But it was Dal Pan's endorsement of Graham's findings that effectively killed this drug, even if it does stay on the market with a black box warning. If Glaxo's legal team wasn't already in crisis management mode, they certainly will be now.

Dal Pan was noticeably reserved about the meta-analysis finding of a 43% increased risk of heart attack linked to Avandia during an early July Congressional House hearing. He was not ready at that point to make any determination on Avandia. Now, he has reached his conclusion: it should be pulled. The benefit/risk profile of Avandia "is not favorable" Dal Pan concluded.

Best case scenario for Glaxo, Graham says, is that Avandia was responsible for 40,000 excessive cardiovascular events in 6.5 years since 1999. Graham puts the real number at 80,000 excess cases. A real nightmare, if true.

Dal Pan gives credibility to Graham's findings that did not previously exist. The only reason the Office of Drug Safety did not make a formal withdrawal recommendation is that the whole drug safety team had not had a chance to review the analysis as of yet, according to Graham.

There is clearly a line in the sand between the Office of New Drugs and the Office of Surveillance and Epidemiology (drug safety) within FDA's Center for Drug Evaluation & Research. OND wants to keep it on the market, OSE wants it off. CDER office of drug evaluation II director Robert Meyer argued eloquently against Graham and Dal Pan's conclusions, adding that he himself had not decided on the appropriate "regulatory action."

But that doesn't mean much anymore. Whether or not it stays on the market, GSK's Avandia is dead.

Avandia and Rezulin: Parallels that Should Make GSK Nervous

History doesn’t repeat itself but it does rhyme. That old Mark Twain saying must be making GlaxoSmithKline sweat as Avandia is starting to look more and more like another Rezulin. By our reading of the tea leaves, Avandia is in much more peril than anyone seems to realize.

GSK is hunkering down for continuing assaults on its number two drug, battered initially by Cleveland Clinic’s Steve Nissen whose meta-analysis showed a 43% increase in heart attack risk for Avandia patients compared to control.

During the company's second quarter conference call, CEO JP Garnier clearly was using the "If you sound like a winner, you are a winner" strategy when it came to discussing Avandia with investors, analysts and media.

"We are still encouraged [about Avandia] because we have seen...a lot of evidence recently," Garnier said of the data GSK has submitted to the agency in advance of a Monday advisory committee fact-gathering meeting. "The evidence is supportive of Avandia's risk/benefit ratio, and of its effect on cardiovascular safety."

GSK is hyping a 400,000-patient epidemiology study of patients on Avandia and Takeda's Actos among other treatments that apparently bodes well for the diabetes drugs.

Glaxo has said that they simply have been unsuccesful in boiling down their message on Avandia to a "7-second soundbyte" which is the reason for the more than 45% decline in new Avandia scripts. " In the US, the media has ... had more of an impact on physician and patient impressions than the data itself," GSK's pharma operations chief David Stout said on the call.

Clearly, the message from GSK is: We stand behind Avandia. Unfortunately for the company, there are some discouraging parallels between their diabetes drug and Warner-Lambert's Rezulin.

Warner-Lambert pioneered the glitazone class, but Rezulin caused liver toxicity that ultimately led to its withdrawal. A recap of the regulatory history suggests some uncomfortable parallels with Avandia and the concerns about cardiovascular safety.

Two months after it got to market in 1997, FDA slapped Rezulin with a stricter warning on its packaging (thanks to 35 post-marketing reports of liver injury). At that point, 500,000 patients were already on the drug. Several "Dear Doctor" letters later, FDA's Endocrine and Metabolic Drugs Advisory Committee reviewed the liver tox issues, and recommended keeping Rezulin on the market, but only for patients not well-controlled on other diabetes drugs. One year later, the drug was taken off the market when reports kept coming in.

For Avandia, the toxicity is different--cardiovascular rather than liver--but the slow motion, repeated regulatory reactions are similar.

Avandia labeling was rewritten to strengthen cardiovascular safety warnings in 2001, and the company issued a "Dear Doctor" letter on the topic at that time. The concerns were raised more directly in the context of the review of Avandia for an indication for use with insulin; that use was ultimately approved in 2003. The Nissen paper now has put the regulatory machinery into fast forward, and an advisory committee will discuss Avandia's fate on Monday.

All of that is uncomfortable enough, but there is another parallel to the end of Rezulin emerging at the worst time for GSK: a Senate Committee is raising concerns that FDA reassigned a medical officer who wanted to put stronger warnings on Avandia.

If that sounds familiar, it should. In early March 2000, FDA senior medical officer Robert Misbin wrote a letter to Rep. Henry Waxman (D-Calif.) expressing frustration over FDA's handling of Misbin's attempts during the previous two months to convince the agency's Center for Drug Evaluation & Research that Rezulin had to be withdrawn from the market. Misbin asserted that FDA officials had stopped him from releasing information related to deaths of Rezulin patients.

One other thing: Misbin was the primary reviewer on Avandia and was taken off of the review several years ago. (Apparently, he's not the whistleblower this time around -- for more speculation on who the whistleblower might be, see the next post.)

All in all, Monday's advisory committee meeting doesn’t look good for Avandia. Even if the medical officers keep quiet, FDA will not be presenting a united front to the committee. That's because the agency is once again going to let its most prominent whistleblower, director for science and medicine in OSE David Graham, make a formal presentation. Graham most recently helped ensure that Merck's Arcoxia died a painful public death before an FDA advisory committee. FDA has apparently concluded that they have to let Graham speak at these meetings rather than wait for him to go to Congress to make his presentations. (Here is our coverage of the Arcoxia debacle.)

On Avandia, Graham has already made his position clear in FDA briefing documents. He argues that the current postmarketing studies (in particular the key RECORD study) can't, statistically, demonstrate a heart attack risk related to Avandia: they're underpowered. In other words, the current scientific evidence is all FDA is going to get to make their decision on the future of GSK's drug. Anyone want to venture a guess at where Graham will stand on Avandia?

And its not like FDA won't let the discussion go into whether the drug needs to be pulled. Quite the opposite. Here is one question posed to the committee: "Does the overall risk-benefit profile of Avandia support its continued marketing in the US (VOTE requested)? If yes, please comment on what FDA should do to maximize the risk-benefit considerations (e.g., limit to certain patients, incorporate a boxed warning….)"

That question means FDA is thinking awfully hard about whether this drug should stay on the market. You could argue that they added the question for political cover in order to leave it on the market, but I'm not buying it. I think they really want to know the experts' opinion.
And what will that opinion be? Nissen himself has said Avandia should remain on pharmacy shelves. NIH's Malozowski told us that he didn’t think FDA would pull it. “They will probably add a warning for a subpopulation of patients and a contraindication for its use with insulin."

I also asked Tom Garvey, a former FDA reviewer who runs his own drug development consulting business, what he thought. He concurs with Malozowski. Sort of.

Rezulin could be pulled off the market with less risk, he argued, because there were two other marketed drugs without Rezulin’s liabilities. Moreover, "the absolute risk found by Nissen is small (if, indeed, it exists) and the benefit conferred by Avandia is not inconsequential, especially in certain types of type II diabetics.”

But then he added, surprisingly: “All of this having been said, I too get the sense that the drug is probably doomed."

In short, as with Rezulin, an FDA advisory committee could recommend keeping Avandia on the market, in a limited way—while, in parallel, the political and historical momentum builds to yank it off. On the scientific front, the data isn’t clear. Nissen's meta-analysis has come under intense fire, but his results were confirmed by FDA's own meta-analysis, and they had access to a much larger data set. Meanwhile, GSK's RECORD study has been inconclusive on the heart attack risk question.

But the political front will evolve in its own way. And if history really is rhyming, if not precisely repeating itself, FDA will have a hard time keeping Avandia on the market.