It's Not About Life-Cycle Management. Really.

Here's the latest fuel for pharma industry critics' fire: Axanum. This drug, a fixed-dose combination of AZ's PPI Nexium (esomeprazole) and low-dose aspirin, received positive agreement for approval Aug. 2 via Europe's de-centralized procedure. By trying to tag Nexium, which loses exclusivity in 2014, onto the back of widely-used low-dose aspirin, AZ, critics may say, risks falling foul of industry's (and its own) claims to be delivering innovation and value-for-money.

Shame on you AstraZeneca, we were going to say. But then we thought, fair enough. The company's under pressure right now, with 80% of its global revenues at risk over the next five years. Meanwhile the more honourably (and obviously) innovative Brilinta, a better-than-Plavix heart drug approved by FDA in July, may be held back by another kind of relationship with aspirin: Brilinta works less well when used in conjunction with high-doses of the drug.

Still, it may be a bit rich to suggest that this drug isn't about protecting the Nexium patent and franchise. Instead, Axanum will fulfill "a clear unmet need for patients that who require low-dose ASA (posh word for aspirin) to prevent CV events, but who risk discontinuing their treatment due to low-dose ASA-related upper GI problems," says the company.

FDA didn't buy it. They bought Vimovo, a Nexium-naproxen cocktail developed with Pozen for osteoarthritis, in 2010, but Axanum got slapped that same year with a Complete Response Letter, as did AZ's attempt to expand Nexium's label to include reducing the risk of low-dose-aspirin-associated peptic ulcers (same ends, different means).

Europe offers drugmakers an alternative route-to-market when the centralized European Medicines Agency path looks risky, though – or when medicines don't qualify for it. Biotech, orphan drugs, gene therapies and those falling into one of six TAs (not including CV or GI) have to go through EMA; those outside these groups can choose to only if they offer "significant therapeutic, scientific or technical innovation".

AZ says it filed Axanum via the decentralized process in 2009 to "reflect markets' interest", but whatever the reason (choose from above), it allowed the Big Pharma to select a reference state (Germany) to approve the product, which other countries could then follow (or not). Apparently 22 European countries, plus Norway, have followed, agreeing to approve Axanum for prevention of CV events in patients taking daily low-dose aspirin who are also at risk of gastric ulcers.

The company claims about a third of high-risk CV patients are also at increased risk of stomach ulcers, and that GI problems are the main reason for stopping low-dose aspirin. "Axanum is the only medicine that ensures every single pill of low-dose ASA comes with built-in protection against gastric ulcers," says the release.

Patients could just take aspirin with some Nexium, though (or, dare we suggest, a bit of generic omeprazole?) AZ claims that, although taking the monotherapies separately "has been demonstrated to be effective," in high-risk CV patients, the CV treatment can't be compromised, and that current adherence to PPIs is poor among low-dose aspirin patients (patients aren't taking enough Nexium, in other words).

"The combination is based on valid therapeutic principles such as simplification of dual therapies," asserts the company.

Improving compliance is an important – and potentially cost-saving – health care benefit. So good luck to AZ in its ongoing pricing discussions with European reimbursement authorities. But with generic PPIs floating about, don't let's hold our breath for a premium. Vimovo's hardly flying off U.S shelves -- and we hear that Pozen thinks it's because AZ tried to push the price too high.

image by flickrer Will Norris used under creative commons

Squeeze That Fruit, Just a Little Bit Tighter: Sanofi’s New Life-Cycle Research Job

We don’t know whether the title (SVP, Industrial Development and Innovation) is Orwellian buracrospeak or in fact quite precise, but we were rather taken by the press release out of Sanofi Aventis today noting that its top international development man – Jean-Philippe Santoni – would now be boss of life-cycle management.

Were this the industry of even two years ago, the new job would have been quite a come-down for Santoni, a railroad siding far from the main train track to new drugs. But this is an industry which is recognizing it’s got far more in common with Coke, P&G, and McDonalds than with Big-Bet Big Pharma 1980 – 2007. That is to say: managers these days are learning to leverage only very modest top-line growth into faster bottom-line growth through cost-savings, bolt-on acquisitions, and rapid introductions of incrementally-improved new products. The traditional, high-risk, high-growth R&D-based model is gone, in case you hadn't noticed.

So.....companies need to squeeze a lot more Euros out of each asset. That means selling branded versions of off-patent drugs in emerging markets or, like GlaxoSmithKline with Ventolin, working with Wal-Mart to make it a store-brand generic. It also means revitalizing what has traditionally been an industry backwater: drug delivery and reformulation. Plenty of companies have life-cycle-managed plenty of drugs but it has never before now been the face of R&D, which has been all about the discovery of new compounds. (Nor has it before now been called 'innovation' as far as we're aware.)

By taking a guy like Santoni and giving him a job most self-respecting development execs would once have turned down before the offer left the boss’s lips, Sanofi is saying that it is in fact an industrial company powered by industrial innovations, which are by economic necessity different than scientific ones (like the scientific success/industrial failure rimonabant).

Should the trend catch on, we might even see drug companies split R&D in two: Novel Products R&D (largely outsourced, we’d imagine, to optionalize the spending) and Innovative Industrial R&D (think combination products, drug delivery, and single-isomer formulations). The goal of the latter: say a 50% rate of Phase II products making it through approval, up from what Booz & Co. and Credit Suisse say is 10% today.

Incidentally, the Sanofi announcement is very good news for drug-delivery companies, which have been flailing about, largely unsuccessfully, for the past 15 years or so (see, for example, this analysis). Their clients haven’t been particularly interested in their wares, at least at prices exciting to drug delivery’s investors. Now with a new economics in place at Pharma, all those arguments for reformulation and delivery will begin to sound just a trifle more interesting.

Image courtesy of Flickr user Omar Eduardo and used under a Creative Commons license.

Talking of Sons-of-Drugs…

Just when we thought that drug companies had given up on some of their more blatant life-cycle management tricks, snubbed by stingy payors who now know their left-handed from their right-handed isomers, out come Sanofi-Aventis and UCB with news of US approval for their new anti-histamine Xyzal. The Wall Street Journal’s Health Blog was quick to make the link—which the companies’ press release somehow omitted—and proclaim Xyzal as son-of-Zyrtec, which, incidentally, will lose patent protection in September.

Not much new drug company behavior there, then. But WSJ’s timely outing of Son-of-Zyrtec reminded IN VIVO Blog of another, somewhat more unusual Son-of-Drug story that you might just have missed.

Remember Lilly’s problematic Xigris, whose market performance has been as disappointing as the pre-launch anticipation was sizzling? In case you don’t: Xigris came to market in 2001, the first ever treatment for severe sepsis, after years of top-notch protein science and engineering inside Lilly, with many hearts and minds at stake.

Xigris is a case study of, simplistically, how too much innovation can backfire (just as too little can, also). Particularly since Lilly appears (with that wonderful thing called hindsight) to have launched the drug in too broad a population, which led to the brand image being tarnished by cases of serious bleeding. Lilly ain’t giving up on Xigris—there's too much money under the bridge for that. It's busy seeking biomarkers to find out which patients can benefit most. “We’re in invest mode” on Xigris, sum up Lilly executives.

But—and here, belatedly, is the point—Lilly was (after some persuading) quite happy to part with son-of-Xigris, theoretically a better-designed molecule, for not very much money and no claw-back to speak of. The Big Pharma last month quietly licensed the Phase I candidate to a relatively unknown Canadian biotech called Cardiome. Unknown, perhaps, except for the fact that Cardiome's CMO is Chuck Fisher, the man behind Xigris’ development and approval at Lilly.

The deal is somewhat personal, in other words. It's Fisher’s chance to make good what, to put it frankly, went bad within Lilly. He had a job persuading his own board to agree to the deal, even though Cardiome paid just $20 million up front and up to $40 million in milestones (which don’t start until 2009) for all possible indications (and there could be dozens). It’s a risky, if relatively cheap, bet for Cardiome: the drug’s father has proved an expensive failure, and although Cardiome is testing Son-of-Xigris for cardiogenic shock in the first instance, that's still a tricky indication with no pre-clinical models.

Still, if Son-of-Xigris does make it to market one day, in anything, it will be interesting to compare its development and approval path within a small, focused biotech with that of its father, who was brought up in Big Pharma: nature vs nurture. As we’ll suggest in the next issue of IN VIVO, the Xigris family of drugs may just be better suited to biotech. Certainly Fisher reckons he can do a better job marketing Xigris’ offspring than Lilly could.