A Boon for Byetta?

As doctors, patients and regulators rush to make sense of the recent NEJM study showing an increased risk of heart attack among patients taking GSK's Avandia, it looks like good news for Lilly's Byetta.

The GLP-1 analog--or 'smart drug', as Lilly execs like to call it, since it stimulates insulin secretion in a glucose-dependent way, reducing the risk of hypoglycemia--has already done pretty well since its launch in June 2005. It suffered a brief blip in sales when Merck's DPP-IV inhibitor Januvia arrived (since Januvia, although less effective, comes in pill form and Byetta is a twice-daily injection) but has since recovered. Sales will be about $700 million this year.

And things can only get better. "Both Januvia and Byetta will benefit from Avandia's problems, and as physicians see that Januvia isn't that great, they'll move to Byetta," David Kliff, publisher of Diabetic Investor, told the IN VIVO Blog.

Januvia seems safe--so far--but doesn't actually work that well, as we explained in a previous issue of IN VIVO. Byetta, on the other hand, not only is extremely effective at controlling blood sugar (it prevents sugar lows plus, because of its effect on glucagon, sugar highs) but also helps diabetic patients lose weight.

And that, frankly, is just perfect, since many diabetics are overweight, and since insulins tend to exacerbate that problem. So rather than being stuck on insulin, getting fatter and with poorly controlled blood sugar levels (only about a third of insulin users actually control their blood sugar effectively), patients "start a cycle of success," enthuses Lilly's global brand development leader for Byetta, David Vondle. "They have more energy, start feeling better, so they take a walk, and that helps with weight loss...and they're just more optimistic," he says.

Lilly's GLP-1 team probably feels pretty happy, too (unlike their cousins in the insulin department, who blew it). Not only has first-to-market Byetta brought a huge improvement to patients' lives, but there's an even bigger paradigm-shift on the way: a once weekly Byetta. "Every doctor is salivating for Byetta LAR," says Kliff.

They'll have to salivate until 2010, but it may be worth the wait: patients will be able to take just one weekly injection, rather than twice daily. That's 13 fewer injections per week.

That's a selling point if ever there was one. And, as with Avandia, where there's a winner, there's a loser. In the GLP-1 space, it might just be Novo Nordisk's human GLP-1 analog, liraglutide. It's due out a year or so before Byetta LAR, but Novo's not always the timeliest, and liraglutide is a once-daily. Read more in the next issue of IN VIVO.

Miscommunicating Risk (Part 2): The Byetta Disconnect Continues...

Byetta's back in the news, and once again not in a good way. "Amylin Reports Four Additional Deaths With Byetta" is how Reuters has it.

As we wrote last week, the Byetta experience underscores some fundamental challenges facing the industry (and investors) in the new era of drug safety. This is a case where there seems to be a big disconnect between the seriousness of a safety issue from the regulatory perspective (where a safety "update" by FDA treated two deaths from pancreatitis as important information for prescribers, but not a call to action) compared to the reaction of investors ("The sky is falling!").

But, whether or not FDA intended to sound the alarm about Byetta, the stock market reaction made pancreatitis a big story. Or, put another way, the sky may not be falling but Amylin's stock price certainly did.

Now, a week after the news broke, Amylin tried its hand at communicating safety information, hosting a teleconference to offer "context" for the FDA safety update.

That included the news of four additional case reports of Byetta patients who experienced pancreatitis and died. For analysts on the call, though, that "news "sounded like a non-event. Amylin carefully explained that those four deaths, though all associated with pancreatitis, were already reported to FDA, before the agency issued its recent safety "update" on the GLP-1 anti-diabetic. In other words, the agency agreed with the sponsor that they weren't worth talking about publicly. In three of the four cases, Amylin says, it has obtained case reports that support the view that the cause of death was unrelated to pancreatitis or Byetta. In the fourth case, Amylin says it has been unable to obtain any additional information.

Amylin also discussed the deaths in the broader context of outlining the overall risk of pancreatitis seen with Byetta (about 1 in 3,000) and the more severe hemmorhagic/necrotizing pancreatitis that triggered the latest alert (less than 1 in 10,000). And, the company says, there is no indication whatsoever that the rate of pancreatitis associated with Byetta is any higher than the expected rate in the overall patient population.

Well, Amylin shares are down again today (as are marketing partner Lilly's).

This raises two more questions in our minds for others in industry to ponder as the new drug safety era takes shape.

(1) FDA recognizes that it needs to do better when it comes to risk communication. But do sponsors?
(2) In a world where the line between partner and prey (cf. Roche/Genentech, Bristol/ImClone) is always fuzzy at best, how does "Safety First" volatility affect the stability of partnerships?

Amylin's investors haven't been shy about voicing their feelings that FDA is being unduly alarmist about the pancreatitis issue. (And, privately, we've heard the same thing from executives who work for the sponsors.) But this is a case where FDA issued safety information in about the least alarmist way it could have--short of keeping its mouth shut.

And if you think keeping its mouth shut is an option for FDA right now, you haven't been paying attention.

But what about the sponsors? The question that begs to be asked is why Lilly and Amylin waited a week to hold a conference call. Analysts who put that question to Amylin say the answer was that the company didn't want to upset FDA by appearing to challenge or contradict its safety communication. (And in holding the call at last Amylin carefully avoid doing so.)

Our response to that objection is: what would an angry FDA do that is worse than what is already happening to Amylin? The stock was down 20% and investors are starting to write off hopes for Byetta LAR.

Still, if Amylin and Lilly were afraid of annoying FDA, then why hold a call at all? The delay made the issue seem ominous. Just the scheduling of the call caused Amylin shares to fall. Then the company said very little that isn't already in the public domain about the context of pancreatitis--and apparently by failing to offer anything new its reward is to see another stock price decline.

We don't claim to know the right way to manage investor communications about these kind of emerging safety issues, but we're pretty sure this isn't it.

What we do know is that sponsors have to prepare now for how they are going to handle a circumstance like this. Amylin and Lilly may have been caught flat-footed by the reaction to the FDA safety notice, but that is no excuse. In today's world, the news could just as easily have been sparked by an international regulator, or by a prominent academic (say, Steve Nissen has been quiet lately hasn't he?), or in the favorite phrase of former FDA deputy commissioner Scott Gottlieb, by any 18 year old with a computer and access to Wellpoint's database.

Our modest proposal for a better way: why not hold this conference call before FDA issues a safety update? It would take a brave sponsor to do that -- in effect announce to investors that it has submitted six fatality reports to FDA. Still, in hindsight, we bet Lilly and Amylin would be better off right now if that was the approach they took.

Which leads into the second issue, since an effective communication strategy presumes that the two sponsors have the same objectives in mind.

Viewed from the standpoint of the Byetta brand team, there is no doubt that the partners' interests are aligned and this safety scare is a huge problem.

But what about from a strategic perspective? The Roche/Genentech deal has already triggered speculation about other biotech buyouts to come, and Lilly/Amylin is on everyone's list of possibilities. Lilly, remember, already showed its willingness to go down this path when it bought its Cialis partner Icos.

If the market is overreacting to the pancreatitis issue, Lilly can do more than just assert its confidence. It can put its money where its mouth is and buy Amylin out. It wouldn't be cheap: Amylin is valued at just under $3 billion. But that is less than half its value a year ago before the pancreatitis issue first emerged.

Then there is this: a new posting on ClinicalTrials.gov showing that Lilly is moving its own GLP-1 agent into Phase III. That certainly got investors' attention. Does Lilly think it has a better product than Byetta?

(Lilly may even have an extra incentive to buy Amylin: according to our Strategic Transactions database, the Byetta contract includes "option compounds" in both Lilly's and Amylin's pipelines to which the partners have reciprocal rights. While the names of the compounds and the option periods have been redacted out, our bet is that the "option compounds" represent possible competitors to Byetta. So if Amylin has got any claims to Lilly drugs -- maybe indeed this Lilly-discovered GLP-1 -- then Lilly would have some extra incentive to buy out Amylin now).

We don't pretend to know Lilly's plans for its Amylin partnership, but we do know that the challenges of mastering risk communication aren't any easier when there are two sponsors involved.

Miscommunicating Risk: The Byetta Disconnect

First things first: we have no idea how serious the risk of pancreatitis with Amylin’s type 2 diabetes agent exenatide (Byetta) really is. Nor do we pretend to be able to guess how the brand will be affected commercially in the hypercompetitive diabetes market by the report of two deaths associated with the drug.

But this we do know: there seems to be a disconnect between the level of warning that FDA chose to issue for Byetta and the size of the financial market’s reaction. And that disconnect underscores an ongoing, critical issue facing the entire pharmaceutical industry in the world of “Safety First” regulation: how to communicate a risk associated with a product without scaring patients that could benefit.

You have to give the Food & Drug Administration credit for diagnosing the problem. The agency is the first to admit that it simply doesn’t know the best way to meet the public demand for transparency in regulatory actions—especially anything involving safety—without needlessly scaring patients, confusing providers, and sacrificing its ability to speak authoritatively on behalf of the public.

That, in a nutshell, is why the agency formed a new advisory committee on Risk Communication in the hopes of bringing a little science to the question of how best to warn consumers about emerging and inherently uncertain safety issues.

Based on what happened to Amylin yesterday, it’s safe to say there is still a lot of work to do.

In case you missed it, FDA issued an update for health care professionals on August 18 about the risk of pancreatitis associated with Byetta. FDA and the sponsors (Amylin and its partner Lilly) first alerted prescribers to the risk back in October, citing 30 reports of acute pancreatitis associated with the brand.

The update cites six new, more serious cases reported since then, involving what the agency describes as “hemorrhagic or necrotizing pancreatitis.” All six cases led to hospitalization, and two patients died. In light of the apparently more serious reports, FDA says it is working with Amylin and Lilly on stronger warnings and advises discontinuation of Byetta when there are any signs of pancreatitis in the meantime.

Amylin’s investors certainly think that’s a big deal: the company’s shares dropped 15% almost instantly on the news, stayed down to the close, and opened even lower today. You can't blame investors for being skittish. Byetta is a huge product for the biotech and has already been struggling a bit commercially. In this climate, the impact of even uncertain safety risks can be dramatic. (Remember Vytorin?)

Last but not least, the issue certainly raises more questions about the regulatory prospects for Amylin's long-acting version of Byetta. (We have written previously about why we think Byetta LAR could benefit from the focus on cardiovascular outcomes for type 2 diabetes products--but if there is some reason to suspect the long-acting version is worse for the pancreas, all bets are off.)

But here’s the thing: FDA chose to disclose the new information about Byetta without much fanfare, simply posting the update on its “MedWatch” drug safety page, with a prominent link on the “What’s New” column of the Center for Drug Evaluation & Research’s home page. The agency did not issue a press release, a formal public health advisory, or host a media conference call, the way it does in other cases where it wants to amplify its warning.

In fact, we first heard about it from the ever vigilant David Kliff, whose Diabetic Investor issued a note at 1:45 pm—by which time the sell off was well underway. (For the record, our copy of the alert via FDA's email list serve arrived at 2:52 pm.)

In other words, Wall Street’s reaction is driving coverage of this particular drug safety issue—not the public health judgment of the regulatory agency. Think about it: if Byetta happened to be sold by a privately held company, or exclusively by a global Big Pharma where it was not the exclusive focus of investor attention, the media coverage would certainly be much reduced.

Again, we don’t claim to know the right outcome here. Maybe it’s best if everyone stops using Byetta altogether. Maybe it’s best that no one stop. But it seems safe to bet that more people will be aware of this risk than would have been without the Wall Street reaction—and that means the impact of the FDA warning will be larger than the agency might otherwise have anticipated.

You don’t have to be an Amylin investor to think that may not be the best way for risk communication to work.

ADA Wrap-Up: Where's The Chocolate?

Trying to understand all that data released at the American Diabetes Association’s 68th Scientific Sessions in San Francisco? Attempting to make sense of the company posturing and resulting fallout in the marketplace? It’s enough to make anyone a little hypoglycemic.

But getting a handle on the market potential of the various medicines in the lucrative Type II diabetes space, such as Januvia and Byetta, is worth a potential sugar low.

Here's a quick review for those who need it. By 2012 a gazillion people in the US will have Type II diabetes--actually only about 25 million but you get the point. BIG MEDICAL PROBLEM. Januvia, the first FDA-approved DPP-4 inhibitor, is proving to be a useful weapon--or at least a highly prescribed one. In 2007, the drug racked up worldwide sales of $668 million. And Catherine Arnold, an analyst at Credit Suisse, projects global sales will grow to $3.1 billion by 2010. But there's competition. (See below.)
The curve for Amylin/Lilly’s Byetta, a GLP-1 analog on the U.S. market since 2005, hasn’t been so steep. At $158 million in revenue for the first quarter, twice-daily Byetta missed its mark due to a number of factors – among them lack of up-take by primary care physicians. That’s one reason why Amylin told the street in January it would speed up its filing for once-weekly Byetta LAR to the second quarter of 2009.

At ADA this week, Amylin reported data showing its Byetta LAR injection improved glucose control at or below ADA’s 7% goal for 72% of patients, with an average weight loss of 9.5 lbs. Jim Reddoch of FBR Capital Markets said, “We think LAR is a potential best-in-class drug, well ahead of the competition.” He’s modeling $2 billion-plus in peak sales for the drug in 2012. But the news did little to help Amylin's share price, which slid June 9 on news from Novo Nordisk and Roche.

Novo released new Phase III results pitting its once-daily GLP-1 analog liraglutide against Byetta. Liraglutide was significantly more effective at lowering A1c and resulted in slightly more weight loss. JPMorgan’s Cory Kasimov noted, “With liraglutide’s approval expected by 1H09, we believe the drug could take significant market share from Byetta.”

Amylin isn't taking the news sitting down--but it will likely have to invest considerable money and resources to keep a leadership position. The biotech's CEO, Daniel Bradbury, told “The Pink Sheet” DAILY the firm is considering head-to-head trials of Byetta vs. liraglutide.

Meanwhile, Roche and partner Ipsen’s taspoglutide (R1583) also demonstrated impressive A1c control. Rate of nausea, however, appeared high at 52% with the 20 mg once-weekly dose, although patients weren’t titrated. The firm announced at ADA that it will begin a head-to-head trial of taspoglutide vs. Byetta. It plans an NDA filing in 2010. Maybe Amylin needs to add another arm to that trial its considering?

(We understand if you are getting a bit dizzy. Great summaries of all the news are available at our sister publication, "The Pink Sheet" DAILY.)

But the news wasn't all GLP-1. The DPP-4 class is looking more crowded as two contestants vie for the prize of being second to market. The Bristol-Myers Squibb/AstraZeneca drug, Onglyza, when taken alone, apparently significantly improves A1c levels compared to baseline in just three doses. Bristol plans to file an NDA for the compound mid-year. Meanwhile, Takeda issued a slew of reports about its alogliptin, widely expected to be approved later this year. Good news for Merck--analysts don't seem to think either drug looks superior to Januvia.

And that's definitely bad news for Takeda. The company has a thin pipeline and is counting on this compound to generate sales to offset the revenue losses caused by the 2011 patent expiration of its blockbuster Actos. (We'll have more on Takeda's strategy in an up-coming IN VIVO feature. )

Which brings us to our final point. How much should we care about HbA1c anyway? In a previous post, we wrote about the ACCORD trial’s finding that lowering hemoglobin A1c levels doesn’t correlate with a lowered risk of adverse events such as heart disease and stroke. Amylin CEO Daniel Bradbury told IN VIVO Blog that he believes the finding won’t result in modified endpoints. HbA1c is still a valid endpoint because it’s directly proportional to microvascular complications of type 2 diabetes, Bradbury said. But if that's just wishful thinking, it could spell trouble for any company currently playing in this arena, necessitating the expensive redesign of clinical trials.

Time for some chocolate while we ponder that issue.

--Pamela Taulbee

(Photo courtesy of Flikr user the Princess of Ilyr via a creative commons license.)

Victoza Gets Past FDA, But....

There are a few caveats. First, a black box warning for the once-daily GLP-1 analog which includes a potential increased risk of thyroid cancer (despite Novo Nordisk's repeated claims that this applies only to rodents, not monkeys or humans). Second, no first-line usage allowed. Third, significant post-approval requirements, including a CV safety study, a 5-year epidemiological study to evaluate thyroid cancer risks, a 15-year cancer registry to monitor thyroid cancer cases, and a REMS.

As such, "it's a worst case label for the product," concluded Sam Fazeli, an analyst at Piper Jaffray in London. "Bittersweet" was how Jefferies' Jeffrey Holford put it, while Citigroup simply cut to the chase with "Commercial success far from certain."

Things could have been still bleaker, though. At least the US approval has finally happened (the drug was filed in May 2008). It might have been pushed out significantly further, given the regulators' apparent problem with the thyroid cancer risk. And on the up-side, there's no need for calcitonin monitoring during Victoza therapy (calcitonin is the marker used in humans for thyroid cancer) and there are no broad contra-indications for the drug. Only patients with a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome, aren't allowed Victoza--and both those indications are very rare.

As such, Novo's management was upbeat during the analyst call announcing the news. The REMS is very remiscent of that recently imposed on Lilly/Amylin's twice-daily GLP-1 analog Byetta, said EVP & CSO Mads Thomsen, and certainly manageable. He added that many diabetes drugs (metformin, the sulphonylureas) have black box warnings, and most new products aren't awarded first-line treatment at their first pass at FDA. Thus, "we're perfectly happy with our monotherapy label," he said. (The product was denied approval as a monotherapy in Europe).

There a big 'but', though--and it's Byetta. That product has not only a five-year head start, but also hasn't got a black box, hasn't got a thyroid cancer risk warning, can be used as an initial therapy, and thus remains "first choice" treatment in this class, according to Fazeli, despite its more frequent administration.

This explains the generally (although not exclusively) down-beat analyst reaction to the news; "we see more room for disappointment than surprise on Victoza," writes Citigroup's Mark Dainty. Never mind the fact that Victoza outperformed Byetta in blood sugar lowering in a recent Phase III head-to-head trial.

Novo's management still thinks it can surprise, however. (They're a confident lot.) They re-iterated their forecasts that Victoza will reach sales of over $1 billion by 2015 (Byetta's currently at about $700 million and it has been on the US market since 2005).

Much will depend on whether follow-on GLP-1 analogs including long-acting Byetta (EQW) and Roche/Ipsen's taspoglutide are stamped with the same thyroid cancer warnings as Victoza. (Amylin's epidemiological study of Byetta is due March 31). Novo's Thomsen is adamant that the thyroid cancer signal seen among rodents is a class-effect among the long-acting GLP-1 analogs, and points to a forthcoming peer-reviewed scientific paper outlining what he claims is a similar pre-clinical effect on thyroid c-cells for Victoza, long-acting Byetta and taspoglutide. "We'll have to live with the notion that long-acting GLP-1 analogs cause c-cell proliferation in rodents," he told The In Vivo Blog. "But there's no reason to believe that these findings have any relevance to higher species," he added.

Whether or not the other long-acting GLP-1s get the same treatment, FDA is unlikely to remove Victoza's black box for several years at least, likely until the 5-year follow-up cancer study data is available.

Meanwhile, though, with its already-expanded US sales force and pricing in line with Byetta at about $8/day for the 1.2mg dose, Novo will be pushing Victoza with all its might and leveraging its wider diabetes franchise where possible. And let's not forget the fundamentals: Victoza is once-daily, can be taken anytime, prompts some weight loss, isn't associated with hypoglycemia or significant nausea, and is relatively easy to titrate.

Those elements may yet trump the worries about cancer in rats.

The Case for Byetta LAR (Part 2)

Amylin and Lilly have high hopes for Byetta LAR, a once-weekly formulation of the incretin mimetic exenatide. Analysts are (as they tend to be) of two minds, with opinion ranging from those who think LAR may fairly quickly become the dominant brand in the entire diabetes class to those who wonder whether it will even make it to market.

We will leave the debate over the commercial prospects to others. But we do think LAR looks to have a winning profile from the regulatory perspective.

That, to put it mildly, is counterintuitive. We just wrote that it is harder than ever to get new type 2 diabetes drugs on the market. And we’ve said previously that it is harder than ever to get line extensions to market. (Remember Cordaptive?) That sure doesn’t sound like a good prognosis for LAR.

But this may be a case where two wrongs do in fact make a right.

How so? Well, first, this is a circumstance where it definitely helps to be developing a line extension rather than a new molecule. Here is how Amylin CEO Dan Bradbury described the situation during Amylin’s second quarter conference call. “The FDA panel meeting really focused on cardiovascular risks associated with new chemical entities,” he said. “That is one of the major differences here.”

Indeed, the panel vote does imply that marketed antidiabetic products just got a little more valuable. In fact, one implication of the latest advisory committee vote is that the decision by FDA to leave Avandia on the market is an even bigger victory for GlaxoSmithKline than it appeared. (An advisory committee voted overwhelmingly last year to allow continued marketed of the drug. FDA’s internal Drug Safety Oversight Board agreed, but by a single vote. And ultimately the decision came down to CDER Director Janet Woodcock, who opted to allow continued marketing.)

Now, Avandia (like other marketed products) will be expected to generate outcomes evidence—but at least it can continue to generate revenues in the meantime. And the odds of another TZD coming into the market any time soon just when down. So maybe, just maybe, GSK will actually see sales of the franchise rebound a bit in the years remaining before patent expiry.

But Byetta LAR is not a case of asking FDA to approve a new agent to lower blood sugar, but rather a case of asking FDA to approve an improved version of an already marketed drug. And, in fact, of a drug that has an attractive cardiovascular risk profile, given Byetta’s effects on weight and lipid levels.

That alone, though, may not be good enough in the current regulatory climate. But here’s the kicker: FDA can use the LAR approval to ensure it gets the outcomes data to support its decision to approve Byetta in the first place. The agency, of course, already asks for that data routinely—but as everyone saw with Avandia, those post-marketing commitments are seldom sufficient to generate definitive conclusions about the kinds of questions the committee now wants answered.

FDA, though, has a new tool it can use going forward: mandatory post-marketing study requirements, complete with the ability to levy fines against manufacturers who fail to deliver data by an agreed upon time. As we’ve said before, this changes everything about Phase IV.

The new authority is much easier for the agency to apply prospectively, to newly approved drugs (or at least new applications for expanded uses, new labeling, etc.). The agency can (and in the case of type 2 diabetes, we bet it eventually will) go back and add post-marketing requirements to already marketed products, but that is a process that will take some time.

So, Lilly and Amylin have a two-fold case for Byetta LAR. It is an improvement over an already marketed drug (since, the companies say, it provides better glucose-lowering control and increased convenience)—and it also gives FDA the opportunity to finalize mandatory outcomes studies for exenatide sooner than it otherwise could.

And, as an added bonus, it fits perfectly with the companies’ commercial positioning of the product. Lilly and Amylin are already planning a large cardiovascular outcomes study based on extensive trials suggesting beneficial effects on surrogate endpoints. So it shouldn’t be hard for them to commit to FDA to do such a study as a condition for approval.

All of which means Byetta LAR may turn out to be the right product for the current regulatory climate.

Of course, if the commercial product isn’t the same as the one used in clinical trials, all bets are off…

Another Snowstorm, Another Complete Response Letter?

The snow is falling and that can mean only one thing – a Complete Response Letter for Amylin Pharmaceuticals’ Byetta LAR (long-acting exenatide). At least that’s what Jon LeCroy, an analyst at Hapoalim Securities, suggests after trying to decipher how the FDA reacts to inclement weather.

For those who weren’t aware, the agency yesterday extended the PDUFA date for the once-weekly diabetes drug from March 5 to March 12. Normally, a delay of a few days isn’t expected to amount to much, if anything. Besides, the agency had signaled PDUFA user fee dates could slip by up to five business days due to the blizzards that shut down the federal government earlier this month.

But LeCroy worries something ominous is under way. Given that PDUFA delays have become the norm, the March 5 date was always uncertain. Until now, in fact, LeCroy assumed the date would just slide by. But the fact that the agency assigned a new and specific date suggests to him that, not only will a decision actually come down on March 12, but the likelihood is it won’t a be positive for Amylin and its two partners, Eli Lilly and Alkermes.

As a result, he’s ballparking approval this way – the odds of a full approval on March 12 are just 20 percent; a Complete Response Letter is a 60 percent bet and there’s a 20 percent chance the FDA will simply miss the PDUFA date. In an investor note, he points out that Xenoport, after all, recently received a PDUFA extension, ostensibly due to bad weather, and wound up with a rejection letter.

In his note, LeCroy writes that he thinks “approval will likely be delayed” until the FDA reviews several studies – including data from ongoing animal trials for twice-daily Byettta – that were requested at the time the Byetta monotherapy indication was approved last October. The last required study on Byetta LAR is expected to be done mid-year and a final report submitted to the FDA next January. “This implies,” he wrote, “that the FDA will not approve (Byetta LAR) until mid-2011."

Unless it keeps snowing, in which case the drug may never get approved.

--Emily Hayes

photo thanks to LD Flickr creative commons

NICE Snubs Novo With Draft Lira Guidance

You'd think that even NICE would have welcomed with open arms a new, effective treatment option for the UK's nearly 3 million diabetic patients--particularly one that not only lowers blood sugar, but also causes weight loss.

Nah. NICE is playing hardball (again). Its draft recommendation for Novo Nordisk's GLP-1 analog liraglutide (Victoza), although not nearly so damning as last week's preliminary guidance around Sprycel and Tasigna, suggests that the drug be used only in limited circumstances by the National Health Service. 'Limited' means a) as part of triple therapy regimens only (that is, for patients already on metformin and a sulfonylurea, or metformin and a thiazolidinedione, where the above combos aren't quite doing the trick), b) among patients with a body mass index equal to or higher than 35kg/m2 (that's high) and c) only at the lower, 1.2mg daily dose.

Ok, so patients that aren't quite so obese as 35kg/m2 could also qualify for the drug, "if it is considered that the drug's use could help to achieve levels of weight loss that could be beneficial in treating other conditions caused by being obese", the NICE press release concedes.

But a quick read of the full appraisal consultation document reveals that even among those tightly-defined patient groups, drug treatment should only be maintained if the individual loses at least 3% of body weight after six months (that's not far off the threshold for an actual weight-loss drug) and sees a reduction in blood sugar levels of at least 1 percentage point.

It seems, at first glance, to be a case of "damned if you do, damned if you don't" for Novo. After all, weight loss is supposed to be a nice side-effect of the diabetes drug--one that could lead to lower incidence of co-morbitidies--yet it's apparently being used to limit its reimbursement.

Although NICE concedes that liraglutide "may have some advantages over insulin...in particular its effect on weight," it appears to rule out the higher dose point blank, and is asking for further analyses on the cost-effectiveness of liraglutide on patients with a lower BMI, which it says were not presented.

NICE was also unsatisfied with the extent of the data comparing liraglutide in triple therapy with other combinations of oral drugs, including for instance DPP-4 inhibitors, and felt that the LEAD-1 trial comparing liraglutide to rosiglitazone used an insufficiently high dose of the glitazone.

It's impossible to cover all the various permutations and combinations in diabetes therapy, however--and Novo did submit data from six trials in over 4000 patients. All except one of the trials showed that the drug reduced HbA1c levels significantly better than comparators, which included rosiglitazone (Avandia), sitagliptin (Januvia, the DPP-4 inhibitor), insulin glargine (Lantus), placebo, and Lilly/Amylin's exenatide (Byetta, the only other GLP-1 out there). The exception: the LEAD-2 trial, comparing liraglutide with glimepiride (Amaryl), which showed up liraglutide's weight advantage although no significant difference in blood sugar lowering.

Perhaps NICE's conclusion isn't such a surprise, though, considering the fate of Byetta in the UK (which you can read about in NICE's Type 2 diabetes guideline document). In brief, Byetta's "not recommended for routine use in Type II diabetes", with the same six-month benefit hurdles as described above, deemed as "expensive" and "not cost-effective for an unselected population as compared to commencing human insulin therapy."

As such, Novo's VP Europe, Viggo Birch, admitted that "given what they [NICE] have done for exenatide, this is what you'd expect in the first round." Still, "I'm not happy with it," he continued. "We have a much better product [than exenatide] and much better data." Novo's looking for reimbursement as second-line therapy, "at least for important patient subgroups," and a relaxation of the BMI-based restriction, since this, Birch claims, "isn't fair; it was plucked out of the sky."

There's a crack in the door, though. NICE will hold another meeting on March 18, allowing Novo and others time to comment and submit further data supporting wider use of the drug. And in its full diabetes document, NICE does acknowledge, with regard to Byetta, some uncertainty as to whether GLP-1s would be deemed cost-effective if the [health economic] model "fully reflected the negative quality of life issues of insulin, including fear of hypoglycaemia, and the costs of support and patient education for modern intensity of insulin dose titration" and added that the "more obese require much higher insulin doses, such that insulin costs alone can easily exceed those of exenatide."

Still, reading between the lines, we suspect this preliminary appraisal for Victoza is a call not just for more analysis, but also for a cost-sharing scheme of some description to help smooth the drug's passage past the cost-effectiveness watchdog.

That's not likely, according to Birch. "It [a cost-share scheme] is not really on the radar for this product right now." Perhaps with reason: after all, Victoza's hardly the most expensive drug to cross NICE's desk--the low dose costs GBP 954 per year, compared to tens of thousands of pounds for some cancer treatments.

But given the growing prevalence of diabetes, "NICE is probably wary of giving free rein to something that [may become] so huge" comments one analyst.

The question is whether its hard-ball stance on Victoza ideally balances the concern over escalating drug costs, with that of the escalating costs of the disease itself (plus consequences), estimated to eat up about 10% of the health care budget.

image by flikrer Roland used under a creative commons license

Novo Hopes Victoza’s EU Clearance Bodes Well for US

As the European Commission today gave its final green light to Novo’s much-anticipated GLP-1 inhibitor liraglutide (Victoza) (no surprise, given the CHMP’s positive recommendation back in April), the company’s still bullish on the drug’s prospects in the US—anticipating not only approval but a none-too-severe risk-management plan as well.

“Our expectation is that the whole post-marketing system that we’ll agree and adhere to in the US will not be of a severity that will be commercially destructive to the product, not prohibitive for easy daily use in the doctor’s surgery,” Novo’s CMO Mads Thomsen told us (but enough, one assumes, to give practitioners comfort and get a leg in versus Byetta…).

Thomsen’s taking heart, perhaps, from the squeaky clean EU approval, which came with no usage restrictions and no contra-indications—despite an earlier split vote from an FDA advisory committee in April over whether Victoza should be approved in the US at all, due to increased cases of thyroid tumors seen among rodents.

The European authorities apparently liked the sound of Novo’s commitment to undertake a global, 9000-patient, five-year post-approval cardiovascular outcomes trial, including not just the classical MACE analyses of CV risk, but also various thyroid-related parameters, according to Thomsen. “The plan is to have the study protocol negotiated with the FDA as well [as the Europeans] by year-end,” he told The IN VIVO Blog—and to start recruiting a couple of months later.

So does that mean US approval’s likely before year-end? Not all analysts are that bullish, given the challenges of monitoring any potential thyroid risk in humans (though the worst-case scenario for some, a black-box warning, doesn't necessarily kill sales--just look at Actos). But as far as Thomsen’s concerned, yes, “we’re assuming that either we have US approval by then, or that we’re so far down the regulatory process that the CV study design will be part of the discussions,” he continues.

Novo’s in a hurry because liraglutide is already late (speed-to-market hasn’t always been Novo’s strength, as we reported in more detail here, although product quality has more often than not made up for this). Lilly/Amylin’s long-acting Byetta (taken once-weekly vs once-daily for liraglutide) is close on Novo’s heels, and these companies, unlike Novo, have an existing GLP-1 platform to build on.

Still, Novo’s going to do its damnedest to leverage its own insulin sales force to get liraglutide out as quickly as possible to a broad prescriber base, says Thomson. Not unusually, the UK and Germany, two of Europe’s largest markets where up-front pricing is free, will be the starting points. “We’ll make some minor adjustments to sales force size in Europe,” he says, “but we’re only talking an additional 100 or so.” Thomson says that a “sizable” part of the insulin sales force will be re-allocated to liraglutide, at least during the launch phase, as the company tries to capture what it hopes will be “positive perception of innovation” at Novo among diabetes drug prescribers.

It won’t just be the specialists, though: since liraglutide is easier to use than insulin (it doesn’t require blood sugar monitoring or dose titration), “we anticipate a broader prescription base [than insulin] and moving into the GP market within several months,” says Thomsen.

Liraglutide will be positioned as “the natural second-line therapy after metformin failure,” explains Thomsen, given its “superior clinical profile, effect on body weight and lack of hypoglycemia.” In this regard, Novo’s racing not just against Byetta and family, but against the (oral, and thus highly convenient, and cheaper) DPP-IV inhibitors, too—like Merck’s Januvia and, shortly, AstraZeneca’s saxagliptin (Onglyza), which last week received a positive EU opinion. Indeed, “the question is whether second-line therapy is liraglutide, or another oral therapy,” summarizes Thomson.

Novo’s leading position in the insulin market means it isn’t about to admit that liraglutide’s success will eat into its core franchise. But even if it does delay progression to insulin somewhat, Novo’s hoping the drug allows to it capture patients earlier on in the course of their disease. The idea is that pre-insulin diabetics become loyal Novo followers, “using our services and devices, and…that later on, when they go onto insulin, they’ll add [Novo’s basal insulin] Levemir”—and not Sanofi-Aventis’ competing Lantus—on top of liraglutide, explains Thomsen.

That argument might well be boosted by recent data—albeit still controversial—linking Lantus to an increased cancer risk, a link Novo is trying hard to ring-fence as a Lantus-specific problem, not one that affects all basal insulins.

For the next chapter in Victoza’s US story, we’ll have to wait until August 6th and Novo’s half-year results. The company in early June met FDA to talk risk-management and to discuss Victoza’s victorious performance in a gutsy two-year head-to-head trial versus Byetta. FDA "didn’t have access to this material prior to the [April] advisory committee meeting,” clarifies Thomsen.

In this trial, liraglutide also showed itself as “drug squeaky clean with regard to calcitonin levels compared to comparator drugs…” hence “the [US] regulators will also believe, like us, that the benefit-risk profile of performing invasive procedures to monitor patients’ calcitonin levels is negative,” asserts Thomsen.

Are you listening, FDA?

“Standstill” Agreements Limit Potential Buyout Deals

A month ago, everyone had the same question: which Big Pharma will be the next to buy-out a biotech partner. First, Roche/Genentech. Then Bristol/ImClone. Who would be next?

So far, the answer is: no one.

It turns out that there just aren’t all that many partnership out there where a buyout is in fact an option. We looked at 12 partnerships cited by analysts and other business media as potential partner-turns-into-prey stories, and it turns out that eight of them involve contracts that prohibit one partner from making an unsolicited offer for the other. (The complete list is published in “The Pink Sheet” this week.)

We got the idea thanks to a sharp-eyed reader of the IN VIVO Blog who responded to one of our posts on Byetta. In a discussion of the disconnect between what struck us as a relatively restrained safety alert by FDA and a hyperbolic panic among Amylin investors, we wondered why Lilly doesn’t just buy out its partner if it believes Byetta is safe.

It ain’t that simple.

As we should have known (since our reader helpfully pointed to the citation in our own database), the Lilly/Amylin agreement includes a comprehensive “standstill” provision that prohibits Lilly from trying to buy its partner.

Similar provisions are included in most of the other deals we looked at.

Most, but not all. It turns out Genzyme can buy out BioMarin any time it chooses, and Genentech is free to bid on either OSI or Biogen Idec—though somehow we don’t think that is a high priority for Genentech right now. And Biogen is free to buy its Tysabri partner Elan—presuming it doesn’t mind triggering the change-in-control provisions in Elan’s Alzheimer’s partnership with Wyeth. (And change-of-control provisions, of course, are a story unto themselves though that particular provision isn't one of the industry's most onerous.)

Nor are all standstill provisions created equal. Lilly is prohibited from buying Amylin for as long as the Byetta partnership lasts—and beyond (unless, of course, Amylin decides to negate the standstill). In other cases—like Bristol/Gilead and Wyeth/Progenics—there are expiration dates that come up soon (as in, during 2009). Other partnerships (J&J/Vertex, Wyeth/Elan) also have standstills that expire—but in those cases the dates are tantalizingly undisclosed.

So if you expected a flurry of Bristol/ImClone style deals to keep you entertained this fall, think again.

Thank goodness ImClone thinks it has another bidder. Its much more fun to watch companies running in place than it is to see them standing still.

PS. Click here for a free copy of all of our coverage of Roche/Genentech...

Whoops! Did We--and Novo--Speak Too Soon?

Did we—and Novo—speak too soon yesterday about Victoza’s chances at the FDA advisory committee next month? We reported Novo’s confidence that its GLP-1 analog liraglutide won’t be required to comply fully with the new FDA diabetes guidance issued last December.

Today, however, Takeda tells us that FDA has said its new diabetes treatment, alogliptin, will indeed be subject to the December guidance, even though it, like Victoza, was submitted earlier. It appears that Takeda will require more data, and, according to JP Morgan analysts, “this provides absolute clarity that FDA will now apply its new guidelines to all new diabetes drug applications.” Oh dear. Misplaced confidence? (Certainly Novo’s investors think so: shares were off about 3% today.)

But Novo’s position hasn’t changed. “Today is no different than yesterday,” Novo’s CMO Mads Krogsgaard Thomsen told The In Vivo Blog this afternoon. Liraglutide’s clinical trial program is more than double the size of alogliptin’s. And they’re completely different drugs: alogliptin is a DPP-IV inhibitor, a class that isn’t shown to improve blood pressure or reduce weight, as Novo claims is the case with Victoza. It’s conceivable, therefore, that FDA might hold DPP-IV inhibitors up to the new guidance—but not GLP-1 analogs, at least, not quite so strictly.

Thomsen also re-iterates that the company has done its MACE analyses (of CV events) with good results—indeed, the JP Morgan analysts appear to interpret this as Victoza actually meeting the new guidance requirements, despite the statistical powering issues (we couldn’t check as they don’t talk to journalists.)

Victoza’s other potential advantage: it’s clearly differentiated from the only other drug in its class, Lilly/Amylin's Byetta, on both efficacy and conveniece. Takeda can’t say the same.

Good for Novo. Why not hold a brave face? If one thing’s clear, though, it’s that victory next month is not a foregone conclusion. But even if Victoza does stumble—and, as one of you kindly pointed out yesterday, pancreatitis is another possible hurdle, given Byetta’s story so far, although Novo doesn’t think it will be more than a labelling issue—Novo might not mind that much (not that it would ever say so.) As mentioned, any delay would likely stall Byetta LAR, too. Which leaves Novo playing in the field where it’s strongest: insulin.

image from flikr user Mel B. used under a creative commons license

The Case for Byetta LAR (Part 1)

Lilly and Amylin say they have one regulatory hurdle to cross before filing for the long-acting formulation of exenatide (Byetta LAR): demonstrating comparability between the clinical formulation of the drug and the proposed commercial supply manufactured by Amylin in Ohio.

Amylin CEO Dan Bradbury told investors during the company’s second quarter conference call July 21 that a recent meeting with the agency gives the company great confidence in its projection of an NDA filing sometime in the next year. The company has said all along that it expects to file by the end of the first half of 2009, Bradbury said; the meeting with FDA suggests that timeline may be conservative, since the agency may end up not requiring a full-fledged clinical crossover study.

At a time when investors are focused on the now clear, unequivocal emphasis on outcomes endpoints for new type 2 diabetes drugs, Amylin’s confidence in a near time filing date for Byetta LAR is big news.

This is a tough time for type 2 diabetes drug development. An FDA advisory committee essentially endorsed the Steve Nissen worldview: that blood sugar reduction is not an end in itself, and new drugs for use by diabetics need to provide sufficient evidence of outcomes benefits—especially cardiovascular outcomes—as a condition for approval.

Our colleagues at “The Pink Sheet” have extensive coverage of the meeting, and—more importantly—FDA’s takeaways from the meeting.

But in case you missed it, after a morning’s worth of warm-up, Steve Nissen—Cleveland Clinic cardiologist and shadow FDA commissioner—went up to the podium and called out the entire profession of endocrinology, telling the committee that they have made glucose reduction a goal in itself and lost sight of the bigger picture. Some committee members fumed visibly—but the panel spent the next day-and-a-half following the agenda laid out by Nissen.

The committee agreed with his premise—that it is no longer acceptable to approve drugs solely based on the ability to reduce HbA1c levels—and with his overall approach to assessing cardiovascular outcomes. They punted on some questions—like exactly how much outcomes research to expect, and under exactly what conditions the studies would be necessary prior to approval instead of as post-marketing commitments.

So what does all this mean, other than demonstrating once again the incredible influence Nissen has on drug development and use in this country at this moment in history?

First, it confirms that the bar is indeed higher for type 2 diabetes drugs, that—in effect—they will be governed by a quasi-superiority standard of the type that FDA has begun talking about for NSAIDs (and now antipsychotics).

That in itself should not be news: Remember Pargluva? But it is now clear that new agents for glucose reduction will be expected to demonstrate some compelling reason for approval—better HbA1c control, evidence of reduced toxicity, something—or else face the risk of being asked for definitive proof of outcomes prior to approval.

So there is plenty of reason to wonder whether Lilly and Amylin can in fact move forward with LAR as planned (or even faster than planned).

We think they can…and we’ll explain why tomorrow.

A Better Way to do Risk/Benefit? (Part 1)

Our sharp-eyed colleagues at “The Pink Sheet” spotted an interesting document last week: a request for proposals issued by the Food & Drug Administration seeking a contractor to explore development of “a more formalized and comprehensive approach to the benefit/risk assessment” for new drugs.

In other words, the agency wants someone to help it create a quantitative tool to use in making the toughest of regulatory judgments: when, exactly, do the risks of a product outweigh its benefits?

It is easy to see the appeal of having such a tool. Among sponsors, there is a desire for a more predictable, rational climate for discussing post-marketing safety surveillance signals and pre-market risk versus benefit decisions. Put another way, many in industry believe a risk/benefit model will do more to capture the benefit side, which sponsors never believe gets enough weight—especially in a “Safety First” regulatory climate.

FDA likes the idea too. The agency wants to respond to concerns about the quality of drug safety oversight and to develop a common framework for weighing risks versus benefits in regulatory decisions.

On both sides, there is the hope that by developing better tools to analyze the risk-benefit ratio, it will be easier to explain to the public why, for example, a small risk of potentially fatal pancreatitis is offset by the broader benefits of blood glucose control in type 2 diabetics. (If you don’t think this matters much, look at what happened to Amylin and Byetta.)

And there is the unspoken desire to take some of the guesswork out of one of the toughest decisions an executive or a regulator in the drug industry will ever face: when is a drug too dangerous to stay on the market?

This is not a new idea. When the number of safety-related drug withdrawals began to creep up in the late 1990s—climaxing with the Vioxx removal in 2004—industry CEOs began to talk about the need for a more quantitative approach to judging risks versus benefits.

FDA also embraced the idea, and it was formally endorsed by the Institute of Medicine in its 2006 report on the drug safety system. FDA and industry even agreed as part of the latest Prescription Drug User Fee program to allow FDA to devote some of the fees to developing a model.

Hence the RFP. The agency is asking a contractor to study how a "more formalized risk/benefit analysis might compare to the human judgments, using less formal analyses, that were made in the FDA review." The contractor will test the model in four different cases--two drugs approved by the agency, and two that were not. If all goes well, FDA will have a report on the results six months after the contract is awarded. And, of course, that is still a long way away from having a useable tool to support regulatory decisions.

But let’s dare to dream. Imagine a world in which everyone—regulators, industry, and society at large—agrees on how to judge whether a relatively rare but serious risk does or does not outweigh a broad but milder benefit. In other words, a world in which there are reports of severe, potentially fatal pancreatitis with a new type 2 diabetes agent like Byetta, and everyone can immediately see whether that information fundamentally changes the rationale for using the drug (or even allowing it to remain on the market.)

Such a tool could revolutionize everything. Post-marketing surveillance would be less chaotic. The drug approval process would be much more predictable. Drug development would be more efficient, as sponsors apply the same methodology as regulators in making go/no go decisions on experimental compounds.

Here’s the thing: we don't think its going to work out that way. Tomorrow, we'll tell you why...

Delivery Delays

Making money in drug delivery has always been tougher than its boosters promise. And 2007 has once again proven that point (for more on this topic see Start-Up and IN VIVO articles here and here).

Most spectacularly, Pfizer dumped the inhaled insulin Exubera (though, realizing its rudeness, it quickly decided to pay its partner, Nektar, $135 million as a kind of a forgive-me gift and make all the right noises about helping it with the insulin supply and technology transfer a new marketing partner would need.

Meanwhile, Procter & Gamble abandoned Nastech and their nasal parathyroid hormone project (good story on this at the WSJ Health Blog). The original deal back in 2006 was trumpeted as worth $577 million to Nastech – though as it turned out Nastech didn’t even get the full $15 million in first-year milestones.

And while undoubtedly some of the management changes are merely coincidental, it’s intriguing to us that the top three names in drug delivery—Alkermes, Nektar and Emisphere—have all gotten new CEOs this year. Only Emisphere’s Michael Goldberg was actually pushed out, but the fact that all of these companies are pretty long in the tooth and still trading at or below their 10 year share-price averages (even, in the case of Alkermes, when you delete from the average the crazy period of 2000) has got to give you some sense of the fatigue that sets into managers who have to run this business. Says a senior official at one of the Big Three: “Boards are saying to the senior executives ‘it's time to deliver on delivery.’"

OK, OK--there's been good news, too. Vivus got its transdermal estradiol spray Evamist approved – and with it a $140 million milestone payment from marketing partner KV Pharmaceuticals. Not bad for about three years’ work – and some evidence of a working economic model.

United Therapeutics saw its stock jump about 50% early this month when its TRIUMPH-1 trial showed that its nebulized formulation of otherwise injected or infused treprostinil boosted walking distance for pulmonary hypertension patients. Next stop: an aerosolized version using Aradigmn’s AERx Essence inhaler.

XenoPort takes more research risk for its programs—prodrug formulations of existing molecules. Its gabapentin prodrug was attractive enough to convince GlaxoSmithKline to fork over $75 million in cash and dangle another $500 million in regulatory and sales milestones for the compound. And the early Phase III data it released a few months after signing the GSK deal certainly heartened investors, who have nearly doubled the price of the stock.

But the XenoPort deal also highlights the challenge that continues to frustrate drug-delivery companies and their investors. XenoPort’s prodrug is a new chemical entity that offers hard-to-duplicate molecular advantages. By and large, the products of drug delivery don't do that. Most don't make a big enough difference in therapeutic outcome to justify a big investment—in partnering terms, in development programs, and in launches.

The Exubera example is instructive. Originally, Pfizer thought inhaled insulin's convenience was enough of an advantage to make the product a winner. And they weren't alone: so did their partner Aventis, the maker of basal insulin Lantus. But certainly within the last few years Pfizer had begun to realize that Exubera needed a superiority claim. And that would be expensive--far more expensive than Pfizer had ever dreamed. Pfizer in fact needed to test Exubera against Lantus. Sanofi, which by then owned Aventis, certainly didn't want to risk Lantus getting shown up and cannibalized by Exubera. So Pfizer had to spend lots of time and $1.3 billion buying out Sanofi’s share before it could get the Exubera vs. Lantus trial going. But Pfizer couldn't wait to launch the drug until it had the comparative data -- so Exubera came onto the market clothed only with convenience. You know the rest.

The Exubera failure will help keep Big Pharma, and investors, on the sidelines of drug delivery. That’s one reason for investors’ indifference to what looked to us like the enormously positive data on once-weekly Byetta LAR: it did a bit better than the twice-a-day Byetta in reducing A1C levels but no better in reducing weight: its basic advantage is that it's a lot easier to use.

Convenience is pretty attractive to mid-sized companies like KV or United Therapetics. And they’re willing to pay for it. For them, a drug with a minor advantage can provide great growth. But they’re limited in what they can sell well. They're not, for example, particularly good at missionary sales—as Cephalon has demonstrated with its underwhelming results on Alkermes’ alcoholism treatment Vivotrol.

Alan Frazier of Frazier & Co., an investor in a variety of drug delivery companies, including XenoPort and Alexza, noted that VCs "always underestimate how much it takes to develop these systems," which can be quite complex. And they've got to be complex, he notes, because they have to provide real thereapeutic advantages over the convential therapy. So you end up with a great deal of investment on the technology side, he says--and then even more on the development side. After all, he says, pharma companies have been burned by drug delivery technology failures so they want more and more clinical data -- including Phase III trials. "Tough to finance,” he laments.


In short, drug delivery--the supposedly cheaper and less risky alternative to NME development--is often just as risky and certainly no cheaper.

Whoa Nelly: FDA Puts the Brakes on Liraglutide

When FDA knows six months ahead of a user fee deadline that it won’t be able to make an on-time approval decision, it’s not exactly a positive sign of a drug’s future prospects.

But that is exactly what Novo-Nordisk is facing with its once-daily human GLP-1 analogue liraglutide—the company’s much anticipated type 2 diabetes therapy.

FDA isn’t scheduled to make a decision on the approvability of liraglutide until March 23 at the earliest. But despite being six months away from the user fee deadline, the agency has already warned the company not to expect an on-time approval.

The delay, Novo says, will allow time for FDA to absorb feedback from an advisory committee review of liraglutide, which has been scheduled for March 2. The agency told Novo that it doesn’t believe the three weeks between the meeting and the user fee deadline will be enough time to complete the review.

“Since the advisory committee meeting is held shortly before...[the user fee] date, the agency has indicated that it will most likely have to extend the date of completing their assessment by a couple of months,” Novo said in a press release.

While FDA has certainly been able to deliver approvability decisions within three weeks of an advisory committee meeting in the past, there are two reasons why it is different this time around for liraglutide.

First, the agency is simply missing more user fee deadlines—something that we’ve been tracking and writing about in The RPM Report. While FDA is allowed to miss approval deadlines under the Prescription Drug Fee User Act, drug reviewers were given a green light to start missing more than usual earlier this year.

Based on some pretty small numbers, we've found that the longer a drug sits at FDA, the less of a chance of a positive decision. So if the agency is indeed just a "couple of months" late on liraglutide, that seems to bode well for the drug's approvability prospects. That is, of course, barring any other unforeseen (or seen) circumstances.

Which brings us to our second point. FDA is obviously taking it a bit slow on liraglutide given the pancreatitis safety signal seen with another GLP-1: Amylin’s exenatide (Byetta). Novo’s challenge at what will surely be a closely watched advisory committee meeting will be to make a convincing case that its product does not carry the same signal as Byetta.

As the Diabetic Investor points out, we’ve already seen this play out in the diabetes market over the cardiovascular safety issues with GlaxoSmithKline’s rosiglitazone (Avandia). As Avandia was imploding, Lilly/Takeda were asked to defend the safety profile of their thiazolidinedione drug product, pioglitazone (Actos). And in that case, they succeeded.

Novo Confident of Victoza Victory at FDA in May

The odds might appear to be stacked against it, but Novo Nordisk sounds remarkably confident that GLP-1 analog liraglutide (Victoza) will get approval from FDA by the end of May.

OK, so it needs to be confident: even if it is approved as expected, the once-daily drug, already about four years behind schedule, will have barely a year to make its mark before Lilly/Amylin’s once-weekly version of the incumbent GLP-1 analog Byetta hits the market in 2010.

But Novo’s up against a very diabetes-resistant FDA, with strong memories of the Avandia fallout, that has recently changed its guidelines in this disease area to require more safety data among patients at high risk of cardiovascular disease. And this, as Novo’s CMO Mads Krogsgaard Thomsen acknowledges, is “just the reverse of how we’ve recruited patients into diabetes trials in the past,” including into the liraglutide Phase III trials.

Traditionally, companies have sought to prove their drug’s safety and efficacy in relatively clean patient populations first. Given the CV signal picked up from Avandia well after that drug was approved, it’s clear why the agency has taken a more severe stand.

Among the 6000 or so patients in the liraglutide Phase III trials, very few suffered CV-related events. That’s good for those 6000, but it’s less good as far as providing sufficient statistical power to convince an edgy FDA to wave the drug through. Worse still, since Victoza’s early April advisory committee meeting is widely expected to provide the test case for the new guidance, FDA will be keen to set examples, not make exceptions.

Still, Novo’s got its defense all lined up--and its fingers crossed. For one thing, argues Thomsen, the guidance relates only to drugs that were not submitted by the time it was published, late last year. (Novo submitted liraglutide in May 2008.) There's some controversy over this, but the guidance, as Thomsen underlines, specifically appears to refer to studies in the planning stage and studies completed before submission of the NDA/BLA. (See pages 3 & 4.)

Plus, he adds, "we did not a receive any letter from FDA to say we would have to adhere to the guidelines with liraglutide, as we did for our [Phase II, not-yet-filed] once-weekly GLP-1 analog NN9535." His second point: when looking at risk factors like body weight, systolic blood pressure or biomarkers of CV events, “our data shows nothing concerning at all,” Thomsen told The IN VIVO Blog.

Sure, but FDA could always retort with: “Nor did Avandia’s. That’s the point of our guidance.” At this stage, Novo is hoping that its willingness to do a post-approval study looking specifically at CV outcomes will be enough to win the agency’s favor. “Even though the event numbers are small, we’ve done the [CV event] analyses that the agency asked for--the same ones it will now require going forward--and this convinces us at least why there’s a good case for not requiring a pre-approval study.” He goes on to say that liraglutide may even provide CV benefits.

Favorable trends aren’t enough, though. But whatever hoops Novo has to jump through, its competitors, BMS/AZ and Takeda, both with DPP-IV inhibitors currently under review and, more pertinently, Lilly/Amylin with Byetta LAR, will have to do the same. And whether Novo has to do its CV outcomes trial before or after approval, at least that data will help it make its case in the next—likely even tougher—regulatory challenge it faces with liraglutide: getting it approved for obesity.

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

No GLP-1s? Never Mind, Says Novo

After a decidedly lukewarm response from the FDA advisory panel yesterday on Novo's GLP-1 analog hopeful liraglutide (Victoza), your IN VIVO Blog team wonders whether Novo actually wants the drug to get out there after all.

Okay, so we were drawn in by the Danish group's absolute confidence prior to the meeting that the drug wouldn't stumble at FDA's cardiovascular hurdles, part of new diabetes guidance that was released after liraglutide was submitted. That confidence stuck even after it was revealed that Takeda's alogliptin--also submitted pre-guidance--would need to meet the higher safety standards.

And Novo was right, it seems, about the CV issue: it wasn't an issue. A majority of the panel voted that there was appropriate evidence of CV safety. In the event, thyroid c-cell tumors seen pre-clinical studies in rats and mice provided the...er, fly in the soup. Only one panelist agreed with Novo that this data was not relevant to humans. (See our Pink Sheet DAILY coverage yesterday.)

On a conference call early this morning to discuss the committee's findings (download a replay here), Novo's CMO Mads Krogsgaard Thomsen declared he was "still convinced that this [effect] is rodent specific." He was also relatively quick to draw in other GLP-1s, though; "this is a class effect. Once-weekly compounds including our own tend to produce c-cell changes in mice and rats, but in my mind not in monkeys or humans based on the data we have today." (Liraglutide is once-daily, but Novo has a once-weekly compound in Phase II.)

So in other words, if we go down, Byetta LAR (which Lilly plans to file at the end of 2Q this year) will go down with us (although LAR's rat studies showed more c-cell carcinomas only at the very highest dose, so it may get away with it). But even if LAR is impacted too, that still leaves Lilly/Amylin with a nice monopoly around the current, twice-daily Byetta--and, as Catherine Arnold of Credit Suisse points out, if LAR and liraglutide are required to conduct similar studies on thyroid cancer risk, LAR wins since the drugs' filings will then be very close together, with GLP-1 virgin Novo Nordisk at a disadvantage.

But--and here's the point, patient blog-readers--maybe Novo secretly (or less secretly) just hopes that liraglutide (and other long-acting GLP-1s) will just go away. Thomsen re-phrased an analyst question about the impact of GLP-1s on the insulin market. "What would happen if the GLP-1 class disappeared? This would not necessarily be a totally negative scenario for Novo Nordisk," he said.

No indeed. Novo's a leader in insulin, and 70-80% of its expected growth in the next ten years comes from modern insulin. Those figures came straight from the company's mouth on this conference call too. So did "If there are no GLPs, you might argue that [our growth] will be even stronger."

"But this is totally hypothetical," Thomsen clarified immediately after, as if coming back down to Earth from some insulin-infused dream. "We're trying to get liraglutide approved, because it offers a significant advance for diabetes patients."

Analysts' first take is that liraglutide is unlikely to get past FDA in 2009, although Leerink Swann adds that a "final rejection also appears unlikely." In between lie the possibilities of a black box warning, higher monitoring requirements and further studies--including pre-approval. None will do liraglutide much good. So we may not be totally off-base in suggesting that Novo wishes it has just stuck with insulin.

image--dreaming--from flikr user h.koppdelaney used under a creative commons license

DotW: Tea Leaves

Bad news on Wall Street this week as the Dow Jones industrial average lost more than 250 points on Thursday and consumer confidence waned. Rising gas and food prices--and the incessant stagflation drumbeat--have prompted a certain proclivity for prognostication stateside. The IN VIVO Blog takes time out to read the industry's tea leaves in this edition of Deals of the Week.

The IN VIVO Blog learned of a major departure this week: Abbie Celniker, head of Novartis's recently launched Biologics division, has left for parts unknown. We aren't really sure what her departure means for Novartis, which announced a major reorganization last October, including the promotion of former Heinz exec Joe Jimenez to run the pharma's drug unit.

News of another major departure surfaced Thursday: David Mott, MedImmune's wunderkind CEO, will be leaving the AZ subsidiary at the end of July for "personal reasons" -- which undoubtedly include too many hours spent burning the candle at both ends within the much more bureaucratic environment of Big Pharma, all the while sitting on a ton of acquisition-related personal cash. And as the clock ran out on what was likely a one-year employment agreement, it's almost certain Mott heard a continuous stream of interesting new investment and management opportunities.

Mott, of course, isn't the only MedImmune executive to announce an exit. CSO Jim Young has also left the company--apparently for a familial and culinary year in France. We suspect biz dev and MediVentures boss Ed Mathers is also considering the next stage of his professional life.

Wholly-owned standalones, à la MedImmune, Sirtris and Millennium, have become common these days as pharmas attempt to transform their business models by purchasing innovative biotechs and ring-fencing them. Mott's departure is almost certain to provoke discussion about the practicalities of the strategy versus, say, Roche's riskier but certainly successful experience with its majority-owned, independently traded Genentech affiliate.

And that, in turn, could promote additional discussion about the need for a diversified business model, particularly as it relates to generics, championed by Novartis and Daiichi and eschewed by Takeda and BMS. Pharmalot's Ed Silverman wonders if J&J is mulling a possible move into generics based on this Wharton interview with CEO William Weldon. Asked about the recent Daiichi/Ranbaxy wedding, Weldon gave this response:

There is a big opportunity in the generic field because of large products going off patent... Each company has its own choices that it has to make. Personally, I think that if you have good research, if you understand the needs of patients and if you can deliver good products into the market, that is the most important thing to be doing and that is where we've committed ourselves so far. But that is not to say that we wouldn't go into generics or other companies. I think that there is a big market emerging and big opportunities in the future.

Meantime, at a forum led by the Institute of Medicine earlier in the week, another approach to drug development emerged, one that Genzyme and Shire (among others)have championed: the orphan drug as blockbuster. For more, check out this post from our own Mike McCaughan. The sludge at the bottom of this blogger's mug is particularly muddy. That means it must be time for...

Genzyme/Isis: Ah, the topsy-turvy ride that is mipomersen. A quick recap: back in January, Genzyme and Isis inked the $325 million up-front alliance on the cholesterol candidate, only to get backfooted by the kerfuffle surrounding Merck and Schering-Plough's Vytorin study, Enhance, shortly thereafter. As we predicted, the regulatory storm in the wake of Enhance (which we've covered extensively--see here) rocked the boat for Genzyme and Isis, which hadn't yet finalized the terms of the mipomersen deal. The companies said in late April that the drug's development timeframe would be reworked in response to an FDA request for more data. For the narrow indication of homozygous familial hypercholesterolemia, that means about a one year delay in filing, from 2009 to 2010. For broader indications including heterozygous FH, a cardiovascular outcomes study will be necessary. So where did that leave Isis and it's truckload of up-front cash and zillions in milestone payments? It took until this week to find out, but the upshot wasn't too bad for the antisense specialist, all things considered. Isis will contribute an additional $50 million to mipomersen's development, reflecting the added cost of the necessary expanded clinical program, and will be eligible for accelerated milestone payments potentially worth $75 million (related to commercial milestones associated with US sales under the heterozygous indication).

Stiefel/Barrier: On Monday came news that privately owned dermatology player Stiefel Laboratories bought all outstanding shares of Barrier Therapeutics for $148 million, or $4.15 a share. The deal price represents a 57.6% premium over Barrier's closing share price on Friday June 20 of $1.76. Stiefel, which makes a variety of over-the counter and prescription medicines, likely saw Barrier as a solid way into the pediatric realm. Two of Barrier's major products include Vusion, an ointment designed to heal pesky diaper rash combined with a yeast infection, and Xolegel, which treats a flaky skin condition called seborrheic dermatitis. Certainly, Stiefel acted opportunistically. As we wrote in this START-UP article, Barrier is one of a number of newly public companies in financial trouble. With less than one year of operating cash remaining, it has seen its share price tumble--back in April, Barrier's stock price was down nearly 78% from its 2004 IPO and in the ensuiing weeks slid even further. Susquehanna Financial analyst Angela Maria Larson told Forbes the deal was "a solid, good offer" but that's likely to be cold comfort to Barrier's VC backers, which include New Leaf Ventures, MPM BioVentures, and TL Ventures. But at least as it pertains to Barrier, these VCs are no longer marooned in the public market.

Novo/Emisphere: As we’ve written elsewhere, Emisphere has had a tough 20 years or so, failing to deliver (no pun intended) on a variety of drug-delivery projects, most spectacularly oral insulin (didn’t work any better than placebo). Now, a little more than a year into the tenure of CEO Michael Novinski, Emisphere has moved from oral insulin, for which needle-less delivery was relatively unimportant, to drugs for which injection is a problem: GLP-1 analogs. To auslanders like us, the different GLP-1’s don’t seem all that clinically differentiated. But Novo’s still unapproved once-a-day liraglutide looks like it will have a delivery advantage over Amylin/Lilly’s marketed twice-a-day Byetta – until, that is, the partners launch once-weekly Byetta LAR. At that point, liraglutide will need extra help – like an oral version. Having worked with Emisphere for at least a year on preclinical studies (with interest significantly heightened by nicely positive clinical studies with Emisphere-designed oral GLP-1), Novo was willing to experiment, modestly. It’s paying a guaranteed $10 million in the first year (modest good news relative to the world of NME drugs, but great for the smaller drug-delivery players like Emisphere – this is its biggest 1st year payment) and, potentially, another $77 million or more in clinical and sales milestones. Emisphere’s stock was, naturally, up on the news – but hardly into champagne territory. The company’s long record of unfulfilled promises is going to keep a lid on the share price until a pivotal trial proves the skeptics wrong.

WuXi PharmaTech/Covance: Although details of the deal still need to be finalized, WuXi and Covance are set to create a 50/50 JV to provide preclinical testing services in China. Covance will contribute $30 million to the project, while WuXi will provide a 323,450 square-foot facility in Suzhou, China. This state-of-the-art facility, expected to be completed in 2009, is designed to meet the US FDA and worldwide regulatory standards. WuXi is one of the leading CROs in China and its success has sparked a wave of interest among VCs and other investors looking to tap into the rapidly growing pharmaceutical business in China. Already, the company has dozens of partnerships with top tier pharmaceutical companies who are looking to off-shore their medicinal chemistry capabilities to China to take advantage of cheaper labor costs. Back in January, WuXi acquired the US biologics firm AppTec Laboratory Services, a move that gave the Chinese firm a US beachhead and greater access to critically important large molecules expertise. This latest deal with Covance, one of the leaders in worldwide clinical testing services, shows that WuXi is interested in extending its offerings beyond chemistry to include GLP tox, drug metabolism, and bioanalytical chemistry services. Although the two companies have yet to team up on clinical trials, that's likely to be another area of interest. For Covance, a tie-up would ease its entry into a lucrative and still largely untapped market. For WuXi, it seems the Chinese giant is positioning itself to become "a truly integrated one-stop shop for offshore and low-cost drug R&D outsourcing in China," says Jinsong Du, an analyst with Credit Suisse in Hong Kong, told our sister publication PharmAsia News.

(Photo courtesy of Flickr user soaleha via a creative commons license.)