GSK’s Promacta at ASCO: Advisory Committee “Show and Tell”

When it comes to finding ways to recruit new members for its advisory committees, the Food & Drug Administration is getting pretty creative.

Having already undertaken various activities to fill vacancies among its expert panels, FDA embarked on the Ultimate Roadshow at the American Society of Clinical Oncology’s annual meeting last week in Chicago: a committee review of GlaxoSmithKline’s eltrombopag (Promacta), a non-peptide oral platelet growth factor for the treatment of idiopathic thrombocytopenic purpura.

As the saying goes, if you can’t bring the candidates to the advisory committee, bring the advisory committee to the candidates. And we’ve got to hand it to FDA: what better opportunity to attract new members then to hold a meeting smack dab in the middle of one of the biggest medical conferences of the year?

FDA has been working to fill advisory committee vacancies for some time—by creating a central database for committee openings and asking medical associations to nominate potential candidates. But there are still more than 100 openings between the drugs and biologics review centers alone. (For a breakdown by advisory committee, check out this chart in the latest issue of “The Pink Sheet.”)

The committee that reviewed Promacta at ASCO, the Oncology Drugs Advisory Committee, or ODAC, currently has four vacancies. Compared to other advisory committees, oncology isn’t doing too badly: the Dermatologic and Ophthalmic Drugs Advisory Committee, for example, has 12 vacancies, and the Anesthetic and Life Support Drugs Advisory Committee has nine.

But the decision to hold Promacta’s review at ASCO is based less on ODAC’s relative need for additional committee members, and more on the vision of the lead oncology reviewer at FDA, Richard Pazdur. (For more on Dr. Pazdur, check out our earlier story in the The RPM Report; those who don’t subscribe can sign up for a free trial.)

Pazdur is quite dedicated to an open, transparent review process. Summaries of ODAC’s meetings, for example, are published in peer-review journals. By scheduling the Promacta meeting during ASCO, oncologists have a “convenient opportunity to observe first-hand the processes and issues that are considered during an ODAC meeting,” FDA says.

With any luck, the agency says, some of those oncology experts in the audience might become interested enough to serve on the committee. Hence, “it can also serve as a recruitment tool.”

Pazdur has done this sort of thing before: Promacta is actually the second committee meeting to be held off-site at a medical conference. At Pazdur’s suggestion, Bristol-Myers Squibb’s dasatinib (Sprycel) for chronic-phase chronic myeloid leukemia was the lucky subject of a committee review during the ASCO conference in June 2006.

We say “lucky” because Sprycel was unanimously recommended for approval, and was quickly cleared for marketing later that month. Likewise, Promacta was recommended for approval by a 16-0 vote, despite concerns that eltrombopag’s marketing plan includes, according to FDA, a risk management program that encourages off-label use.

With a sample size of two—and FDA's final say on Promacta's approvability still outstanding—we suppose it is premature to assume that a cancer treatment would have an easier time getting past an FDA advisory committee held in the midst of the greatest oncology R&D love fest in the world. But it is something to think about.

So far, none of the other FDA review divisions have followed Pazdur’s lead. But it may make good sense. Consider this: the Dermatologic and Ophthalmic Drugs Advisory Committee May 29 review of Sirion Therapeutics’ difluprednate (Durezol) convened with just four voting members. That's a lot of power in the hands of just a few people.

REMS to the Rescue? Why FDA's Drug Safety Tools May Mean More Approvals This Year

The statistics aren't encouraging: fewer new drugs approved by FDA so far this year than last--and last year was arguably the worst year all time for the innovative industry.

But we are boldly predicting a big finish to the year, in part for an unlikely reason: FDA's new mandatory post-marketing safety tools that allow it to compel labeling changes, Phase IV studies, and--most significantly--Risk Evaluation & Mitigation Strategies.

The REMS authorities kicked in in March, and we’re learning a bit more about how FDA is using its new tools. And while there was much nervous anticipation as industry braced for FDA to start wielding its new (now mandatory!) risk management tools, the reality has been pretty positive.

There have been a lot of required post-marketing studies, and relatively few full-fledged REMS programs for new molecular entities. In fact, it looks like REMS is turning out to be a way to revive applications that once looked dead (or at least terminally “approvable”).

FDA has applied the new drug safety tools to three new molecular entities so far this year--CV Therapeutics/Astellas’ Lexiscan, UCB’s Cimzia, and GSK/Adolor's Entereg. And in every case the sponsor has been thrilled to have a product to market at all. (Read about some of the early experiences with REMS here.)

That's just the tip of the iceberg.

A REMS is definitely in the works for GSK’s platelet growth stimulator Promacta (eltrombopag), and Lilly has hinted that its antiplatelet agent Effient (prasugrel), partnered with Daiichi Sankyo, could have some form of a REMS – although Lilly is suggesting it would be on the less intensive end of the spectrum. Both NDAs received three-month review extensions, an emerging pattern for reviewing REMS proposals.

The premature press release snafu for Amgen’s Nplate also revealed that a REMS program called NEXUS is slated to accompany the approval of romiplostim, a fusion protein that, like Promacta, treats idiopathic thrombocytopenic purpura.

FDA’s new authority opens a new parlor game of guessing which applications could be REMS-worthy. According to Pharmaceutical Approvals Monthly, there are at least 30 NMEs pending with user fee deadlines coming up during the second half of the year. Which ones could have a REMS?

Pfizer/Ligand’s Fablyn (lasofoxifene) for treatment of post-menopausal osteoporosis: The post-Evista SERM class has had trouble clearing the final approval hurdle at FDA, in part because of safety issues. Prior to the Fablyn submission Jan. 15, lasofoxifene (then Oporia) was found not approvable for prevention of PMO in 2005, and then not approvable again, for treatment of vaginal atrophy, in 2006. Wyeth’s SERM Viviant (bazedoxifene) has been approvable twice for osteoporosis prevention and once for treatment. Further data was requested on stroke and venous thrombotic events.

Johnson & Johnson’s paliperidone palmitate: Can the once-monthly version of J&J’s antipsychotic Invega do better than the “not approvable” letter issued to Lilly’s fellow atypical antipsychotic Zyprexa for its once-monthly depot, Zyprexa LAI? The long-acting injection formulations may have a new risk of excessive sedation. Given J&J’s flagging public enthusiasm for the project, and its renewed interest in Alkermes’ claim that its technology can now support a once-monthly version of Risperdal Consta, does J&J really care?

Schering-Plough’s Bridion (sugammadex): The prospect of the first selective relaxant binding agent, which was just approved in the EU, has stirred up the anesthesia market. But signals from FDA could indicate caution. The agency extended the user fee goal by three months to review a hypersensitivity study. And in an unusual set of events, a March advisory committee supported approval, but could not make a formal recommendation because data had been submitted shortly before the panel met.

Moving beyond the bounds of pending NMEs opens a plethora of potential REMS. One likely candidate is Cephalon’s fentanyl product Fentora. The advisory committee review of a breakthrough cancer pain indication for the approved drug focused on the inadequacies of the existing RiskMAP. Other extended-release pain products, like Labopharm’s tramadol formulation, are also potential REMS contenders.

Review the list yourself and play along at home. What else looks REMS worthy to you?

--Bridget Silverman

Wacky World of Generics: Thalidomide Edition

Even the title has to cause shivers or a good shake of the head. Thalidomide? Generics? The two words don’t belong together: it can’t be possible.

How can thalidomide (the infamous teratogen and source of the crisis that led to the 1962 FDA efficacy amendments) be the source of a debate about generic use? This is not wacky. This should be inconceivable.

But it’s not.

Celgene’s highly successful Thalomid brand of thalidomide, with sales last year just short of $450 million, has passed its tenth year on the market. And it faces a generic challenge from Barr Labs, which has an ANDA pending for the drug’s initial orphan indication, treatment of the cutaneous lesions of erythema nodosum leprosum.

Now, a struggle is developing on the ability of generic companies to replicate the tight risk management program that Celgene developed to make thalidomide a commercial product.

To get Thalomid to the market, Celgene developed a strictly controlled distribution and patient contact /education program called STEPS. The company devotes more than 175 employees to maintain its risk management programs. The program is so important to the commercial use of the product that Celgene has a patent on the program itself.

STEPS may represent a steep barrier to generic copies; at least that is what Celgene hopes. The company has laid out its arguments against FDA approving generics in a petition filed with the agency a year ago: Sept. 20, 2007. (For an anlysis of the Celgene petition, see our coverage in “The Pink Sheet.")

FDA’s eventual decision as to whether the thalidomide risk management program can be copied or mimicked will be of major significance to the entire industry.

As FDA begins to require more risk management programs (now called REMS – Risk Evaluation & Mitigation Systems) as integral parts of NDA approvals, these post-market controls have the potential to significantly lengthen the life of brands.

Or as Celgene pointedly argues to FDA: "In many ways, the survival of the company depends on the successful implementation of its novel restricted distribution plans." Give away its risk management program to another marketer and FDA will give away the core of Celgene’s ability to market thalidomide safely. The company notes that it has successfully prevented patients from experiencing the horrors of the teratogen. If another company is distributing the ingredient less carefully, it would hurt the public, the drug industry and Celgene’s brand.

But FDA was specifically instructed in the FDA Amendments Act (passed a year ago in September 2007) to prevent companies from using REMS as barriers to generic competition. Something is going to have to give.

The decision on STEPS will be one of the important early precedents arising from FDAAA. It is significant that Celgene used ex-FDA general counsel Dan Troy to craft its arguments to protect STEPS and Thalomid.

Not only is Troy a prominent figure on the issue of FDA’s ability to control industry marketing practices, he has also recently become the general counsel of GlaxoSmithKline – assuring that the issue of the value of REMS as a way to block generics will get the attention of at least one other major pharma player. Indeed, GSK has been--by accident if not design--one of the most active early players in shaping how the REMS authority will be used, having already agreed to three programs for its new products, and with a fourth pending for Promacta.

In the wacky future world of generics, companies will have to learn how to replicate post-marketing control programs as well as how to replicate the chemical structures. The safety programs may turn out to be harder to copy.

The REMS Pioneers: GlaxoSmithKline Edition

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

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

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

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

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

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

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

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

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

GSK finds itself as the early leader in that learning.

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

Deals Of The Week: The Sputnik Edition

Outside the deal making arena, the word garnering significant air time this week was “innovation.” During this week’s bipartisan date night, also known as the State of The Union address, President Obama mentioned the word at least nine separate times, as he channeled Survivor’s Jeff Probst. “We need to out-innovate, out-educate, and out-build the rest of the world.” He called on the country to “get behind innovation”, exhorting “this is our generation’s Sputnik moment.”

One could well ask if this is Big Pharma’s Sputnik moment as well. The biopharma industry is well aware of the need for innovation. Indeed, the stricter pricing environment in Europe and the US (where payers are pushing back on multiple classes of drugs even if NICE-like decision making isn't yet a reality), has already forced a wholesale shift, with a greater emphasis on devising drugs for unmet medical need and actually demonstrating said value.

As the industry wrestles with its innovation gap, there are a number of puzzles to solve. The first, and potentially easiest, to come to grips with is access to new products and new ways of thinking. It’s one of the primary reasons biopharma companies are cutting deals with academia and not-for-profits with such regularity, none more so than Pfizer, which rolled out its New York-based Center for Therapeutic Innovation(CTI) just hours before the Prez made his way to Capitol Hill.

A thornier question is what actually constitutes innovation these days. Ask a completely random group of industry execs and the answer almost certainly would be new drugs (or devices) to address some unmet medical need: lupus, major depressive disorder, Alzheimer’s. Undoubtedly those are areas deserving investment; so too, however, are improvements in care delivery in high cost arenas like diabetes or hypertension, where the problem isn’t lack of therapy, but actual compliance. There’s a growing opportunity on the service side, and some companies – Sanofi in diabetes, Novartis via its collaboration with Proteus Biomedical – are taking important, albeit early steps, in this direction.

For pharmas to “win the future”, maybe they, too, need to reinvent themselves, like the Michigan-based mom and pop roofing company run by the Allen brothers, which Obama highlighted in his SOTU challenge. One way to do so is by embracing new definitions of innovation beyond the canonical: a new drug hitting a novel target that historically garners a premium price tag. We remain an industry where “better” might mean “faster” (or more convenient) but it almost never means “cheaper”. Why not?

It's a question worth pondering for big drug makers; as Obama rightly reminds us, "Our destiny is our choice." Meanwhile it's time to take a spin through another weekly deal-making wrap up...

Novartis/Genoptix: This week Novartis launched a $470 million cash tender offer for cancer specialty testing lab Genoptix, which offers personalized diagnostics services related to hematological malignancies – and to a lesser extent solid tumors – to community-based oncologists. The acquisition will add more muscle to the Swiss pharma’s two-and-a-half-year-old Molecular Diagnostics unit. As the pharma’s division head of pharmaceuticals, David Epstein, told investors on the company’s quarterly earnings call on Jan. 27, the move ensures companion diagnostics would be “readily available as we launch our new pharmaceuticals.” Indeed, the acquisition gives Novartis infrastructure and also know-how not normally found in pharma-based R&D that should smooth the transition from biomarker identification to actual companion diagnostic test development, which could range from home brew tests run at Genoptix’s lab to more broadly distributed test kits. As such, the deal is another indication of the confidence the pharma has in its pipeline of targeted cancer drugs, largely for hematological malignancies, and their belief in biomarkers – a marching order unaltered since the formation of the Novartis Institutes for Biomedical Research, whose resources directly fuel much of the effort of the Molecular Diagnostics unit. (To learn more check out this issue of IN VIVO.) Even as the industry has turned more and more towards outsourcing R&D, Novartis continues to drive translational research from within via NIBR. By taking on the risk of bringing in and supporting a diagnostics development infrastructure, it’s making a similar statement in the testing realm. – Mark Ratner

Amgen/BioVex: Amgen's Jan. 24 earnings call promised a plan to invest more heavily in research & development. On the same day, the company put its money where its mouth is.
Amgen deepened its commitment to oncology, revealing plans to acquire biologic vaccine developer BioVex for a $425 million cash upfront payment as well as milestone payments totaling as much as $575 million. Cash-rich (the big biotech has around $18 billion in its coffers), Amgen's massive upfront commitment - the largest for any privately held biotech in at least two years, according to Elsevier's Strategic Transactions database - is a powerful vote of confidence in cancer vaccines, the area in which BioVex has concentrated most of its efforts. The agreement is also easily the largest deal in the sector since April 2010, when Dendreon received approval for Provenge. The deal represents a payday for the well-funded BioVex, which has raised $175 million from at least 15 firms since its spinout from University College London in 1999. For BioVex, the sale to Amgen – especially at this price tag – makes obvious strategic sense. With two Phase III trials underway on its OncoVex product, an immunotherapy for both metastatic melanoma and head and neck cancers, the company faced increasing commercial costs that would require an alternate source of funding. "Getting to the public markets is hard in the current circumstances," Coffin told sister publication "The Pink Sheet" DAILY. "Amgen has amazing resources, and we felt that on balance, this was the best overall opportunity." – Paul Bonanos

Ligand/Cydex: For biotechs, the truism “it’s good to have a revenue stream” has never been more important than in today’s capitally constrained environment. The logic of regular income underpins Ligand Pharmaceutical’s purchase this week of privately-held Cydex Pharmaceuticals for $36 million, nearly all of which – $31.2 million – was paid upfront. The move diversifies Ligand, a classic drug development play founded in 1987 that has been moving away from that paradigm to a model described on the company’s website as “developing or acquiring royalty revenue generating assets and coupling them to an efficiently lean corporate cost structure.” Not including new licensing revenue or accelerated growth of the San Diego biotech’s Promacta, the deal is expected to double Ligand’s projected 2011 revenue relative to what it stood to pull in as a stand-alone and moves the firm forward in its goal of becoming a profitable entity. In 2010 Cydex chalked up $16.3 million in revenue thanks to its proprietary drug reformulation Captisol technology, which works by surrounding drugs with specially modified cyclodextrin molecules to allow tighter control of a medicine’s delivery. The Kansas-based Cydex, which will continue to operate as an independent subsidiary of Ligand following the close of the acquisition, already has numerous partnerships with industry players, including Onyx Pharmaceuticals and Prism Pharmaceuticals for the creation of Captisol-enabled IV formulations of carfilzomib and amidarone respectively. And in terms of regulatory risk, the formulation technology is something FDA seems comfortable with – it’s already included in five marketed medications. If Ligand believes it can earn a pretty penny from the Captisol franchise, Cydex’s investors, which include among others SR One, Eastman Ventures, and Techno Venture Management, have barely achieved an exit. Since its inception in 1993, Cydex has raised around $27 million in financing; like so many other private companies, it tried – and failed – to go public in 2008. – EFL

Teva/Corporacion Infarmasa: Teva Pharmaceuticals has conspicuously shied away from the sometimes frenzied investment in China, India and other emerging markets, noting the high valuations and intense competition. It is targeting Latin America for growth, however, as it progresses with plans to increase revenues from $14 billion in 2009 to $31 billion in 2015. Thanks in part to its 2006 acquisition of rival Ivax, it now has operations in Venezuela, Mexico, Argentina, Chile, Brazil and Peru. With this week’s acquisition of Corporacion Infarmasa, one of Peru’s top ten pharma companies, it makes additional in-roads into this Latin American market. Terms weren't disclosed, but Corporacion Infarmasa is owned by two American investment groups: The Rohatyn Group and Altra Investments. Infarmasa manufactures and sells a portfolio of more than 600 branded and non-branded generics, focused largely on antibiotics, antihistamines, analgesics and corticosteroids. By combining Infarmasa with its existing Peruvian organization, Corporacion Medco, Teva will be the number two player in a market that had a CAGR of 12% between 2005 and 2010 and could reach $1.8 billion by 2015. Expenditure per capita on pharmaceuticals in Peru is one of the lowest in Latin America, leaving ample opportunity for future increases, Teva said. – Wendy Diller

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