The Wacky World of Generics: Risperdal Edition

They don't call them atypical antipsychotics for nothing.

Here are two things that keep Big Pharma CEOs up at night: (1) the growing power of payors—actively encouraged by the Medicare program—to drive therapeutic substitution in blockbuster product classes; and (2) the potential for government run comparative effectiveness studies to undermine the market position of newer medicines.

However, if two of the biggest players in the atypical antipsychotic market are to be believed, the impact of the first major patent expiration in that class will stand those fears on their head.

Johnson & Johnson’s risperidone (Risperdal) goes off-patent in June and generics are lining up to enter the market. That will clearly be a big hit for J&J to absorb: Risperdal sales in the US were about $2 billion in 2007.

In other blockbuster classes, a major patent expiration has meant big headaches for other brands in the class. Think of how Lipitor has seen its market share erode and discounts soar since Zocor went generic.

So Lilly’s $2.2 billion olanzapine (Zyprexa) and AstraZeneca’s nearly $3 billion quetiapine (Seroquel) are in big trouble, right?

Not so, say those two companies.

First off, the Medicare program’s overall generics-first emphasis is more than offset by the Centers for Medicare & Medicaid Services requirements that managed care plans cover all products in the atypical antipsychotic class (and five other protected classes). So plans will be free to switch Risperdal patients to the generic, but will find it difficult if not impossible to drive therapeutic substitution from other brands, as we wrote here.

Or, as AZ CEO David Brennan put it during the company’s January 31 earnings call, “the antipsychotic market is quite unique. A product is a product. There is not a history of therapeutic substitution in that area, and we expect to continue to grow our Seroquel franchise.”

Lilly CEO-designate John Lechleiter took it one step farther, telling investors during a January 29 earnings call that Lilly plans to “retain the broadest possible access for Zyprexa” by emphasizing the “superior efficacy evident in CATIE the longer the duration of therapy.”

You remember CATIE, right? That is the government run comparative trial completed in 2005, with headlines at the time declaring it showed that older off-patent antipsychotics are just as good as the atypicals.

That interpretation, needless to say, has not won out in the marketplace, since Lilly, AstraZeneca and the other companies in the market astutely anticipated the negative headlines and worked diligently to develop alternative interpretations.

How successful were they? Well, less than three years later Lilly will be using CATIE to help support continued use of Zyprexa over a generic from the atypical class itself.

And there is nothing typical about that.

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Botox, Friday Afternoon Press Calls and the Nissen Effect

Blaming the media will never go out of fashion, at least not when it comes to drug safety scares.

Here is Schering-Plough EVP Carrie Cox, summarizing the battle to rebuild Vytorin after the ENHANCE debacle during its earnings call February 12: "Physicians ... understand that the furor around ENHANCE is largely a media driven event."

And GlaxoSmithKline’s recap of the Avandia meltdown of 2007: it resulted from a “distortion of the media” about the risk profile seen with the Type 2 diabetes drug, outgoing CEO JP Garnier said February 7.

There is no question that front-page headlines and national news broadcasts can do immediate and lasting damage to even the most well-established brands, damage that may go far beyond any appropriate medical response to new data.

But that only begs the question: what prompts some safety scares (or, in the case of ENHANCE, a failed efficacy trial) to create a media feeding frenzy, while others seem to pass with barely a ripple?

One answer, to borrow a phrase from religious themed bumper stickers, could be WWSNS: What Will Steve Nissen Say? There certainly does seem to be a strong correlation between the Cleveland Clinic cardiologist’s reaction to new data and the amount of play it gets in the media.

Wall Street seems to believe in the Nissen effect. In a February 11 note, Wachovia’s Larry Biegelsen argued that investors over-reacted to an “early communication” about a potential safety issue involving Allergan’s Botox. The issue, announced by FDA February 8, involved serious adverse events primarily associated with off-label use of Botox in children with cerebral palsy. Investors worried that a safety scare could significantly impact Botox widespread cosmetic use.

Not to worry, says Biegelsen. An “ENHANCE-like impact” on Botox use is “unlikely in our view.” Why? Well, for one thing, “Dr. Steve Nissen has not spoken out against Botox,” the way he did against Vytorin.

Talk about a case where silence is golden.

Biegelsen, of course, knows it isn’t quite as simple as that. Nissen’s silence is one of four factors the Wachovia analyst sees as reassuring differences between the Botox safety issues and the ENHANCE fallout. Only one is under the control of the sponsor: “There does not appear to have been any delay in the reporting of the serious adverse events.”

The other three involve reactions by external parties who have no formal regulatory role: (1) Nissen’s silence; (2) “Congress has not started an investigation into the handling of the Botox data”; and (3) The media coverage of Botox is more benign than the coverage of the ENHANCE data.

How so? “We couldn’t find a story in the print version of the New York Times on Saturday, whereas ENHANCE was front page news the day after the results were released.”

Of course, that last point is not entirely good fortune for Allergan. As we pointed out, FDA issued the “early communication” about Botox on Friday afternoon—part of what is becoming a pattern at the agency. (A safety update on Pfizer’s emerging blockbuster Chantix came out the week before Botox, and FDA’s first response to ENHANCE came the week before that.)

It so happens that Friday afternoon is the time least likely to generate significant news coverage. FDA swears there is no deliberate strategy to bury drug safety events. (At least, they assured Pharmalot of that—you can read more here.)

It certainly is plausible that FDA didn’t get all its ducks in a row to issue the early communications until Friday afternoon. We’ve talked to media savvy FDAers over the years (both in the press office and elsewhere) who routinely lament the review divisions’ habit of issuing approval letters at or after the close of business, often on Fridays, thereby all but assuring that even the most important new drug approvals would not be covered in the national news broadcasts, and sometimes even receive scant notice in newspapers.

The fact is that if FDA is not taking the news cycle into account when making safety announcements, it should be. Overblown safety scares do not serve the public health, so FDA certainly could justify Friday afternoon announcements as a way to better ensure that important new information gets into the public sphere in a more measured fashion.

On the other hand, the news media is the best way to amplify an urgent safety message. If that is the goal, the agency is better served by getting the news out early in the day and early in the week whenever possible.

In fact, that’s what FDA did on Monday February 11, when it announced that Baxter is suspending production of heparin due to severe adverse events--an announcement with urgent public health implications.

As far as we know, Dr. Nissen didn't weigh in on that one...

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AZ Makes Its Move in GI

Back in November we broke the news that AstraZeneca may be spinning out its gastrointestinal R&D. (Those news outlets that only read the Swedish papers caught up on the news this week.)

Well we can report now that the Big Pharma has made its move, though it's not the move that some reports were salivating after. In fact, it's quite modest in scope compared to most rumors, even if it is a strategic leap for AstraZeneca.

AZ has teamed with Nomura Phase4 Ventures to create a new Swedish biotech, Albireo, around one clinical and an undisclosed number of preclinical GI assets from AZ. David Chiswell, a founder of Cambridge Antibody Technology and a man who knows his way around the European biotech scene, is the firm's executive chairman.

AZ is hanging onto a significant minority interest in the newco, which has raised $27 million out of a planned total $40 million Series A from Nomura, TVM Capital, and Scottish Widows Investment Partnership. AZ retains its GERD franchise (namely the blockbuster Nexium) and reflux R&D.

As we said at the time: AZ is simply too big to manage the internal research it’s got – let alone depend on the notion that it can afford big bets on areas unlikely to generate big advances in medical care. (For an in-depth discussion of GI R&D strategies, see this story in the November IN VIVO).

It isn't the first pharma to spin off its GI assets--Movetis took a handful of Johnson & Johnson projects when it spun out backed by €49 million from Sofinnova et al. back in early 2007. But this is the first such move in any therapeutic area from AZ--a taste of what's to come?

image from flickr user red5standingby used under a creative commons license

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Nektar Takes A Deep Breath

Deep breath in. Deep breath out. Nektar execs, have you found your quiet place, yet?

It's been a stressful few months for Nektar employees. The company's 13-year marriage with Pfizer soured last October when the pharma unexpectedly decided to stop selling its inhaled insulin Exubera. True, Pfizer did cough up a hefty divorce settlement--a $135 million forgive-me gift, plus a promise to help with insulin supply and on-going clinical trials. (For more on the future of inhaled insulin, see here.)

Yesterday came the news that Nektar is eliminating approximately 150 positions--110 existing jobs plus 40 unfilled openings--as it restructures the company to "transition form a drug delivery service provider to a therapuetics drug development organization." In addition, the company announced that Hoyoung Huh, the company's COO and head of its pegylation business unit, is leaving to become CEO of BiPar Sciences, an up-and-coming biotech developing oncology therapies.

We've said it before. (No doubt, we'll say it again.) It's a terrible time to be in drug delivery. Making money in this space has always been tough--it's not enough anymore to take an existing molecule and dress it up with a PEG molecule to extend its shelf-life or aerosolize it for delivery to the lungs. Payers and physicians want proof that a new formulation isn't just convenient, but that it's superior to existing available medicines. As David Steinberg, an analyst with Deutsche Bank, told START UP in December: "The old model of drug delivery is completely broken down. To be successful you have to think far more innovatively."

Thing is, it takes a lot of money--and risk--to engineer a delivery system robust enough to deliver a real therapeutic advantage. Look at the field's lone success story in recent years--XenoPort. The company's share price has increased more than six-fold since its 2005 IPO, thanks to the success of its gabapentin pro-drug, XP13512, for restless leg syndrome and neuropathic pain. Last February GlaxoSmithKline agreed to fork over $75 million in cash and another $500 million in development, regulatory, and sales milestones for the compound. (Just for the record, Xenoport raised approximately $270 million in equity capital and another $160 million from partners to get enough data to convince the pharma of XP13512's value.)

So, the big lesson from XenoPort's success? Delivery technology ain't enough. XenoPort was only able to sign this monster deal with GSK because XP13512 is a new chemical entity with hard-to-duplicate molecular advantages. (The nifty formulation technology is an added bonus to investors -- a key part of its discovery platform.)

Of course, there is a corollary to this lesson (This IS a Windhover publication.) To be successful in drug delivery today means spending research dollars on two fronts: not only do you have to spend money to engineer the delivery system, but you also have to spend money to discover and develop novel, first-in-class or best-in-class compounds. Which leads this IN VIVO blogger to wonder, why even bother with the delivery piece of the puzzle?

Seem's like Nektar's board and CEO, Howard Robin, have been asking the same question. As part of the company's restructuring, Robin noted in a press release that "We are transforming Nektar into a world-class drug development company."

My friends and colleagues know I'm a big believer in the "I think I can" strategy. But it's tough to see how Nektar's transformation will occur near term. True, the company's inhaled amikacin, which is being co-developed with Bayer AG, is expected to enter Phase III clinical trials later this year, and its two leading PEGylated small molecule programs, PEG-irinotecan and oral PEG-naloxol, just entered Phase II clinical trials. But will there be the leadership to push these two products through development now that Nektar's PEG champion and resident brainiac, Hoyoung Huh, is jumping ship to take the helm of BiPar Sciences?

Maybe "the decision to step down as COO was a difficult one," as Huh asserts in another press release issued today. After all, he hasn't severed ties with the company completely. He'll be serving on the company's Board of Directors until 2009 or until a replacement has been identified according to SEC documents. Or maybe, Huh, whose CV lists an MD, a PhD, and a stint as a McKinsey partner, saw the darkening skies and approaching stormy seas and left for the relatively calmer waters of private biotech.

February 27 should be an interesting day. That's when Nektar will release results for the fourth quarter and full year of 2007. Meantime, Nektar employees, remember: deep breath in; deep breath out.

Photo courtesy of Flickr user Transguyjay through a creative commons license.

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Sanofi Aventis: Sign of the Big Pharma Times?

Sanofi-Aventis’ 2007 results presentation on Tuesday provides a nice little snapshot of Big Pharma circa early 2008.

The company reported rather paltry sales growth (you can see all the numbers here), but boasted about its cost- and head-count cuts and its shareholder-sweetening dividend payouts (how else do you keep your investors, with top drugs going off patent and new ones not coming through fast enough?).

It also provided pointlessly hypothetical? useful? information such as what pharmaceutical sales growth in 2007 would have looked like (up 6.4%) excluding the impact of generic Ambien IR in the US, and Eloxatine in Europe (as if to day, “it’s not our fault; we weren’t expecting it.”).

More significantly, perhaps, Sanofi provided numbers to back up the growing importance of vaccines to the group’s current and future growth. Rarely before have so many of Big Pharma's slides been devoted to this once-unfashionable category. Vaccines sales were up 14.5% in 2007—over double even the buffed-up pharmaceutical growth figure--and now account for 10% of group revenues, the largest among any of the Big Five. (And these numbers aren’t thanks to the cutting-edge cancer vaccine Gardasil, marketed in Europe by the Merck/Sanofi JV SPMSD, since Sanofi doesn’t consolidate SPMSD’s sales. They’re driven by more pedestrian things: seasonal flu, pneumonia, travel vaccines…)

So, we’re reminded, vaccines are no longer a backwater, they’re a “strategic pole.” At Sanofi, they’re the only segment where headcount’s going up, not down, and they saw by far the largest growth in R&D spend at the French group in 2007 (and are unlikely to be the target of this year’s R&D budget freeze).

Elsewhere, entire slides were devoted to developing markets China and Brazil—another sign of the times. In China, sales were up 36% (including vaccines), and the company has certainly joined most other Big Pharma in its China investments, whose value we discuss in the February issue of START UP. Who used to care about Brazil? Never mind; the market will be worth over €11 billion in 2011 and Sanofi claims to be the number one international company there.

More telling perhaps is Sanofi’s highlighted new franchise in Brazil: Generics. Copycat drugs are no longer the domain of generics groups; Big Pharma is playing in this field too, even though to do so often blatantly contradicts all the talk of innovation and R&D investments. (It’s also playing in the large-molecule equivalent of generics, as you'll read in February's IN VIVO.) Indeed, authorized generics and price-adjustments in response to generics was the first example that EVP Pharmaceutical Operations Hanspeter Spek provided to illustrate how Sanofi is “anticipating and adapting to the increasingly complex pharma landscape.”

As for where Sanofi’s focusing its innovator efforts: Diabetes. Move over metabolic syndrome, then—since fat-buster Zimulti’s high-profile flop at the US regulators, the French group, it seems, is sticking to diseases that it can define. But since Sanofi doesn’t have an innovative new diabetes drug to highlight just yet, it stuck with an old favourite: insulin. Sales of long-acting Lantus, launched in the US in 2001, surpassed €2 billion in 2007 (and Sanofi is surely still gloating over its decision to sell its share of blighted Exubera for a cool $1.3 billion).

And to our last sign of the times message: Sanofi talked as much about life-cycle management for Lantus (earlier insulin usage and various combinations), manufacturing improvements and emerging market opportunities as it did about exciting new compounds. Still, waiting in the wings are a GLP-1 agonist (entering Phase III; not the first), an SGLT-2 inhibitor (still in Phase II), and, you guessed it….rimonabant.

We've seen that last one before, haven't we? The drug that’s still looking for its disease.

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The Blockbuster Model is Dead, Sort Of

The numbers are in, and it’s not a pretty picture.

No, we’re not talking about today’s Potomac presidential primary. We’re referring to the latest IMS Health figures on the state of the pharmaceutical industry, and as Diana Conmy, corporate director of market insights put it, they are “sobering and possibly a little alarming.” Conmy was kind enough to preview the 2007 numbers for the Health Industry Group Purchasing Organization’s National Pharmacy Forum; the official data won’t be released for a couple more weeks.

Unfortunately for industry, Conmy’s numbers don’t leave much to cheer about. The US market growth for pharmaceuticals and biotech products slowed to 3.8% in 2007—the worst growth rate since 1961.

Part of that is a result of tough comparisons against the big pay-off pharma received from Medicare Part D in 2006. But a lot is simply due to a general market slowdown for the drug industry. While some of the latter months of 2006 saw market growth approaching 12%, by December 2007, month-over-month growth was in the negative range, Conmy reported.

And if you’re thinking the next big launch will turn around that trajectory, think again. New chemical entities aren’t contributing as much to market growth as they have in the past. In fact, if you look at the average launch curves for the top 10 new chemical entities over the past several years, 2007 had the weakest results since 2003. “Fewer of these NCEs are top-performing, contributing much less to growth,” Conmy said.

So what does this mean for the blockbuster model? Well, as Conmy put it—and Windhover publisher Roger Longman keeps driving into our heads—“the blockbuster model isn’t dead, but perhaps the primary care-driven market is.”

And it sure seems that way: 2007 marked the first time that industry saw a decline in the number of primary care blockbusters (29 in 2007 versus 33 in 2006), IMS data show. At the same time, there was an increase in specialty care blockbusters (30 in 2007 versus 25 in 2006).

That’s evidenced by the fact that the primary care market declined over the last seven months of 2007, contributing a negative 18% to overall market growth for the year, while specialty care contributed a positive 118%. The growth rates per therapeutic area tell the same story: specialty care grew 10.5%, while “branded products” grew 2.9%--a rate almost a full percentage point below the total market.

In fact, of the four launches for 2008 that Conmy believes have blockbuster potential, three are specialty products: UCB’s certolizumab (Cimzia) for Crohn’s disease, Bristol-Myers Squibb’s ipilimumab for melanoma and Wyeth’s desvenlafaxine (Pristiq) for depression. (The fourth potential blockbuster on Conmy’s list is MedImmune’s respiratory syncytial virus antibody Numax.)

So is there any good news in all these doom and gloom? Luckily for pharma, there are lessons to be learned. Here’s the bottom line: specialty care is increasingly where pharma needs to be. And given the generally slower uptake of specialty care products, executives may have to adjust their expectations when it comes to launch curves.

That kind of “slow and low” attitude has another benefit in today’s increasingly risk-averse environment. “You might hear manufacturers say that ‘our strategy is more lower octane, so we can have a more controlled environment, we can make sure it’s safe, and we don’t have any major incidents,’” Conmy says.

That’s quite a departure from the “fast and furious” model of the DTC-infused primary care market. My, how far we’ve come.

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Starring Role for Follow-On Biologics

You have to hand it to the players in the follow-on biologics debate: they are pulling out all the stops. Just when you thought you thought you had seen everything, it shows up on YouTube.

The Richmond, Va.-based biotech company Insmed Inc. posted a video (below) on YouTube starring Mike Coleman, an Insmed scientist who exhorts the values of follow-on proteins, and encourages others to post their thoughts on the issue as well. The video, "Follow-On Biologics--Tell your Story," has been viewed about 1,000 since Insmed posted it on February 8.

Insmed already markets the insulin-like growth factor mecasermin (IPLEX), and wants to position itself as the first US marketer of follow-on biologics--when and if Congress gives the Food & Drug Administration the green light to establish a regulatory pathway.

The issue died down after Congress failed to attach a measure to the FDA Amendments Act last year, but was back in media reports last week after President Bush mentioned follow-on biologics in his FY 2009 budget request.

That annoucement had its own YouTube-like quality when Jim Dyer, the agency's operations chief, had to correct statements that FDA would be forwarding legislation to Congress on a regulatory pathway this year. Instead, the agency will continue helping Congress develop a bill--and the budget request is only intended to express the Administration's eagerness to see the legislation enacted this year.

We're not sure how many congressmen watch YouTube, but their staffers are sure to be clued in. Will the Internet ad be just a fun cocktail party story? Or will it prod Congress back into action? Check back to find out.

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