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.

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.

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’.

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.

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.

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.