The Food and Drug Administration (FDA)’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 14 to 2 against the approval of empagliflozin 2.5mg as an adjunct to insulin for adults with type 1 diabetes, stating that the risk/benefit profile of the drug does not support approval.
Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, works by reducing the renal reabsorption of filtered glucose, thereby increasing urinary glucose excretion. The supplemental New Drug Application (sNDA) included data from the phase 3, randomized, double-blind, placebo-controlled EASE program, which determined empagliflozin 2.5mg in combination with insulin led to a statistically significant reduction in HbA1c (0.28%) vs insulin with a matched placebo. Additionally, secondary end points of the EASE trials showed reductions in weight (1.8kg) and systolic blood pressure (2.1mmHg), vs insulin with a matched placebo.
In meeting documents, the FDA pointed out limitations in the available evidence submitted for review. Specifically, they noted that the applicants only submitted data from one phase 3 trial evaluating the 2.5mg dose (EASE-3), while another study (EASE-2) only evaluated higher doses of empagliflozin (10mg and 25mg). “The size of the database submitted to support safety of the 2.5mg dose is relatively small and of short duration. Only 241 patients were randomized to 2.5mg in a single phase 3 trial with 225 patients being on-treatment at Week 26,” the panel stated.
Regarding safety, results from the clinical trial program showed the frequency of adverse events in the empagliflozin plus insulin treatment arm were similar to that observed in the insulin plus placebo arm. Moreover, the incidence of diabetic ketoacidosis (DKA) was comparable between the treatment arms. However, the panel again noted the limitation in data, stating that “these data are derived from only 1 trial of only 26 weeks duration, and the small number of DKA events limits the ability to discern meaningful differences between groups.”
Commenting on the meeting outcome, Mohamed Eid, MD, MPH, MHA, VP, Clinical Development & Medical Affairs, Cardio-Metabolism & Respiratory Medicine, Boehringer Ingelheim Pharmaceuticals, Inc, said, “[…] We see today’s meeting as an important means of elevating the discussion around the challenges of managing blood sugar levels for those with type 1 diabetes and the need for new treatment options. We continue to believe the totality of data from the EASE program indicates a favorable benefit-risk profile for empagliflozin 2.5mg in adults with type 1 diabetes and look forward to continuing to work with the FDA in this review process.”
Although not bound by the committees’ recommendations, the FDA does take them into consideration when making decisions on approval.
Empagliflozin (Jardiance; Boehringer Ingelheim and Lilly) is currently approved for use as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) and also to reduce the risk of cardiovascular death in adult patients with T2DM and established cardiovascular disease.
The product is available in 10mg and 25mg strength tablets.