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

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

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

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

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

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

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

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Yule Blog: The Virtual Are Only Virtuous Thanks to the Substantial

It’s time once again to sing the great Christmas Paradox—the annual carol that venerates the Immaterial in the temples of the Material.

And as everyone knows, it’s just fine that we do. Our economy’s fortune ebbs and flows with the CPI – the Christmas Paradox Index. That’s why – as some significant fraction of us proclaim that the only present we want is you or family or world peace -- the news we evidently want to hear is about the health of retail sales.

We are not, however, going to babble on about this particular holiday cliché. Instead, we want to point out that our industry has a parallel Paradox – the Infrastructure/Anti-Infrastructure theme now playing in the drug business almost as insistently as Deck the Halls in shopping malls.

At Windhover’s Bio/Pharma Partnerships conference, for example, Randy Woods noted that his old biotech company, Corvas, needed plenty of scientists just to get to the clinical-stage deal its investors wanted. Now, given the gap in Pharma’s late-stage pipeline, VCs want to fund the development themselves, entirely without partner money -- but with only enough infrastructure to manage the CROs and consultants they hire to do the work. Investors want all their dollars to go into development – not offices and certainly not salaries.

That’s exactly what happened with Woods’s more recent employer—NovaCardia (12 people; two products; sold with just one of the products to Merck for $350 million) and what will likely happen with current company Sequel (which inherited the same people, NovaCardia’s second product, and its investors).

Or Bristol-Myers Squibb. Senior BD director Lynne Croucher spoke about its “selective integration” strategy (and discussed at greater length here, here, and here) which, along with risk reduction, effectively reduces requisite infrastructure – off-loading costs and responsibilities onto primary-care partners. That’s why Bristol can without significant business pain cut some 4800 jobs.

And now Peter Corr, the former R&D boss at Pfizer, the industry’s most fully infrastructured business, has ended up at Pfizer’s philosophical opposite, the anti-infrastructuralist private-equity player Celtic Therapeutics (here’s the savvy assessment by the WSJ’s Health Blog).

The fund (an outfit we first wrote about in late 2005) is an ambitious follow-on to private-equity pioneer Celtic Pharma, which has deployed nearly all its $250 million in capital (plus an additional $151 million in debt) in buying up nine development-stage programs, whose development it funds using a network of CROs. It then wants to sell the successful programs to the highest bidders (so far it’s sold one and lost one). The new fund apparently hopes to do the same thing but on a much larger scale--according to the Financial Times, it’s aiming to raise $1.5 billion. Corr expects the first close of the fund this January.

Big Pharma’s infrastructure “isn’t meeting its needs,” he says. In fact, despite billions spent on R&D, drug companiest don’t even “have the flexibility to fund new projects, or more from one project to another based on science” because they’re funding infrastructure instead. Celtic Therapeutics will employ maybe 65 people managing 20 projects.

You see the paradox, no doubt. It’s not that the infrastructure doesn’t exist. It’s still there—in CROs, for example. And it’s still there in the companies that ultimately fund Celtic’s returns. If it weren’t, Celtic would have neither advantage nor customers (low-infrastructure Big Pharmas could presumably license the same programs Celtic can).

In sum, most of those caroling along about the virtues of a virtual industry know that without the infrastructure someone else is paying for they wouldn’t have much to sing about at all.

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Prasugrel: Lilly Tries to Stop the Bleeding (Part 1)

We were a bit taken aback by Lilly CEO Sidney Taurel’s editorial in the Wall Street Journal earlier this week recounting the damage done by the frenzy of speculation about the prospects for the platelet aggregation inhibitor prasugrel.

Taurel takes financial journalists to task for trading in “leaks and rumors where scientific data are concerned” and calling on “would-be pundits” who “have not had firsthand exposure to the scientific results or specialized knowledge under discussion” to “qualify your comments if you must make them at all.”

Its not that we disagree with Taurel. Like most self-respecting journalists, we are only too happy to join in any critique of the sloppy practices of our competitors (since we of course are the exception that proves the rule, right?).

No, what took us aback about the piece was its premise: the almost quaint notion that pharmaceutical companies can somehow put the genie back in the bottle and have the final say in when or how information about their products—even unapproved products like prasugrel—will be disseminated to the public.

Taurel’s argument, in effect, is that journalists, analysts and investors should have waited patiently for the release of the pivotal trial data on prasugrel (the TRITON study) at the American Heart Association meeting November 4, rather than engaging in a frenzy of speculation based on news that Lilly had suspended two other trials of the drug. Lilly decided to report that data there, and in a companion piece published by The New England Journal of Medicine.

Lilly, of course, couldn’t release the data early because it committed to an embargo prior to the AHA presentation. “Such guarantees of exclusivity are not only common, but also appropriate, in focusing expert attention on important research,” Taurel writes. “A definitive source and a ‘zero hour’ of first-hand disclosure for complex scientific data help to limit misinformation.”

Ah, the good old days. Things used to work that way for sure. But in the era of the internet, clinical trial registries, managed care claims databases, FDA drug safety newsletters, and emerging active surveillance systems, it is simply no longer possible for drug sponsors to hope to control the information flow about their products. (Not too mention the unbelievable proliferation of would-be pundits known as bloggers.)

In this case, Taurel laments, “10 days before our ‘zero hour,’ word leaked out, causing us to confirm that the two prasugrel trials had been suspended, although our promises to NEJM and AHA prevented us from explaining why.”

The truth, as Taurel explains, was that prasugrel performed very well in the pivotal trial, but that there were “three small subgroups of patients” in whom a risk of excessive bleeding appeared to outweigh the benefits. “Based on the small chance that patients in the three identified subgroups might be given prasugrel and experience serious bleeding, we advised our researchers to suspend the two trials pending a review,” Taurel writes.

But the damage was done. “The media entered a feeding frenzy, catered by commentators on Wall Street and elsewhere who speculated that prasugrel posed broad risks and had probably failed its major trial. Our stock began its trip south and, more seriously, some doctors and patients were left with false impressions.” Lilly’s shares recovered somewhat after the data were finally reported on November 4.

We might quibble a bit with choosing prasugrel as the case to make this argument—claims of patient harm seem overdone here when we are talking about a drug not yet approved by FDA. Commercial harm, yes. Harm to Lilly’s investors, yes. But it is a bit of stretch to say patients were harmed.

But still, Taurel is right about the potential for media feeding frenzies to cause tremendous harm. Its happened before, for sure. Maybe Avandia is an example, or even Baychol—cases where coverage of an unexpected side effect led many patients to discontinue treatment on their own, leaving at least the possibility that more harm was done by untreated diabetes or high cholesterol than by the adverse events in question.

Even so, Taurel sounds a bit like Lear raging against the storm. We understand his concern, but it is hard to imagine any way he or any other industry CEO can reverse the winds.

We aren’t the only ones who think that. Plenty of smart people in government and industry are talking about the revolutionary changes in information flow about medicine—including a whole bunch of executives at Lilly. In fact, though this is impossible to handicap, we would be willing to bet that Lilly is at the forefront of recognizing and adapting to a world where the pharmaceutical company sponsor is no longer at the center of the information flow about drug products.

We have heard several Lilly executives speak publicly and privately on this very theme. During a panel discussion on clinical trial policy at the University of North Carolina in February, one Lilly executive talked about the move towards active surveillance as potentially engendering a “Wikipharmacy” model in which product use information is no longer generated by FDA and the sponsor in labeling negotiations, but rather by a global community of users exchanging information on real-world experiences with the drug.

And Taurel himself has talked about it. During a policy address at the Cleveland Clinic early this year, Taurel focused on the revolutionary potential of healthcare IT advances. He even talked about the importance—and benefits—of public access to data once jealously guarded by manufacturers.

“For businesses that generate health data and new knowledge, it’s time to learn the benefits of openness," Taurel said in Cleveland. He went on:

"We need to open our minds to the notion that electronic outcomes data – once the privacy of individual patients is protected – represent a legitimate ‘commons,’ a resource to which access should in most cases be widespread and easy.”

“That’s not to ignore the fact that great effort and expense goes into collecting many types of health information. Certainly at Lilly, we spend hundreds of millions of dollars every year on clinical trials. But the key insight in our situation, and I think it applies quite broadly, is that unlike most other assets, health information actually becomes more valuable the more it is used, studied, and applied. It does not depreciate.”

So what gives with the Journal editorial? Did Lilly decide that openness is wrong? Hardly. Taurel even repeats his argument that openness is critical for industry: “Trust hinges on our openness in sharing everything we know about who should use our products—along with when, how and at what dose—and who should not.”

What we are really seeing here is not a vain attempt by a pharma company to turn back the storm, but an example of one way to try to advance against the wind.

The frenzy around prasugrel hurt Lilly, but it also provided an opportunity for the CEO to talk about the product in a prominent forum. The fact is that Lilly (and its partner, Daiichi Sankyo) plan to submit a new drug application based on TRITON to FDA before the end of the year. Anything Lilly can do to shape the climate for that review is critical.

When you look at it that way, maybe the most important line in the editorial is the sentence at the end of the fifth paragraph, citing a quote from the Journal’s earlier reporting on prasugrel: “If you can't get a drug on the market with that kind of data, we should stop developing drugs.” That is a message not just for business and science reporters, but for FDA reviewers as well.

So will Lilly get this drug on the market with this kind of data? Coming Monday, one would-be pundit will share his thoughts on what it will take to make that happen.

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Nail in the Coffin for GPC?

Turns out FDA’s ODAC committee had a point when it announced, in July, that it would wait for overall survival (OS) data from GPC Biotech’s prostate cancer drug satraplatin (Orplatna) before considering review. Topline OS data—released today, sooner than expected—was negative. It wasn’t as if the p value just missed, either: it was 0.8. Median survival in the placebo arm was if anything a little longer than that in the treatment arm.

At the time, there were cries of despair: refusing to consider interim data around progression-free survival marked the FDA’s new ultra-conservative stance, noted some analysts, as we reported here. This was the end of accelerated approval.

Now the story looks rather different. This time it’s only about GPC—and whether it has a future. The overall survival data, one analyst predicted to IN VIVO Blog in July, “will decide the fate of the company, not just satraplatin.” Indeed, the ODAC decision to hang approval on a single end-point, rather than consider interim progression-free survival data as well, turned it into a make or break event for the company.

So is this the end of GPC? It’s not clear yet—we’ll find out more on the conference call scheduled today at 12.30 GMT. GPC’s shares lost over 60% first thing this morning, to add to the hammering they took in the summer. As your blogger blogs, analysts are downgrading the stock to sell on questions around long-term viability. Management's credibility, already shaken by the events in July, will probably be in tatters.

Indeed, given strong interim data, the accelerated approval granted by FDA in April 2007 (hah! what use now) and GPC officers’ general confidence, some analysts before today felt that the chances of good overall survival data were reasonable. For them it was a question of re-adjusting their time-lines for approval and questioning whether GPC could afford to maintain its full clinical program for satraplatin.

Today’s release looks more like a nail in the coffin for satraplatin. When GPC withdrew its NDA following the ODAC decision, it didn’t expect overall survival data to be available until 2008; a spokeswoman told us in July that top line data would take six months to collect. Yet sooner than that, GPC is announcing a “re-evaluation of the development plan”, the negative impact on satraplatin’s EU review led by partner Pharmion, and an almost valedictory 'thank you' to those taking part in the blighted trial.

Even if GPC could afford to continue developing the drug in other indications, would it (or a potential acquiror) want to? The drug's patent life is relatively short--to 2015 with extensions, according to one London-based analyst. As for potential acquisition, the shareholder suit filed against GPC in July--accusing the company of using "improper methods" to measure satraplatin's effectiveness--pretty much guards against that.

So to the lessons (yes, always a lesson or two): partner your drug before Phase III (look, after all, at the value of proof-of-concept stage deals!). Hedge your bets. Don’t get too excited about your wonder-drug’s approvability, even if the need is unmet. Diversify--not so much as to lose the plot, but enough to avoid this sort of thing. And, ok, this time FDA looks justified in having asked for overall survival data as proof that the drug does indeed have some beneficial effect. But that still doesn’t mean the agency’s any better disposed towards cancer drugs developed by small biotechs. In fact, the satraplatin saga is only likely to have made FDA warier still of early approval based on interim analyses.

UPDATE: There wasn't a lot of new information on the conference call. GPC CEO Bernd Seizinger, MD, PhD, noted that while there are upwards of 20 subgroups of patients still to be analyzed, he didn't want to raise anyone's hopes that a subgroup analysis could trump today's bad news in any way. He also flagged up GPC's November 8th third quarter results as a time when the company would be more prepared to discuss its strategies with regards to sataplatin as well as its corporate future.

GPC still considers satraplatin an asset of value--a "Phase II asset," Seizinger said. Finally, he noted, this is "certainly not the end of GPC biotech. We have a strong cash position and an excellent team , and we still have important assets in the company." The market may be disagreeing. The stock is down about 62%, valuing the company dangerously close to its cash position, which was €93.1 million ($134 million) as of the end of June 2007.

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How to Improve Drug Development? Fail Fast!

In this morning’s PSA panel on “Development Dilemmas and Opportunities,” Michael Clayman, MD, VP of Lilly Research Laboratories at Eli Lilly & Co., presented a unique option for optimizing clinical pipeline success. Perversely, it depends on failing fast. Clayman heads Lilly’s Chorus division, an organization that is trying to create a new model for drug development built on not reducing attrition but increasing the chances post-clinical proof of concept that a drug will make it to market. We took an in-depth look at Chorus in May in IN VIVO.

Clayman estimates that 90% of drugs in development will fail anyway, so why devote the time, the resources—the dollars—driving a product forward if it’s not going to make to market? The goal of his group: cut costs, and dramatically narrow the time to a decision point—typically proof of concept in man, what Clayman jokingly refered to today as “pull out your checkbook”—down to as little as twelve months.

It’s a goal Clayman claims Chorus is well on its way to achieving. To date, the company has shown that it can shave 12 to 18 months off the time it takes a drug to reach proof of concept and reduce the R&D dollar spend from $30 million to $3 million.

But, outside these metrics, there aren’t obvious ways to measure the group’s success. It’s not as if the company can use drug approvals as a measure, since the goal of Chorus isn’t to get drugs on the market, but to de-risk them as much as possible. Indeed, it’s an organizational tool to manage Lilly’s vast portfolio of drug products so that the bias is on the ultimate winners. And while nearly 80% of Lilly molecules might be pushed forward according to this program, to date the strategy has been applied to just 10.

According to Clayman, one critical component of the strategy is that Chorus is compound agnostic. No one on the 24-person team has a driving loyalty to a molecule that might sway him or her to push one project forward over another. The group also operates as an autonomous division within Lilly so that it is not hide-bound by the operational infrastructure of the larger organization. “Once a molecule is transferred to us, it’s no longer worked on by Lilly scientists. We outsource the experimentation,” he says.

That level of outsourcing is likely to be troubling to most other major pharmas. It seems unlikely that many outfits would be willing to adopt such a strategy unless there were significant proof that it improves R&D productivity. Until such time, expect the refrain to remain simply Lilly’s chorus.

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FDARA: Changing Drug Development in the Guise of Safety Controls

The Food & Drug Administration Revitalization Act is famously the “drug safety law”—the once-in-forty-years major overhaul of FDA authority to bring the agency’s drug safety activities back up to par with the agency’s focus on drug efficacy.

But don’t overlook the fundamental changes that the new law will impose on the drug development process. It is likely to change drastically how companies seek FDA approval and how they support marketed products with further research. Some previous analysis of incentives in FDARA can be found here.

The separate versions of the law passed overwhelmingly in the Senate (S1082) and House (HR2900) over the last four months are being forged into one bill in active pre-conference discussions.

Two former FDA commissioners see fundamental changes stemming from the FDARA tools. They pointed out two of the major changes during a September 12 briefing on drug safety in Washington, DC, hosted by American University.

Phase IV--no longer the unchallenged province of drug sponsors: Mark McClellan, MD, says Phase IV, strategic research will never be the same again. The new public-private post-marketing surveillance project that is featured in FDARA will change the dominance of Phase IV by drug sponsors.

The “post-marketing period will move out of the control of the pharmaceutical industry,” McClellan declared. McClellan was the first FDA commissioner in the George W. Bush Administration (2002-2004). He currently heads the Engelberg Center for Health Care Reform at the Brookings Institution.

Faster NDA/BLA approvals for narrow, precise indications: David Kessler, MD, stresses the need for the agency and drug sponsors to act more creatively in the initial approval process.

Kessler sees an opening for FDA to encourage sponsors to study smaller patient populations in return for faster approvals and FDARA may provide the right tool for making that implicit deal occur. FDARA offers a form of tighter safety controls through risk management plans and post-marketing surveillance that could represent a new version of conditional approval. Kessler, vice chancellor of medical affairs at the University of California-San Francisco was FDA commissioner under George H. W. Bush and Bill Clinton (1990-1997).

The impact of FDARA on Phase IV cannot be under-estimated. For over two decades, pharma has lavished resources onto Phase IV to support extended indications, improving ties to medical thought leaders, generating cost data and justifications and gaining access to large user groups. The industry has also made commitments to FDA to carry on work on issues raised by FDA during premarket review.

After the American University event, McClellan was asked by Alicia Mundy (author of Dispensing with the Truth, a book on the Fen-Phen drug interactions) about the likelihood that FDARA would increase corporate compliance with FDA Phase IV requests. Asking whether the industry would still be able to use “stall tactics” to delay Phase IV regulatory commitments, Mundy expressed the general skepticism that has grown around the FDA-agreed Phase IV work.

McClellan chose to answer the question from a broader perspective: looking more at who controls Phase IV rather than whether companies meet or don’t meet FDA commitments. He noted that the new law will jump-start a big effort in post-market surveillance and increase that amount of research on commercially marketed products. The law’s encouragement of a public-private partnership and the $25 million initial funding for the program will start a separate effort—beyond the funding and control of pharma.

McClellan looks to other stakeholders in drug treatments to provide competing funding for post-marketing research: primarily health insurers, academic centers and employers. If those groups feel that post-marketing surveillance will help to cut down unsafe or unnecessary drug use, they clearly would have an economic and quality stake in supporting studies.

While pharma’s dominance of Phase IV appears to face a FDARA challenge, another part of the new law appears to provide a surprising boost to the effort to shorten drug trials and achieve faster initial approvals.

Kessler stated the opportunity for changing drug development in a call for a deal between industry and FDA to adopt smaller trials based on genotyping and a target of smaller patient populations. “The industry is in a conundrum,” Kessler said, is it “willing to narrow the number of patients it sells the drug to?” He believes FDA may soon be in a position to create incentives to get sponsors to aim at the smaller populations.

FDA could tell sponsors, for example, that one, redesigned trial incorporating genotyping information could suffice, Kessler suggested.

Kessler, who still frequently slips into the first person pronoun when describing FDA options, said: “Let’s say we are going to allow you to do one trial and we are going to ask you to genotype everybody in that trial.” The sponsor could use data from the first half of the trial to identify a predictive gene panel. The sponsor could then apply that genetic profile to the second half of the trial to determine whether the drug has a “high degree of effectiveness.” That type of development trial could be used toward a conditional or tightly controlled approval.

FDA is already moving in that direction, asking for information on very specific patient populations and then turning that information into very tight risk management plans.

That tailored market approach, in essence, is an updated version of a conditional approval. It is likely to be used more frequently following FDARA when the agency explicitly receives authority to create risk management plans for each approved product through the REMS (Risk Evaluation & Mitigation Strategies) provisions of the law. Kessler recognizes the potential larger role for REMS.

Risk management plans under the REMS procedures “could be no more than what the agency does now or it could be a drastic change in the way the agency controls drugs,” the former commissioner said. But he predicted that FDA will use the authority expansively and REMS will be applied to a “wide array” of products.

Sponsors will be required to submit information on the level of REMS program that they believe fits their product. A clear definition of the target audience will be an important part of those submissions and are likely to become a fulcrum for future FDA approval decisions. If a sponsor can show a well-defined population and a way to make sure that the product is used on that population, the route to approval will be much faster.

(Originally posted at The RPM Report.)

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Another Co-Promote Bites the Dust

When Merck and partner Neuromed yesterday pulled the plug on Phase II chronic pain treatment NMED-160/MK-6721, another co-promote bit the dust, too.

More proof, then, that most co-promote options built into today’s biotech-pharma licensing deals are just window-dressing—comfort cushions for biotech investors dreaming of drug revenues and spec pharma success. Earlier this year we laid out in IN VIVO some of the reasons why fewer than 10% of co-promotes actually turn into market-place reality.

That statistic reassures the Big Pharma partner—most of which hate the thought of sharing their commercial spoils with inexperienced biotech, even if some of them say otherwise. But the main reason co-promote promises don’t often become reality is product discontinuation, as in this case, which helps no-one.

Luckily for Neuromed, the aborted program, an N-type calcium channel blocker, wasn’t its lead. Not since April 2007 anyway, when the biotech licensed US rights to a Phase III extended-release opioid analgesic OROS Hydromorphone from Johnson & Johnson’s Alza.

This deal means Neuromed may yet fulfil its dream, shared with most other biotechs, of setting up its own specialist sales force. And Neuromed may yet get to co-promote products with Merck, since the 2006 deal granted the biotech the option to co-promote to US specialists any N-type calcium channel blockers emerging from the collaboration—and the partners say they’ll keep looking for others.

But with NMED-160/MK-6721 gone, at least in pain, Neuromed will miss out on at least $202 million in milestones, and possibly more. It also paid $30 million up front for OROS. That product had better make it onto the US market (it's approved in Europe, but still not in the US, seven years after an approvable letter ). Otherwise private Neuromed may be in danger of biting the dust, too.

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Is Partial Agonism the Key to PPAR Success?

In case you haven't had your fill of TZD news this week, we bring you word that Dr Reddy's Labs and Rheoscience have dosed their first patient in what will be the first of several large Phase III studies of their partial PPAR gamma agonist balaglitazone.

Say what?

The timing of the trial's launch missed the Avandia circus by only a day and suggests there are companies out there willing to put in the time and money and Herculean effort to make their case for potentially differentiated products in a problematic class. Some senior industry executives think the odds are stacked against success.

Among those skeptics is Wyeth R&D chief Bob Ruffolo, who when interviewed by the IN VIVO Blog only six weeks or so ago, asked (rhetorically): "Who is going to bring a new, improved version of Avandia to market" given the regulatory mountain the FDA will surely make such a company climb?

And it's a fair question, particularly in light of the past few months' events. Let's review.

• GSK's Avandia, subject of everyone's favorite meta-analysis, though allowed to remain on the market for now, will get slapped with some stern patient- and doctor-scaring warnings. Takeda's Actos has avoided the whirlpool so far.


• The PPAR class hasn't exactly had smooth safety sailing prior to Avandia's snafu. Warner-Lambert's Rezulin kicked off the parade back in 2000 and so-called next-generation dual gamma/alpha PPAR agonists like AZ's Galida and Merck's MK-767 and Merck/BMS' Pargluva eventually followed.
  
• Clinicians and patients may be moving beyond the PPARs in any case. The RPM Report has reviewed the winners/losers: Actos may have seen a bump in the wake of the initial Avandia news, but that hasn't lasted. Merck's first-in-class DPP4 inhibitor Januvia is enjoying wild success in its first year on the market and observers are salivating over potential newcomers like Amylin's once-weekly Byetta and Novo Nordisk's liraglutide.

Nevertheless, Rheoscience presses on. If Actos is now the TZD safety standard bearer, it makes sense that to get to market now companies will have to prove their drugs as safe or safer than Takeda's (in fact, European drug regulators require such an active comparator to prove non-inferiority). Rheoscience is aiming to do just that. The first balaglitazone Phase III will be a European "six-month, double-blinded, randomized, placebo-controlled multicenter trial in which type 2 diabetes patients will be given daily doses of either 10 or 20 mg of balaglitazone versus the active comparator Actos (45mg/day) as an add on to stable insulin treatment," according to Rheoscience.

Our interest piqued, we got in touch with Rheoscience CEO Philip Just Larsen, MD, PhD. (For background on Rheoscience, check out our 2004 profile of the company.) Rheoscience's September 2005 deal with Dr. Reddy's got the Danish biopharma company European and Chinese rights to balaglitazone in exchange for taking responsibility for execution and costs associated with the drug's US/EU Phase III program and US regulatory submission (Rheoscience will also receive an undisclosed milestone payment if an NDA is approved and undisclosed royalties on US sales). Novo Nordisk once held rights to the drug, but returned them to Dr Reddy's in 2004, back when dual PPARs were still expected to dominate the class, says Larsen.

Larsen stresses the benefits of balaglitazone's partial gamma agonist properties. "It doesn't take full agonism for full glycemic control," he argues, pointing out that Phase II studies of the drug as well as preclinical models suggest that 20mg of balaglitazone is comparable to 45mg of Actos in that regard.

What's more, he says, balaglitazone shouldn't raise the same safety concerns as other TZDs, since in vitro models and preclinical trials suggest it causes less fluid retention than Avandia and Actos and is less adipogenic than those drugs. The second Phase III trial for the drug is an international long-ranging study to generate a safety database; again that trial will use Actos as a comparator, but Larsen says he doesn't expect either drug to generate the same cardiac ischemia safety signals that have plagued Avandia.

"It's worth emphasizing that it's not the class as such that is under suspicion for inducing cardiac ischemia," he says. "Actos is not associated with cardiac ischemia," a notion backed by FDA's David Graham during Avandia's recent panel meeting, he says.

Nevertheless the series of trials required to get balaglitazone onto the European and US markets will be very costly (Larsen declines to say exactly how costly). Patients and clinicians may be wary of TZDs and hamper trial enrollment (a suggestion Larsen disputes, particularly in terms of European patient accrual). The future of diabetes treatment may indeed by combination therapy, but whether or not TZDs are a mainstay of those combos remains to be seen as newer drugs like the GLP-1s make progress. The regulatory environment--for all drugs, it sometimes seems--is increasingly tricky. Larsen remains optimistic.

"I'm not worried about the regulatory environment. The advisory panel was in favor of drugs in this class, they're a necessary tool in the toolbox," he says. "Treating diabetics is a challenge and by limiting the options you put yourself in a difficult position, and these [TZD] products are quite efficacious."

As for the class' past failures, he points out that "the entire concept of pursuing the dual agonists was a blind alley, and it took those Phase III trials to show that is the case. That is how the selective PPAR agonists like balaglitazone were revitalized," and now shown that pursuing partial agonism could control the side effects related to full agonists like Avandia.

Rheoscience and Dr. Reddy's have competition. A second partial-PPAR gamma agonist in late stage trials belongs to Metabolex and Johnson & Johnson (we wrote about their innovative deal last summer). But don't expect any winners for quite some time. Balaglitazone's NDA won't be filed before late 2009 at the earliest.

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Even Cancer Ain't Exempt

No drug is exempt from FDA’s ultra-conservative stand, it seems, even those, like GPC Biotech’s satraplatin (Orplatna), that allegedly improve survival among cancer patients with few if any treatment alternatives.

An oncology advisory committee (ODAC) yesterday recommended that FDA delay considering prostate cancer candidate satraplatin for approval until overall survival data from the company’s 950-patient SPARC study is available. This recommendation came despite interim analysis strongly supporting the efficacy and safety of satraplatin, which was granted priority FDA review in April 2007.

Still, it wasn’t a complete surprise, at least since the rather negative FDA briefing documents released last week. These raised five “issues” including questions over the company’s assessment of pain progression, and, more importantly, over the definition and composition of one of GPC’s two key primary end-points used in the trial, progression free survival (PFS).

According to GPC’s “greatly disappointed” CEO Bernd Seizinger, GPC had communicated intensively with FDA throughout the application process and amended various aspects of the trials in accordance with FDA suggestions—including suggestions on what pain score to use. In sum, they’d done everything possible to make this work. (Listen for yourselves here.)

But FDA wasn’t having it. According to one analyst, “GPC walked into a complete stitch-up—FDA primed the advisory committee that they didn’t want this to happen.” Reading the briefing document, we’re inclined to agree.

Now, sources tell IN VIVO Blog that there’s no love lost between GPC and FDA—the ODAC meeting was “hostile and antagonistic,” according to one observer. Combine this with FDA’s overall caution (the last thing they want is to be hauled in front of the Senate for injudicious approvals) and you have a recipe for delay, if only temporary.

Still, GPC isn’t just an innocent victim here. Let’s go back to that issue of end-points. The briefing documents state that FDA had all along warned GPC that a PFS end-point may be problematic. Yet GPC failed to communicate this concern to the investment community.

That’s why analysts are so pissed—many had buy ratings on the stock, even after the review documents were released last Thursday. GPC shares fell 35% back then, and about the same again today. “Trust has been lost,” says one in London. “When it comes to the investment community, GPC are on their own.” (They can sulk in a corner beside Sanofi Aventis, which hasn't won any prizes for transparency among the investment community either, particularly with regard to Zimulti's rocky ride, on which we've reported extensively, including here.)

It’s a worrying time for the German biotech. All of a sudden, the overall survival data for satraplatin—which is the other primary end-point, alongside PFS--has become a make-or-break issue for the company. If it’s positive, the drug will probably still make it, although not in an accelerated fashion. If it’s not, the drug may not get onto the US market at all—which could prove fatal for GPC.

The rest of the sector has cause for concern, too, though (not to mention androgen-independent prostate cancer patients that have failed first-line therapy). This bleak little episode—besides showing up personal clashes between applicants and the agency, which, it seems, do matter—may mean that regulators’ caution is spreading beyond primary-care drugs like Avandia or the Cox-2s, where the main concern is safety.

Today, it seems, the tough hurdles can come from anywhere--including from non-safety-related issues like how pain is measured. Some might call this nit-picking.

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Sometimes the Bear Gets You: Idenix Pharmaceuticals Edition

Idenix Pharmaceuticals announced this morning that FDA had placed a clinical hold on its Phase II valopicitabine hepatitis C polymerase inhibitor.

FDA made its decision following an assessment of the overall risk benefit profile observed in clinical rials to date, according to Idenix CEO JP Sommadossi, who addressed analysts on a conference call today. "We were very surprised," he said, adding that along with its partner Novartis, Idenix is evaluating its options. "But i am not optimistic about further development of valopicitabine in the future," Sommadossi added, and later re-emphasized.

So what happened? "FDA looked at all of the Phase IIB data ... and concluded that the GI side effect profile was not commensurate with the antiviral activity we were seeing," said Doug Mayers, CMO. Idenix, the executives said, had seen similar signals such as nausea and vomiting, but were eager to play with the doses of valopicitabine in further trials in an attempt to find a workable risk/benefit profile. FDA had different ideas.

Valopicitabine, previously dubbed NM283, was the furthest-along HCV polymerase inhibitor in clinical development and the first of a next-generation set of targeted HCV therapies. The polymerase class hasn't received as much attention as HCV protease inhibitors, which have been the subject of some pretty sizeable deals--Vertex's alliance with Johnson & Johnson and Intermune's alliance with Roche, for example. But Idenix had maintained that the future of HCV antiviral therapy would be combination, a sentiment shared by many, and so pushed ahead with development despite only moderate clinical success with the compound.

The biotech's partner Novartis must have agreed; the companies have a broad alliance whereby Novartis gets first right of refusal on any Idenix compound when it hits Phase II. For valopicitabine, Novartis had to pony up more than half a billion dollars to maintain its share of the drug. Novartis owns upwards of 57% of Idenix.

Today's news is the second clinical hold placed on a Novartis-in-licensed HCV candidate this year. Last summer FDA halted trials of Anadys' ANA975 drug, a TLR-7 agonist in Phase Ib, after a preclinical toxicology study unearthed a potential safety signal.

HCV dealmaking has definitely been a hot space, and will likely continue to be so despite this spate of clinical difficulties. For our roundup of drugs in development for HCV, see this late-2005 IN VIVO story.

UPDATE: Idenix shares are off about two bucks, or 35%, at about 11:30a.

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Phase II is the new Phase III

It's what you might call a slow news day for us so we figured we would dip back into our colleague Roger Longman's presentation from our Euro-Biotech conference last week. Roger's on vacation, see, so he can't stop us from pilfering his slides.

One of the points he emphasized during his talk and illustrated with some data from our Strategic Transactions Database is the idea that products that have cleared clincal proof-of-concept, i.e. the Phase II hurdle, are attacting the kind of deal dollars only seen previously for Phase III-stage products. The value of relatively scarce Phase III products these days is another thing altogether.

Taking a look at this phenomenon using upfront payments as a proxy for deal value, above, and you can see what we mean. So while those biotechs that excel at drug discovery can in fact sustain themselves by selling IND-stage candidates, which we pointed out last week, others can play on the next valuation inflection point at proof-of-concept.

Are Phase II deals a remotely new feature of the biopharma dealmaking landscape? Of course not. But the volume of deals for Phase II products has shot up in the past few years, and upfront payments are simply booming. A few recent examples include Novartis and Antisoma's deal around the oncology product AS1404 ($75mm up front), Bayer and Regeneron's deal on ex-US rights to Regeneron's VEGF-trap product in ophthalmology ($75mm u/f), and going back to last summer, Johnson & Johnson's ex-North America, ex-Japan deal for Vertex's hepatitis C protease inhibitor ($165mm u/f). Follow the links to a more detailed analysis of each deal.

Various pharma execs have chalked the rise in Phase II prices up to their own companies' inability to reliably and predicably get products through proof-of-concept themselves. This is excellent news for clinical-stage biotechs. A few, like CNS-focused Synosia, have set themselves up as proof-of-concept specialists, in-licensing compounds in preclinical or IND or even Phase I, shepherding them through a human efficacy trial, and licensing them on for a significant profit.

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Sometimes the Bear Gets You: Coley Pharmaceuticals Edition

Coley Pharmaceuticals shares lost more than half their value today after its partner Pfizer discontinued work on its lead lung cancer compound.

The nail in PF-3512676's coffin was an independent data safety monitoring committee's verdict that a mid-trial analysis suggests the compound plus chemotherapy works no better than chemo alone.

PF-3512676, previously known as Promune (and also as CPG7909), was snatched up by Pfizer in 2005 in a deal worth up to $515 million. The compound was supposed to work by triggering the immune system through stimulating toll-like receptor 9 (TLR-9).

This is the second TLR-modulating drug that has crashed out of the clinic after being dealt to a big pharma for top dollar. Novartis bought rights to Anadys's ANA975 drug, a TLR-7 agonist, for hepatitis C only a few months after the Coley/Pfizer deal. That drug's Phase Ib program remains on clinical hold by the FDA after preclinical tox studies unearthed a potential safety signal last summer. Merck also signed a broad TLR deal with Idera in late 2006; that deal is ongoing.

Coley will hold a conference call later this afternoon.

UPDATE: Coley's call provided little in the way of further information specific to '676. Pfizer is leading the data analysis, according to Coley CEO Bob Bratzler, who described the company as "dumbfounded" and "shocked" at the news.

CSO Art Krieg aimed to confine the bad news to these particular trials and drug combinations, saying "this is a setback for this approach to the treatment of lung cancer in these particular combination regimens ... [but] the mechanisms are validated and we don't think the impact of this will be enormous beyond these approaches." Cancer drug development is challenging, he added, and a lot of successful drugs have failed multiple clinical trials before approval.

Perhaps. But the snafu puts Coley in a tight spot. At last glimpse--end of Q1--the firm had $97 million in cash reserves; yesterday's news sunk Coley's market cap to $91 million. Even considering the firm's estimated burn of about $3 million per month, the market is now placing zero value on its technology platform, its partnered projects with GSK and Sanofi-aventis (and the future of the Pfizer collaboration), as well as its various preclinical activities in RA, lupus and oncology. There is blood in the water.

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