"The Trenton Patient"

In Tuesday's New York Times, biotech writer Andrew Pollack has an overview of the work in progress to reach a cure for HIV, a story that we covered in the October issue of Start-Up.

Our favorite part of the story is Pollack's quotes from the anonymous HIV-positive patient whose early-stage clinical results were highlighted in September by Sangamo BioSciences. Sangamo's treatment SB-728-T aims to replace an HIV-positive person's immune cells with versions that lack the CCR5 receptor, the virus's main avenue of infection, and render them resistant to HIV.

The patient, who participated in a Phase I trial of SB-728-T at the University of Pennsylvania, was a lively interview. Identified only as "the Trenton patient," he told Pollack that the Sangamo treatment has made him feel both "like Superman" and "like Oliver Twist," the Dickensian orphan who held out his empty bowl and asked for more, please.

He might get his wish. As we explained in Start-Up (excerpted below), the Trenton patient's results were remarkable enough to encourage two more clinical trials, including one in patients who carry the same genetic quirk: 

The Penn trial also included a three-month interruption of the patients' HAART regimens to see if the gene therapy had any effect on viral load. In one patient, viral load went down until the virus was undetectable and stayed that way until the end of the treatment interruption. That patient turned out to be heterozygous; one of his two CCR5 genes was already mutant, which means the treatment resulted in a higher amount of biallelic modification in the patient – in other words, mutations to both copies of CCR5 genes. It's what [Sangamo CEO Edward] Lanphier calls "an important clue" that biallelic modification could have a strong correlation to reduction of viral load, and it will be the basis for Sangamo's next two studies scheduled to start in the first half of next year, with their clinical phase not yet determined. One study will focus on heterozygous patients specifically to see if results from the Penn trial patient can be repeated; the second study will use engraftment enhancement techniques already in use for cancer treatments to boost biallelic modification and make SB-728-T potentially applicable to a much broader HIV-positive population, not just heterozygotes.

For more on the revival of hope in HIV treatment, as well as some hard questions about who will fund the important work, read our story and let us know what you think.

Image courtesy of flickr user Sully Pixel via a Creative Commons license. 

2011 Alliance Of The Year Nominee: Lilly/Boehringer

It's time for the IN VIVO Blog's Fourth Annual Deal of the Year! competition. This year we're once again presenting awards in three categories to highlight the most interesting and creative deal making solutions of the year. The categories are: M&A Deal of the Year, Alliance Deal of the Year, and Exit/Financing Deal of the Year. We'll supply the nominations (a half 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™.

It's one of the biggest risk-sharing deals ever. It has oral drugs. It has insulins. It has biosimilars. And it's still making waves (including deal-breakers) in the already-choppy ocean that is diabetes.

Who would have expected Indianapolis-based Lilly to marry its struggling diabetes franchise with what's still only a pipeline at private German group Boehringer Ingelheim? The culture clash in itself deserves a DOTY nomination, but then there's so much more besides.

The January 2011 deal saw Lilly and BI agree to develop and market two of BI's oral diabetes compounds, a DPP-4 inhibitor Tradjenta (linagliptin) and a SGLT-2 inhibitor, and two of Lilly's basal insulin analogs, including a potential biosimilar version of Sanofi's Lantus (basal insulin glargine). So far, so fair. Except that BI gets an initial $388 million up front from Lilly, plus an option to co-develop and co-promote Lilly's chronic kidney disease antibody once it reaches Phase III.

Deal of the year for BI, then, perhaps, which gets paid to enhance its emerging diabetes portfolio and to tap into the services of an experienced diabetes marketing partner. This perceived imbalance is in part explained by Lilly's desperation, as it faces one of industry's steepest patent-cliffs, with the recent US expiry of $5 billion schizophrenia drug Zyprexa compounded by that of Gemzar in 2010, and by Cymbalta and Evista in 2013 and 2014. It's also in part about Lilly's defiant anti-M&A stance.

So to those ocean waves that, along with the chunky upfront, sheer number/size of big drugs involved (combined peak sales of $10 billion, predicts BI...), and not-to-be-sniffed at regulatory-milestones (over $800 million for BI for its hopefuls, and $650 million for Lilly for the insulins) make this a mightily strong DOTY candidate.

The effects of the Lilly/BI deal have rippled well beyond these two unlikely spouses. The deal provided a window onto the fascinating dynamics of the diabetes market, and -- importantly to those dynamics -- triggered Amylin's walk-out from its own Lilly partnership on the first-to-market GLP-1 agonist Byetta (exenatide) and once-weekly follow-on Bydureon. (No-deal-of-the-year nominee, perhaps?)

After almost ten years in bed with Lilly, Amylin felt let down by Lilly's agreement to co-commercialize BI's Tradjenta, which it felt would compete with its GLP-1s, even though the latter are injectable. After a lawsuit, Amylin paid (up to $400m in up-fronts and milestones) and left. Now the question is which of the diabetes leaders (Sanofi, Novo?), or indeed, which diabetes hopeful (GSK, Pfizer?) will buy Amylin? (Let's make that deal a 2012 nominee ... see, we're just so ahead of ourselves).

If the big-picture twisting-and-turning plot of this deal haven't convinced you yet, consider some of the commercial back-stories in the fast-moving diabetes space: can third-to-market Tradjenta carve out any niche in what has become a comfortable playing field for Merck & Co. Inc.'s first-to-arrive Januvia (sitagliptin)? And do safety concerns raised by an FDA panel over BMS/AZ's dapagliflozin, the first SGLT-2, spell the end for BI's second asset in the deal? As such, is Diabetic Investor's David Kliff right in saying that "Lilly has made a huge mistake" with this deal?

Meanwhile, can Lilly, whose strength has lain in insulins, rather than oral diabetes drugs, successfully apply the aggressive pricing tactics that have recently bought it some time (and market share) in existing insulin markets, to its insulin glargine candidate?

The story of Lilly-BI and the sub-plots it has generated is un-putdownable. There will be further series to follow. It's not a single DOTY, its a whole DOTY (and non-DOTY) franchise. Never mind those 'biggest ever', or 'most-creative ever'. Vote for the most interesting -- and get more bang for your vote.

image by flickrer watch4u, used under creative commons

2011 Exit/Financing of the Year Nominee: Ascletis

It's time for the IN VIVO Blog's Fourth Annual Deal of the Year! competition. This year we're once again presenting awards in three categories to highlight the most interesting and creative deal making solutions of the year. The categories are: M&A Deal of the Year, Alliance Deal of the Year, and Exit/Financing Deal of the Year. We'll supply the nominations (a half 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™.

Emerging biotech Ascletis Inc. is embarked on a truly ambitious attempt to create a trans-global pharma company and, in doing so, has raised one of the largest Series A rounds ever in biopharma -- $50 million in the first tranche, with another $50 million guaranteed to follow when the company hits certain milestones. Based on those achievements alone, Ascletis surely qualifies as a top-gun deal-maker of 2011.

The money speaks for itself—only 10% of 2011’s year-to-date Series As raised more than $40 million—and of those, only one other, Hua Medicine, also a Chinese biopharma, raised $50 million.

Asceltis’ round was the largest by far but the company is distinct in other ways that enable it to creatively exploit a host of industry-wide trends. Its strategy is to search globally for appropriate clinical-stage in-licensing candidates, which it can develop and eventually commercialize in China. It also plans to discover new drugs internally and bring them through mid-stage trials before seeking global partners for large-stage development and commercialization.

The aim, it says, is creation of a true hybrid model, poised, on the one hand, to capitalize on the innovation and strategic expertise of Western trained executives and scientists and, on the other hand, China’s capital efficiencies and opportunities for accelerated research. To drive its point, Ascletis recently broke ground on a new China headquarters and R&D center in the Zhenjiang Province in China and is planning a U.S. headquarters in Research Triangle Park, NC.

With la creme de la creme Western-trained management talent moving to China, more opportunities for savvy in-licensing deals exist there. The therapeutic areas of interest are oncology and infectious diseases, reflecting the expertise of its co-founders and scientific advisors, Jinzi Wu, a former VP, global HIV drug discovery at GlaxoSmithKline, Xiao-fan Wang, a professor of cancer biology at Duke University Medical Center, and Allan Baxter, former global head of medicines development at GSK.

And the financial largesse stems from the generosity of one angel investor, real estate billionaire Jinxing Qi, with additional commitments from unnamed private investors in the U.S. and China and elsewhere. That in itself is a trend, as angel investors, stepping in seem likely to be playing increasing, albeit limited, roles in early-stage biotech financing. And, of course, China itself is a massive commercial opportunity for the right talent, with a CAGR of 17% estimated between 2011 and 2015, according to IMS Health, which predicts China will be the world's second largest pharma market by 2016, up from No. 3 in 2010.

Of course, finding solid development stage assets is a hurdle, even for large, deep-pocketed companies. And the hybrid U.S.-China combined development strategy didn’t pan out for some earlier companies. But Ascletis, by dint of its multi-faceted strategy, highly experienced, globally-oriented management team, and angel-backed financial cushion, is de-risked more than most, even as it positions itself to benefit from one of the industry’s biggest current opportunities. A deal-maker of this caliber surely deserves Deal Of The Year recognition.

Guest Post: Advancing Next-Generation Combo Therapy in Oncology

By Aidan Finley, Consultant, Health Advances

We are all well aware that oncology is rapidly undergoing significant changes. Encouraged by recent FDA guidance, we've begun a transition from empirical combinations developed post-approval to rational combinations co-developed in the clinic. In this month's IN VIVO, Health Advances addresses the past and future of combination therapy for oncology.

As demonstrated by the recent launches of Xalkori and Zelboraf, the right ingredients are finally in place: more comprehensive genetic and biologic understanding of tumors, better tumor pathway definitions, availability of companion diagnostics, and a burgeoning armamentarium of clean targeted single and multi-kinase inhibitors. To transform these ingredients into successful drugs is no mean task: both clinical trial design and dealmaking need to change.

Fortunately, clinical trials are changing. We see an increase in combination trials, not just of established assets, but of novel agents early in development. For example Novartis recently combined its novel mTOR inhibitor Afinitor with Pfizer’s aromatase inhibitor Aromasin to great effect in breast cancer, showing PFS and OS survival benefits. And Syndax Pharmaceuticals released findings at AACR showing beneficial combination of its HDAC inhibitor entinostat with exemestane in breast cancer, and published a trial of entinostat in combination with Vidaza in NSCLC.

We also see more development of precisely dual targeted kinases, like Roche’s dual PI3k/MTOR inhibitor (GDC-0980) or Novartis’s competing dual P13k/MTOR inhibitor (BEZ235), or VEGF/FGF inhibitor dovitinib. Clinicians are also embracing the potential of new agents and combinations to affect resistance, a durable unmet need: At this moment at the MGH there are 4 trials opening for patients resistant to BRAF inhibitor in melanoma and 10 trials for patients with resistance to targeted agents in lung cancer. Collectively, these trials and abstracts represent the growing consensus around next generation combination therapy and the route by which sponsors, clinicians, regulatory authorities, and patients can advance care.

But biopharma partnership strategies need to evolve to allow for testing of more and better drug combinations (and we see more room for improvement here). Ultimately, developers need to balance the control of intramural development with the flexibility and risk-sharing of partnerships and joint ventures. AstraZeneca and Merck famously began their ALK and MEK collaboration in 2009 in part because their research directors bumped into one another at a security queue while traveling to a conference. Despite growth in cancer-specific partnerships since (e.g. Merck-Serono and Sanofi in 2010, Roche and BMS in 2011), has a better mechanism for identification and execution of partnership been identified?

One necessary change is a tighter coordination between R&D and BD. R&D efforts can no longer be siloed, or pursued in isolation without consistent reference to corporate strategic goals. BD efforts need to be partially focused on identifying both potential strategic partnerships and as well as agent-extending in-licensing efforts. Staying on top of the literature, BD can work to bring in complementary agents to better achieve dual inhibition of a target (e.g. to achieve something like the demonstrated benefits of trastuzumab and pertuzumab in Her2+ breast cancer) or actively seek agents targeting newly validated targets like EML4-ALK rearrangements after high-profile publications.

Given these factors, it makes perfect sense that oncology deal-making is aggressively moving earlier (pointed out by Campbell Alliance, here). But in-licensing alone cannot satisfy Pharma and Biotech’s need to mitigate risk. Companies need to get better at working together, using the Merck/AstraZeneca joint venture as a template. Sharing risk by sharing assets, development costs, trial designs, and ultimately regulatory risk will be necessary to capture full value for these complex oncology assets.

The situation gets even more complicated when biomarkers are considered. Using an established biomarker developer like Roche or Abbott will make negotiations between the existing two members of the partnership more complex, but these players may be the only ones capable of arbitraging the clinical and economic risk of companion diagnostic development. Pfizer and Abbott had their own difficulties developing their partnership over crizotinib, though the companies surmounted these difficulties with a successful joint application. Unfortunately for Abbott, they will receive only $1,500 per patient, compared with Pfizer’s $9,600 per month.

The market is already focusing on modular, diagnostic-aware, targeted therapies that can be slotted into multiple therapeutic lines and extended by combination or mechanism into adjacent indications. We want to see both intelligent in-licensing driven by R&D/BD alignment and data-driven opportunism as well as more structured joint ventures and collaborations focused on mitigating risk and better delivering complex, multi-company, multi-agent trials of out-of-the-box combination therapies. These are exciting times in oncology, and it is important to create the types of agents and combinations capable of dramatically advancing standard of care.

2011 M&A of the Year Nominee: Daiichi/Plexxikon

It's time for the IN VIVO Blog's Fourth Annual Deal of the Year! competition. This year we're once again presenting awards in three categories to highlight the most interesting and creative deal making solutions of the year. The categories are: M&A Deal of the Year, Alliance Deal of the Year, and Exit/Financing Deal of the Year. We'll supply the nominations (a half 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™.

In an era in which biotechs struggle to get financing and Big Pharma is hungry for new drugs (but typically favors deals that delay rewards), Plexxikon was dealt a top R&D hand and played its cards exceedingly well. Its strategy culminated in one of the priciest private buyouts in recent history, its $805 million up-front acquisition by Japan’s Daiichi Sankyo Co. Ltd. And if that don't scream M&A of the year, we don't know what does.

You want more? OK how about a deal that validates Plexxikon's previous partnering strategy, around a drug (the BRAF inhibitor Zelboraf/vemurafenib, which was at the time in pivotal studies) that wowed FDA so much the agency approved it later in the year in a brisk three and a half months? That drug was already half-owned by Roche, Plexxikon's partner since 2006, but the other half stayed at partner-rich Plexxikon, which cannily (some over the years would have said unnecessarily) hung on to its co-promotion rights.

Maybe what'll sway you even more is that little bit extra in earn-outs, cash that could take the value of the deal to $935 million? Or perhaps the estimated 12x return on the average venture investment dollar? (Plexxikon had raised only about $67 million from a syndicate that included Advanced Technology Ventures, Alta Partners and Astellas Venture Capital, thanks largely to its ability to bring in non-dilutive partnership dollars.) Or is it the surprise victor in what was clearly a competitive bidding process for Plexxikon, the seemingly suddenly deal-hungry Daiichi Sankyo?

The truth is there are many reasons to vote this deal to the top of a competitive DOTY field in the M&A category. Not least that Zelboraf, alongside Bristol-Myers Squibb's Yervoy, is one of only a pair of drugs approved to treat melanoma in a decade.  In a year of big approvals and some big deals, Zelboraf and the acquisition of Plexxikon are among the biggest.--Chris Morrison & Emily Hayes 

image from flickr user mrdelayer used under creative commons license

2011 Alliance of the Year Nominee: Forma/Genentech

It's time for the IN VIVO Blog's Fourth Annual Deal of the Year! competition. This year we're once again presenting awards in three categories to highlight the most interesting and creative deal making solutions of the year. The categories are: M&A Deal of the Year, Alliance Deal of the Year, and Exit/Financing Deal of the Year. We'll supply the nominations (a half 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™.

For years now, acquisitions of private biotech companies have more often than not resembled alliances, with their upfront-and-milestone deal structures. Isn't it about time alliances borrowed some characteristics of acquisition -- like liquidity for investors?

In fact, in 2011 we saw just that. And though it's not the first, the licensing agreement between private Forma Therapeutics and Roche's Genentech unit, announced in late June, is at least for now, the best specimen of the rare but intriguing species.

Forma's a drug discovery company. The kind of drug discovery company that goes after tough targets. The biotech's focus is on oncology, using its platform to generate compounds against targets in epigenetics and tumor metabolism. And its early progress -- the biotech emerged from stealth in early 2009 and had pulled in nearly $50 million in funding from Lilly Ventures, Bio*One, Cubist Pharmaceuticals and Novartis Option Fund -- attracted Genentech to take a look at the start-up's technology.

Though the large company has only licensed worldwide rights around Forma compounds targeting a single tumor metabolism target, the deal -- structured as an option-to-buy -- could provide Forma's backers with an exit, CEO Steven Tregay told START-UP this year. All while keeping the rest of Forma, and the additional value it may generate for investors, intact.

Genentech will pay the biotech an undisclosed up-front fee plus research funding and can acquire Forma's program against that undisclosed target, at a predetermined point for a predetermined sum. In the long run, the deal allows Forma to do what most biotechs cannot: build value by maintaining a focus on a potentially extremely lucrative platform while at the same time driving a solid exit for investors by pushing a single, promising program forward on someone else's dime.

And not just anyone else's. "Genentech is one of the best in the world in patient stratification and rapid clinical trials. There is no one better to do a deal with," said Tregay at the time. Meantime, Forma can stay centered on "what it's good at, without taking on the risk, cost, and burden of building a clinically focused organization," he said.

Forma's alliance with Genentech is more than a rare bird. It's a new, and potentially replicable, way to sustain a thriving, discovery-focused biotech company. And that's a rare opportunity --and worthy of a Deal of the Year nomination -- indeed. -- Chris Morrison & Ellen Licking

How Do Drug Firms Get New Pills In Front of Doctors?

How indeed? The U.K NHS has never been the fastest at adopting new medicines and technologies, and the emergence of new, regional-level gatekeepers looks set to make things worse.

As U.K health care reforms grant commissioning powers and budgetary levers to local groups of community doctors, with similar decentralization in other European countries, including Spain and Italy, a big question for drug firms is how to get their new pills in front of those community doctors. They no longer have battalions of sales reps. Nor, we're told, can they rely on the use of key opinion leaders (KOLs), since they're mainly hospital-based specialists, while adoption decisions are being made by a mix of advisors, managers and local doctors, many of them new to the process.

"Through no fault of their own, many of these people don't have the necessary experience or skills to understand what is being put in front of them, or to make informed decisions on new technologies," says Sally Chisholm, head of a small group of NHS planners, called the NHS Technology Adoption Centre (NTAC).

NTAC is attempting to accelerate adoption of new drugs and technologies in the U.K, having spent the past four years looking at the widespread, numerous and often unexpected barriers to uptake.

It appears that some basic skills are lacking when it comes to exchanging the old for the new. Quite often, Chisholm reports, no-one knows the steps that need to be taken to adopt a particular technology, how to measure the change that it causes, or how to halt or decommission traditional practices. "It really is quite tricky," Chisholm said.

NTAC's still tiny -- just 12 researchers -- and it has remained largely under-the-radar since its 2007 inception. But the group has intimate knowledge of procurement, budget setting and process management within the NHS, and is now starting to come up with structured procedures that can be followed by industry and doctors to speed the adoption of new technologies. For example, it has shown how barriers could be overcome to adopting a lymph node assay to check, during an operation, if breast cancer has spread. The barriers to adoption include its effects on operating theatre use, and nurse rotas, in addition to the actual cost of the assay.

Small wonder, then, that NTAC is beginning to attract interest from drug firms keen to explore its expertise to help them overcome adoption barriers. They may even be willing to fund its work.

NTAC wants to avoid any accusation of being an industry mouthpiece, although Chisholm says she is not averse to industry commissioning its work. A similar NHS organization, the National Institute for Health and Clinical Excellence (NICE), has in the past piloted the provision of advice, for a fee, to other organizations and companies.

Thus far, NTAC has produced an online tool called "generic adoption process" to help NHS organizations, and has pulled together some detailed analyses of approved technologies it believes the NHS should take on.

NTAC doesn't endorse the use of products in the same way that NICE does. It just provides a roadmap of how a new technology could be adopted, after it has been granted approval. As the route to new tecnology and drug adoption gets more complicated, NTAC's roadmaps could yet emerge as an increasingly important tool for drug firms seeking to get their products introduced into clinical practice.

Financings of the Fortnight Gives Thanks

You'll have to forgive your fortnightly columnist. Thanksgiving, our favorite holiday, always makes us a little maudlin. Too few people do what the holiday intends us to do: stop, smile, look at the faces around the table, and be thankful for what we have, wherever we are.

We won't be gnawing turkey legs with her tomorrow, so we want to give our thanks today to Ellen Licking, our friend and colleague, who is moving on to work for our former boss. (You can follow her odyssey tweet by tweet at @RealEndptsEllen when it goes live.)

Ellen has been one of many colleagues from whom we learn every day; we're thankful for those generous with their knowledge, and we're thankful for being able to write about an industry filled with folks who, once past the elevator pitch and into a more expansive mood, just might blow your mind. When we were young, Mama FOTF told us, "Try to learn something new every day." No better way than to be a journalist. Folks in our profession have many and various reasons for doing what they do, not all of them savory, but for us, being able to talk regularly with brilliant people working on fascinating, often intractable problems is a main reason we get out of bed in the morning. (Oatmeal with walnuts and brown sugar is another.) We're also thankful that we can say, "I don't understand, please explain," and on the whole people are happy to do so.

We're thankful for a few days off, and to spend those days with family, which the people we write about sometimes don't have time to do. Please do so; as we all learned this week, life can play cruel tricks. We wish everyone a happy, healthy and safe Thanksgiving.

Agios Pharmaceuticals: Agios has plenty to be thankful for. Nowhere close to having a compound in the clinic, the Cambridge, Mass. firm closed a Series C financing on Nov. 17, bringing in $78 million to help fund new research in rare genetic disorders. Agios CEO David Schenkein said the money would help fund the company’s research for the next “three to four years” and that it will allow the pre-clinical company to bring “multiple programs into the clinic simultaneously.” The cancer metabolism firm was backed by previous investors Third Rock Ventures, ARCH Venture Partners, and Flagship Ventures, along with Celgene and three undisclosed public investment funds. Agios previously raised $33 million in a Series A and struck a lucrative deal with Celgene for its pre-clinical cancer metabolism research in April 2010. The deal included a $130 million upfront and gives Celgene the exclusive option to any products that result from the platform. The deal included a modest equity investment. Celgene extended the deal in October 2011, providing Agios with a $20 million payment and gaining further equity in the company. The new research program will focus on diseases caused by inborn errors in metabolism and will give Agios some distance from its partner, Celgene. The close relationship was exactly why Schenkein decided to gauge the interest from public investors and begin research in an area outside cancer metabolism. Prior to the recent round of financing and the new research platform, Agios was so closely tied to Celgene that it cut off any chance that it could be bought by another company. -- Lisa LaMotta

Idenix Pharmaceuticals: Now that Hepatitis C competitor Pharmasset has been snapped up for a stunning $11 billion by Gilead Sciences, Idenix is one of two firms remaining with unpartnered nucleotide polymerase inhibitors, or "nucs," in the clinic to treat HCV. The firm raised needed cash in a registered public offering of its stock Nov. 21, selling 9.4 million shares at $6.50 a piece, but its timing was unfortunate; since the Pharmasset news, Idenix shares have traded nearly a dollar higher (they're were at $7.45 in mid-day trading Nov. 23). The clinical-stage biotech, which is focused on developing oral, direct-acting antiviral drugs for Hepatitis C, lately has placed its bets mainly on Phase II nucleotide polymerase inhibitor IDX184. Even before the Pharmasset announcement, Wedbush Securities analyst Duane Nash wrote Nov. 15 that Idenix itself could be ripe for a merger or acquisition, as it and Inhibitex own the only unpartnered nucs in the clinic, and virtually every player in HCV believes such a compound will be part of the next HCV standard of care. Meanwhile, Idenix has suspended development of its other Phase II asset, IDX375, a non-nucleoside polymerase inhibitor, also for HCV. During its quarterly earnings call Nov. 2, the Cambridge, Mass. firm reported $64.7 million cash on hand as of Sept. 30 and a nine-month net loss of $33.9 million, attributable mainly to R&D spend. The biotech noted its net loss was $11.5 million lower than a year earlier, due in part to the shelving of ‘375. -- Joseph Haas

Oxyrane UK: In a bid to trump Shire and Genzyme at their own rare diseases game, British biotech Oxyrane on Nov. 17 pulled in $26.5 million in a D round led by Morningside Group, with participation from Forbion Capital Partners and existing investor New Science Ventures. The round hardly wins any records for size, but the idea’s nice: to create enzyme replacement therapies (ERT) for orphan diseases that are more effective, and cheaper and easier to manufacture, than current ERT drugs like Genzyme’s Cerezyme (imiglucerase). The funds will be used to advance a pre-clinical ERT candidate in Pompe’s disease, and to validate Oxyrane’s technology platform, which uses the Yarrowia lipolytica yeast to produce human lysosomal enzymes that are taken up faster by cells, and are more targeted, than existing commercially-available versions. Relatively simple batch production processes may also allow Oxyrane to scale up manufacturing so as to “dramatically alter” production economics, according to investors. It wasn’t just the prospect of cheaper ERTs that pulled investors in. Oxyrane’s technology could have far broader application, for instance, in more efficient antibody production. That opens the door to future partnering deals with companies looking for large-scale antibody production capability, or with those trying to create cheaper biosimilars. -- Melanie Senior

Portola Pharmaceuticals: It’s tough to partner an anticoagulant these days, thanks to an increasingly crowded market that already includes Bayer and Johnson & Johnson’s Xarelto (rivaroxaban) and Boehringer Ingelheim’s Pradaxa (dabigatran), and which may soon feature Bristol-Myers Squibb and Pfizer’s Eliquis (apixaban). Case in point: Astellas Pharma gave up on Phase II candidate darexaban in September after failing to find a partner. Portola Pharmaceuticals could have been in the same boat after its two-year arrangement with Merck concerning Factor Xa inhibitor betrixaban fell apart in March, but instead the eight-year-old company has turned to private investors yet again, securing $89 million in new Series D funding that will give it enough cash to launch a Phase III trial on its own. Portola will also bring a companion Factor Xa antidote into the clinic. The new money brings the total invested in the company to $306 million, not counting a $9 million equity investment from Biogen Idec last month in connection with a partnership for spleen tyrosine kinase inhibitors; the company also has received non-dilutive money from Novartis for its 2009 elinogel partnership, as well as $36 million from Biogen and Merck’s $50 million up-front payment from the since-scuttled deal. Eastern Capital of the Cayman Islands and Temasek Holdings of Singapore led Portola’s new round, which also included longtime VC backers Frazier Healthcare Ventures, Advanced Technology Ventures, Alta Partners, MPM Capital, Prospect Venture Partners, Clarus Ventures and Sutter Hill Ventures. -- Paul Bonanos


Photo courtesy of flickr user Sugar Daze via a Creative Commons license.

Hopes Dashed For Biosimilar Enbrel?

Not a happy start, we think, to the Thanksgiving break for the likes of biosimilar hopefuls Merck & Co., Celltrion, Teva and Hospira. Late on Nov. 22, Amgen declared, in a thoughtfully-timed, rather succinct missive, that the patent life on RA and psoriasis blockbuster Enbrel (etanercept) had just been extended by 17 years.

Enbrel had been widely touted as one of the first complex biological likely to appear in biosimilar form, with protection assumed to expire in late 2012 in the U.S., and three years later in Europe. It was going to mark the start of the real returns for biosimilars, after their lackluster first round. Now it may be that the frontrunner copycats' race may have been futile.

Ok, so we're not patent lawyers. But U.S. patent 8,063,182, issued to Roche (and via exclusive license to Amgen), “describes and claims the fusion protein that is etanercept, and by statute, the ‘182 patent has a term of 17 years from today.” It looks pretty real to us, and composition of matter patents (which is what this is) are usually stronger than the kinds of formulation and process patents that had apparently been defending the drug to date.

Merck in June 2011 signed a deal committing it to pay up to $720 million for Korean Hanwha’s Phase III copy of the fusion protein (up-front money wasn’t revealed, nor whether this patent was factored in, so we won't get too hung up on numbers. But let's just say it has been an expensive week for Merck). It was one of the “eight to ten” compounds in Merck’s biosimilars pipeline that BioVentures chief Mike Kamarck has been particularly excited about.

Merck doesn’t feel it’s appropriate at the moment to share its feeling towards ‘182.

Others do. “This is HUGE,” declared one senior lawyer who has followed biosimilars for many years. And although the new U.S FDA 351 (k) pathway for biosimilar drugs in theory allows for patent litigation to begin, and thus potentially be resolved, early (e.g. before the product is launched), it also has some serious drawbacks that make it unclear how widely it will be used. (Kamarck, however, has said that Merck plans to use 351 (k).)

Perhaps Merck has anticipated and figured its way around this patent; after all, it was filed back in 1995. And even if not, '182 needn’t stop Enbrel competitors, such as Abbott’s Humira, Roche’s Rituxan or J&J’s Simponi from facing generics. Nor need it stop generic Enbrel in Europe.

Either way, any resulting litigation from the unexpected issuing of ‘182 could provide a meaty test for the dispute-resolution provisions in the new FDA biosimilar pathway.

Deals of the Week, Arlo, Ellen, and Eleven Billion Reasons to Invest in Biotechs

No 'official' Deals of the Week post this week, but we wanted to drop in and wish all stateside and US expat IVB readers a Happy Thanksgiving. The rest of you too -- enjoy either a long, turkey-scented weekend or a couple of quiet days before Saturday.

We'll be back next week with the launch of this year's Deals of the Year competition. For now our only deal-related comment is this: Eleven Billion Dollars for a Phase II Biotech? Eleven Billion Dollars for a Phase II Biotech.

Meanwhile, enjoy IVB's take on an old classic. And join us in wishing well Ellen Licking, who's off for challenges anew and who among much else wrote the parody below that we dust off each Thanksgiving week. In Vivo magazine readers will continue to see her by-line now and then, but we'll miss her around the virtual office and in our small, hopefully sharp, and sometimes sarcastic corner of the internet. All the best. --CM
  This post is called Deals of the Week, and it's about deals, and the week, but Deals of the Week is not the name of the blog, that's just the name of the post. And that's why I called the post Deals of the Week.

Now it all started four Thanksgivings ago; it was four years ago on Thanksgiving, when Chris Morrison and I started writin' a blog about deals, but not every day, just once a week. And writin' about deals once a week, you know it's a lot of work. (Hint. Hint.)

And there's a lot of garbage you gotta sift through, but we decided it would be a friendly gesture on behalf of readers. So we trolled around the Internet with our shovels and rakes and other implements of destruction (a.k.a. EBI's Strategic Transactions database) looking for deals to analyze. But then a big bad editor (also known as Officer Roger) said why are you doin' that? We are closed on Thanksgiving.

And we had never heard of a blog closed on Thanksgiving before (we don't get out much) so with tears in our eyes we drove off into the sunset looking for another place to dump our garbage -- I mean our deals.

We didn't find one. So we wrote our post anyway, went back and had a Thanksgiving Day that couldn't be beat, went to sleep, and didn't get up until the next morning when we got a call from Officer Roger... And it's been a recurring feature here at IVB ever since.

But fortunately, not another case of American blind justice since we always arrive at the truth of the matter and it doesn't even require 27 eight-by-ten color glossy pictures with circles and arrows and a paragraph on the back of each one.

In honor of the day, we hope you consider joining the IN VIVO Blog Movement. All you've got to do is walk into the office wherever you are, just walk in and say ,"You can get anything you want at IN VIVO Blog." And walk out.

You know if one person, just one person does it, they might think he's really sick and they won't take him... And can you, can you imagine fifty people a day, I said fifty people a day (okay, we'd really like 1000) walking in, quoting a line from IN VIVO Blog and walking out?

And friends, they might think its a movement. And that's what it is, the IN VIVO Blog Movement.

Remember Deals of the Week? (This is a post about Deals of the Week.)

Without further ado, we bring you this week's installment. Feel free to sing along in four-part harmony. With feeling. Cuz'...

You can get anything you want at IN VIVO Blog.
You can get anything you want at IN VIVO Blog.
Log right in, it's a click away.
Just a finger tap. You don't have to pay.
You can get anything you want at IN VIVO Blog. (Excepting Roger.)

Changes at Versant

Last week’s column in Fortune Magazine by venture capitalist Lisa Suennen of the Psilos Group appropriately asked “Hey, where are all the health care investors going?” As evidence, Suennen cited the departures of CMEA Ventures from medical devices and Highland Capital from health care (both of which were reported in Start-Up several months ago). But Exhibit C – “that Versant Ventures appears to be on the verge of reducing its health care practice” – surprised us.


After a few days of beating the bushes and collecting rumors by the bushel, we reached Managing Director Ross Jaffe, one of the founders of the firm, to get the details. Jaffe (careful not to tread into talk of fund raising so as not to violate securities regulations) did speak to changes that will occur at Versant.

The good news is the firm isn’t going anywhere. Versant will raise a new fund, although we believe that it will likely be smaller than the $500 million partnership it closed in 2008.

The less than good news is the roster of Versant managing directors is shrinking. Jaffe says four of the firm's managing directors opted out of participating in the next fund.   The departures shouldn’t impact the firm’s overall investment strategy. Two of the departing partners – Brian Atwood and Camille Samuels – invested in biopharmaceutical companies while the other two – Kevin Wasserstein and Rebecca Robertson – managed medical device investments. The firm generally balances its fund between the two sub-sectors. Jaffe declined to discuss specifics of a fund but said their fund size always derives from the number of partners sitting around the table

All four will continue to invest from Versant’s fourth fund. The decisions not to continue as active investors came during Versant’s planning for a fifth fund, Jaffe said, when each managing director was asked outright if they’re in for the long haul of a 10-year partnership. “If you are going to build a venture capital firm for the long haul you need to be thinking about individual partner’s plans and how the firm itself will evolve,” Jaffe says.

The four partners in question either declined comment or did not return requests for comment for this story.

According to Jaffe, Atwood and Wasserstein intend to remain active in the life sciences industry, while Samuels and Robertson are backing away from active investing. Atwood will concentrate on his current portfolio and may assist in new deal flow but won't be taking on new board seats. Wasserstein will work more closely with smaller device companies, including possibly some within Versant's portfolio.

Versant did promote Kirk Nielsen in January to managing director. He joins Bill Link in Versant's Orange County office while Brad Bolzon, Charles Warden, Jaffe and Samuel Colella work from Menlo Park.

No doubt, some might see Versant's decision as another knock on the prospects for life sciences investors as firms like Prospect Venture Partners and Scale Venture Partners scrap plans for raising news funds. Jaffe says Versant’s intentions shouldn’t be seen as a sign of weakness for the firm or the industry. “While everyone agrees this is a challenging investment environment with the FDA, reimbursement and other issues, we continue to see great opportunity for firms that have capital,” he says. “And we’ve had pretty good success.”

The firm was an early investor in several medical device companies that commanded significant prices from acquirers including LenSx, developer of surgical lasers for the eye, atrial fibrillation company Ablation Frontiers, balloon sinuplasty device marker Acclarent, laser vision correction company IntraLase,  and St. Francis Medical, maker of a spinal implant.

On the biopharma side, the firm exited Amira Pharmaceuticals this summer through a sale to Bristol-Myers Squibb for $325 million upfront plus earnouts. More recently it participated in the much-anticipated IPO of Clovis Oncology, in which Versant and other investors bought more than 40% of the offering at the $13-a-share offering price. That leaves Versant holding 2.2 million Clovis shares, worth about $27.6 million at the end of trading Monday, November 21.  

Like other biopharma investors, Versant has recently explored new models in acknowledgment that the traditional build-a-biotech strategy is increasingly difficult to justify. One idea, which sprang from the Amira exit, is a drug discovery kitchen dubbed Inception Sciences (we wrote about it here) that will spin out compounds into separate corporate entities that let potential buyers choose assets a la carte instead of having to buy the whole restaurant. The second idea binds a potential acquirer to a start-up right away, which Versant did recently with the cancer genomic analysis firm Quanticel Pharmaceuticals. At launch, Celgene paid $45 million upfront for exclusive technology rights, a small equity stake, and exclusive options to buy Quanticel a few years down the road. 

Several non-Versant sources familiar with the firm's plans told us that Versant is under the same pressures as its peers, as LPs become increasingly fearful of larger funds and unwieldy teams. Jaffe sees it differently: “We have a very different business culture at Versant. Each of my partners is thoughtful about how we approach our business and how we handle our careers. People will believe what they want to believe but this is what is going on.”


Alex Lash contributed to this report.

Alex Barkas

From Prospect Venture Partners

It 
is
 with
 great
 sadness 
that 
we
 share 
the 
news
 that 
our 
partner 
Alex
 Barkas
 passed
 away 
on
 November
 21,
 2011, 
suddenly
 and
 unexpectedly. 
Alex
 was 
an 
extraordinary father, 
and
 husband, 
friend
 and
 colleague,
 deeply 
admired
 and 
respected
 by 
all 
who
 had
 the
 special 
privilege 
to 
know
 and
 work
 with 
him. 
In
 nurturing
 those 
that
 he cared
 about 
the 
most,
whether
 it 
was 
his 
family,
 friends,
 colleagues, 
entrepreneurs or 
his
 charitable 
interests,
 Alex 
brought 
passion,
 wisdom, 
sincerity
 and 
an 
unrivaled love 
of 
life.
 Alex
 leaves 
behind
 for 
us 
a 
legacy 
of hope
 and
 commitment 
to 
achieve
 greatness 
with 
kindness,
 care 
and 
perseverance.
 He 
will 
be very 
deeply 
missed.  

Our condolences to his family and all who knew him.

The Avastin Decision: Bad For Genentech, But Good For Industry?

On its face, FDA Commissioner Margaret Hamburg’s decision to rescind Avastin’s breast cancer claim is a clear (though likely not unexpected) blow for Genentech, which waged an aggressive, creative and undoubtedly expensive battle to maintain its blockbuster VEGF-F inhibitor’s accelerated approval for first-line metastatic disease.

But, look a little deeper and you’ll understand why the decision should be (and perhaps already is) being cheered by the larger biopharmaceutical industry.

Hamburg’s 69-page opinion is confirmation that the accelerated approval mechanism is alive and well, and this is because the regulatory pathway’s accelerated withdrawal mechanism has now been validated.

“The Pink Sheet” touched on this briefly in our initial coverage following the two-day Avastin hearing in June (“Avastin’s Breast Cancer Claim: Will FDA’s Hamburg Take A Middle Road?” “The Pink Sheet,” July 4, 2011). However, now that Hamburg’s verdict is in, we think the issue warrants further exploration.

Think of the chaos that would have been created for FDA and industry if Hamburg agreed with Genentech’s view that accelerated approval can and should be maintained until there is practically no hope of confirming clinical benefit?

How many CDER review division directors do you think would be willing to approve a novel therapy on the basis of an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint other than survival or irreversible morbidity, knowing that it would take an act of God to get a drug off the market when the sponsor ultimately either can’t (or won’t) confirm the benefit in post-marketing studies?

How many review division directors would want to go through the scrutiny, and at times embarrassment, that the oncology review division faced during the course of Genentech’s 11-month long battle?

Hamburg lays it all on the line on page 55 of her opinion:

“Withdrawal here is the essential counterpart to accelerated approval. When the accelerated approval pathway was established, it was done with full recognition of the risk that drugs might be approved and later found not to confer clinical benefit to patients. FDA deemed this risk worth taking for life-threatening illnesses in need of additional therapies, but also found it essential to mitigate that risk by providing for follow-up studies and withdrawal when benefit is not confirmed. The program has, on the whole, worked very well, making many new drugs available, particularly to cancer patients and AIDS patients, years before they would otherwise have been on the market. But when follow-up studies fail to confirm benefit, it is essential that approval be withdrawn in order to protect patients.”

If the accelerated withdrawal hammer had been rendered meaningless, we predict you would have seen a lot fewer accelerated approval announcements coming out of CDER in the years ahead. Better to wait three, four, five years for survival data, or confirmatory evidence on some other “hard” endpoint, before making an approval decision than having to face both the embarrassment and time-consuming work of defending your revocation decision at a public hearing, all the while wondering if your own commissioner was going to back you up.

Hamburg’s comments highlight the strengths and weaknesses of progression-free survival as a surrogate endpoint. Though the agency is still reticent of giving hard targets, as sponsors would prefer, it lays out that in many first-line settings, it is the only practical option and one the agency is happy to review. The level of benefit that counts as “clinically meaningful” may be a matter of debate, but even Genentech acknowledged during the hearing that FDA’s granting the MBC approval was “progressive thinking” on the part of the agency. For other sponsors, the Avastin process has added some clarity on FDA’s expectations surrounding PFS – in particular, that quality of life benefits could serve as evidence that the benefit is clinically meaningful. So the Avastin withdrawal shouldn’t just dissuade sponsors from using PFS, it should encourage them to design trials with supportive measures that can themselves turn into additional claims. (Indeed, Incyte’s Jakafi (ruxolitinib) just cleared FDA with a patient-reported outcome based symptom claim.)

By withdrawing Avastin’s MBC indication, Hamburg has introduced some predictability into the accelerated approval regulatory pathway, both for agency staff and drug developers. We’d be surprised if industry, and its investors, didn’t see that as a good result. -- Sue Sutter 

Deals of the Week Takes a Backseat to Non-Deal Newsiness

Not quite a goose-egg

Deals, Schmeals. What about Geron's stem-cell about-face? Denner's departure from Icahn's shop? And how about an IPO that wasn't underwater? Don't even get us started on MLB re-alignment or seeing Papelbon in a Phillies uniform. The news this week came thick and fast; it just didn't come for the most part in the form of alliances and M&A.

It has definitely been a big week for financings: Clovis Oncology took the prize when it took the rest of its Series A to the public markets, raising $130 million to fund its ambitions in tough-to-treat cancers. Staying private (for now) was Agios Pharmaceuticals, which raised a whopping $78 million in Series C funds to move beyond cancer metabolism (courtesy its existing venture backers and corporate partner Celgene, but also some shiny new-but-unidentified crossover types). And we haven't even mentioned molecular diagnosticians Biocartis' $100 million venture round, but at this point we'd better move on before FOTF smacks us over the back of the head with a shelf financing.

It's also been a big week for regulatory action: today's unsurprising surprise announcement from FDA Commissioner Hamburg revoking Avastin's metastatic breast cancer approval will not draw an appeal from Genentech even as it draws supporters' ire. But a couple nifty approvals for some niftily named new orphan drugs (Incyte's Jakafi and Erwinaze from EUSA Pharma) should dampen the enthusiasm of FDA-bashers. And of course there was the news that FDA may soon have some new approval mechanisms at its disposal, Progressive Approval and Exceptional Approval, as detailed in this piece from Monday's "The Pink Sheet".

Deals of the Week will take a break next week -- don't worry, you'll get your Alice's Restaurant -- as we gear up for our fourth annual Deals of the Year competition. But of course we've got a few nuggets to tide you over until December. Take a gander at...

Sanofi Pasteur/Curevac: The option-deal signed Nov. 15 between the private German biotech CureVac and Sanofi's vaccine division provides some measure of validation for the former's RNA-vaccine technology. It also gives the French drug maker rights to certain infectious disease programs, with R&D partially underwritten by Uncle Sam. On the same day Sanofi and CureVac said they were teaming up, the two companies also announced a $33.1 million, four-year R&D collaboration with further partners In-Cell-Art, a French nanotech company, and the US Department of Defense's Defense Advanced Research Projects Agency (DARPA). Because it has an option on the programs that in essence are being funded by the four-way collaboration (mainly by DARPA), Sanofi gets to kick the tires on CureVac's platform before committing significant cash. Its option rights -- based on pre-agreed license terms around vaccine programs against 'between five and ten' pre-defined pathogens -- are linked to the fulfillment of certain criteria within the DARPA-funded validation program. Pulling the trigger could cost Sanofi up to €101.5 million per pathogen in upfront and milestone payments for global marketing rights. That figure jumps to €150.5 million in the case where a prophylactic and therapeutic vaccine are developed. -- Melanie Senior

Shire/Shionogi: Shire has landed a Japanese market partner for undisclosed elements of its flagship ADHD franchise. The company said Nov. 18 it would team up with Shionogi & Co. to co-develop and co-commercialize ADHD meds in Japan, in exchange for an up-front fee and sharing future costs, though specific terms weren't released. Deal-wise, Shionogi has been more active in ex-Japanese markets this year (acquisitions in China and the US, for example) than at home, where it said earlier this year it would open a new R&D center. Compatriots like Daiichi and Ono Pharmaceuticals, which in recent months has licensed in Japanese rights to products from BMS, Merck-Serono, Servier, and KAI, have been more actively seeking out assets to sell in Japan. Shionogi has some experience in ADHD through its 2008 acquisition of Sciele Pharma, which sells Methylin for the condition. Hey, is that a goose in the back seat of an old Beamer?-- Chris Morrison

Genzyme/CFF: Genzyme (a Sanofi company) and the Cystic Fibrosis Foundation said Nov. 16 they would together work to identify "corrector" compounds that could fix malfunctioning CFTR proteins in patients with the disease's most common mutation, Delta F508. The collaboration will benefit from Genzyme's and Sanofi's extensive compound libraries, the companies said in a statement, and build not only upon past collaborations between the biotech and the CFF but also Genzyme's ongoing efforts in CF R&D. The company holds an option for global rights rights in all territories outside the US and Canada -- in all indications (except Duchenne/Becker muscular dystrophy) to PTC Therapeutics' ataluren (formerly PTC124), including CF, where the compound is in Phase III. The development of ataluren, which is being developed for a variety of genetic disorders involving nonsense mutations, was also partially funded by CFF grants. -- C.M. [Ed Note: the original version of the post misstated the territories/indications for which Genzyme has an option on PTC's ataluren. We regret the error.]

Medicis/Graceway: Medicis is buying the U.S. and Canadian pharmaceutical assets of bankrupt Graceway Pharmaceuticals for $455 million, subject to approval by Graceway’s board of directors. Graceway was founded in 2006 by private equity firm GTRC Golder Rauner and Jefferson Gregory, a co-founder and former chairman of King Pharmaceuticals. It filed for bankruptcy in September 2011. Details about the bankruptcy and other aspects of Graceway’s business are sketchy but the deal gives Medicis, a specialty pharma with projected 2011 sales of more than $730 million, a commercial portfolio with six key drugs with combined revenues of more than $125 million. The Graceway products complement Medicis’ focus on dermatology and aesthetics; they include Aldara (imiquimod) cream for basal cell carcinoma, Atopiclair for dermatoses, Maxair Autohaler (pirbuterol acetate inhalation aerosol) for bronchospasm, and Estrasorb (estradiol topical emulsion) for menopause. The deal also gives Medicis a small R&D program, including an undisclosed Phase II dermatology compound and a women’s health compound in Phase II. At the time it formed Graceway, GTRC said it would put up to $200 million into the company. Later, Graceway acquired the branded pharmaceutical business of 3M for $875 million, and rolled in with it another GTRC portfolio company focused on dermatology drugs, Chester Valley Pharmaceuticals. GTRC had formed that company in 2004 with an investment of $75 million. -- Wendy Diller


image by flickr user smohundro used under creative commons license.

Guest Post: In Oncology, Is Early Partnering The Name Of The Game?

By Jonathon Fendelman, Senior Practice Executive, Campbell Alliance

The Celgene/Quanticel tie-up announced November 4, typifies a trend we’ll be discussing in greater detail at the coming Therapeutic Area Partnerships meeting: the trend of partnering early in oncology. Under the terms of the agreement, Celgene will commit $45 million to Quanticel during the initial three-and-a-half-year alliance term, with the ability to extend the collaboration in exchange for additional funding. Celgene will also take an equity stake in Quanticel and retains an exclusive option to acquire the company.

As IN VIVO Blog outlined in this post, Quanticel will utilize its platform to conduct single-cell genomic analysis of patient tumor samples and to identify predictive biomarkers for Celgene’s investigational drugs. Quanticel will also perform its own drug discovery, and via the acquisition option, Celgene retains the ability to access those pipeline candidates.

The upshot? As competition for good assets strengthens, pharmas are beginning to lock up rights to assets long before proof-of-concept data are in hand. To put some numbers on the trend, Campbell Alliance used Elsevier’s magic eight ball – also know as Strategic Transactions-- to identify the total number of alliances year-to-year with upfront payments of more than $10 million. We were only interested in deals centered on assets (as opposed to those centered around the resolution of patent disputes or R&D support, for example).

Using this metric, we found that the total number of licensing deals completed over the last several years has remained relatively consistent. In 2008, there were 62 deals completed based on our criteria. This was followed by 61 deals in 2009 and 62 in 2010. This year should see a similar number of deals, given 42 deals were completed as of the end of September.

What does this have to do with oncology deal making? In 2008 and 2009, 24% of the alliances were for oncology products. 2010 saw a slight downward blip, with only eight of the 62 deals, or 13%, in this therapeutic area. But oncology deals appear to have bounced back in 2011, with 28% of the 42 deals year-to-date involving cancer medicines.

Further analysis showed that in 2008 and 2009, there was a bias in the oncology deals toward products in Phase I and Phase II development. But in 2010, that bias swung even earlier, with five of the 8 oncology deals revolving around assets that were in preclinical or Phase I development.

As we'll discuss at TAP, that trend has continued in 2011. Of the 42 deals completed thus far this year, 12 involve oncology products, with half of those in Phase I development or earlier. These six alliances all involved first-in-class compounds that work via new mechanisms of action.

We see a clear enthusiasm for early-stage oncology deals. In the context of this enthusiasm, we anticipate any new oncology deals will also center on early-stage products, particularly compounds that work by a novel mechanism of action. Such assets offer the differentiation payers are more likely to reimburse for upon approval.

Not wanting to be caught with me-toos, drug makers are forced to tie-up rights earlier, before proof-of-concept, hedging their risk with option style alliance structures. As competition continues –and let’s face it, nearly every big pharma wants to be a top player in oncology – that energy will create a positive feedback loop, creating further incentives for earlier oncology partnering.

Image courtesy of flickrer Carol Myra used with permission through a creative commons license.

DOTW: This Is Spinal Tap Edition

In the immortal words of one Bobbi Flekman, "money talks and bull**** walks."

And on 11.11.11, a day some are lauding corduroy and many are honoring our veterans and active service men and women, we look across the pond for the big money deal.

That's right. In a week when "most blokes, you know, will be playing at ten," Lundbeck and Otsuka took it to eleven with a multi-faceted alliance centered around two late-stage products from the Japanese pharma and up to three earlier stage programs from the Danes. (No word yet on whether Lundbeck's CEO Ulf Wiinberg or Otsuka's President Tatsuo Higuchi will play the role of Nigel Tufnel, alas.) The pipeline- and profit-sharing, co-development, co-commercialization deal requires Lundbeck to pay Otsuka 1.1 billion Danish Kroners, or 200 million George Washingtons, up front and potentially another $1.6 billion in development, regulatory, and sales milestones.

In spirit, Lundbeck/Otsuka recalls the major alliance Lilly and Boehringer Ingelheim struck in diabetes earlier this year --the consequences of that deal, as you will read about below, are still causing ripples. Interestingly today's eleven alliance sees two companies -- both heavily dependent for the bulk of their revenue on a single product that will soon go generic -- try to diversify not only their pipelines but also geographic reach. That Lundbeck is the one on the economic hook stems from the fact that its patent cliff is not only steeper but also arrives in a few months time.

The $200 million upfront Lundbeck is undoubtedly hefty, but analysts and investors in Denmark didn't smell anything rotten, sending the company's stock price, which trades on the Copenhagen exchange, up nearly 10% on the news. "We see this deal as clearly positive for Lundbeck and it bodes well for long-term revenue, top-line diversification and company perception" Nordea analysts wrote in a note to clients.

The reason for the optimism? Recall that Lundbeck is overly dependent on Cipralex (which is partnered with Forest in the US where it is sold as Lexapro) for sales revenue. In 2010, close to 40% of the company's DKK 14.8 billion in revenue came from the antidepressant, whose key patents begin to expire in 2012. And for this upfront payment, Lundbeck gets co-dev/co-commercialization rights in certain regions (North and Latin America, Europe, Australia, and "some other countries") to two late stage Otsuka products that can help smooth its revenue line starting in 2013.

The first is the Japan pharma's depot formulation of aripiprazole, which is the same active ingredient in Otsuka's anti-sychotic juggernaut, Abilify, a drug that is partnered with BMS and goes off patent in 2015. The second is OPC-37415, a partial D2 dopamine receptor agonist in Phase III trials for schizophrenia and major depressive disorder. According to the press release announcing the deal, Otsuka plans to submit an NDA for aripiprazole depot to US regulators "soon" -- and to EMA authorities in 2013.

Lundbeck has done other big deals in the past in a bid to deemphasize its reliance on Cipralex, including its 2009 acquisitions of Ovation and Life Health to gain access to the chorea treatment Xenazine. Those deals certainly helped bolster Lundbeck's US CNS presence (especially after the failed 2008 $100 million alliance with Myriad Genetics around Alzheimer's therapy Flurizan), but are nothing compared to the potential it might reap with this Otsuka alliance, should aripiprazole depot and '37415 both make it to market and enjoy strong payer traction.

And reimbursement remains an open and intriguing question, especially for aripiprazole depot. Note that $1.4 billion of the milestone payments are tied to development and regulatory advances not actual reimbursement, meaning Lundbeck is still on the hook, even if payers ding the next-generation anti-psychotic. And that could well happen. The anti-psychotic market is not only competitive, but ripe with cheaper alternatives, including since October 2011 a generic version of Lilly's Zyprexa. Over a year ago Medco and genetic test developer SureGene, meantime, launched a research project to validate biomarkers that could improve the cost effectiveness of atypical antipsychotic treatments.

For its part, Lundbeck and Otsuka seemed to play up in the press release the known safety and efficacy of the depot formulation, noting there may be an outcomes-based reason to prescribe the more patient-friendly version of Abilify. After all it has been designed to "reduce the chance of reoccurence of symptoms for the patients who sometimes forget to take their medication". Patient adherence to anti-psychotic regimens is admittedly a big problem; whether Otsuka has data convincing payers of this benefit is another question. It's also one that the Japanese pharma, and now Lundbeck, will need to answer effectively to make the economics of the new alliance work for both parties.

As David St. Hubbins would no doubt tell you it's such a fine line between stupid and clever. In the meantime, turn the amperage all the way to the right 'cuz you'll feel much worse if you aren't under such heavy sedation. With none more black than IVB, it's time for...


Merck Serono/Ablynx: In a move that might reduce the sting of last week’s announcement that Pfizer was handing back a pair of anti-TNF-alpha programs, Ablynx said this week that partner Merck-Serono would expand its alliance with the Nanobody specialist. The new deal will see the partners co-discovering and co-developing Ablynx’s brand of single-domain antibodies against two targets in osteoarthritis. Ablynx gets €20 million up-front (paid as two tranches over the next three months) and will conduct and fund all pre-clinical work on the programs. Merck-Serono can then opt in at IND stage at a price of €15 million per program, after which Ablynx gets the choice to move forward as a 50/50 partner or choose a more traditional milestone/royalty-based licensing structure. This is the two companies' third deal since 2008; they’re currently also working on programs in oncology, immunology and inflammation. The deal has done little to reverse the slide in Ablynx’s market value since the Pfizer news, however. That drop worsened this week when Ablynx said its lead proprietary asset, the IV-formulated anti-vWF ALX-0081, did not meet its primary endpoint in Phase II studies. – Chris Morrison

Salix/Oceana: Gastroenterology-focused Salix Pharmaceuticals will expand its product portfolio and increase its revenues almost immediately with the planned $300 million acquisition of privately held Oceana Therapeutics. Announced during Salix’s third-quarter earnings call Nov. 8, the acquisition brings the specialty pharma two marketed products – Solesta for fecal incontinence and Deflux for vesicoureteral reflux. The company’s optimism about Oceana seems largely based on the upside potential of Solesta, an injectable gel approved by FDA as a Class III medical device in June, to win a large share of the fecal incontinence market. Oceana launched Solesta in September at a price of $3,690 per treatment. It can be administered on an out-patient basis without anesthesia. By contrast, surgical methods for treating fecal incontinence are thought to cost about $30,000 per patient. Salix did not say how much Solesta has earned to date but CEO Carolyn Logan predicted the product could produce peak-year sales greater than $500 million. Also an injectable gel, Deflux was approved by FDA in 2001. It is indicated for children affected by Grade II to Grade IV vesicoureteral reflux, a bladder malformation that can result in severe kidney infections and irreversible renal damage. It also is approved and marketed in 40 countries outside the US and posted net sales of about $26 million through the first nine months of 2011. –Joseph Haas

Amylin/Lilly: Once a fruitful partnership, the nine-year tie-up between diabetes specialist Amylin Pharmaceuticals and Eli Lilly around the GLP-1 agonist exenatide is being unwound. Although the agreement produced an $800 million drug in Byetta, a twice-daily injectable compound that stimulates insulin production in the pancreas, and a potential blockbuster follow-on in the once-weekly Bydureon, the writing’s been on the wall for some time, as their relationship became frostier over time. Lilly co-developed a different drug, DPP-4 antagonist Tradjenta (linagliptin) alongside Boehringer-Ingelheim; that led to a lawsuit, as Amylin believed Lilly breached their confidentiality agreement by using a shared sales force for both Byetta and Tradjenta. To remedy the situation, Lilly will return worldwide exenatide rights to Amylin in exchange for $250 million up-front plus 15% of sales, the latter of which could be worth up to $1.2 billion. All related litigation will be dropped. The separation occurs as Amylin awaits approval of Bydureon in the US; the drug has a PDUFA date of January 28, 2012. In the meantime, as this "Pink Sheet" Daily story discusses, Amylin plans to build its domestic sales force while seeking an international partner to sell Bydureon, which is already approved in Europe. Some observers, however, think Amylin could be acquired by another pharma instead. – Paul Bonanos