Despite its unique ability to block sodium-glucose linked transporter 2 (SGLT2) in the kidneys and SGLT1 in the intestines, Lexicon’s Zynquista (sotagliflozin) has had difficulty negotiating regulatory hurdles.
Last year, Lexicon broke its losing streak with the FDA when the agency approved sotagliflozin for heart failure and it was dubbed as Inpefa. But on Halloween afternoon, Lexicon was haunted again as an FDA advisory committee voted 11-3 that the benefits of Zynquista do not outweigh the risks when the treatment is used as an accompanying medication to insulin for those with type 1 diabetes (T1D).
With a revised application to treat a narrower patient population, Lexicon is hoping to clear the medicine for patients with T1D and chronic kidney disease (CKD). The FDA, which usually adheres to the recommendations of its advisory groups, will decide whether to approve Zynquista in the indication by December 20.
A persistent issue for the SGLT1/SGLT2 inhibitor is that it can increase the risk for diabetic ketoacidosis (DKA), a life-threatening condition that occurs when the liver breaks down fat too quickly and produces a build up of ketones. People with T1D are much more likely to develop severe cases of DKA than those with T2D.
While the adcomm vote was decisive, some panelists agreed that the drug could benefit sub-populations of those with type 1 diabetes and CKD. Lexicon CEO Mike Eston said in statement that while the company was “deeply disappointed by the vote,” it also was “encouraged” by the discussion that sotagliflozin may be appropriate for some patients.
“Insulin is essential to managing this disease, but it is not sufficient in keeping patients within appropriate blood glucose ranges,” Steve Edelman, M.D., the founder and director of Taking Control Of Your Diabetes (TCOYD), said in the release. “Only 20 percent of people with T1D currently achieve adequate glycemic control with insulin alone. Zynquista, if approved, would be the first oral medication for people with T1D, with potential to impact renal and cardiovascular outcomes, especially in those with CKD who face even greater disease progression risks.”
The tantalizing potential of sotagliflozin drew the interest of Sanofi in 2015 when it ponied up $300 million for a licensing deal and committed $1.4 billion in possible milestone payments.
But in 2019, following an 8-8 vote from an FDA advisory committee, sotagliflozin was rejected to treat Type 1 diabetes patients who can’t control their blood sugar with insulin. A year later, after Lexicon appealed the decision, the regulator swatted it back again.
After the initial FDA rejection, Sanofi paid Lexicon $260 million to exit the partnership. The funding allowed the Texas-based drugmaker to continue to develop sotagliflozin.
Regulators in Europe approved sotagliflozin as Zynquista for T1D in 2019 but three years later, the holder of Zynquista’s marketing rights in the region, Guidehouse Germany GmbH, withdrew (PDF) the marketing authorization, saying it did not wish to commercialize the product.
In 2022, as Lexicon worked through an application to treat heart failure in T2D patients, the company yanked its filing to work through what it termed “technical issues.” A year later, the FDA signed off on the treatment in the indication.
In a strong field of powerhouse SGLT2 inhibitors, including Boehringer Ingelheim and Eli Lilly’s Jardiance and AstraZeneca’s Farxiga, Lexicon has struggled to drum up business for Inpefa. In the second quarter, it generated just $1.6 million in sales.
Despite the troubles for sotagliflozin, it still draws interest for its unique potential. Last month, Viatris paid $25 million upfront to obtain the rights to sell Inpefa in all global markets beyond the U.S. and Europe.