Fat Chance for Rimonabant

Tomorrow is a big day for Sanofi-Aventis’ fat-buster rimonabant. FDA’s Endocrine and Metabolic Drugs Advisory Committee will scrutinize whether the drug’s beneficial effects on weight, triglyceride levels and cholesterol outweigh its side-effects, most significantly depression and suicidal thoughts.

The odds don’t look good for Sanofi. The timing is terrible—this review comes amid huge political controversy over FDA’s role in assessing drug safety, inflamed most recently by the cardio-vascular concerns raised around another drug the endocrinologist experts know well: GlaxoSmithKline’s diabetes drug rosiglitazone (Avandia).

What’s more, Sanofi hasn’t been known for its smooth relations with FDA; nor, say analysts, was it fast to get endocrinologists on its side. The French group is said to have cosied up early on in its rimonabant campaign primarily to the cardiovascular experts it knew already through anti-platelet drug Plavix. (Don’t forget that rimonabant, an cannabinoid receptor antagonist, is one of these multi-faceted treatments that act on a number of pathways, making it both incredibly effective in addressing metabolic disease, says Sanofi, but also incredibly dangerous in terms of unknown or unwanted side-effects, say detractors.)

Small wonder, perhaps, that the FDA review document released yesterday has no qualms about washing rimonabant’s dirty linen in public. The document highlights a statistically significant increase in suicidal thoughts and behavior, a high drop-out rate in the rimonabant trials, in part due to depression side-effects, and reels off various neurological side-effects seen with greater frequency in patients taking rimonabant.

Now granted, the drug is already approved in Europe, as Acomplia, although Sanofi still faces marketing and reimbursement challenges (many European countries consider obesity treatments as life-style medications; a convenient excuse to avoid huge payouts). So won’t six-months’ worth of post-approval data from over 78,000 European patients help reassure the US gate-keeper?

Seems not. The FDA document lists over 2300 cases of adverse reactions in the UK and Germany, “frequent” reports of nervous system disorders “driven predominantly by dizziness”, and describes in detail a handful of individual cases including a man who attempted to strangle his daughter, and another who beat his wife while on rimonabant.

This degree of detail may very well be standard Advisory Committee meeting practice. The experts will know to consider these adverse events in the light of the thousands of patients using and potentially benefiting from the drug.

But rimonabant’s path to the US market has already been bumpy. Its sponsor’s ambition has been heavily clipped by US regulators: Sanofi submitted its NDA in May 2005 for three indications besides weight management (Type II diabetes, dislipidemia and metabolic syndrome), none of which were approved. Even for the obesity indication, FDA in February 2006 requested additional data—you guessed it, on adverse events. Even the Advisory Committee meeting was hurled at rimonabant at the last minute: back in 2006, it wasn't considered necessary. Not to mention the FDA's requested name-change: just to make life a little more challenging still for Sanofi, rimonabant will be known as Zimulti in the US.

If it gets there.

Rimonabant’s Risky Business

You know a weight loss drug doesn’t stand a chance when even morbidly obese patients are afraid to take it.

During the highly anticipated review of Sanofi-Aventis’ rimonabant by FDA’s Endocrine and Metabolic Drugs Advisory Committee yesterday, Lynn McAfee, the director of medical advocacy at the Council on Size & Weight Discrimination, told committee members that rimonabant was far too dangerous a drug to be allowed on the US market.

“This is a very scary drug,” she told the committee. “I lived through Redux and fen-phen and the calls in the middle of the night from dying people. Nobody wants to live through that again.”

Yikes. That’s a pretty damning statement from a group of people who are so desperate for weight-loss options that they spend nearly a $1 billion a year on dietary supplements—products that never cross the desk of an FDA medical reviewer.

But let’s be serious. As the IN VIVO Blog made clear in an earlier post, when a drug is linked not only to depression and suicidiality, but also a litany of neurological adverse events like seizures and multiple sclerosis, you don’t exactly have a slam-dunk on your hands. And did I mention the 50% chance of losing just 5% of your body weight?

So it should have come as no surprise that the advisory committee voted unanimously against approval. Frankly, the only folks that might have expected a different outcome were from Sanofi-Aventis—a company not exactly known for its sophisticated dealings with FDA. It’s common for a drug sponsor to become so invested in a drug that they can’t see the forest through the trees. But on rimonabant, Sanofi is in a totally different place—like la-la land.

That said, as far as advisory committee management is concerned, Sanofi did a surprisingly good job at trying to convince members that rimonabant deserved their seal of approval. Executives stressed no fewer than a half-dozen times that rimonabant was not for everyone, and totally inappropriate for those that have had or currently have psychiatric problems. And they proposed a pretty decent risk management program, including a controlled launch while they worked out the kinks.

But in the end, there’s only so much you can do with a risky drug. And rimonabant, unfortunately for all those obese patients out there, is a really risky drug.

Could've Seen That One Coming

Talk about trying to hide bad news on a Friday night.

Sanofi-Aventis sent out two press releases on Friday afternoon, one announcing that it was submitting updated safety data on its blighted rimonabant (approved last year in Europe as Acomplia) to the European authorities, and the other to say that it’s withdrawing its US NDA for the drug.

Neither is particularly surprising. Of course EMEA is “reviewing the available data on psychiatric events” associated with the drug. There are 200,000 patients in Europe taking a compound that 14 US experts unanimously judged unfit for approval in an advisory committee vote earlier in June. (An outcome which, as my colleague argues this month in The RPM Report, wasn’t particularly surprising either.)

Judging from the Q&A session on the conference call—held at 6pm Paris time, about an hour after we received the press releases, but nevertheless caught by more analysts and journalists than Sanofi probably expected--there’s still some confusion over data. A meta-analysis of trial data studied by FDA advisors showed up some rather different results when it came to suicidality rates than those submitted in Sanofi-Aventis’ original package. “We disagree with the FDA analysis,” noted Marc Cluzel, SVP Science and Medical Affairs, on the call.

Still, the company has withdrawn its NDA filing, since, it feels, there wasn’t enough time to discuss with FDA the various points raised by the advisory committee before the July 26th PDUFA date.

Is it an admission of defeat? Not a bit, said the Sanofi SVPs. “We feel it’s our duty to try to allow US patients to benefit from such a drug. Unfortunately though there’s a misunderstanding” over its risk-benefit profile, the executives said.

Indeed there is. Sanofi still thinks it can get the drug approved for a subset of obese patients, those with various co-morbidities. It’s still downplaying the depression issue. Indeed, “we found that in animals models rimonabant even had anti-depressant activity,” noted Cluzel.

Nice try. But if rimonabant, a cannabinoid receptor antagonist, works by reversing the "munchies" effect associated with taking cannabis, it seems logical—quite apart from whoever’s data interpretation you believe--that it could also reverse the mood-enhancing effects, too. Either way, it’s clear that no one yet understands the cannabinoid system sufficiently well to be entirely sure. And that’s not a good situation to be in given today’s super-safety-conscious FDA. Indeed, as Cluzel acknowledged in the call, most of the key rimonabant trials "were done between 2001 and 2004, before Vioxx."

Though not impressed by Sanofi-Aventis’ Friday night trick, if that's what it was, IN VIVO Blog can only commend the company for keeping its chin up, publicly at least. Remember colorectal cancer drug oxaliplatin (Eloxatin), Cluzel pointed out: it got turned down in 1999 by an advisory committee, due to unconvincing data on survival benefit, but later, post re-submission, received one of the fastest approvals ever.

That was three years later, though. Rimonabant may yet arrive in the US, for some patient groups, but it won’t be in the second half of this year. Even data from the long-term Crescendo trial investigating the drug’s impact on cardiovascular events, due to report in 2010, may not do it--some advisory panel members said none of the ongoing trials of rimonabant are designed to provide sufficient clarity over adverse events. Much later than that (the drug’s key patent expires in Europe in 2019) and Sanofi-Aventis might just be moving straight onto its two back-up compounds.

Meantime, keep an eye out for a shopping bag marked ‘Bristol-Myers Squibb’.

When Life Gives You Lemons, Make Lemonade (Caution: side effects may include forgetting you made lemonade)

Developing drugs that block the pain receptor TRPV1 just got a whole lot more complicated.

A study published in today's issue of the journal Neuron suggests these drug candidates may interfere with learning and memory, and that this action may be responsible for the reported psychiatric side effects of Sanofi-Aventis' rimonabant, as well.

A quick search through our Strategic Transactions Database throws up at least two recent TRPV1 deals--by Eli Lilly and Wyeth--to gain access to inhibitors of the receptor (which goes by the full and catchy name of transient receptor potential vanilloid 1). Lilly paid Glenmark $45 million up front plus milestones for access to the TRPV1 inhibitor GRC6211 just last November and Wyeth teamed up with Mochida Pharmaceuticals in January (naturally, Deals of the Week! was there to cover these for you in real-time). Activation of TRPV1 causes pain associated with inflammation and is triggered by molecules like capsaicin, which is found in chili peppers.

Wyeth and Lilly and others (such as NeurogesX, Pfizer, and Merck) aren't intending to mess with the brain, of course, they're targeting the receptor in the peripheral nervous system to ease pain associated with osteoarthritis, neuropathy, and other maladies. But the researchers, led by Brown University's Julie Kauer, working with slices of rat brain demonstrated for the first time the function of TRPV1 receptors in the CNS, where they appear to be part of the neural circuits of learning and memory in the hippocampus.

From the press release accompanying the paper:

“The broad distribution of TRPV1 receptors in the brain suggests that these receptors could play a similar role in synaptic plasticity throughout the CNS.” ... The researchers said their findings suggest that drugs targeting TRPV1 could act not only on pain receptors in the PNS, but in the brain as well. They also wrote that their findings and those of other researchers “indicate that drugs that bind to CNS TRPV1 receptors are likely to influence more than just pain-related functions.”

Kauer and colleagues also noted that TRPV1 was inhibited by rimonabant, possibly introducing new headaches for Sanofi-aventis and other -abant hopefuls like Merck & Co. (the latter has yet to officially comment on the abstract referring to some poor Phase III data due to be presented later this month at the big ACC meeting in Chicago).

But wait, you say, we understood there was to be lemonade? Fair enough. Despite the fact that Kauer's findings "have important implications for the development of drugs targeting TRPV1," and that they "cloud the prospects of TRPV1 analgesics," there may be some good news, according to the authors of a preview of the paper (also in Neuron), Benedict Alter and Robert Gereau, from the pain center at the Washington University School of Medicine.

Apparently, TRPV1 inhibitors that act both in the periphery and in the brain actually work pretty well at soothing pain. And what's more the drugs could find uses in other brain disorders, such as epilepsy, Alter and Gereau write.

Pain is a notoriously tricky clinical space that is nevertheless receiving quite a bit of pharma attention--Pfizer devoted more time to pain at its recent analyst day than to any other therapeutic area, to our surprise. Though this is just one study, in rats, and concerns just one target, it's another reminder that the science of pain and pain relief is complex, and in its early days.

Hat tip: Reuters

A June Wedding for Bristol/Sanofi?

Something tells me that talk of a potential acquisition of Bristol-Myers Squibb by Sanofi Aventis will heat up again in exactly one month.

The on again/off again speculation about a merger of the Plavix partners is decidedly off at the moment. And yes, yes, I know that my fellow IN VIVO bloggers think that Bristol's deals with AstraZeneca and Pfizer will make a Sanofi bid economically dumb. But two events coming up in mid-June could spur some desperate action.

For Richer, For Poorer

On June 15, BMS expects to be officially released from the terms of a deferred prosecution agreement it signed two years ago. The DPA has been the sword of Damocles hanging over Bristol, making it essentially untouchable for would-be-suitors—especially once Bristol ran into further trouble with its spectacularly misguided attempt to settle patent litigation over Plavix.

Bristol has now agreed to settle charges arising from that debacle—and says it has been assured that the deferred prosecution agreement will be released on schedule as long as it stays out of trouble between now and June 15. (That seems easy enough, but given Bristol’s history, its probably best not to count the chickens just yet…)

And, since “interim” CEO Jim Cornelius pulled off a Dick Cheney style CEO search—ending with himself as the new CEO—there is no reason to assume that Bristol is committed to independence for the long run.

But the real impetus for renewed speculation will probably come two days before June 15, when Sanofi Aventis’ much touted obesity therapy rimonabant goes up before an FDA advisory committee.

Sanofi insists the meeting is a good news event for the troubled application. Maybe. But given the company’s misreadings of FDA so far, Sanofi’s optimism probably shouldn’t inspire too much confidence. I think Kate Rawson has it right in the May issue of The RPM Report: Sanofi will be lucky if the drug gets even a strong minority support from the committee.

This does not seem to be a good time to take a big drug before an FDA advisory panel. Especially one with a safety signal. Perhaps most especially one with a safety signal (in this case depression) that dovetails with a major focus of congressional scrutiny. Did you see what happened to Arcoxia?

If rimonabant suffers a similar setback before the committee, Sanofi will be under even more pressure to make another move. So expect the merger speculation to heat up just before summer arrives.

Cordaptive Was a Red Rag to FDA Bull

In an article in this month's IN VIVO, we suggested that Merck’s presenting Cordaptive to FDA might be likened to waving a red rag at a bull.

Admittedly, we added a few mitigating statements, and the overall tone of the article was positive, reflecting a number of analysts' bullish outlook for the drug. Cordaptive is, after all, a seemingly uncontroversial combination of extended-release niacin (an age-old product with plenty of safety data) with the anti-flushing agent laropiprant, whose effects are, we're told, restricted to just that--minimizing the nasty (but non-fatal) side-effect that has limited niacin's uptake.

In the event, though, the bull/rag analogy was right on: FDA yesterday issued a not-approvable letter for Cordaptive. (And, adding insult to injury, it said it didn't like the name, either.)

Ok, so given recent events, we probably all should have seen this coming. FDA also late last week rejected Merck’s application for a fixed-dose combination of Singulair and Claritin, as we reported here (and updated here.) Notwithstanding FDA’s rather stringent requirements for all combination drugs (sponsors must prove each component’s safety and efficacy as a standalone and show that the combination affects neither), one might be forgiven for suspecting that the red rag is actually a combination drug application on Merck headed paper.

Merck is after all one of the ENHANCE sponsors (alongside Schering-Plough); that saga called into question the clinical effectiveness of yet another combo, Vytorin. It probably didn't help that Merck also recently halted enrolment in one Cordaptive trial that was designed similarly to ENHANCE.

Still, ENHANCE’s effects have rippled—and will continue to ripple—far beyond Whitehouse Station. FDA this month poured cold water over Isis’ cholesterol-lowering hopeful, mipomersen—yes, the one that Genzyme in January agreed was worth $325 million up front and up to $825 million in development and regulatory milestones. The partners need outcomes studies, the Agency says, for all indications other than the highly specialist, and life-threatening, familial hypercholesterolemia. (Luckily for Genzyme, the deal terms aren’t confirmed, so watch out for lower-value Version B of the deal--and, we'll venture to suggest, a tonne more regulatory contingencies and conditional language in tomorrow's term-sheets.)

Now Merck’s doing outcomes studies with Cordaptive, but results from their 20,000-patient THRIVE trial won’t be out until 2012 or so. Small wonder, then, that some analysts have already removed four years’ worth of revenues for the drug, and its follow-on, MK-0524b.

This is the last thing Merck needs. From 2010, $4.2 billion worth of its products start to lose patent protection—Cozaar/Hyzaar that year, and Singulair two years later. Cordaptive and its follow-on could have helped fill about a third of that hole, according to analyst Catherine Arnold at Credit Suisse; now they’ll barely have any impact at all.

Nor does FDA’s harsh stance on safety requirements and outcomes studies bode well for two further Merck late-stage candidates. Can CETP inhibitor anacetrapib survive the aftermath of Pfizer’s torcetrapib blow-out? And does taranabant (a cannabinoid receptor inverse agonist) really have a chance, given FDA’s unswerving rejection of Sanofi-Aventis’ rimonabant (Zimulti)?

Maybe we’re being too cynical. Maybe it’s just a question of time: time for THRIVE results to pour in, and/or for Merck to sort out whatever the actual problem is with its Cordaptive NDA. “We plan to meet with FDA as soon as possible and submit additional information to enable the agency to further evaluate the benefit/risk profile of MK-524A,” was all a Merck spokesman would reveal to IN VIVO Blog. (The European regulators this month approved the combo--albeit as Tredaptive--though as we saw with rimonabant, a green light across the Atlantic is irrelevant to FDA.)

So nobody knows what’s wrong, and we’ll only spend one paragraph speculating. It’s tempting to assume that laropiprant is the culprit, since this is the only NCE component of the cocktail (and a couple of journal papers point to elevated liver enzymes associated with the compound). Merck’s Senior Director for Cardiovascular Clinical Research, John Paolini, MD, PhD, told us in March that since laropiprant--a selective prostaglandin D2 receptor-1 antagonist--acts on the final step in the flushing pathway, the chances of any unwanted additional effects are reduced, at least in theory. The company also boldly ventured that Cordaptive’s safety profile is “similar to that of extended release Niaspan.” But “similar” may well not be good enough (assuming this theory is right). Particularly when you’re tampering with a side-effect that, if uncomfortable, is hardly fatal.

What we know for sure is what my quicker-off-the-mark colleagues have already said: there’s no such thing as a low-risk drug. Certainly, combination products don’t any longer represent no-brainer life-cycle extension tools. When it comes to getting past the FDA bull, it seems they’re up there with even the newest of NCEs.

photo by flickr user pmorgan used under a creative commons license

Sanofi Aventis Walks the Talk

Sanofi Aventis had already promised at their September R&D meeting that they wanted to increase the number of biologics in their pipeline, and to be “more proactive” in business development. Today they showed that they meant it, by announcing a wide-ranging fully-human antibody collaboration with Regeneron.

Sanofi will pay Regeneron $85 million up front and up to $475 million in research funding over the next five years ($75 million in the first year and up to $100 million in years 2-5), during which time Regeneron will lead research efforts across a range of antibodies, developed using its VelociSuite of technologies. At IND-stage, Sanofi has the option to co-develop candidates identified within the collaboration, and if it chooses to do so, will take the lead and foot most of the cost.

Indeed, although the press release describes development costs as “shared”, Regeneron will only pay its portion if the candidate is successful. “We’ll fund 100% of Phase I and Phase II,” said Jean-Michel Levy, SVP Business Development, and 100% of the Phase III costs in the first indication. Additional Phase III trials would be 20% funded by Regeneron, and the biotech will “reimburse half of the overall development costs from its share of future profits to the extent that they are sufficient for this purpose,” according to the release.

Will they be? Well, Regeneron will receive 50% of profits in the US, although Sanofi will lead commercialization and consolidate sales. Elsewhere, the smaller party will receive between 35% and 45% of the profit pie, although its co-promote option—still a popular deal feature these days, even though there are signs that might change—is on a worldwide basis. If aggregate sales reach $1 billion, Regeneron will be entitled to up to $250 million in sales milestones (which would help with the development-cost pay-back…)

Big Pharma laying rich stakes in antibodies is hardly a new concept; we’ve tracked the trend extensively, including here. What’s perhaps more surprising is that this is but a licensing deal. Granted, Sanofi has increased its 4% stake in Regeneron to 19%, for $312 million. But a standstill agreement prevents it from increasing its share beyond 30% four years hence.

By that time, it’ll be clearer whether the deal’s as productive as Sanofi needs it to be. The most advanced candidate, targeting the IL-6 receptor, has already begun clinical trials in rheumatoid arthritis and a follow-on antibody to Delta-like ligand-4 (an anti-angiogenic approach) should reach the clinic next year. The deal’s potential output “will reinforce our presence in oncology and internal medicine” (including RA), noted Jean-Claude Muller, SVP, Admin and Resources, “but it’s not limited to these areas. Any target coming out will help our portfolio.”

Indeed, Sanofi’s a bit desperate these days, following the rimonabant (Acomplia) flop and a large patent expiry cliff due at the end of 2012. So why didn’t they just buy Regeneron? Management didn’t answer that question on the call. Perhaps they don’t think exclusive rights to the technology are necessary--Regeneron in February this year licensed its technology, for the first time ever, to AstraZeneca, and shortly after to Astellas. “We don’t expect this deal to have any impact on those arrangements,” Sanofi said.

Besides, Regeneron hasn't got a drug on the market yet. And Sanofi already has a large stake, through a 2003 collaboration, in Regeneron's most advanced program, VEGF Trap (aflibercept), which began Phase III trials in prostate and non-small-cell lung cancer in August.

Sanofi may feel it doesn't need to spend billions of dollars (Regeneron’s market capitalization was about $1.1 billion this morning, although well short of its Spring peak) buying a group that may work better as a standalone. It wouldn't be the first time the Roche/Genentech-style model has been emulated. And anyway, with Sanofi holding a 19%-plus stake, any other predator’s going to struggle.

Lilly's Prasugrel Widens the Gap

The gap just got wider.

No, we’re not talking about the income inequality gap, or the gender gap, or the generation gap. We’re talking about the approval gap for new drugs and biologics between Europe and the United States.

Some critics of the Food & Drug Administration argue that FDA is more conservative than its counterparts in Europe. (This is what we think of as the “too slow” contingent. FDA is also criticized from other stakeholders—like Sid Wolfe and Chuck Grassley—of being too fast.)

FDA disagrees with both sides. As Office of New Drugs director John Jenkins said at FDC-Windhover’s FDA/CMS Summit for BioPharma Executives, “We review each application on its own merits—not against some goal that we will approve 25 applications this year. Those that meet the standards under the statute get approved; those that don’t, don’t get approved.”

But with last Thursday’s news that prasugrel—Eli Lilly and Daiichi Sankyo’s beleaguered blood thinner candidate that is still sitting at FDA—received a positive recommendation from the European Union’s Committee for Medicinal Products for Human Use, the noise from the “too slow” contingent is likely to get louder.

In an effort to discredit those critics, Jenkins presented data at the FDA/CMS Summit from a preliminary analysis of new molecular entities reviewed by FDA and the European Medicines Agency between January 2006 and October 2008. What Jenkins found was that EMEA approved slightly more novel products than FDA, but that the agencies had a similar approval rate.

Jenkins then looked at new molecular entities that were reviewed by both the Food & Drug Administration. Of those 29 products, FDA approved two that the European Medicines Agency has not, and EMEA approved seven that FDA has not. (Once Lilly and Daiichi receive final approval from the European Commission—which should come in two or three months—prasugrel would make that eight.)

Jenkins argued that the numbers are too small to support any conclusions that FDA is more conservative than its counterparts in Europe—especially given that one of the EMEA-approved drugs (Sanofi-Aventis’ weight loss drug rimonabant) has already been withdrawn from the market.

Pointing to the list, Jenkins said: “Here’s where all the statements about the EMEA being faster are coming from.” But some investors still see the data as a troubling trend. The prasugrel approval in Europe is only likely to feed those beliefs. (You can read all about that debate in the latest issue of The RPM Report.)

So what's up with prasugrel at FDA?

As we’ve reported, FDA is looking at February 2009 for an advisory committee meeting. Assuming that happens, an answer isn’t likely much before March 2009—which would double prasugrel's review time to 12 months. The user fee deadline was initially set for March 2008, but on two occasions was pushed back three months—most recently to September. Since then, it has become just one of a number of missed deadlines at FDA.

Cleveland Clinic cardiologist Steve Nissen, who has accused FDA of being both too fast and too slow, thinks Lilly and Daiichi deserve an answer one way or the other. What do you think? Is FDA more conservative than EMEA? Or is the difference too small to draw any conclusions?

Photo courtesy of flickr user StevenBulman44.

Obesity Drugs: Another One Bites the Dust

From time to time here at the IN VIVO Blog, we write about something not because it’s a clever deal, or a shocking policy out of Washington, or an interesting industry trend that we think you should be aware of—but simply because we were right.

This is one of those times.

Merck has decided to discontinue development of taranabant, its cannabinoid-1 receptor blocker in Phase III development for obesity. Why? Well, in short, the only doses that were effective in weight management also had an unacceptable level of psychiatric adverse events.

Indeed, Merck had already dropped the two high doses of taranabant in clinical studies (4 mg and 6 mg) due to statistically significant differences in crying, mood swings, anxiety and depression. At the lowest dose (2 mg), patients reported the same adverse events, although the results were not statistically significant.

The problem was that the efficacy at that low dose wasn’t terribly impressive. Among those patients, 57% lost 5% of their body weight and 28% lost 10% of their body weight. That sounds nice, but when you consider that these are obese patients with a body mass index of at least 30 kg/m2, it’s really not that much to lose—especially in light of the psychiatric adverse event trend.

Given that taranabant is in the same class of drugs as Sanofi-Aventis’ rimonabant (once Acomplia, later Zimulti), and had pretty much the same profile, we saw this one coming. We probably weren’t alone in that thinking, but we’ll continue with the shameless self-promotion anyway—click here for that story in The RPM Report.

But we also have to applaud Merck for having the courage to put a dead drug down—instead of being so blinded by dollar signs as to fail to see that there’s no chance for FDA approval until deep into the drug review process. Of course, when you bank much of a future franchise on a single product, it can be hard to see the forest through the trees.

The taranabant failure happened despite—or perhaps because?—Merck hired two prominent FDA officials that could offer advice on the application: Robert Meyer, the FDA division director that was in charge of reviewing taranabant, and Peter Honig, who was a prominent drug safety official in his days at the agency.

Perhaps it was that expertise that helped convince Merck of the bigger picture. FDA isn't going to approve a relatively ineffective drug that has that kind of a safety signal—especially given the agency's recent crackdown on drugs with psychiatric adverse events.

Or maybe Merck knew that already. Regardless, one thing is clear: like so many others before it, cannabinoid-1 receptor blockers are proving to be a tough drug class. Taranabant is just the latest drug to fall.

Has Sanofi-Aventis Lost its Friends in Government?

Sanofi-Aventis may have fallen out of bed with the French government.

When Sanofi-Synthelabo gobbled up its larger peer Aventis in 2004 after a prolonged struggle, it was widely believed that Sanofi's president Jean-Francois Dehecq had received a little help from his friends in high places (read: the French president Jacques Chirac). The government wanted a large, national pharmaceutical flagship just as much as Dehecq wanted to crown his M&A record with his biggest acquisition to date.

They don't seem that friendly any more, though.

Far from embracing its national champion's new fat-buster drug with open arms, the French reimbursement authorities today gave it a distinctly lukewarm approval.

Acomplia (rimonabant, approved in the EU in June 2006 but reimbursed so far only in a handful of countries, including Sweden and Denmark) is relegated to the lowest tier reimbursement--35%--which corresponds to treatments of 'minor therapeutic value'. What's more, only obese patients with diabetes will be eligible for the 35% reimbursement (and even then, docs have to fill out the prescription on a special form--an "ordonnance d'exception"). The overweight lot with risk factors, though included on the label, will have to stump up the full €70 per month if they want the drug.

Yet it's not as if France can any longer claim to be a nation of slimmies, even though in the past their red-wine and foie-gras lifestyle was known as the "French paradox" because it didn't make them fat. These days, 1.2 million French people eat in McDonalds each day, and childhood obesity is growing at 17% annually. At this rate, reports the Roubaix journal in Northern France, the French could be as fat as Americans by 2020.

Still, despite initiatives such as National Weighing Day for French children on January 7, and significant political involvement (the Socialists in particular are jumping on the healthy eating bandwagon to try to muster support ahead of May's elections), the French government doesn't see Acomplia as a big part of the answer to bulging waistlines. Nor, incidentally, do the Germans: they refused point blank to reimburse Acomplia at all, dismissing it as a life-style drug.

Is there a trend here?

Either way, the pressure's on the Acomplia reps to get friendly with docs and persuade them to prescribe the drug anyway--but only for, er, patients with that particular combination of cardio-metabolic risk factors (that docs all know about and have time to measure).

Sanofi executives have always claimed that "this isn't an obesity drug". The authorities appear to agree.

DotW: Angst

The mood of the nation is undeniably dark. The turmoil on Wall Street is enough to give even the most steady individual palpitations. And the antics on the Hill--don't get us started. Even Silicon Valley, that bastion of wealth and exorbitantly priced homes, looks to be in jeopardy according to today's New York Times.

Despite the counter-cyclical nature of the biopharma industry and its relative immunity to the widening credit crunch, skies in biopharma land are also far from rosy. Roche still hasn't managed to close the deal with Genentech, but according to the WSJ, remains steadfast that it has the capital it needs to get it done. So what if the two companies haven't agreed on a price? (It's worth noting that if negotiations drag on much longer, the Swiss pharma's original offer of $89-a-share may start to look better and better given the roiling market and the news that Raptiva use has now been linked to at least one case of PML. Hmm. Maybe patience is a virtue.)

Moreover, discussion of biopharma's lack of R&D productivity has been replaced by talk of an "innovation crisis" in certain circles. A small but intrepid group of readers weighed in with their own thoughts: 63% agree their isn't enough innovation to sustain the industry, while 37% remain more optimistic. (Note there's still time to have your say if you haven't already.)

We aren't sure if the folks at Pfizer and Merck see the innovation glass as half-empty or half-full, but we're guessing the former based on this week's news flow. Forced to take a hard look at their pipelines, both Merck and Pfizer responded this week by terminating R&D programs that were suddenly too expensive to justify. In the case of Merck, it was their troubled Phase III obesity drug, taranabant, a close cousin of Sanofi-Aventis’ rimonabant (Acomplia/Zimulti). Pfizer announced an even bigger retrenchment, forsaking early stage R&D in heart disease, obesity, bone health, and other areas, an amazing turn-around for a company's who bread-and-butter has been primary care blockbusters such as Norvasc and Lipitor.

And then there's the news that Lilly is ImClone's mysterious suitor, but not quite ready for its big reveal. In a statement released Wednesday night, Carl Icahn announced that “the large Pharma company has completed due diligence and made a proposal not subject to financing or further due diligence," but has asked ImClone to stay mum about its identity until the negotiations are finished. Oh, Carl you are so coy. It's enough to make a grown person cry.

If your calls for mommy dearest have gone unheard, fear not. We have the antidote for your furrowed brow--and no, it's doesn't call for watching send-ups of Sarah Palin or spiking the water supply with antidepressants. (We're pretty sure that's already been tried.) It's time once again for...


Genentech/GlycArt/Roche: The boards of Roche and Genentech may not be able to agree on a price for Genentech, but that isn't stopping scientists at the two companies from working together. (Isn't it special when family members play nice?) On Friday came the announcement that the South San Francisco biotech was teaming up with Roche's subsidiary to develop GlycArt's GA101 molecule, a humanized, souped-up anti-CD20 antibody currently in early stage clinical trials for various leukemias. As part of the deal, Genentech will record $105 million in R&D expenses as part of its third quarter 2008 results. The three companies will, however, share certain development costs and Genentech will receive US commercialization rights in the US. This is not Genentech's first foray into the development of an anti-CD20 antibody. The company, of course, markets Rituxan, which was developed by scientists at BiogenIdec. But that drug is far from perfect and a certain percentage of patients fail to respond to the antibody. That's allowed next-generation antibody players such as GlycArt, Xencor, BioWa, and GlycoFi (now part of Merck) to develop souped up versions of the molecule using optimization technologies as we discussed here. In fact, this latest announcement may spell trouble for Xencor. Back in 2004, it inked a deal with Genentech to develop a better version of Rituxan using its own protein engineering technologies.

Wyeth/Advanced Life Sciences: It's no secret that public biotechs walk a tight-rope when they sign alliances--the deals give them some necessary cash and validation, but investors don't always like them. How to solve this conundrum? Sign a development pact that's limited to a geographic area of the world. On Wednesday Advanced Life Sciences and Wyeth announced a commercialization pact for ALS's long delayed antibiotic, cethromycin. Wyeth will market the drug, which is related to Sanofi-Aventis's Ketek, in all parts of Asia except Japan, where Abbott Labs has rights to the compound. As part of the deal, Wyeth is purchasing a 4.9% equity stake in ALS and will pay the company milestones and sales royalties based on the future development of the antibiotic. The commercial partnership is a significant step forward for Advanced Life Sciences, which has worked hard to shore up its balance sheet by inking debt and equity financing agreements so that it can remain in business until cethryomycin's approval. Unfortunately concerns that Advanced Life Science's drug may also cause the liver toxicities and patient deaths observed with Ketek use have meant that the antibiotic must complete additional trials before it can be approved in Asia. (Advanced Life Sciences recently submitted the drug to the FDA for approval.)

Ortho-McNeil-Janssen Pharmaceuticals/Advinus: Yet another company goes to South Asia to access cheaper drug discovery and early clinical development expertise. On Tuesday, Advinus, an India-based CRO, and Ortho-McNeil, a division of Johnson & Johnson, announced they were teaming up to develop molecules against a variety of undisclosed disease targets. Historically OMJP's interests have been in pain, infectious disease, and GI disorders, while Advinus has focused on metabolic diseases. Like the previous deal Advinus signed in 2006 with Merck, the agreement with OMPJ gives Advinus responsibility for discovery and clinical work through Phase IIa, at which point the J&J group has the option to advance promising candidate drugs into late stage clinical trials. If it does so, OMPJ picks up responsibility--and the tab--for worldwide commercialization. Deal terms were slightly richer for the CRO this time around, perhaps proof that the company has established itself as one of Asia's service companies of choice. As was the case with the Merck tie-up, Advinus will receive an upfront payment of an undisclosed amount. If it delivers two targets to OMJP, it will receive an additional $247 million plus royalties on sales of any future drug products. (In its deal with Merck, the Indian company gets just $149 million plus royalties on future sales for delivering the same number of targets.)

GE Healthcare/MicroCal: General Electric, GE HealthCare's parent company, continues to get beaten in the market, announcing Wednesday that it would gladly accept $3 billion from Warren Buffett (So would we!). But the financial upheaval didn't stop the med-tech group from acquiring the privately-held instrument maker MicroCal for an undisclosed sum. MicroCal's proprietary platform dovetails nicely with GE Healthcare's existing BiaCore platform, providing scientists with detailed information on the structure, function, and binding properties of biomolecules like proteins and antibodies. The move shows that GE Healthcare continues to eye the competitive tools space, and should give pause to companies like Perkin Elmer and Thermo Fisher. Indeed, the conglomerate has inked four other deals this year alone, including the take-out of Whatman PLC, maker of filtration and cell sample preparation technologies, for $702 million and the recent $990 million purchase of respiratory device specialist Vital Signs. Massachusetts-based MicroCal was pretty long in the tooth despite its private status--it was founded in 1977 by John Brandts, a U. Mass. chemistry professor. The private equity group Riverside Partners, which first invested in MicroCal in 1999, was the instrument maker's primary owner.


Covance/WuXi: Just months after unveiling plans to create a JV for preclinical drug testing services in China, WuXi PharmaTech and Covance have scuppered the deal. When the deal was first announced in June, it was heralded as a positive step for both companies: the Covance name appeared to give WuXi added credibility outside Asia, while the collaboration helped the Princeton, NJ-based CRO access the lucrative China market. But the deal wasn't necessarily balanced from the start: WuXi had committed to building the facilty, and for its work Covance was ponying up just $20 million. Though details haven't been fully disclosed, it seems likely that this imbalance coupled with competing priorities at Covance may have derailed the agreement. Recall that Covance recently acquired Eli Lilly's drug development campus in Greenfield Indiana for $50 million. Our sister publication PharmAsia News has the full story.

image from flickr user 'stuck in customs' used under a creative commons license.

Is FDA Killing Research?

It sounds crazy. But it’s what Wyeth’s R&D chief Bob Ruffolo fears if the unprecedented political storm currently engulfing FDA continues to force the agency to raise drug safety hurdles.

“Who is going to bring a new, improved version of Avandia to market,” asks Ruffolo, given the likely trial-size FDA is going to request? How will any company be able to prove that their drug doesn’t have the safety issues associated with Avandia, if these (whether or not they are real) only become apparent from Steve Nissen’s meta-analysis of trials involving 28,000 patients?

No drug is risk-free, and no company-sponsored clinical trial can feasibly replicate real-world drug usage over a number of years. Yet people [politicians, patient groups, Public Citizen, and now FDA] "are demanding absolute positive safety,” Ruffolo tells us.

Now sure, comprehensive safety data within the reasonable bounds of clinical trials is crucially important to getting a drug approved. But if, as Ruffolo contends, regulators—whether or not under pressure from politicians and lobbyists—become obsessed with safety and fail to grant equal attention to benefit, there may be little point in even pursuing drug development within certain classes. Hence, “I’m worried that what saw with Avandia will kill off an entire area of research.” (Add, perhaps, CB1-antagonists to the list, since rimonabant was unanimously rejected by an FDA advisory committee yesterday.)

Avandia, like Lilly/Takeda's Actos (which will also get a black box warning following the NEJM report) is a PPAR gamma agonist. Developers of such single PPARs have already had a rocky road: despite many attempts, they remain the only compounds in their class on the market (there used to be three -- until the FDA forced Warner-Lambert (now Pfizer)’s Rezulin off the market). And Avandia and Actos already in 2002 had their labels updated to reflect safety concerns around congestive heart failure resulting from fluid retention. Meanwhile, every one of the next generation dual alpha-gamma PPAR agonists to get close to the FDA has also failed: remember AstraZeneca’s Galida, discontinued last year because of kidney toxicity; or Merck & Co.’s MK-767; or the compound Merck in-licensed to replace it, Bristol-Myers' Pargluva (whose main antagonist, like Avandia's, was Cleveland Clinic's Steve Nissen).

One might argue, given the list of casualties, that the PPAR class is doomed and it is in fact better that researchers leave it well alone. After all, who wants me-toos? We have a couple of PPARs already out there, the safety-scare will discourage their further usage, and that will force the industry to look elsewhere, for ‘real’ innovation.

But ‘real’ innovation and progress don’t generally happen in giant leaps, they happen in increments. There are plenty of reasons for bringing new versions of Avandia to market, Ruffulo argues, just as there are plenty of good reasons to have a variety of Cox-2 drugs, or a palette of cancer treatments. It’s well known that individuals respond differently to the same drug; in cancer, there’s also the issue of resistance.

Getting back to the PPARs: designing drugs that target different ratios of PPAR alpha, gamma and delta receptors might just improve the side-effect issues that Nissen highlighted, if indeed they are worthy of a black box warning. Despite the failures, companies including GlaxoSmithKline and Sanofi-Aventis are still working on next-generation subsets of PPARs, including dual PPARs and PPAR delta agonists.

So why is Ruffolo so riled up? Wyeth doesn’t have a PPAR agonist (it isn't in diabetes), and, for that matter, doesn’t have a Cox-2 either. In fact, Ruffolo contends, the company has been a little more protected than some from the worst of the safety storm around primary care drugs, in part thanks to its focus on more specialist areas like rheumatoid arthritis (and CNS in primary care, where FDA appears particularly open to new treatment options).

But Wyeth has been hit by its fair share of safety crises—including the Women's Health Initiative study in 2002 which apparently showed an increased risk of breast cancer, among patients taking Wyeth's combined estrogen/progestin hormone replacement therapy Prempro. Positive benefits such as a decrease in hip fractures were overlooked, contends Ruffolo. So are more recent data analyses this year reversing some of the earlier findings on heart attack risk. In today's regulatory reality, meta-analyses count when they’re negative on safety, but not when they’re positive on efficacy. In other words, drug labels can only get worse.

The industry itself is partly to blame for this onslaught, though. Its behavior hasn't exactly been squeakly clean--think enquiries into dubious promotional techniques, accounts of negative trials being swept under the carpet, and the 'dodgeball' that reps were encouraged to play with Vioxx when faced with difficult questions.

Ruffolo acknowledges that the industry makes mistakes. But that won't help the sector out of its plight, nor will blaming eager politicians and watchdogs. For that, drug firms should start rebuilding consumer trust. Perhaps this safety storm will push them into doing so--the silver lining in an otherwise black cloud.

While You Were BBQing

For those of you struggling to keep up after a beautiful holiday weekend, here's a quick roundup of recent news and health care goings on ...

• Whatever you think of Congressional oversight of FDA, this news out of China suggests there are harsher ways to deal with failure to lead a food and drug regulatory body. The New York Times is reporting this morning that Zheng Xiaoyu, who headed China's Food and Drug Administration from its foundation in mid-1998 until 2005, was sentenced to death today after pleading guilty to corruption and accepting bribes.



• Via Reuters, analysts are wary that GSK's Avandia problems will hurt the regulatory chances of Sanofi-Aventis' Acomplia/Zimulti. We think rimonabant's chances were pretty slim to start with, but agree the current climate isn't helping the French drugmaker.



• Speaking of Avandia, the recent turmoil might mean serious trouble for GSK's long-term safety study Record. Patients are dropping out of the 4,450-patient trial in the wake of the NEJM study, says the NYT, and GSK is worried about whether it can complete the trail, which is scheduled to run through 2008.



• Via the recently redesigned Pharmalot, FDA has called out companies whose time-released cough and cold medicines incorporate the substance guaifenesin. Good news for Adams Respiratory Therapeutics, the only company with FDA approved drugs that contain the substance. Adams was up 10% on Friday on the Nasdaq. See the letter from FDA here, and the new sleek and sexy version of Pharmalot here. Looking good!

Deals of the Week: Dark Clouds

It seems we'll end the month without a big oldfashioned biotech-pharma licensing deal to crow about in Deals of the Week. A few pharma-pharma co-promotes, a handful of biotech acquisitions, sure. Probably a coincidence, right? But maybe this observation from earlier in the week is the metaphorical dark cloud on the horizon (the actual dark cloud above was in this blogger's backyard on Wednesday afternoon). Will investor antipathy and skepticism toward biotech dealmaking generally (and the validation that used to come with a Big Pharma's stamp of approval specifically) put a semi-permanent funk on the sector's alliance activity? Here's to going out like a lamb. On to ...


Lilly/Sanofi-Aventis: Sanofi-Aventis sales reps have some extra time on their hands – thanks mostly to the regulatory delay – kindly put -- on rimonabant (for analyses and summaries, see here, here and here). Meanwhile, Lilly, slicing the erectile dysfunction market yet thinner with its recently approved low-dose, daily version of Cialis, needs some sales help. On March 13th, they signed a two-year co-promotion with a one-year option, which we learned about from our smart friends at The Wall St. Journal Health Blog.

We wish them both luck. In apparent anticipation that the co-promotion, like many others, will stumble a few times before hitting its stride, Pfizer has increased its Viagra sales calls by about 25%, according to ImpactRx (Viagra was approved 10 years ago yesterday, notes the WSJ in another post). Indeed, the advantages of the new low-dose Cialis hardly seem easy to explain. The daily version is for men who want to have sex more frequently – say, twice a week, says a Lilly website. But for twice-a-weekers, old Cialis – with its 36-hour window –works just fine. And there’s no cost difference between the low- and high-dose versions. On the other hand, the new dosage – which can be taken daily -- may help Lilly position ED in the patient’s mind in the same way he thinks about his chronic diabetes or hypertension. If you’re taking an ACE inhibitor every day, why not just pop a low-dose Cialis along with it?

Shire/TAP: Shire has teamed with recently torn-asunder TAP Pharmaceutical Products to co-promote its once-daily mesalamine (Lialda) mild-to-moderate ulcerative colitis treatment in the US. Specifically Shire is tapping (sorry) the former Abbott/Takeda JV for the services of 500 GI-focused and primary care sales reps to augment its current 120 specialty-rep efforts. The three-year deal should give Lialda quite a boost. The relatively new formulation of mesalamine (approved in January '07 and launched last March) has enjoyed a quick start in the market, taking an 8% share in its first nine months on the market (sales in '07 were about $50mm in the US). The terms of TAP's dissolution entitle Takeda to the group's GI assets (which include the soon-to-be-genericized blockbuster PPI Prevacid) while Abbott takes over oncology assets including the JV's only other marketed drug leuprolide (Lupron), and $1.5 billion paid out over five years. TAP had sales of $3.1 billion in 2007, dominated by $2.3 billion in Prevacid revenue. Surely the addition of Lialda will help take the sting out of that drug's impeding genericization. Terms of the Lialda deal weren't disclosed.

Philips/TOMCAT Systems: Philips Healthcare has entered into quite a few partnerships recently, but it’s not just tomcatting around. In February the Healthcare IT business of Royal Philips Electronics NV announced that it was restructuring its informatics strategy for the hospital in order to “seamlessly integrate islands of information, rather than focus on a single application or department” according to a press release. To that end, the company’s been on a tear, acquiring eight companies since early 2006 in various segments of IT and patient monitoring, (we list them in our discussion of the Respironics acquisition in January’s IN VIVO) Yesterday Philips snared a ninth acquisition target, TOMCAT Systems Ltd., the leading provider of information systems to hospital cardiology operations in the UK and Ireland. TOMCAT offers a comprehensive and integrated system for managing all of the clinical and administrative needs of cardiology patients in the hospital, that means everything from displaying test results to making appointments for patients, and it fits into Philips’ goal of offering a continuum of care in clinically focused business segments. Building the infrastructure that follows a patient from the home to the hospital and then back again is a daunting undertaking involving many moving parts, but Philips appears to be tackling it single-handedly, and if any company can succeed, it probably can. The parent company posted 2007 revenues of $36.8 billion in revenues, with the Healthcare division accounting for $8.9 billion of that Royal sum.

... and finally, your Howie Mandel/Noel Edmonds moment and excuse for us to break out the best example of our MS Paint skills comes courtesy of the on-second-thought termination of Raven Biotechnologies and Vaxgen's reverse merger agreement, announced this morning. Chalk one up to shareholder activism, and we suppose in this case, good sense. MPM BioEquities opposed the deal back in December along with other investors. MPM wrote at the time:

"VaxGen had over $75 million in cash and marketable securities, or over $2.30 per diluted share at the time of the proposed merger, yet management is still supportive of a merger with the stock trading at a market value of approximately $15 million, or $0.42 a share. Even with an outstanding convertible loan due in 2010, VaxGen owns other substantial assets, including a state-of-the-art biologics manufacturing facility, a clinical- ready anthrax program, and significant tax loss assets that net to a substantial premium over the current market valuation. In any scenario other than the current merger proposal, we believe VaxGen is worth over $2.00 per share."

GSK Option Deal With Concert Is Just Like Lots of Other GSK Option Deals, Only Heavier

a hydrogen isotope AND a Canadian death-metal band? you betcha.

It seemed a few weeks back when Concert Pharmaceuticals announced they'd been granted patents by the USPTO on deuterated versions of rimonabant and mosapride that one kind of validation could quickly lead to another.

As Derek Lowe has pointed out, the molecules crossed a major threshhold: if one could be patented, why not the rest? Today the other shoe dropped: GSK has entered the fray with another one of its many option-alliances, and Concert's technology has passed yet another test.

GSK paid the biotech $35 million up-front (which includes $16.7 million for equity priced consistent with the price of the shares sold in its $37 million 2008 Series C) in exchange for options on three Concert projects: CTP-518 (a deuterated version of BMS's atazanavir HIV protease inhibitor that is scheduled to enter Phase I this year), a preclinical compound in chronic kidney disease, and a third undetermined compound. Like most of GSK's option-deals, the Big Pharma can choose to opt into a program at clinical proof-of-concept (generally post Phase IIa but in the case of '518 post Phase I).

Concert will also create deuterated versions of three additional molecules for GSK, and hand those off after lead optimization. The deal's milestones total more than $1 billion and are heavily weighted to the three option candidates, says Concert's chief business officer Steve Bernitz. What's more the majority of the payments are for clinical and regulatory accomplishment, as opposed to sales-based payments. Concert will get a double digit royalty on compounds from its pipeline and an undisclosed royalty on deuterium-containing molecules from GSK's pipeline.

Replacing hydrogen atoms with deuterium atoms (hydrogen atoms saddled with a neutron) essentially creates new NCEs, getting Concert around existing composition-of-matter IP. But "it does not change the physical characteristics of a drug," president and CEO Roger Tung, PhD, told us today. After leaving Vertex where he led that company's drug discovery efforts (and co-invented the successful HIV PIs Lexiva and Agenerase) Tung co-founded Concert with Richard Aldrich and Christoph Westphal in 2006, and has largely kept things under wraps until recently (though we were sufficiently intrigued back then to include them in our inaugural A-List of that year's top Series A financings). "So we're retaining the way a drug interacts with receptors and the pharmacology of a drug, with respect to its positive effects and selectivity profile, is unchanged."

But, says Tung, deuterium forms stronger bonds with other atoms in comparison with hydrogen, because of its greater mass. And that increase in bond strength can change the rate of a drug's metabolism and the relative ratio of its metabolites, which in turn can affect the safety and tolerability and even efficacy of certain drugs, he says.

All this remains to be seen in the clinic, but if it works out, Concert's deuteration approach (also embraced by biotechs like Auspex and Protia) seems to be the ultimate in life-cycle management. In an interview both Tung and Bernitz kept returning to the low-risk nature of the company's approach. "Generally we've been able to move from concept to the clinic in about two years," says Bernitz. And Concert doesn't take on "the risk of new biology" that many pharmaceutical companies are now embracing. "That lower risk-approach to drug discovery and development is recognized in this deal," given the substantial terms Concert has garnered for its preclinical programs, he says.

It seems logical that Concert's window for patenting deuterated versions of existing molecules is finite, perhaps now even closed since industry should be wise to deuterated drugs by now, though Tung doesn't see it that way. "Industry will take this up in the coming years, but we believe we have the poll position now and are the leaders in the use of deuterium."

And beyond deuterated versions of marketed drugs there are "tens of thousands" of compounds available that showed promise but for one reason or another did not become marketed therapies, he says. "I think we're going to be very busy for quite some time."

And so for now, what about Bristol-Myers? The company's Reyataz (atazanavir) remains on-patent and according to Tung will likely still be on-patent by the time '518 should be hitting the market. Though Tung says Concert talked to BMS prior to the GSK deal it's unclear whether BMS was in the running for the compound. For Concert, finding a partner with strength in HIV was important.

A bonus? "The deal validates that [the originator] isn't the only company we can work with" when dealing deuterated compounds, says Bernitz.

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.

At Least the Europeans Appreciate Novo's Victoza

It’s all smiles again at Novo Nordisk following yesterday’s news that EMEA has recommended approval of its GLP-1 agonist liraglutide (Victoza).

The positive opinion followed a decidedly lukewarm US advisory committee outcome earlier this month, where concerns were raised not over cardiovascular safety (a possibility, given FDA’s more stringent diabetes guidelines) but over a raised incidence of thyroid c-cell tumors in rodents during pre-clinical trials. (We cheekily suggested thereafter that Novo might not mind so much about GLP-1s anyway.)

The European regulators, however, appear to agree with Novo’s CSO Mads Thomsen that “the mechanism [behind the raised incidence of thyroid c-cell tumors] is one that mice and rats are sensitive to, but that monkeys and humans are not.”

The regulators haven’t even requested that the company take any additional measures—such as thyroid cancer screening—to rule out the potential risk. “There are no restrictions on usage” as a result of the pre-clinical thyroid cancer data, Thomsen told The IN VIVO Blog. “It was a clean approval.”

Well, a clean recommendation anyway; the European Commission must still issue the final marketing authorization, expected in about two months. With that in hand, Novo will begin to sell Victoza in various European markets over the summer.

This un-restricted European thumbs-up for Victoza matters not just for the drug’s EU commercial potential. China, for instance—a key emerging market for Novo--requires a sponsor to have home-market approval before it can even submit a new therapy. And there will be positive knock-on effects of a European approval in other markets, too, adds Thomsen, since "some countries simply base their approval decisions on the European outcome."

Unfortunately, the US is not one of them. FDA is due to decide late next month whether to approve Victoza, but based on the split advisory panel outcome and an almost entirely risk-focused (as opposed to benefit-focused) discussion, things don’t look good. Analysts including Matthew Osborne, SVP at Lazard Capital Markets, reckon that the best case would be that Victoza launches on time during the second half of the year but with a black box warning and/or monitoring for thyroid cancer. Other options: a 6-12 month-delay due to a request for additional data, or outright rejection. Not a great outlook for a drug predicted to become a blockbuster by 2012.

This isn't the first time European regulators have approved a drug that FDA has rejected or at least prevaricated over. Sanofi-Aventis' obesity candidate rimonabant (Acomplia; Zimulti in the US) was another. Given what happened to that (rejection in the US, withdrawal in Europe), it's interesting--comforting?--to see that FDA's ultra-risk-focused conservatism isn't rubbing off too hard on the Europeans just yet.

image by flikrer sean-b used under a creative commons licence

Reputation Counts

Merck has fallen a long way from the days when its CEOs adorned the front cover of Time magazine as respected business leaders (George Merck in the 1950’s) and icons of cutting edge scientific research like the (Roy Vagelos in the 1980s and 1990s).

The image of Merck as the “moral corporation,” the respected leader in innovative pharmaceuticals and research, has suffered blow after blow in the past four years. The most recent hit is a non-admission settlement with the Justice Department and state authorities of charges that the company abused the Medicaid best price rebates and marketing practices. "Non-admission" meaning, "We'll pay the fines, agree to give the government extensive future rights to oversee pricing documents and marketing practices--but we will not admit wrong-doing."

The accumulating financial costs of the bad news events keeps rising: the loss of the $2.5 billion Vioxx franchise; a $4.85 billion agreement to settle liability claims from that product; an 8% drop in total prescriptions in the Vytorin/Zetia group due to the failed ENHANCE trial; and now $670 million in payments to the feds and states to settle the Medicaid case.

But the real cost may be in the future, when Merck takes this new public image with it into efforts to get approval for drugs like the weight loss product, taranabant.

Merck has made some smart hires along the way to prepare for a careful review of the cannabinoid compound including a former senior officials from the FDA review group that will look at taranabant, Robert Meyer, (see here) and the former top FDA drug safety manager, Peter Honig. Their experience should help inform Merck’s handling of the application for the obesity drug and provide solid, knowledgeable advice on ways to assure FDA that the company knows how to address the psychiatric side effects that derailed Sanofi-Aventis’ Zimulti (rimonabant) application.

One of the likely prerequisites for getting an anti-obesity product through FDA, however, is for the sponsor to convince the agency that it will control use of the product carefully and find a patient population for whom the benefits clearly outweigh the risks.

Here is where Merck’s new reputation of pushing in every way it can to extend the market for its products will work against it.

When Merck commanded a high-road image, the company treated its reputation as a corporate asset, a strength that it could use for ambitious but trusted efforts to open new drug categories. The company may have given up some of that strength.

Merck used to have PR people assigned to watch and protect its long-term reputation, paying attention to more than the short-term news cycle and the liability wars. One of those execs, John Doorley, currently the director of NYU’s masters program in public relations, literally wrote the book on “Reputation Management”.

Maybe Merck needs to get a new copy of the book and pay some more attention to rebuilding the trust of the public and regulators before heading into promising but perilous new drug categories.

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.