Novo Scraps Inhaled Insulin

The dismal failure of Pfizer/Nektar’s Exubera loudly called into question whether inhaled mealtime insulin was commercially viable at all.

The answer—surprise, surprise--is that it’s not, at least according to Novo Nordisk. The Danish firm announced last night that it was scrapping its Phase III inhaled insulin program, which uses Aradigm’s AERx liquid aerosol system.

The slight irony here is that the (already painfully delayed) AERx program was killed because it failed to show “sufficient clinical or convenience benefits” over the various insulin analogs already available to patients—including, prominently, those using Novo’s own FlexPen, a discreet and simple-to-use injection device.

Novo’s decision doesn’t mean that other late-stage inhaled insulin wannabes, including Lilly/Alkermes and MannKind will follow suit. But as we argued in this IN VIVO feature, Pfizer’s snafu means the going will be tough. Novo was at best going to be third to market, and the brick-sized device (far larger than Lilly/Alkermes’) had long been recognized as a problem—that’s why Novo had begun a next-generation program in-house. And the product required refrigeration.

So the writing was on the wall. In fact it’s somewhat of a relief that Novo has finally put this long and expensive project to bed, taking a non-recurring cost of about $260 million (DKK 1.3 billion), which will hit 2007 operating profit. Mads Krogsgaard Thomsen, CSO and EVP of Novo Nordisk had already last year acknowledged that “this is not going to be a huge product.” Now it won’t be one at all.

Not that this spells the end of pulmonary delivery for Novo. The problem with all of the current batch of inhaled insulins, according to Thomsen, is that they’re short-acting, meal-time insulins that must be taken alongside basal insulin—the ones available with tiny, pain-free injection devices. Exubera's failure showed that patients (and payors) understandably, were reluctant to add onto that regime something even more complex. And Pfizer, for reasons we outline here, failed to reverse the treatment sequence by persuading physicians to prescribe insulin earlier on.

So given that meal-time insulin is typically a fifth or sixth step in diabetics’ chain of medication (which progresses from diet-and-exercise, through oral anti-diabetic drugs to GLP-1s and then basal insulin) why did drug companies focus their inhaled efforts on this and not basal insulin? “Becase we had no choice,” says Thomsen, technological limitations meant that prandial insulin was the only one which could be formulated for inhalation.

Those limitations are no longer, he continues. Novo now intends to focus on developing pulmonary forms of basal insulin and GLP-1. We outlined in a feature last summer the importance of glucagon-like-peptide (GLP-1) analogs (and Phase III GLP-1 analog liraglutide in particular) to Novo’s business, so it’s no surprise that GLP-1s feature in the firm’s fresh set of pulmonary delivery plans.

These are a way from the market, however—liraglutide itself can’t be formulated for inhaled delivery because its half-life is too short; nor can Lilly’s first-to-market Byetta. Still, “we’re not starting from scratch, either; we have an inhaled, bioavailable GLP-1 candidate in late-preclinical trials,” asserted Thomsen on a conference call following today’s news.

Novo’s shares were down nearly 4% this morning; chances are Aradigm might have a bad day when the US exchange opens. But Novo’s put on a brave face. “We’re going from being followers in a commercially unattractive area, inhaled meal-time insulin, to leaders in a highly commercially-attractive area—a new generation of inhaled long-acting basal insulins and GLP-1 analogs.”

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Pelikan Scoops up a Pouchful of Cash

A wonderful bird is the pelican. In his beak, he can hold food for a week.

And also great wads of cash such as that gathered up by the bird’s namesake, Pelikan Technologies.

Pelikan (that’s the German word for pelican) announced this morning that it raised $69 million in cash and another $20 million in venture debt, bringing funds raised to date to a grand total of more than $150 million.

That sounds like an enormous amount of cash for a device start-up, but it’s not really, not for a company trying to take on the Big Four (Roche, Johnson & Johnson, Abbott and Bayer) in consumer glucose testing, a $7 billion world wide market.

Besides its great big maw, the pelican has other fine attributes. CEO Dirk Boecker told us, “The sea bird is perfectly adapted to its environment and is particularly efficient at catching fish just below the surface of the water, never diving deeper than necessary, nor causing excess ripples or waves.”

That’s how Boecker wants people to see Pelikan Technologies, which is trying to improve compliance in glucose testing. Today, diabetes patients generally don't comply with the clinical recommendations for testing, understandably, since conventional blood sugar tests require them to stick their fingers with a sharp object several times a day to draw blood.

Spun out of Agilent in 2001, Pelikan Technologies is developing a single small device that, with a single push of a button, can draw out a blood sample in a pain-free manner, feed it through microfluidic channels in the device for analysis, and read out results.

The company is still developing this integrated testing platform, which will get rid of all the paraphernalia that patients with diabetes have to carry around today—separate lancing devices, lancets, test strips and a glucose meter--but it has already introduced, as a first stage, a pain-free lancing device, the Pelikan Sun, which it is selling over the Internet.

Pelikan Sun has been launched in Australia and Europe, and the company is on the eve of its US launch. The device still pokes people in the finger, but the company claims it doesn’t hurt because it lances at an exact pre-determined and adjustable depth to reach the capillary loops without perturbing nerve endings, thereby avoiding pain altogether (so they say), and it only needs a tiny blood sample to do its job—60 nanoliters, the smallest requirement in the industry, Boecker says.

Not just any diabetes start-up working to make glucose testing pain-free and convenient can command the kinds of funds that Clarus Ventures LLC, HBM BioVentures Ltd. Global Life Science Ventures, Mannheim Holdings LLC, and Bio*One Capital have put into Pelikan. Non-invasive glucose monitoring companies, for example, are pretty much anathema to VCs because so many have failed, or if they haven’t failed yet, have consumed ten years worth of cash with still nothing to show for it.

Pelikan is attractive because it’s innovating along the same lines as those other icons of success in glucose monitoring, MediSense, and TheraSense, which made incremental but meaningful improvements to conventional blood glucose testing. Both were acquired for a premium by Abbott Laboratories.

MediSense introduced a biosensor-based point-of care blood glucose meter for home use that was more accurate and less expensive than competing products. TheraSense moved testing off the sensitive finger tips to other sites of the body that were less painful to puncture. In fact, this has been the most successful strategy since the very beginning of consumer glucose monitoring back in the 1980's; pioneer LifeScan’s success was due to added convenience; its test strip didn’t need to be blotted and wiped like the tests that came before.

Pelikan still has to face the demands of manufacturing a medical-grade device on the scale of consumer electronics--the challenge of making a complex but robust product in high volumes-- but it doesn’t have to break new ground here either.

Insulin pump manufacturer Insulet Corp., which was struggling to meet an overwhelming demand for its disposable pods of insulin, recently signed an agreement with contract manufacturer Flextronics International, which will help it get up to its goal of producing 200,000 pumps per month by the end of 2008 to meet demand. Coincidentally, Flextronics is Pelikan’s manufacturer too. (Check out the next issue of START-UP for more on glucose monitoring start-ups.)

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Science Matters: A small personalized medicine bailout for Cox-2s?

There was little attention paid to last week's paper suggesting that PPAR delta agonists might be used to prevent the cardiovascular side effects of Cox-2 inhibitors (coxibs) such as Vioxx and Celebrex.

The study in the Journal of Experimental Medicine (JEM) showed that Cox-2 suppresses the expression of tissue factor (TF) -- the primary activator of blood clotting and a proximal cause of coxibs' CV problems -- via the activation of PPAR delta.

Of course, there are no approved PPAR delta drugs, although pharmas including GSK have tried developing them to treat cardiovascular disease. (One news outlet suggested GSK's drug could be an "unlikely savior" for Vioxx, but that's a far stretch.) And no one would think to couple a PPAR delta with a coxib for use as a combination analgesic--the risk/benefit ratio of that presumably is way off.

But there's another, intriguing aspect to this research result.

The problem with Vioxx is that it is associated with cardiovascular complications in a small number of patients. "We should look at these patients in terms of their TF levels and other clotting parameters," suggests Timothy Hla of the University of Connecticut Health Center and a principal author of the JEM paper. "Is the TF gene in these people somehow different? Is it regulated differently? Are they more sensitive or more resistant to the effects of the PPAR delta they produce? Instead of looking at the selectivity of Cox-2, let's look at patients' sensitivity."

Hla has a longstanding interest in Cox-2's role in normal blood vessel physiology and angiogenesis: he cloned the gene from human vascular cells in and named it Cox-2 in 1992, while at the American Red Cross Research Institute.

A first step would be to measure TF levels, which can be easily collected from plasma, in patients taking Celebrex and correlate them with treatment results. It's all well and good to talk about testing PPAR delta agonists for their therapeutic effects regulating the TF gene. (The most advanced may be GSK's GW 501516, which the Hla group used in its experiments. GSK in-licensed the compound from Ligand Pharmaceuticals, but its development has lagged at Phase II. Ligand's most recent 1o-K says the drug's development is 'on hold' pending the review of preclinical studies, and there is no mention of it on GSK's own clinical trials web site or in any recent publicity [clintrials.gov lists a 'completed' Phase II study], so for all we know it has been terminated.)

So that's a long way off. Most of the focus on the mechanism of Cox-2 has centered on its effect on platelets. A simple blood test might go a long way towards refining that effort.

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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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While You Were at ADA

Here are a few of the stories that IN VIVO Blog picked up on over the weekend ...

• Not technically a weekend event, but late on Friday Congress introduced legislation that would change the tax treatment of carried interest from a capital gain to regular income, effectively jacking up the tax rate on VCs, hedge funds and private equity shops from 15% to 35%. Spirited discussion continues over at PE Hub, but comments encouraged here too. Will this truly hurt the pace of innovation in the US, as has been and will be argued? Or are undertaxed investors only looking out for #1? Both?


• The American Diabetes Association's annual meeting kicked off in Chicago. Among the companies presenting data was Merck. Reuters reports on some new Januvia data that suggests the drug added to standard therapies (study 1: metformin, study 2: metformin plus sulfonylureas) improves blood sugar better than those therapies alone. The incidence of hypoglycaemia, however, was up in the Januvia groups in each study when compared to the control.


• In other ADA news, Lilly and Amylin presented solid data from a long-term study of Byetta, including progressive weight loss over a three and a half year period. Novo Nordisk's liraglutide is no slouch either. See this June IN VIVO story for the low down on Novo's diabetes prowess.

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It must be two-for-one week on private biotechs

It was always a question of when, not if. Amgen needed to do something to provide for its post-EPO future; now the action has started. Today's acquisition of private Alantos, for $300 million in cash, takes this week's shopping bill for Amgen up to $720 million. Just a couple of days ago it snapped up Ilypsa for $420 million.

Ilypsa fits nicely with Amgen’s existing nephrology franchise: the company’s focused on renal disorders and has a Phase II candidate to treat high blood phosphate in dialysis patients. But Alantos takes Amgen into new, uncharted territory: diabetes.

Now granted, diabetes is a huge and expanding market—that’s why, as Amgen’s executives made clear to IN VIVO last month, it’s a development priority (along with cardiovascular disease). It’s the only primary care area where sales forces are increasing, not shrinking; the number of US reps has doubled to 10,000 in the last five years.

But it’s also gotten highly competitive, with Big Pharma including Merck & Co., Novartis and Roche all piling in. Amgen may have taken faith from the spectacular performance of Merck’s DPP-IV inhibitor Januvia, in the same class as Alantos lead Phase IIa program. But will there be room for many more in the same class?

Not according to Novo Nordisk, who pulled out of the oral anti-diabetics space earlier this year. They might just have sour grapes, since their own DPP-IVs failed several years ago, and the variety of DPP-IVs out there all bind the target differently, with differing degrees of safety and efficacy. But there’s another shadow over the class: GLP-1 analogs (glucagon-like peptide-1 analogs).

For a variety of reasons that you can read about in the forthcoming issue of IN VIVO, many experts believe that GLP-1s, not DPP-IVs, are the place to be in diabetes. Sure, DPP-IVs are oral, GLP-1s are injected. But, getting back to Amgen, it’s not as if they don’t know about proteins.

All that said: good for Amgen. At least they’re doing something, and who knows, maybe Alantos’ DPP-IV will trump Merck's in efficacy or safety (although if so, Amgen will want to take back ex-US rights, which were licensed last October to Servier). Meanwhile Alantos’ investors have done okay—the company has raised a little under $60 million since its foundation (as Therascope AG) in Germany in 1999. --Melanie Senior & Chris Morrison

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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.

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More Insulin Problems

Pfizer isn't the only company having problems with an alternative delivery form of insulin.

Emisphere Technologies has been working on oral insulin for more than a decade--and finally its board got fed up.

In October 2006, the company reported disappointing Phase II results with its oral insulin--no difference from placebo. The stock tumbled by more than 50%. By January the long-time CEO, Michael Goldberg, MD, was out. The firing was led by Mark Rachesky, who joined Emisphere's board in 2005 when his fund, MHR Institutional Partners, loaned the company $15 million, later changing the straight debt to a convert--at $3.78 a share. That's unprofitably close to the company's current stock price (and less than half the Emisphere price when Rachesky did the covert deal).

Goldberg was blamed for poor execution of the key trial (as well as the fact that the company hasn't made much progress in its nearly nineteen years of life). The original trial design called for the oral insulin to be tested in very sick but stable patients; to accelerate the enrollment, the company apparently relaxed the criteria. In a subsegment look at patients who met the original criteria--an often unreliable analysis--oral insulin apparently did perform well. But now the company needs a new trial to prove the point. And this isn't the first trial that wasn't well executed: its oral heparin test was hurt by a poor liquid formulation whose taste turned off patients.

The company is by no means dead--it's managed to hire a new CEO, Michael Novinski, the former president of Organon USA. And it's brought on a board of big-name diabetologists to advise it on trial design and execution. It's got a new formulation with apparently three times the absorption of the older version--thus reducing cost-of-goods and increasing patient convenience.

But oral insulin won't win on convenience. And it won't win by eliminating the pain of injections. New smaller needles make taking insulin relatively painless. The big advantage will be eliminating embarassment, says one insider: "What diabetics hate is at a restaurant having to pull up their shirt and stick themselves in the stomach with a needle." Exubera doesn't solve that problem: puffing on a big device is no less inconspicuous than sticking one's belly with a needle.

A pill should be a lot more acceptable. And yet that's not enough. The market for insulin reformulations is being shaved by better needle technology and by new products, like the injectable Byetta and the oral Januvia. And as Pfizer is learning from Exubera, managed care doesn't want to pay for convenience. Emisphere's product, to be truly important, will have to show better outcomes. It may be able to get on the market by showing equivalency to injectable insulin--but to make Emisphere, and oral insulin, a success, it will need to keep diabetics healthier, too. That's a much more expensive task than most proponents of oral protein delivery ever figured they'd have to accomplish.

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Take a Deep Breath, Pfizer, and Think Again

It's just what Pfizer didn't need: another expensive failure.

Less than six months after the much-vaunted Lipitor-replacement torcetrapib tanked, it's now official that the Exubera launch is a flop. The numbers say it, the newspapers say it, and even Pfizer’s own executives acknowledge that “we still need to figure out how to market Exubera.”

Not surprising, perhaps—Pfizer isn’t exactly a large molecule expert, and Exubera, as the first ever inhaled insulin, presents even more challenges for its sponsor than your average biologic.

First, doctors must be convinced of the drug’s advantages over existing treatments; not just longer-acting insulins such as Levemir, marketed by diabetes-leader Novo Nordisk, but also since late 2006, Merck & Co.’s star DPP-4 inhibitor sitagliptin (Januvia), a rare industry success story (to be followed by recently-approved Janumet, a combination of Januvia and metformin).

Then, time-constrained docs must learn how the inhaler device works (and adapt dosages, which are different when insulin is inhaled rather than injected). If they get past that hurdle--and aren’t swayed by detractors such as Dr. John Buse, president-elect of the American Diabetes Association, who says that Exubera may present a safety risk in Type I diabetics--then their patients must get used to carrying an umbrella-sized device around with them (and paying more for the privilege: Exubera costs $2-3 more per day than injectable insulin).

So Exubera is being chosen for just one in 500 insulin prescriptions in the US, despite Pfizer’s investment—900 part-time diabetes educators, over six months of doc-targeted marketing, and considerable sales rep resource, in part diverted from other more profitable drugs. Analysts have slashed Exubera sales forecasts, in some cases to barely more than $300 million by 2012.

But Pfizer’s not giving up. “Don’t write Exubera off,” warns a senior executive at Pfizer. “We’ve screwed up before on launch, and the drug has come back.”

The company will soon launch a fresh marketing campaign, a summer DTC advertising splurge (very unfashionable), and reckons that transferring Exubera promotion to its highly successful CV team might make the difference.

Chances are it won’t. Marketing inhaled insulin—effectively a niche drug, despite initial forecasts of peak-sales of up to $2 billion—isn’t like marketing a primary care pill. You can’t use the same tricks.

“Patients will be inhaling insulin over the next few years,” insist Pfizer executives. Sure, but how many, and whose product? By the time Pfizer figures out its promotional game, competition will be even worse, even if there is a market. The handful of inhaled insulin alternatives in Exubera's wake have smaller, more discreet devices, and will benefit from Pfizer's experience in figuring out how to make breathing in one's insulin more attractive than injecting it.

“You may wonder whether Exubera could be right for you,” says Pfizer’s product website to prospective customers. Despite its brave face, Pfizer must be wondering whether this drug is right for it, too.

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Reporting on Exubera: an A-Buse

Many analysts have questioned the potential of Pfizer’s inhaled insulin, Exubera. Nonetheless, it was more than surprising to see the comments about the drug attributed to American Diabetes Association president-elect John Buse, MD, this week.

In a widely circulated AP story on March 21 about Exubera, Buse was quoted saying "I think Pfizer will wish they had never gotten into this. I doubt they'll regain their investment…There is no advantage to Exubera and there may be a safety risk. I see it as my job to talk people out of (using) it."

Buse has spoken to IN VIVO in the past, and we know him to be a highly credible and extremely careful commenter who focuses on medicine and avoids discussion of company issues. His statements on Exubera and Pfizer therefore seemed unusually pointed, all the more so given that he had said “There’s cause for tremendous optimism” following the product’s approval in 2006 for the treatment of type 1 and type 2 diabetes in adults.

When asked in an email last night about the accuracy of the AP story, Buse replied: “Not fair. The comments were specifically about treating type 1 diabetes. Not about treating type 2 diabetes.”

That makes sense. Indeed, last year he pointed out the possibility of a safety risk for type 1 diabetics, who must use Exubera in combination with longer-acting insulin. The inhalation device “is a little too cumbersome to be used in multiple daily therapies like we use in type 1 diabetes, but certainly that would be an option,” he said then, adding that the drug is “mostly going to be used in the type 2 population that's just getting started in the insulin business,” as an alternative to or in combination with rapid-acting insulin injections or oral drugs. Safety issues are also amplified in type 1 patients because “they are likely to be exposed for 50-plus years,” Buse added in his recent email to us.

As for the reported comments about Pfizer’s ability to recoup its investment, he would only say that “I may have said it” in the course of reflecting on the competition Exubera faces in both the type 1 and type 2 markets from Lilly-Amylin’s Byetta, “even better [incretin mimetics] on the horizon, better pens, much greater acceptance of long-acting insulin, increasing price pressure from managed care and the interest in long-term safety demonstration.” --Mark Ratner

Did the AP inhale?

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Galvus Misses Its Window; Is this All Good for Merck?

The Galvus delay is terrible news for Novartis.

Competitor Januvia, from Merck, has already seen the single best launch in recent memory for an anti-diabetes product. With a 40% share of new written scrips just four months after introduction, it may be the best launch of any new drug into a crowded category. Given its labelling -- “similar to that reported with placebo” -- doctors are rushing to prescribe what one clinician called a "no-brainer drug": zero training required in administering it; once-a-day dosing, with or without food, with or without any other medication. Once they're comfortable with Januvia, why would doctors switch to anything else, unless they're dramatically differentated?

Originally estimated to be three months behind Januvia, Galvus was already at a big timing disadvantage. Things are now much worse. Galvus seemed to have little differentiation over Januvia before (and therefore little chance of gaining a market-share advantage--now its only differentiation is negative: the skin lesions in primates, linked in FDA's mind to the toxicities seen with the drug at very high doses. That won't encourage doctors to try new patients on Galvus, particularly if, as a number of experts believe, Galvus' label--granted the drug's ultimately approved--comes with restrictions on use.

The potential time bomb for Merck is that Galvus' problems will redound to its detriment--just as the problems around Merck's own Vioxx KO'd Pfizer's Celebrex. FDA's metabolic division has been under severe scrutiny and it's possible they could do the cautious thing and start looking at lot more closely at Januvia. And when they do, will doctors too start thinking a lot more before prescribing what was once a no brainer?

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AZ-BMS Diabetes Deal: Two Paths for Big Pharma

If there is a schism among Big Pharma it is between those companies clinging on to the notion that pharma's future role is--as it is today--as a massive marketer of mass-market drugs, and those that see specialism as a means to avoid imploding under the weight of their own infrastructures.
The diabetes deal announced yesterday by AstraZeneca and Bristol-Myers illustrates the pursuit of each strategy: AstraZeneca, eager to play in what one pharma CEO described this week as "the disease of our epoch," has paid BMS $100 million upfront for worldwide (except Japan) co-development and co-commercialization rights to two late-clinical stage diabetes projects. For BMS the move is another big step back from primary care marketing and confirmation that the company's future lies along a specialist path.

AZ will fund the majority (75%) of development costs through 2009, the companies said, after which costs will be split 50-50. Should each of the two drugs--saxagliptin, a DPP-4 inhibitor currently in Phase III and dapagliflozin, a SGLT2 inhibitor in Phase IIb--reach global markets BMS will earn $650 million in pre-commercial milestones and could land an additional $300 million per drug in sales milestones. Post launch expenses and profits will be split evenly on a global basis and BMS will manufacture both products and book sales.

Acquisition of diabetes projects to shore up its primary care portfolio has been high on AZ's agenda since the PPAR agonist tesaglitazar (Galida) crashed out of clinical trials in May 2006; ironically the decision to yank Galida was based on thought-leader and regulatory reaction to BMS's own PPAR, muraglitazar (Pargluva) and intimations that Galida was in for similar treatment. Pargluva was killed after analysis published in JAMA by Cleveland Clinic CV chair Steve Nissen, MD, questioned the safety of PPARs and FDA said further long-term clinical studies would be needed to approve the product. (See "Anything but Academic: Lessons from the PPAR Failures," The RPM Report, June 2006.)

By the time saxagliptin hits the market the best AZ and BMS can hope for is only two entrenched competitors: Merck's Januvia and Novartis' Galvus will likely await. Dapagliflozen is a sodium glucose co-transporter-2 inhibitor, which blocks the re-absorption of glucose from urine in the kidney; a more novel, yet riskier prospect.

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