Ketosis

The FDA is raising repeat safety and efficacy questions ahead of an advisory committee meeting on Thursday for Lexicon Pharmaceuticals’ SGLT2 inhibitor sotagliflozin, which the agency rejected in 2019 for type 1 diabetes. The original application was turned down after the FDA found an unacceptable level of risk of diabetic ketoacidosis compared with the drug’s benefit, according to briefing documents from the agency released Tuesday . The agency said that Lexicon has since changed its proposed indication to include those with chronic kidney disease, and is looking to win approval for those patients through post-hoc analyses of three Phase 3 clinical trials. Since the rejection five years ago , the FDA and Lexicon have gone back and forth over a path forward in type 1 diabetes. In May 2022, the drug was approved for use in adults with type 2 diabetes who have chronic kidney disease and other cardiovascular risk factors, to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visits. It’s sold under the brand name Inpefa. In December, the FDA told Lexicon that for the new indication, the company needed to provide a rationale for its proposed chronic kidney disease population, “with statistically and clinically meaningful evidence of glycemic control.” “The FDA also clarified that it considered the evidence of renal benefits of sotagliflozin to be exploratory and that a resubmission that relied on potential, but not demonstrated, renal benefits may be challenging,” the agency said. On Thursday, the agency will seek advice from its Endocrinologic and Metabolic Drugs Advisory Committee on several issues related to sotagliflozin’s benefits and risks, including on the evidence and uncertainty around diabetic ketoacidosis in those patients. The FDA also said it’s seeking perspective on Lexicon’s interest in applying evidence of benefits in patients with type 2 diabetes to patients with type 1 diabetes.

iStock, aprott While the regulator has not approved their use in type 1 diabetes, off-label prescribing for GLP-1 receptor agonists has sharply increased, according to researchers, who warn about the risk of serious side effects such as ketoacidosis. GLP-1 receptor agonists, including the blockbuster drugs semaglutide and tirzepatide, are increasingly being prescribed to patients with type 1 diabetes, despite having no FDA approval for this indication, according to a study published Wednesday in the Journal of the American Medical Association . From 2010 to 2023, the percentage of type 1 diabetes (T1D) patients that were given GLP-1 therapies surged from 0.3% to 6.6%. This increase was statistically significant, with a p-value less than 0.001, according to the study, which looked at electronic health record data from the healthcare database Epic Cosmos. Overall, the study included data from nearly 950,000 patients with T1D. Novo Nordisk’s semaglutide—marketed as Ozempic for type 2 diabetes (T2D) and Wegovy for weight loss—saw the biggest jump in T1D uptake, jumping from 0.2% in 2018 to 4.4% in 2023. Meanwhile, Lilly’s tirzepatide—approved as Mounjaro for T2D and Zepbound for obesity—was prescribed to 1.3% of T1D patients within a year of its initial approval in 2022 . Of note, the researchers pointed out that GLP-1 receptor agonists were most commonly prescribed to T1D patients with obesity. Aside from GLP-1 analogs, researchers also looked at the prescribing patterns of SGLT2 inhibitors—another popular class of T2D medication—and found similar trends. In 2010, 0.1% of T1D patients were treated with SGLT2 inhibitors, rising significantly to 2.4% in 2023. Corresponding author Hui Shao, of the Emory University Rollins School of Public Health, in a statement cautioned that the use GLP-1 and SGLT2 therapies in T1D “has increased sharply over the past decade,” despite their safety concerns in this indication—including ketoacidosis—a serious and potentially life-threatening complication that develops when the body fails to produce enough insulin. “This increase is likely to continue due to their significant benefits in weight management and cardiorenal protection observed in individuals with type 2 diabetes and the general obese population,” Shao said, noting that “urgent studies are needed” to better elucidate the benefits and risks of the GLP-1 and SGLT2 drug classes in T1D. Meanwhile, “caution should be used” when treating T1D patients with these medications. The warning from researchers comes amid the potential myriad of therapeutic benefits of GLP-1 receptor agonists beyond diabetes and obesity. Novo Nordisk in March won the FDA’s approval for Wegovy to lower the risk of cardiovascular death, heart attack and stroke in overweight or obese patients with cardiovascular diseases. Meanwhile, Lilly is also positioning Zepbound as an answer to obstructive sleep apnea , with an FDA decision expected as early as the end of the year. In addition, several studies have also detected signals of efficacy for a variety of other conditions, including Alzheimer’s disease , opioid overdose , tobacco use disorder and cirrhosis in metabolic dysfunction-associated steatotic liver disease .

Dive Brief:Lexicon Pharmaceuticals is selling rights to its only marketed drug outside of the U.S. and Europe amid a restructuring and push to expand into Type 1 diabetes.Viatris has agreed to pay $25 million upfront for rights to sotagliflozin, Lexicon said Wednesday. Lexicon will also be eligible for royalties and payments for meeting certain regulatory and sales milestones. The milestone payments could add up to about $200 million, Jefferies analyst Andrew Tsai wrote in a note to clients.Lexicon currently sells the drug under the brand name Inpefa to reduce the risk of cardiovascular complications among patients with heart failure or Type 2 diabetes, chronic kidney disease and other risk factors. The drug brought in revenue of $1.6 million in the second quarter of this year.Dive Insight:The deal is a boost to Lexicon, because the company was unlikely to try to sell Inpefa outside of the U.S. on its own, according to Jefferies Tsai. Meanwhile, the drug fits into plans by Viatris to expand its presence in the cardiovascular market.Lexicon is pinning its future hopes on broader use of the medicine. On Oct. 31, a Food and Drug Administration advisory panel will meet to review the drugs use in improving glycemic control in patients with Type 1 diabetes and chronic kidney disease who are also taking insulin.The FDA meeting follows a years-long battle by Lexicon to win approval in Type 1 diabetes. The FDA first rejected Lexicons application to sell sotagliflozin for Type 1 patients in March 2019 amid safety concerns and then denied the companys bid to reverse the decision. Rejections for similar drugs vying to win approval for Type 1 patients followed, including in 2020 for Eli Lillys empagliflozin, sold as Jardiance.Lexicon kept working with regulators and finally targeted a subset of Type 1 patients who also suffer from chronic kidney disease, a more difficult-to-treat population. The FDA will likely ask its advisory panel to focus on the threat of diabetic ketoacidosis, which has been associated with drugs in sotagliflozins class, Tsai said.Approval for the new use would open up a U.S. market worth about $400 million for sotagliflozin, per Tsai. He expects the stock to move as much as 40% in either direction based on the outcome of the meeting and the FDA briefing documents released beforehand.The struggles with sotagliflozin, which would be sold under the brand name Zynquista for diabetes, have played out in a larger restructuring of the company. In August, Lexicon said it was laying off staff as it readied for the potential launch of Zynquista. In September, the company lost its president and chief operating officer Jeff Wade, who had previously served as chief financial officer. '