Perlmutter: We're Not Abandoning Japan

Signing over Japanese rights to 13 development assets and selling the Japanese subsidiary doesn’t mean Amgen is abandoning Japan, insisted Roger Perlmutter, EVP R&D, in a phone interview with IN VIVO Blog a few hours after the Big Biotech announced its $300 million up-front double-deal with Takeda (see our post below). “We’re just saying that partnering is the right way for us now."

But Perlmutter acknowledged that most Western firms haven’t exactly sailed into the world’s second-largest market, where local knowledge and relationships still count for a lot. “Japan is a very special market, requiring special expertise. The process of getting into Japan [for a foreign company] takes decades, and requires a large investment.”

The money bit’s the problem: Amgen can’t afford large investments, since its annus horribilis in 2007—which may be repeated, possibly even more horribly, in 2008. Indeed, Amgen’s taking a “more strategic look” at its wider international expansion plans, according to Perlmutter. In other words, Japan might not be the only place Amgen pulls back, or partners. “Things we had anticipated we could do…we now can’t do in the same time-frame.”

But at least there are scores of willing collaborators standing by. Takeda apparently won a highly competitive bidding process for the broad alliance announced today—perhaps made more attractive since Amgen hadn’t insisted on any particular structure. “We let potential partners suggest the best way to ally” in Japan, insists Perlmutter. (Given its sellers’ advantage, Amgen would have called the shots, mind you—it has kept a co-promote option in Japan, for instance, should its fortunes change down the line.)

Worldwide rights to Phase III cancer candidate motesanib weren’t originally part of Amgen's Japan proposal--these were being advertised separately. "The compound needed more investment," clarifies Perlmutter--not least, one assumes, to help distinguish this VEGF-targeting multikinase inhibitor from its on-market competitors. Still, Takeda’s interest in that, too, helped it secure the lot: one partner’s easier than two.

Perlmutter isn’t expecting any more multi-molecule, broad ranging deals like this one anytime soon. But the party still isn’t over for those seeking biotech pipeline assets, and who have the money to pay for them. Amgen's currently partnering some of its earlier-stage molecules, too, for which it expects more valuable cash. After all, noted Perlmutter, "not a lot of folk have assets like ours."

And while not a lot of folk face quite the same near-term revenue risks, they aren’t home free, either. Big Pharma will see products with $73 billion worth of US sales lose patent protection by 2012. Which means that the kind of out-licensing and risk sharing Amgen is now doing is likely to be increasingly common among other large drug companies, too.

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Amgen Cashes out of Japan; Follows Bristol's Risk Sharing Example

It’s a sign of the times when Amgen starts licensing its drugs to mid-sized Japanese pharma.

Sure, we knew that troubled Amgen, hit by declining sales of EPO drugs and growing competition--including from forthcoming biogenerics--was looking for ways to cut costs. It had already last year declared workforce culls and its intention to partner certain R&D assets.

But this double-deal with Takeda, announced this morning, is still worth a second look. In Part I, Takeda gets Japanese rights to 12 of Amgen’s pipeline assets in exchange for $200 million up front, up to $340 million in development costs—not just for Japanese, but for worldwide development—plus up to $362 million in sales-linked milestones, and royalties. The Japanese firm will also buy Amgen’s Japanese subsidiary for an undisclosed sum.

That regional deal’s interesting enough: Amgen, while touting its wider international expansion outside of the US, is exiting Japan. It wouldn't be the first; other companies have acknowledged that this tough market is best tackled by locals, who’ll pay dearly for access to assets. Amgen's move is also about cutting infrastructure—a trend, and need, that we’ve talked about in the context of Big Pharma’s unwieldy bureaucratic machines (and Amgen, too, is increasingly compared to Big Pharma, as we noted in this IN VIVO feature.)

Part II is the most telling bit of this deal, though. For another $100 million upfront and $175 million in additional success-based milestones, Takeda takes on worldwide rights to Phase III motesanib, a small molecule angiogenesis inhibitor for cancer. It'll pay double-digit royalties on Japan sales, but will also cover 60% of ongoing development expenses outside of Japan, and share profits on a 50-50 basis.

This, in case you hadn't noticed, is Amgen doing risk- and cost-sharing, big time—like Bristol Myers Squibb did via monster deals in early 2007 with AstraZeneca and with Pfizer. Amgen's not only got itself a partner in a market that's now clearly non-core, but has also secured a good chunk of its ex-Japan costs, too, on all 13 molecules.

Amgen didn’t used to do out-licensing, at least, not until a lonely deal with InteKrin last January. Now it knows it has to: it needs the cash to help cushion some of the EPO blow (which may yet get worse following the next ODAC meeting in March) and, with commitments to cut 14% of staff, it doesn’t have the development muscle to deal with its entire pipeline in-house.

Not that motesanib is the crown jewel; far from it. It'll hardly be the first tyrosine kinase inhibitor to market, after all--hence Bear Stearns analyst Mark Schoenebaum's comment that the motesanib terms are particularly good for Amgen, since "we believe that the molecule's future is bleak."

Osteoporosis candidate denosumab is the company’s big hope—some say its only life-line—and Japanese rights to that went to Daiichi Sankyo last year, for what may now appear a rather paltry $20 million up front and $150 million contribution towards global development costs.

But Takeda’s nevertheless doing ok here. Twelve of the 13 Amgen assets are large molecules, granting the Japanese company its own foothold in biologics door, following similar moves by compatriots Astellas and Eisai Co. (along with most Western Big Pharma). Many of those were acquisition-driven, though (read more about the various strategies here).

By effectively signing a regional Japanese deal, Takeda gets to cut its teeth in biologics development alongside experts—albeit paying a price for that privilege—and will likely enjoy the comfort of ex-Japan approvals for some of the compounds before taking on the task itself at home.

And worldwide rights to motesanib—a small molecule—ticks another of the boxes on Takeda’s wish-list: international expansion. All Japanese firms (at least, all the larger ones) are desperate to expand outside their domestic market because of sluggish growth and harsh price cuts. That’s in large part what drove Eisai’s $3.3 billion cash acquisition of US spec pharma MGI Pharma in December 2007—a headline-grabbing transaction that Takeda will have badly wanted to answer to, if not, this time at least, out-do. (Read more about Eisai/MGI here.)

Photo "Pharma Spam Tower" by Flickr user shimown used under a Creative Commons license

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While You Were Eating Chili and Drinking Beer

Sometimes coming up with a headline for our weekend roundup can be difficult. This was not one of those times.

While we went with what we figured was the most universal of Super Sunday experiences, we had choices. Also considered: While You Were Watching It For the Ads, While You Were Giants, While You Were Eli-d, While You Weren't Going Undefeated, While You Were Choking, While You Were Jumping Off the Pats' Bandwagon, While You Were Participating in the Unauthorized Use of Game Footage Without the Express Written Consent of the NFL, and While You Were Praying There Would Be No Tom Petty Wardrobe Malfunction.

Some of us here at the IN VIVO Blog are Eagles fans (no, really, we probably haven't mentioned it before) and so the only suitable Superbowl outcome would have been for both teams to get disqualified somehow. But alas, at least it was a tight game.

Believe it or not there was more than Super Sunday and Super Tuesday prognosticating going on this weekend. Or so we heard.

• Amgen and Takeda inked a broad alliance to develop and commercialize 13 Amgen products in Japan. In a second and related deal, Takeda becomes Amgen's worldwide partner for the Phase II oncology candidate AMG-706 (motesanib). Amgen gets up-front payments of $200 million and $100 million respectively, and a further hundreds of millions in milestones and R&D expense sharing, plus royalties on Japan sales (and worldwide 50/50 profit sharing on motesanib). Takeda is also acquiring Amgen's Japanese subsidiary Amgen KK.
  
• From the Financial Times: a preview of GSK's forthcoming results this week with one key question--can the Big Pharma get FDA approval for Cervarix? We weighed in on this question on Friday.
  
• [Self Promotion Alert] The line-up for our Pharmaceutical Strategic Outlook conference in New York (March 18-20) keeps on getting better.

Photo from Flickr user jwinfred used under a Creative Commons license

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Cervarix: Big Step for FDA; Can GSK Make the Decision Easier?

Citi's Kevin Wilson is out with a comment on Glaxo's pending Cervarix application at FDA that seems right on point to us.

Extrapolating from some forthright comments by a senior official from FDA's vaccine review division on January 30, Wilson surmises that FDA is feeling the pressure of a big decision on the new generation of vaccine adjuvants -- especially those that may act on toll-like receptors to trigger the innate immunity system in the body.

FDA's Office of Vaccine Research & Review deputy director Florence Houn gave a presentation (of her personal views) on January 30 (see here). She noted concern that the agency does not fully understand the mechanism of action of adjuvants which enhance immune response. And she noted pointedly that the products will get used on broad populations.

The wide array of adjuvants under development for use in vaccines -- to improve the protective qualities of the products, to permit the use of lower doses of antigens, and to confer proprietary positions on the product sponsors -- represent a major step for the industry and a major risk for regulators. We have been saying that for over a year and a half (see here): adjuvants are a big opportunity, but they require a big decision from FDA.

As the new products with adjuvants approached the market, FDA tried to assuage concerns that there might be unusual regulatory burdens by saying that the current system for reviewing new products was adaptable to applications of products with adjuvants.

Now that the regulators face the prospect of having to make a decision on products that could go into wide use rapidly following commercial approval, the agency may be having second thoughts. Cervarix, after all, is headed into a big market, especially if GSK tries to compete strongly head up against Merck and Gardasil.

National Institute of Allergies and Infectious Diseases head Tony Fauci is generally an advocate for the new adjuvants. His institute has been aggressively funding work on adjuvants for the flu vaccines as well as other products. Even he, however, recognizes the pressure on FDA with the first approval of a product with an new adjuvant.

Fauci has said publicly that he understands why FDA would get cautious as the final decisions approach. He told an Institute of Medicine session on drug development at the end of 2007 that he recognized why FDA would want to examine these first applications carefully.

FDA's Houn spent a good part of her presentation pointing out that the agency is getting more interested in risk management programs for vaccines as well as drugs. She noted that the Acambis smallpox vaccine carries a full RiskMAP program--even though the product will be used primarily in the very controlled military patient population.

Reading further between the lines of Houn's speech, maybe risk management plans offer the way out for sponsors of the new adjuvant products.

Sponsors could relieve some of the pressure facing the agency by agreeing to programs to track the products broadly in the post-market arena. That is costly, but it may be one way to break what appears to be a developing log-jam over the new generation of vaccines.

This looks like a landmark decision for FDA, not an impasse. It will be interesting to see what GSK does to smooth the process.

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Deals of the Week: Deal--or No Deal

The debate over Vytorin's medical benefits and, by extension, the utility of all cholesterol meds, continues to rage. Meantime, the Zyprexa marketing scandal reared its head: new this week, the NY Times reports Lilly is in talks with federal prosecutors to settle investigations into its marketing of the antipsychotic. If an agreement is reached, it could cost the pharma $1 billion, the largest fine ever paid by a drugmaker for breaking federal laws governing a medicine's promotion.

And, it was earnings week, with fourth quarter reports from Wyeth (up, but flat forecast for '08 due to generic Protonix), AZ (down), BMS (down, and WSJ's Health Blog highlights concerns that this big pharma may be affected by the sub-prime mess), Novo Nordisk (down, but did beat analysts' expectations sending the stock up), and Merck (down, thanks to Vioxx settlements) among others.

All in all, a crazy week, but not necessarily on the deal-making front. That's prompted this IN VIVO blogger to ponder the deals that happened--and those that did not. Without further ado, the Deal or No Deal edition.

First, a look at the actual deals that got done...

Inverness/Matria: On Monday Inverness announced its third major acquisition in the health management space, buying Georgia-based Matria for $900 million and the assumption of $280 million in debt. Definitely the big money deal of the week, though Wall Street reacted negatively to the news. Inverness continues to build through acquisition: the Matria deal is its twelfth in the past 12 months. (For more on Inverness's acquisition strategy, click here.) The company's recent emphasis on health management suggests another trend we've been following: the expansion of the diagnostic business model to include services not exclusively related to in vitro tests or reagents. Such business activity has muddied the waters stretching the definition of what it means to be a diagnostic company.

Sepracor/Nycomed: A few weeks ago when Nycomed got FDA approval for its inhaled corticosteroid ciclesonide we figured Sanofi-aventis, the original partner of Altana (bought by Nycomed in '06), still had US rights to the drug--we hadn't heard otherwise, after all. So we were a little surprised on Monday when Sepracor picked up rights to the drug (Alvesco) for $150 million upfront plus various development and sales milestones. Nycomed will also receive payments for manufacturing and royalties on sales. Alvesco's route to the US market has been chock-full of speed bumps. Way back in 2002 Altana suggested the drug might be approved in 2003, but an NDA wasn't filed until December 2003. Altana and Aventis received an approvable letter in October 2004 and the drug was launched in 2005 in Europe.

Iroko Pharmaceuticals/ Merck: Specialty pharma Iroko inked a deal with Merck for non-US commercial rights to Aggrastat, a drug used alongside heparin in patients with unstable angina to prevent cardiac ischemic events. Financial terms of the deal were not disclosed. This is the third product Merck has out-licensed to Iroko and the second in the beleaguered cardiovascular space. Last spring the company acquired rights to Indocin, for rheumatoid arthritis, and Aldomet, a hypertension treatment, from the big pharma. As we reported here, the independent futures of many spec pharmas are in question, as product-poor pharmas gobble them up in hopes of fattening their pipelines. Still, primary care remains a popular space for many, especially as big pharma eschews risky products in the cardiovascular and metabolic disease space.

(Clearly someone forgot the briefcase models.)

BiogenIdec/Genmab: Perhaps we should say "No deal, yet." This week BiogenIdec was once again in the news thanks to manueuvers by Carl Icahn to install three supporters onto the company's board. Also swirling in the ether, rumors that BiogenIdec intends to buy Genmab. Certainly, such a deal would scupper any attempts by Icahn to sell the company to another entity. Adding Genmab's pipeline would go a long way to securing an independent future for the Cambridge, MA-based biotech. But such a deal won't come cheap. In part, because it seems likely that GSK might up the ante. The British pharma, after all, has three partnerships with Genmab, including a very rich co-development, co-promotion deal for the biotech's HuMax-CD20, an antibody to treat cancer and rheumatoid arthritis. Until now, GSK's had no real reason to bring Genmab in-house--it's already got rights to the antibody cow's milk, after all. But it may not be willing to stomach the risk associated with a change in Genmab ownership, deciding its worth the hefty price tag to nail down its rights to its partnered products.

Lilly/Gastrotech: Deal or No Deal? Here's an odd one for you. On Jan 28, Denmark’s Gastrotech Pharma announced it was in-licensing Lilly’s GLP-1 analog GTP 010 for IBS and functional dyspepsia. That’s a deal, not a non-deal, surely? Well, depends on how you look at it. Simply turn it over and you get….a non-opt-in by Lilly.

Lilly and Gastrotech had been collaborating on GTP 010 since 2004, when Gastrotech took over Phase II trials of this Lilly compound in IBS and dyspepsia (in part thanks to the biotech’s ownership of some use patents for GLP-1 analogs in IBS, according to chairman Hans Schambye, though no, that wasn’t mentioned in the release).

That—four years ago--was arguably the real licensing deal. And that was also when Lilly received an option to later take over development and commercialization of the compound in return for milestones and royalties.

This week's news is that Lilly didn’t take that option, which means Gastrotech gets to keep the compound, instead, paying Lilly royalties. “Sure,” Schambye acknowledged to IN VIVO Blog, “you could look at it both ways. Either party could have licensed the drug.”

See? Hmm, exactly. Now ok, we know that small biotechs need all the positive spin they can get, but we're getting pretty close to "Press Release of the Week" territory here. Perhaps Gastrotech will do something big with 010, who knows (Lilly did take an equity stake). But please, a bit of clarity and objectivity wouldn’t go amiss.

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"Consensus is not our goal": A Conversation with FDA's Top Drug Reviewer

Drug companies aren't the only ones worried about the sinking rate of new drug approvals. Food & Drug Administration officials are equally concerned over the innovation drought. After all, the number of new drugs making it to market is at its lowest since 1983.

FDA's Office of New Drugs Director John Jenkins, who oversees all new drug applications within the drug center, is especially preoccupied with the lack of results from the drug development process. "We agree that it’s very disheartening that despite the rather massive expenditure of research dollars, we’re not seeing a growth in the number of NMEs submitted to the agency for review," Jenkins says of new molecular entities getting aproved by the agency. "We are seeing a continued growth in the number of new commercial INDs submitted, so there still seems to be a lot of innovation. It’s a question of how to get them out the other end of the pipeline."

Jenkins also addressed other issues ranging from drug safety to how FDA plans to prioritize implementing the new drug reform regulations under the FDA Amendments Act. In particular, he addressed the public disagreement between the drug review and drug safety groups during the Avandia advisory committee meeting last July.

"Consensus is not our goal," Jenkins says. "That strikes some people as odd when they first hear me say that, but I think that if you’re in a regulatory organization and people think that consensus is the goal, that leads to a subtle pressure to conform to the prevailing viewpoint even though you may not agree with the prevailing viewpoint and you may in fact be right."

You can read the whole interview in The RPM Report by clicking here. Free registration for non-subscribers is on the left side; subscribers should just log in.

I would love to hear your comments on Jenkins' views on FDA, drug companies and drug development.

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Neuro Companies Causing Headaches

Ever since President Bush (the First) declared the 1990s to be the Decade of the Brain, hopes have been high for device innovations to treat a variety of neurological conditions ranging from stroke to migraines to depression.

For all the promise these therapeutic areas hold, neurological device applications have proven to be among the most inscrutable for entrepreneurs and investors, replete with technological and clinical challenges, not the least of which is the difficulty of conducting neuro trials, e.g., the inherent problems in enrolling acute patients for stroke studies.

Several recent announcements have done nothing but confirm how challenging the neuro space is. In fact, this year is starting out to be one that neuro investors would just as soon forget. Highlighting the bad news cascade was Northstar Neuroscience Inc.'s announcement that its EVEREST pivotal trial failed to meet its primary efficacy endpoint. This caused Northstar's stock to immediately plummet by nearly 90%, hovering today at just above $1 per share. Coming off what many investors called the most successful device IPO of 2006 (raising more than $100mm), Northstar's stock took an unexplained hit not long after going public, but there is no doubt about the reason behind this most recent crash.

Hopes surrounding Northstar were high. The EVEREST trial was designed to determine whether cortical neurostimulation, together with rehab therapy, would improve hand and arm function in stroke survivors better than rehab alone. Not only did the initial four-week data fail to show any meaningful difference between the investigational and control groups, but a preliminary review of the longer-term (24-week data) appears to show similar results. John Bowers, Northstar's president and CEO, during a conference call discussing the trial results, noted, "To put it mildly, we are extremely surprised and disappointed" by the study's outcome, and couldn't explain why EVEREST failed to reflect the positive results demonstrated by the company's two previous feasibility trials.

Northstar remains well-financed--the company reported having more than $80mm in cash and investment on hand as of year-end 2007. While feasibility studies are still being explored for possible applications of Northstar's Renova technology to treat tinnitus, aphasia and depression, Bowers acknowledged that it is unlikely the company will make sufficient progress in any of those areas to launch a new pivotal trial this year.

Northstar is not the first high-profile failure in the hot neurostim/neuromodulation space. Cyberonics' decision to no longer focus on treatment-resistant depression with its vagus-nerve stimulation technology--concentrating instead on epilepsy--has been well documented. Northstar's fall may, however, cause investors to pause and assess what progress other players in this area are making before committing additional funds.

Other recent examples of bad neuro news come from one particular therapeutic area: PFO closure (a hole in the heart that fails to close after birth) thought to possibly cause both migraines and stroke. NMT Medical Inc. just announced that it was shutting down its MIST II PFO/migraine trial, primarily due to patient enrollment difficulties, to concentrate on its CLOSURE I pivotal PFO/stroke trial. Investors didn't take the news well, driving the company's stock price down as much as 35%, although it has regained about half of that lost value in the last couple of days.

Indeed, one whole area of PFO closure technology--so-called energy-based approaches that use sources including RF-energy to seal the PFO--has apparently proven unworkable. Cierra Inc., a company out of The Foundry incubator, is in the process of winding up its operations, and, according to executives familiar with this space, CoAptus Medical Corp., the other player in this space using an energy-based approach, may soon follow suit.

Lest we leave you with a completely negative take on the prospects for device-based neurological therapies, here's one recent positive development: earlier this month, the FDA cleared Penumbra Inc.'s system, which is a tool-set designed to treat ischemic stroke by removing occlusions from the brain's larger vessels. Penumbra's approach is designed to provide neuro-interventionalists with an approach that can be used beyond the narrow, three-hour window during which the drug tPA is indicated, as the company's system can be employed within eight hours of an ischemic event.

"Human Brain" by Flickr user Gaetan Lee used under a creative commons license.

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