FDA Reviewers Express Concerns Over Sotagliflozin's Safety for Type 1 Diabetes Patients with CKD
核心洞察
FDA staff have raised concerns regarding the safety of sotagliflozin for type 1 diabetes (搜索) patients with chronic kidney disease (搜索), particularly regarding the risk of diabetic ketoacidosis (搜索).
The Endocrinologic and Metabolic Drugs Advisory Committee will assist the FDA in determining if the data supports sotagliflozin as an adjunct to insulin for glycemic control in T1D patients with mild-to-moderate CKD.
Sotagliflozin previously faced rejection due to concerns about DKA risks, and the FDA reviewers are still questioning the durability of its treatment effect in T1D patients with CKD.
The FDA is again considering sotagliflozin as a treatment for type 1 diabetes (搜索) (T1D), but this time for a subset of patients with chronic kidney disease (搜索) (CKD). However, FDA staff have raised familiar safety concerns about the drug, particularly regarding the risk of diabetic ketoacidosis (搜索) (DKA).
On Thursday, members of the Endocrinologic and Metabolic Drugs Advisory Committee will convene to help the FDA decide whether the available data support the dual SGLT1 (搜索)/SGLT2 (搜索) inhibitor as an adjunct to insulin to improve glycemic control in T1D patients with mild-to-moderate CKD.
The Need for New Treatments
Despite the widespread use 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 briefing documents. While dapagliflozin (Farxiga) and empagliflozin (Jardiance) are approved for CKD in adults at risk of progression, treatment guidelines do not currently recommend SGLT2 (搜索) inhibitors in these patients due to concerns surrounding DKA and hypoglycemia.
Sotagliflozin's Troubled Past
Sotagliflozin has faced previous challenges in gaining approval for T1D. The FDA rejected the drug 5 years ago as an adjunct to insulin for adults with T1D, citing that the drug's benefits were outweighed by DKA risks, even with a mitigation strategy in place during the phase III trial program.
New Data for CKD Subgroup
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.
Efficacy and Safety Data
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's Role
Committee members 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 (搜索)/SGLT2 (搜索) 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.