FDA’s cardiovascular safety requirements for diabetes drugs will delay yet another new entry in the U.S. This time the drug impacted is Sanofi’s once-daily glucagon-like peptide-1 (GLP-1) agonist lixisenatide. The company announced Sept. 12 that it will withdraw the NDA for lixisenatide, which it filed in February, to await the full results of an ongoing cardiovascular outcomes study, ELIXA.

European authorities already approved the drug in February, and Sanofi markets it there as Lyxumia. Sanofi’s decision will push back the launch of lixisenatide in the U.S., however, by about three years. It was not based on any specific safety issue, according to Sanofi, but discussions with FDA about how the agency planned to review interim data from ELIXA submitted with the NDA. Public disclosure of early interim data could compromise the integrity of the full ELIXA study, which is expected to complete in 15 months, the company said. Thus, Sanofi decided to await the full results of the trial.

The delay gives some breathing room to competitors in the GLP-1 field, namely Novo Nordisk AS, which sells once-daily Victoza (liraglutide) and Bristol-Myers Squibb Co./AstraZeneca PLC’s twice-daily Byetta (exenatide) and once-weekly Bydureon (exenatide). The U.S. market for GLP-1s is estimated to be a $2 billion market, according to some analysts.

The news could benefit the Bristol/AstraZeneca joint venture, as it establishes Bydureon in the market following the drug’s launch in 2012. The companies kicked the marketing strategy for Bydureon into gear only this year after acquiring Amylin Pharmaceuticals Inc., the maker of exenatide, last year. Timing is essential since widespread uptake of Bydureon is viewed as being dependent on the availability of an easier-to-use dual-chamber pen device, which is targeted for launch in 2014. The current formulation is cumbersome and has to be reconstituted before administration.

With the new delay, lixisenatide would be unlikely to launch before 2016. Though the product would be the fourth GLP-1 to the U.S. market, it shouldn’t be discounted given that Sanofi is a strong diabetes marketer. The French pharma has been planning to leverage its strength in insulin, where it sells the market-leading basal insulin Lantus, to position lixisenatide as the best option to be used in combination with insulin Also see "On The Wings Of Lantus: Sanofi Sees Clearer Skies Ahead In Diabetes" - Pink Sheet, 15 April, 2013..

LixiLan Pen Remains On Track

Sanofi’s best prospects for carving out a space in the GLP-1 field, therefore, could come from a fixed-ratio product combining lixisenatide with Lantus, which the company is developing under the name LixiLan. The U.S. NDA delay will not impact the timing of LixiLan, which remains on track to enter Phase III studies in the first half of 2014, Sanofi said.

The company originally had planned to develop a “fix-flex” pen, combining a fixed-dose of lixisenatide with a flexible dose of Lantus, but pushed that plan back after the company ran into a development snag with the device.

Novo Nordisk also is developing a combination of Victoza with its ultra-long-acting insulin Tresiba (insulin degludec). But like Sanofi, Novo Nordisk has run up against its own challenges at FDA in regard to cardiovascular safety. The agency rejected Novo’s application for Tresiba and another insulin product, Ryzodeg (insulin degludec plus insulin aspart), in February to await cardiovascular outcomes data, pushing back that approval by years ([A#14130211002]). The cases are similar in that Tresiba also has been approved by European regulators, but different in that in the case of Tresiba, FDA said it found a CV signal in its evaluation of clinical data involving the product.

Additionally, Sanofi initiated the event-driven ELIXA outcomes study in patients with high CV risk in June 2010, well ahead of the regulatory review, so that target enrollment of 6,000 patients already has been reached and results are expected in just over one year, making the delay a little less impactful.

Deutsche Bank analyst Mark Clark called the setback a “minor negative,” noting that the delay impacts less than 1% of the research firm’s 2016 sales estimates for Sanofi. Clark forecasts €300 million ($399 million) in U.S. sales for the drug in 2016 and said consensus sales estimates are similarly modest.

“Crucially, the development plans are unaltered for a combination of this product with long-acting insulin Lantus (LixiLan), seen by many observers as having substantially higher sales potential than ‘plain’ lixisenatide,” he said in a Sept. 12 research note.

The lixisenatide delay also impacts the Danish biotech Zealand Pharma AS, which discovered the drug and licensed it to Aventis SA before Sanofi acquired Aventis in 2004. Zealand stands to receive royalties on sales of the drug [See Deal]. In a statement, Zealand said its expectations to receive revenues in 2013 from royalties on sales of lixisenatide in regions where the product has been approved, including Europe, Japan, Mexico and Australia, remain unchanged.

Zealand has other drugs in development and other partners, but lixisenatide is its first drug to reach the market and provide a steady revenue stream. The company’s stock fell 15% on the news to close Sept. 9 at 66 kroner on the Copenhagen exchange, while Sanofi’s stock fell 2.3%.

FDA CV Requirements Sideline Sanofi’s Lixisenatide

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