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FDA staff raised familiar safety concerns about sotagliflozin as a treatment for type 1 diabetes (T1D) as the agency again considers an approval, though now for just a subset with chronic kidney disease (CKD).

On Thursday, members of the will help the FDA decide whether the available data support the dual SGLT1/SGLT2 inhibitor as an adjunct to insulin to improve glycemic control in T1D patients with mild-to-moderate CKD.

Despite the widespread adoption of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), the "risk of progression of CKD remains a significant issue for patients with T1D and comorbid CKD," FDA staff explained in released ahead of the meeting.

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 the SGLT2 inhibitors in these patients. And concerns remain surrounding the risks for diabetic ketoacidosis (DKA) and hypoglycemia with SGLT2 inhibitors in T1D.

Sotagliflozin has faced a difficult path in T1D. The FDA 5 years ago as an adjunct to insulin for adults with T1D after the agency determined that the drug's benefits were outweighed by DKA risks, even with a mitigation strategy in place during the drug's phase III trial program.

Primary support for the new proposed indication includes post-hoc data on the CKD population from three phase III studies -- inTandem1, inTandem2, and inTandem3 -- that formed the basis for sponsor Lexicon Pharmaceuticals' original application.

In the briefing documents, FDA's reviewers again raised concerns about DKA, along with the durability of sotagliflozin's treatment effect for the proposed indication in T1D with CKD -- defined here 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.

Together, the trials showed that sotagliflozin helped lower HbA1c over insulin alone. At week 24, pooled data from the identically designed inTandem1 and 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/min/1.73 m²:

• 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)

Differences compared with placebo shrank by week 52, but still favored sotagliflozin.

Given the general problems with post hoc analyses, conclusions cannot be considered definitive, FDA staff said, but added that "it appears that the treatment effect on A1C in patients with T1D and eGFR ≥60 mL/min/1.73 m² may approximate the treatment effect observed in the overall population (i.e., around 0.3 to 0.4%)."

Glycemic control came at the expense of excess DKA events, however, with a number needed to harm of 26 (95% CI 20-39) in the overall T1D population. Only seven incident cases of DKA occurred in the CKD subset, "with a nominal treatment difference not favoring sotagliflozin" in each eGFR subgroup of the pooled inTandem1/inTandem2 data.

Among the group with an eGFR of 45 to <60 mL/min/1.73 m², three events occurred among 47 participants randomized to sotagliflozin versus none in the 42 participants randomized to placebo.

"In the absence of additional clinical data, one cannot exclude the possibility that patients with T1D and mild-to-moderate CKD treated with sotagliflozin could have an increased risk of DKA compared to the risk observed in the overall [phase III trial] program," the FDA reviewers noted.

Committee members on Thursday will be asked to consider the efficacy data for sotagliflozin in T1D patients with mild-to-moderate CKD, discuss whether the magnitude of DKA risk has been sufficiently characterized, and weigh in on whether there is a greater benefit with respect to microvascular disease in patients with T1D with CKD (vs those without CKD) for any given HbA1C reduction.

As part of the new application, Lexicon also included data on sotagliflozin in type 2 diabetes patients with moderate-to-severe CKD. The SGLT1/SGLT2 inhibitor last year gained approval (marketed as Inpefa) to reduce the risk of cardiovascular death and urgent visits or hospitalization for heart failure in adults with heart failure, and also in adults with type 2 diabetes, CKD, and other cardiovascular risk factors.

The FDA advisors will be asked if the benefits in those populations can be extrapolated to support a benefit in T1D with CKD and whether other established advantages of sotagliflozin can be factored into the benefit-risk assessment for the proposed indication.

While the FDA is not required to follow the advice of its advisory committees, the agency typically does.

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