Sanofi’s surprise decision to pull the US filing for its new diabetes drug Lyxumia substantially delays an important product launch for the French pharma giant. The company said the move was made to protect the integrity of a large, ongoing cardiovascular outcome study, but other forces must have been at play.
It seems likely that the French drug maker was anticipating an advisory committee to review the filing, and there are certainly several reasons to assume that this would have been the case. Concern that the regulator would want to see the full outcome data might also have swayed the decision. At the end of the day, Sanofi must have felt it had more to gain than lose by the delay, and results from the outcome study, called Elixa, now take on even greater significance.
The filing for Lyxumia, or lixisenatide, contained the first look at cardiovascular outcome data generated by a GLP-1 agonist. This was in the shape of an interim analysis from the ongoing Elixa study, a 6,000 patient trial designed to see whether the drug can cut the risk of cardiovascular events or death in type II diabetics with a history of recent heart problems. Final results should be available at the end of 2014, Sanofi said today.
Only a very small group of “firewalled” Sanofi employees are aware of the interim results, a spokesman for the company told EP Vantage today, adding that the final decision to pull the filing was made by people without knowledge of the data.
But the company judged that the regulatory process risked revealing this information. This could have come on approval, contained in the label or summary basis for approval document, but the most likely avenue would have been during an adcom meeting.
All GLP-1s to reach the market to date have been in front of an FDA advisory committee and given the apparent hardening in the regulatory environment for diabetes drugs in the US lixisenatide would have been no exception. Add to this the eagerly awaited outcome data in the filing, albeit early outcome data, and an adcom looks a dead cert.
Four outcome studies are ongoing for the GLP-1 class, but Elixa will be the first to report by a fair margin (Roche’s long-odds aleglitazar bet points to others chasing the cardio dream, July 11, 2013). Sanofi’s statement suggests that protecting the Elixa study was the main reason for its decision.
The concern seems to be that publication of interim data – positive or negative – would run the risk of introducing bias into the trial, and eroding the power of any conclusion. A finding that lixisenatide reduces the risk of cardiovascular events or death would certainly be a huge event for both the company and the GLP-1 class overall. Outcome studies to report with another class of incretin mimetic, the DPP-IV inhibitors, have failed to show any evidence of cardioprotection (Move along, nothing to see here: Onglyza Savor trial result leaves diabetes world unrocked, June 19, 2013).
But other concerns might well have contributed to the decision. In particular, the distinct possibility that the FDA would require full Elixa data before granting approval. The surprise rejection of Novo Nordisk’s new long-acting insulin Tresiba provides precedent for this, and could have been enough to tip the decision in favour of pulling the filing at this stage.
Sanofi was very keen to stress today that the decision had nothing to do with safety issues, and this seems likely. Aside from the reputational damage of hiding a safety concern at this stage, lixisenatide is about to enter a combination study with Lantus, the company’s biggest selling product, and it seems very unlikely that Sanofi would risk tainting the long acting insulin’s reputation after endeavouring for years to disprove various safety scares.
The market for GLP-1 antagonists is only going to get more competitive. Three products are already entrenched on the market, GlaxoSmithKline’s albiglutide is with US and European regulators and Eli Lilly’s dulaglutide is queuing up in phase III. As such, any signal of cardioprotection would be a huge differentiator, although at the same time probably be considered a class effect.
The progress of albiglutide will be interesting to compare – Glaxo is not running a cardiovascular outcome study – and the FDA last month pushed back making a decision on the product by three months, to 15 April, 2014.
So Sanofi’s gamble could pay off if the Elixa study generates a strong signal, and if other new contenders in the class are also held up by a cautious regulator. But the delay is undoubtedly disappointing - Sanofi shares slipped 2.4% today and partner Zealand Pharma fell 15%. The company needs to set out more clearly what it believes it will gain from this move.