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An FDA panel on Thursday recommended against sotagliflozin as an adjunct to insulin for patients with type 1 diabetes (T1D) and mild-to-moderate chronic kidney disease (CKD).

With a vote of 11-3, the said the benefits of the dual SGLT1/SGLT2 inhibitor do not outweigh the risks in this patient population, with a majority of members saying the data provided by sponsor Lexicon Pharmaceuticals contained too much uncertainty.

"I have a really hard time voting to approve a drug when there is so little relevant data, and I very much want an adjunctive drug for my patients with type 1 diabetes," said committee chair Cecilia Low Wang, MD, of the University of Colorado in Aurora.

The FDA 5 years ago for the same indication but for the broader population of adults with T1D, due to the risks of diabetic ketoacidosis (DKA) observed in trials. The agency's decision followed a split vote from the Endocrinologic and Metabolic Drugs Advisory Committee.

"There is too much uncertainty about potentially fatal consequences and not enough new information or data to change the recommendation that this committee made in 2019," said Martha Nason, PhD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

The crux of the problem for most of the panelists stemmed from the fact that the primary support for the new proposed indication comprised post-hoc data from three phase III studies -- inTandem1, inTandem2, and inTandem3 -- that formed the basis for the original application.

Lexicon's new application included data on the trial participants who had CKD -- defined as those with an estimated glomerular filtration rate (eGFR) of 45 to <60 mL/min/1.73 m² or an eGFR ≥60 mL/min/1.73 m² and a urine albumin-creatinine ratio of ≥30 mg/g, which FDA considers as mild-to-moderate CKD.

The company also cited results from the phase III SCORED trial -- in which sotagliflozin was shown to demonstrate cardiovascular benefits among patients with type 2 diabetes and CKD -- and suggested that those benefits could be extrapolated to patients with T1D and CKD.

"I was on the 2019 panel, and I have the same frustrations now as I had then," said Marvin Konstam, MD, of the Tufts University School of Medicine in Boston.

"We don't have in our datasets of the trials any direct information about the clinical benefit to the patient," he added. "It's very frustrating because there's no easy way to go from glycemic control and jump all the way to mortality benefit."

Clear 'Unmet Need'

"There clearly is an unmet need," said Konstam.

"People are suffering," he added. "The question is whether this body of data shows us what they need, and I can't get from here to there."

While dapagliflozin (Farxiga) and empagliflozin (Jardiance) are approved for CKD in adults at risk of progression -- an indication that does encompass people with T1D and CKD -- treatment guidelines do not currently recommend these SGLT2 inhibitors for patients with T1D. And the labeling for the drugs notes they are not recommended for glycemic control in T1D and warns about the potential risk for DKA.

Several committee members, even those voting "no," indicated there may be a positive benefit/risk with the drug in patients with an eGFR ≥60 mL.

"I voted yes, but I was very conflicted," said Barbara Onumah, MD, of the Diabetes and Endocrine Wellness Center in Largo, Maryland, noting that patients with T1D have very limited treatment options and that SGLT2 inhibitors are already being used off-label in this population.

"My vote comes with the caution that this should be used with strict risk mitigation instructions for patients and providers," she said.

Study Details

The post hoc analysis from the InTandem trials did shows that sotagliflozin helped lower HbA1c over insulin alone. At week 24, pooled data from the identically designed inTandem1/inTandem2 trials suggested significant declines in HbA1C with the 200 mg and 400 mg daily doses of sotagliflozin, respectively, versus placebo among the groups with an eGFR ≥60 mL:

• eGFR ≥90: least squares mean change of -0.28 (95% CI -0.39 to -0.17) with both doses
• eGFR 60 to <90: -0.39 (95% CI -0.50 to -0.30) and -0.46 (95% CI -0.56 to -0.36)
• eGFR 45 to <60: -0.27 (95% CI -0.64 to 0.11) and -0.21 (95% CI -0.57 to 0.14)

But that glycemic control came with excess DKA events, with a number needed to harm of 26 (95% CI 20-39) in the overall T1D population. In briefing documents ahead of the meeting, FDA staff noted that seven incident cases of DKA occurred in the CKD subset, "with a nominal treatment difference not favoring sotagliflozin" for each eGFR subgroup in the pooled inTandem1/inTandem2 data.

Among the group with an eGFR of 45 to <60 mL, three events occurred among 47 participants randomized to sotagliflozin versus none in the 42 participants randomized to placebo -- a finding FDA reviewers said was "not reassuring."

That risk of DKA in this patient population was a critical factor among panel members who voted against sotagliflozin.

"I've been thinking about this for weeks," said Connie Newman, MD, of the New York University School of Medicine in New York City, who agreed that sotagliflozin seems to provide a modest benefit in patients with an eGFR ≥60 mL. "What I'm struggling with is how to balance that against the real risk of DKA."

"DKA is life-threatening and is a very serious adverse event," she pointed out. "Whether it has been properly characterized in the different eGFR groups is still uncertain. If we had more data we would know if there is any difference -- but I don't think we see that with the data available."

While the FDA is not bound by the recommendations of its advisory committees, it typically follows their advice.

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