Sotagliflozin Receives Split FDA Vote
Drug/Device: Sotagliflozin - Drug
Sponsor: Sanofi Aventis, U.S., LLS
Committee: Endocrinologic and Metabolic Drugs Advisory Committee
Indications：an adjunct to insulin in adult patients with type 1 diabetes
Question 1: Does the available data suggest that the benefits outweigh the risks and support approval of sotagliflozin, administered orally once daily, as an adjunct to insulin to improve glycemic control in adults with type 1 diabetes mellitus?
Vote Results: Yes 8 No 8 Abstain 0
Related Documents:
Sotagliflozin Background:
The application seeks marketing approval for sotagliflozin as an adjunct to insulin therapy to improve glycemic control in adult patients with type 1 diabetes (T1DM). Evidence from three phase 3 randomized trials (309, 310, and 312) were included to support the proposed indication. Design of studies 309 and 310 were identical, aimed at demonstrating superiority of either 200 mg or 400 mg of sotagliflozin versus insulin only on change of HbA1c (in percentage) from baseline. Study 312 had the same patient characteristics but differed in design by eliminating an insulin optimization period and having a shorter follow-up period. The primary objective of study 312 was to demonstrate superiority of 400 mg of sotagliflozin versus placebo in attaining “net-benefit”, which is a composite of the proportion of patients with HbA1c < 7.0% at Week 24 and no episode of severe hypoglycemia and no episode of diabetic ketoacidosis (DKA) after randomization.
Unique Challenges:
Statistical Analysis
For analysis of the continuous efficacy endpoints, a mixed-effect model with repeated measures (MMRM) under the restricted maximum likelihood method for estimation on the 24-week core treatment period was applied by the sponsor. Binary or composite efficacy endpoints were analyzed using the Cochran-Mantel-Haenszel (CMH) test.
Multiplicity in statistical testing of efficacy endpoints in studies 309 and 310 were addressed by first grouping sequential tests into 7 families each of which had two parallel tests corresponding to two sotagliflozin doses vs placebo for each endpoint, taking 2-sided p-values of ≤ 0.025 as achieving statistical significance. Multiplicity was accounted in study 312 by a “step-down” testing approach.
To address missing values, the applicant conducted a wash-out analysis that assumed, after discontinuation, subjects discontinued from the experimental arm will exhibit a response similar to subjects in the placebo arm. The imputations were performed for HbA1c, body weight, and FPG and the final results for these traits were based on imputed data.
Efficacy and safety
Superiority was achieved for the primary endpoint in all three studies. A statistically significant treatment effect of ~ 0.3- 0.4% reduction of HbA1c from baseline in subjects taking sotagliflozin was observed. Aligned with the primary efficacy findings, more subjects achieved HbA1c < 7% in both of the sotaglifozin groups than in placebo. The long-term extension period was used to support the primary efficacy analyses for studies 309 and 310.
In terms of safety, there were more DKA events in the sotagliflozin groups than in the placebo groups, however severe hypoglycemia overall did not show a significant difference between sotagliflozin and placebo. The FDA noted that although the applicant defined endpoint for study 312 achieved statistical significance, this was primarily driven by HbA1c reduction and not reduction in DKA, as most DKA events occurred among subjects who did not achieve A1c < 7% at the end of the treatment.
Risk
According to the FDA estimate, sotagliflozin was associated with an approximately 8-fold increase in DKA risk vs. placebo (95% CI: [3.1, 19.9]). Subgroup analyses showed a consistently elevated DKA risk associated with sotagliflozin with estimated hazard ratios ranging from 4 to 11. Subgroup analyses also revealed that subjects with characteristics such as prior DKA history are at highest risk of DKA, irrespective of treatment allocations. DKA risk associated with SGLT2 inhibitors among T1DM patients was further explored through post-marketing data from the FDA Adverse Event Reporting System (FAERS) database.
Benefit –risk analysis
The applicant attempted to partially assess the overall benefit-risk profile through the use of a composite endpoint which the applicant coined as “net-benefit.” However, the FDA expressed the concerns about the clinical significance of the composite endpoint, as it may not capture all of the important benefits and risks. While they are profoundly interested in the methodology taken, such assessments are less likely to inform approval decisions if the benefits and risks are not framed in a clinically meaningful way. As an example, FDA presented the case of another antihyperglycemic agent that is now approved for T1DM. Pramlintide was initially found to be associated with an increased risk of severe hypoglycemia in combination with insulin relative to insulin alone. Further assessment identified a patient population and method of use that generated a favorable benefit risk profile thereby supporting an approval decision.