Sanofi withdraws lixisenatide NDA submission from FDA, electing to wait for CVOT results and give FDA full package in 2015 – September 12, 2013

Sanofi and Zealand just announced earlier this morning that Sanofi was withdrawing its FDA new drug application (NDA) for its GLP-1 agonist candidate Lyxumia (lixisenatide) due to risk of CVOT ELIXA interim results disclosure compromising the ongoing full ELIXA study; Sanofi will re-submit once ELIXA has been completed, presumably in 2015. Given the complexity of recent regulatory decisions — the FDA’s four year delay of Novo Nordisk’s Tresiba (insulin degludec), which also delayed the company’s combination GLP-1/basal iDegLira, comes to mind – we are unsurprised that Sanofi is unwilling to take any risks with its monotherapy GLP-1, even though there is no reason to believe there “should” be any safety issue. While we don’t believe there was strong evidence of any safety issue with degludec, the FDA’s action on the drug may have caused Sanofi management to decide against revealing interim results from ELIXA if doing so could hinder the future progress of the study.

We had been speculating that FDA’s reliance on interim CVOT data to instruct decisions like lixisenatide approval was going to start to become quite complicated; and so it is. The CVOT saga continues. The FDA, as a result of its CVD guidance from 2008, is requiring CVOT interim results from Sanofi for lixisenatide before it will approve it in the US; in turn, and (increasingly) understandably so, Sanofi would be concerned about what happens in the trial if interim results are publicly disclosed (i.e., at an Advisory Committee meeting) and so for them, the trade off is not to risk a delay that could impact lixi-Lantus rather than celebrate the benefit of a lixi approval that would not necessarily result in significant revenue anyway. This is a conservative decision, to be sure, although perhaps not surprising given the increased unpredictability of the FDA regulatory process and the likelihood that as monotherapy, lixisenatide would not have resulted in significant revenue for Sanofi and Zealand short-term.

No matter what the ultimate reason for Sanofi’s decision, which won’t be known for years (if ever), there are a range of possibilities that could be driving the reasoning. We can speculate about several scenarios involving the interim data: (i) While the chance of interim ELIXA data showing superiority (through cardioprotection) is low at this point, it is theoretically possible. Public disclosure of an interim superiority result or trend toward superiority (however that might be interpreted) could sway patients in this double-blinded trial to drop out and ensure that they are on a cardioprotective GLP-1 agent. Significant drop outs would, of course, compromise the integrity of the trial; (ii) if results were neutral on the CVD risk front, that could also prompt patients to drop out who had hoped they were in a cardioprotective arm; this would seem a lower risk, no doubt; and (iii) finally, since most CVOTs are designed to first assess non-inferiority and then assess superiority, public disclosure of data could compromise investigators’ blindedness to non-inferiority results and preclude a superiority assessment. This was the case with J&J’s CANVAS, where unblinding of the interim results precluded any potential superiority analysis.

We see Sanofi’s apparent conservative move as an understandable step to prevent shake-ups in ELIXA. For this reason, they took a pass on FDA's willingness to accept interim CV safety data to enable submission of an ELIXA NDA. We wonder if Sanofi will set a trend with this decision, with other companies also delaying submissions due to risks associated with interim result disclosure. This is an issue that may also arise for many upcoming drugs with planned submissions based on interim CVOT data including Novo Nordisk’s new basal insulin Tresiba (insulin degludec), Lilly’s dulaglutide (once weekly GLP-1) and Orexigen’s obesity drug Contrave (bupropion/naltrexone), among others. Takeda’s DPP-4 inhibitor Nesina (alogliptin) managed to glide through the FDA’s review process its second time around without an Advisory Committee meeting to discuss interim CVOT results for EXAMINE – but we imagine this sill be the exception rather than the norm since interim results are not always straightforward to interpret.

The most valuable part of Sanofi/Zealand’s lixisenatide franchise is LixiLan, the combined GLP-1/Lantus product whose development timeline hasn't changed as a result of the lixi delay (phase 3 begins in the first half of 2014). A major irony here is that, during its recent Avandia advisory committee meeting, FDA itself raised the question about whether results of CVOTs should be required pre-approval for every T2DM therapy, FDA’s current policy.  It is not clear if or when FDA will start to change its this policy, but it is plausible that it will relax the requirement for drugs that are third or fourth to class — just as is the case for ELIXA. But, this change will come too late for ELIXA, of course. Both Lyxumia and Tresiba are already on the market in Europe because CVOT data were not required for their approval there.

The FDA’s CVOT requirement has had one positive effect for patients — had FDA not put in place requirements for CVOTs, they may not be taking place. These are very valuable data to have, particularly if they ultimately demonstrate cardioprotection. With ongoing follow-up, these trials can also help resolve other safety issues, such as pancreatitis. This Sanofi decision is a slight positive, of course, for Novo Nordisk and BMS/AZ/Amylin, who will have one fewer competitor on the GLP-1 front in the US than expected over the next couple of years - although we had been looking forward to watching Sanofi marketing on the GLP-1 front in the US, which will have to wait some time, and we imagine competitors would have benefited from increased marketing of the class.

The saga continues – we look forward to hearing from FDA its view on when and how it will modify its CV safety guidance for diabetes drugs  in the wake of questions raised about the value of the pre-approval requirement at the recent Avandia/RECORD meeting.

                  -- by Jessica Dong, Manu Venkat, and Kelly Close