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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While You Were ...

So what were you up to this weekend. Perhaps you were flying to Hamburg for the BIO shindig? Or throwing back a few half-pints at the (outstanding) Woking Beer Festival? Re-reading "The Naked and the Dead," maybe. Whatever your poison (ours was Tryst Brewery's Carronade IPA) we hope you had a good weekend.

• Novo Nordisk tells the Times: Exubera may have gone up in smoke, but inhaled insulin isn't dead yet. We'll be taking an in-depth look at the future of inhaled insulin in the next IN VIVO.


• Medical meeting season rumbles onward; at the American College of Rheumatology, on Saturday, NicOx presented further Phase III data from its '301' study of naproxcinod. Specifically, the company reported positive GI- and blood pressure-related safety and adverse event data for the drug candidate, a nitric oxide-donating form of naproxen that some analysts hail as a blockbuster alternative to the blighted Cox-2s. We've written extensively about naproxcinod here.


• Drug-coated stents are the new eggs. First they're good for you. Then they're bad for you. Now, apparently, good for you again. But manufacturers aren't holding their breath for a massive rebound in sales. The New York Times reports.


• Has Merck been punished adequately in the whole Vioxx debacle? Not everyone thinks so. Pharmagossip rounds up the usual suspects.

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R&D: Worth It Only When You Don’t Pay for It

The late Michael Sorrel, one of biotech’s most perspicacious analysts, had a few basic rules for investing, one of which was the call option. Did the biotech have not merely a lead program, which could anchor the company’s valuation, but something else the stock buyer could get for free.

Same holds true with pharma. Analysts are now so skeptical of early-stage Big Pharma R&D that they want it for free. Or at least that’s the implication of some intriguing calculations from Craig Maxwell, European equity research analyst at JP Morgan.

Maxwell summed the estimated value of the six major European pharmas based solely on their current products plus their Phase III pipelines – the “embedded value” -- and then compared it to their current share prices (see chart). The closer these values came to the share value, the less the market—theorizes Maxwell—is valuing research. And that means the less the investor is paying for R&D.

Conversely, the bigger the gap between product value and share value, the greater the value the market is putting on research. No free R&D option—and a poor deal for investors.

Best value on the European market: Novo Nordisk (products equal 104% of share price). Worst deal: GSK (products equal just 74%).

Now, you can disagree with Maxwell’s estimates of product value. Maybe he’s discounting the value of GSK’s products and inflating Novo’s. But the fact that he won’t pay for R&D—that he wants it for free, and apparently can get it—seems about as damning an indictment of the value of R&D as we’ve heard in a long time.

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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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Europe's Best-Kept Biotech Secret?

European investors pining for a biotech champion used to muse about the lack of a Genentech- or Amgen-equivalent on the Continent. (Despite Amgen's recent woes--of which you can read a detailed analysis in May's IN VIVO--a few probably still wish for one.)

But maybe some are overlooking what’s in their own back-yard. Shares in Denmark’s Novo-Nordisk have almost doubled in the last two years as the firm has quietly pushed to number one in the insulin market, beating big guys Eli Lilly and Sanofi-Aventis.

With sales of €5 billion ($10 billion) last year, and a market cap just short of $40 billion, Novo’s only half an Amgen. But its challenges aren’t half as big, either.

For one thing, Novo doesn't face a Mircera-equivalent competitive challenge to its insulin portfolio. Nor does it face safety issues--in part since insulin isn't widely used in indications outside diabetes. Insulin's also less expensive than many other protein drugs, so, although on payors' hit lists for bio-genericization, it faces not quite the same reimbursement risk as EPO. (That's probably why insulin is almost completely absent from European biosimilar firms' pipelines.)

Although patents on basic recombinant insulin are long gone (while Amgen still holds on to EPO and sons), engineered analogs have a while to run. And anyway, new entrants still struggle, it seems, even Pfizer-sized ones.

More importantly, the glucose-control pathway offers a related protein, GLP-1, for Novo to take mastery of. Glucagon-like peptide is a hormone that enhances insulin secretion in a glucose-dependent way. Shame for Novo that Lilly and Amylin are already there, selling first-in-class Byetta and doing fine, thank you.

Still, Novo's CSO Mads Thomsen told the IN VIVO Blog they can do better with likely second-to-market GLP-1 analog liraglutide; in terms of administration, dosing and side-effects. Meantime Novo is hedging its bets in the growth hormone space, in hemostasis management, and with newer efforts in inflammation and cancer.

But unlike Amgen, whose pipeline betrays a future with many more small molecules, and in many more therapeutic areas, Novo is sticking to its core capabilities—protein engineering. That’s why it yanked its oral anti-diabetic efforts in January (too competitive, too genericized, and what can follow Merck's Januvia anyway?).

Novo needs liraglutide to work as well as says it does. But if liraglutide does come good--we could know early in the second half of this year when the first batch of Phase III data is due--Novo may yet be likened to Europe’s Amgen. Albeit, perhaps, the Amgen of last year, not this year.

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