The FDA convened an advisory committee meeting to help its review of Sanofi’s diabetes drug Zynquista, but has ended up with a split decision that means it effectively has the casting vote.
The panel voted eight to eight when asked if the overall benefits of Zynquista (sotagliflozin) outweighed its risks as an add-on to insulin treatment for adult patients with type 1 diabetes, leaving the FDA’s decision – due by 22 March – too close to call.
Sanofi and partner Lexicon Pharma have developed the orally-active SGLT1 and SGLT2 inhibitor for this indication on the grounds that it could help type 1 diabetes who struggle to control blood sugar using insulin alone. If approved, the drug would be the first oral antidiabetic (OAD) drug to reach the market for this use, and Sanofi and Lexicon have previously suggested this gives it blockbuster potential.
It is also a key element in Sanofi’s plans to rebuild its diabetes franchise after the loss of patent protection for big-selling basal insulin Lantus (insulin glargine), which has seen sales slump from $8.5bn in 2014 to around $4.5bn last year.
The advisory committee’s main concern seems to have been Zynquista’s safety, and specifically the risk of diabetic ketoacidosis (DKA), a side effect that in severe cases can lead to kidney damage, respiratory failure and death.
Lexicon’s trials of the drug in type 1 diabetes showed an eight-fold increase in DKA in Zynquista-treated patients compared to placebo, according to FDA briefing documents (PDF) published ahead of the meeting. The agency is also concerned that the imbalance occurred despite efforts to minimise DKA, suggesting the side effect may be “unpredictable.”
Some of the panellists who voted in favour of Zynquista did so on the premise that the FDA would ask for a risk evaluation and mitigation strategy (REMS) to try to manage DKA, while others only backed the lower of two doses included in the marketing application.
Zynquista is intended to be given as a 200mg dose before the first meal of the day, with an option to double that up to 400mg if the drug is tolerated but glucose control isn’t achieved. Both dose levels were associated with DKA
Zynquista’s dual action on SGLT2 is thought to reduce glucose absorption in the gastrointestinal tract and glucose reabsorption by the kidneys, as well as stimulate the release of GLP-1. Current SGLT2-selective drugs – such as Johnson & Johnson’s Invokana, Eli Lilly/Boehringer Ingelheim’s Jardiance and Farxiga from AstraZeneca – are approved only for type 2 diabetes. According to Lexicon, sotagliflozin is also being tested in type 2 diabetes with phase 3 results due this later year.
Shares in Lexicon dropped almost a third after the panel meeting, suggesting investors are not confident the FDA will come down on the side if approval, while Sanofi also dipped slightly. Analysts have suggested that the FDA may ask for more data on measures that can be taken to guard against DKA, which would likely delay the review.
Sanofi licensed rights to sotagliflozin from Lexicon in 2015 for $300m upfront and up to $1.4bn in development, regulatory and sales milestone payments plus double-digit royalties.