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Still, the company has withdrawn its NDA filing, since, it feels, there wasn’t enough time to discuss with FDA the various points raised by the advisory committee before the July 26th PDUFA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