As the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes, Lexicon’s sotagliflozin has tantalizing potential. But getting the pill to pass muster with the FDA has been problematic.
The latest setback with the U.S. regulator came five weeks ago when Lexicon pulled back a submission for approval in Type 2 diabetes patients with heart failure. That came on top of an FDA rejection for sotagliflozin in 2019 in Type 1 diabetes.
All the while, sotagliflozin has generated promising data. Saturday, at the American College of Cardiology (ACC) meeting in Washington, D.C., Lexicon highlighted results from a trial of sotagliflozin in Type 2 diabetes and kidney disease patients that showed the drug not only reduced heart failure by 26% but that it also provided a reduction in the risk of heart attack and stroke.
A follow-up analysis of the trial revealed consistent reductions in major adverse cardiovascular events (MACE) in two subgroups—a 21% reduction in MACE in patients with cardiovascular disease and a 26% reduction in MACE in those without cardiovascular disease.
For Lexicon Chief Medical Officer Craig Granowitz, M.D., Ph.D., the benefit of sotagliflozin in heart failure is no surprise. It’s a class effect that has been shown for other SLGT2 inhibitors, such as Eli Lilly and Boehringer Ingelheim’s Jardiance. But the heart attack and stroke findings could prove an advantage for the medicine against its rivals, Lexicon figures.
“What was seen in this study, which hasn’t been seen with SGLT2 inhibitors, is a benefit in reducing heart attack and stroke, whether or not that patient has had a prior heart attack or stroke or has another diagnosis related to cardiovascular disease,” Granowitz said. “That is why the ACC selected this as a presentation today.”
The study chair for the SCORED trial, Deepak Bhatt, M.D., a professor at Harvard Medical School, also noted a consistent benefit for sotagliflozin in three other vascular disease groups—coronary artery disease, cerebral vascular disease and peripheral artery disease.
“The data are very strong,” Bhatt said. “I hope (sotagliflozin) gets approved. I think it might be the best in class.”
Bhatt said it’s too early to tell whether there are added benefits from sotagliflozin because of its dual action, but upcoming studies will leave no doubt.
“Is there anything beyond SGLT2 from the SGLT1?" Bhatt asked. “There’s some randomization data that suggests there might be independent benefits.”
By pooling data from phase 2 and phase 3 trials testing sotagliflozin in more than 20,000 combined patients in both Type 1 and Type 2 diabetes, Lexicon has shed more light on the drug’s benefits.
“If you look at those (other) studies, which were not designed to look at cardiovascular events—they were just designed to look at blood sugar management—you still see a reduction in stroke and heart attack,” Granowitz said. “That’s never been seen before. That’s pretty remarkable.”
In the field of diabetes candidates, sotagliflozin is distinguished by its ability to block SGLT2 in the kidneys and SGLT1 in the intestines. Sanofi recognized the drug’s potential in 2015, paying Lexicon $300 million upfront and committing $1.4 billion in milestone payments to get a piece of the action.
But in 2019, while Lexicon gained approval in Europe to treat Type 1 diabetes patients who can’t achieve adequate control of their blood sugar with insulin, it had no such luck in the same indication with the U.S. regulator.
After an advisory committee deadlocked 8-8 on whether to recommend a nod, the FDA rejected it twice—in March of 2019 and upon appeal nine months later, citing the risk of diabetic ketoacidosis.
Also in 2019—after some mixed trial results—Sanofi bailed on the project, paying $260 million to return full rights to Lexicon.
Three years after losing the Type 1 bid, Lexicon has not given up on an approval in that indication, Granowitz said.