FDA unconvinced by Sanofi’s Zynquista in type 1 diabetes

Sanofi’s hopes of getting its dual SGLT inhibitor sotagliflozin approved alongside insulin for type 1 diabetes in the US have been dashed by the FDA.

The US regulator has issued a complete response letter (CRL) for Lexicon Pharma-partnered sotagliflozin, a dual SGLT1 and SGLT2 inhibitor that has the proposed trade name of Zynquista, even though it has already been recommended for approval in Europe by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP).

Sanofi issued a terse statement in response to the FDA’s rejection of its application to use sotagliflozin in combination with insulin for the treatment of adults with type 1 diabetes, simply saying that it would “work closely with the FDA to determine the appropriate next steps.”

So far, AstraZeneca’s Farxiga SGLT2 inhibitor (dapagliflozin) has also been recommended for approval as an oral add-on to insulin to improve blood sugar control in type 1 diabetes in the EU, getting a green light from the CHMP last month, and was also filed with the FDA for this indication last year.

The FDA’s verdict doesn’t come out of the blue, as an FDA advisory committee delivered a split eight to eight vote on sotagliflozin as an oral add-on to insulin last month, which made the FDA verdict something of a coin toss.

The panel was concerned about a higher risk of patients developing diabetic ketoacidosis (DKA) – which can lead to acute kidney injury, respiratory failure, and death – compared to using insulin alone.

In trials, a higher risk of DKA was seen in patients on the combination compared to insulin alone, even though patients and physicians were given advice about avoiding the side effect, and committee members said they were concerned it could be a bigger problem in real-world use.

There was no word from either Sanofi or Lexicon on the explanation in the CRL, with Lexicon CEO Lonnel Coats saying on a conference call late Friday that the company had only just received the latter and had not held a discussion with the FDA on its contents.

He would not be drawn on the call in any questioning relating to the potential need for an additional clinical data or a new trial – that might result in a lengthy delay – or indeed on the explanation for the divergent approach between the EMA and FDA.

“The FDA said it couldn’t approve the new drug application “in its present form”, he added, saying that Lexicon is determined to get the drug available to patients with type 1 diabetes “as soon as possible.”

Gabelli analyst Kevin Kedra predicted the FDA’s rejection of sotagliflozin, and thought the FDA would ask for additional information on a risk mitigation strategy to reduce DKA, which he said was a “manageable hurdle" but would take additional time to get in place.

Sotagliflozin has been tipped to make sales of $1 billion or so if it can get speedy approval in type 1 and type 2 diabetes, but with only a few years left on its patent life – estimated to expire in 2026 in the US – any protracted delay will eat into the return on Sanofi and Lexicon’s investment.

Shares in Lexicon closed down almost 22% in the aftermath of the CRL announcement, as investors considered the possibility of a long delay to the company’s sizeable milestone payment stream for sotagliflozin, with around $220 million tied to approval and launch in the US and Europe for both type 1 and type 2 diabetes.

Lexicon is also eligible for up to $110 million in milestones related to development of the drug in type 2 diabetes, with most of the clinical readouts expected this year, said Coats.

For Sanofi, the drug is key to its hopes of retaining a lofty position in diabetes that has been undermined in the last few years by the loss of patent protection for its biggest-selling product Lantus (insulin glargine) and disappointing take-up of newer long-acting insulin product Toujeo.

Zynquista is one of the few candidates coming through the pipeline to make up the shortfall as Sanofi has been re-focusing its R&D towards other areas such as inflammatory and rare diseases.