Ketoacidosis worries could scupper Lexicon

US approval of Lexicon and Sanofi’s SGLT inhibitor in type 1 diabetes hangs in the balance after an adcom tie.

Lexicon and Sanofi’s hopes of getting the first approved oral drug for type 1 diabetes might not have been completely extinguished, but they are looking much dimmer today. The companies were unable to convince an FDA advisory committee that they could manage the risk of ketoacidosis with their SGLT1/2 inhibitor sotagliflozin.

Lexicon believes that the groups still have time to put things right before the FDA makes its approval decision, which is due by March 22, though of course it could be delayed by the US governmental shutdown. But investors did not seem convinced – the company’s stock was trading down 22% this morning.

What the FDA panel’s stance means for another SGLT player, Astrazeneca, is also unclear. The UK group is developing Farxiga for type 1 diabetes but that project, like sotagliflozin, has been linked with ketoacidosis (ADA – Lexicon and Astra’s oral drugs face off in type 1 diabetes, 26 June 2018).

Astra has filed Farxiga in Europe for type 1 disease, and told Vantage that it also submitted the drug in the US last year, as planned.

The company is probably not too worried about Lexicon’s slip-up becoming contagious: type 2 diabetes, for which Farxiga is already approved, accounts for the entirety of the drug’s $2.4bn 2024 sales forecast, according to EvaluatePharma sellside consensus.  

Still, Farxiga is used off label in type 1 disease, and these sales could be in jeopardy if ketoacidosis worries stop doctors from using it here.

Dead heat

The stakes are much higher for sotagliflozin, branded Zynquista, as type 1 disease is its lead indication – specifically, as an adjunct to insulin. And its chances here do not look good after yesterday’s adcom, which saw panellists split on whether the project should be approved: the vote was a highly unusual 8-8 dead heat.

Safety was the main issue, which could make the FDA particularly reluctant to approve the project. Many panellists were concerned about the risk of diabetic ketoacidosis, a known complication of diabetes. They also questioned Lexicon and Sanofi’s risk-management strategy, asking why this had not included giving patients ketone-monitoring equipment.

When asked during a conference call whether Lexicon might take this step, its chief executive, Lonnel Coats, replied: “It’s something we have to have a conversation with Sanofi about, whether it’s something we want to do and if it’s practical. We’re committed to going back to the agency and finding out what is the right way to approach this.”

Stifel analysts reckon sotagliflozin still has an outside shot at near-term approval. They noted that patients moving from injected insulin to insulin pumps also had an increased risk of diabetic ketoacidosis, but this had been made manageable, in part through increased awareness.

However, even if sotagliflozin does get the go-ahead, the safety worries could hit sales. There is also the chance that the FDA could approve the 200mg but not the 400mg dose, echoing its decision with Lilly’s rheumatoid arthritis drug Olumiant last year after a mixed adcom.

Sotagliflozin is also awaiting an approval decision in Europe, due in the second quarter.

Type 2 hopes

An FDA knockback would hit sotagliflozin’s 2024 consensus forecast, which has already come down in recent months, and currently sits at $718m. Given that its US market exclusivity runs out in 2026, the chances of it ever achieving the blockbuster numbers of other SLGT inhibitors look slim.

Around half of sotagliflozin's 2024 sales are now expected to come in type 2 diabetes, where the project is in pivotal development, with data due this year. However, any hopes that Lexicon can pivot to type 2 disease should be tempered by the prospect of competition from established SGLT inhibitors here, including Farxiga and Lilly/Boehringer’s Jardiance.

Lexicon and Sanofi are obviously aware that going up against these players would be a hard task; the latter has taken the bold step of testing sotagliflozin against Jardiance in one of its many phase III trials, called Sota-Empa

Even so, the companies would no doubt like to be able to start with the white space of type 1 disease. In a couple of months we will find out how far the FDA’s lenience extends.

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