Regulatory Decision Summary for Steglatro
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
This new drug submission was filed to obtain marketing authorization for the use of Steglatro (ertugliflozin tablets), as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes mellitus (T2DM) for whom metformin is inappropriate due to contraindications or intolerance, or who are inadequately controlled on their existing antidiabetic therapy (add-on combination with metformin or add-on combination with metformin and sitagliptin).
Why was the decision issued?
The efficacy of Steglatro was adequately supported. Efficacy was assessed in 7 Phase 3 clinical trials. Across these trials, 3,413 patients were randomized to receive ertugliflozin, 766 patients randomly assigned to receive placebo and 684 to receive active comparators during the main treatment period, ranging from 26 to 52 weeks. Steglatro improved glycemic control when given as monotherapy or added to the regimens of patients inadequately controlled on either metformin, or metformin and sitagliptin. Based on the primary efficacy endpoint in 3 Phase 3 studies considered as pivotal by Health Canada, statistically significant placebo-adjusted reductions in glycated hemoglobin (HbA1c) ranged from -0.69% to -0.99% for ertugliflozin 5 mg and from -0.76% to -1.16% for ertugliflozin 15 mg. In the active comparator study, non-inferiority was shown only for ertugliflozin 15 mg dose compared to glimepiride but with clinically relevant reductions in HbA1c for both doses maintained throughout the 52-week treatment period. Other secondary glycemic control endpoints, including post-prandial glucose and fasting plasma glucose reductions, were generally consistent with the HbA1c results. Modest reductions in body weight and sitting systolic blood pressure were observed with Steglatro. In the dedicated moderate renal impairment trial, HbA1c reductions from baseline at week 26 in the overall cohort (Stage 3 Chronic Kidney Disease [CKD] subjects) were not significantly different in the ertugliflozin 5 mg and 15 mg groups compared to placebo. Therefore, Steglatro should not be initiated in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 and should be discontinued if eGFR falls below 45 mL/min/1.73m2.
The safety of Steglatro was adequately supported based on the data from 3409 patients exposed to ertugliflozin in the Phase 3 studies. The primary assessment of safety was conducted in a pooled analysis of Phase 3 placebo-controlled clinical trials where 1,544 subjects were randomized and received at least 1 dose of study medication. The most frequent adverse event (AE) seen with Steglatro was genital mycotic infections. Other safety concerns for ertugliflozin include increased urination, urinary tract infections, hypoglycemia, decreased renal function, increases from baseline in hemoglobin, serum phosphate, low density lipoprotein-cholesterol (LDL-C) and total cholesterol, hypotension/volume depletion, and ketoacidosis. Patients with moderate renal impairment treated with ertugliflozin showed increased serum creatinine and decreased eGFR compared to placebo. In addition, a higher incidence of renal-related adverse reactions (for example, acute kidney injury, renal impairment, acute prerenal failure) was seen in patients with moderate renal impairment (particularly those with an eGFR ≥30 and <45 mL/min/1.73m2) treated with ertugliflozin. The overall safety profile of Steglatro was comparable to that of the currently approved sodium-glucose co-transporter (SGLT2) inhibitors. However, cases of lower limb amputation were observed in the clinical trials. While the increased risk for lower limb amputations with ertugliflozin was based on a limited number of events, the imbalance was particularly concerning given the finding of a similar risk for these events with another member of the class. In order to assess the cardiovascular safety of Steglatro, results of the ongoing cardiovascular outcomes study have been requested as they become available. Steglatro was not studied in pediatric patients, pregnant or breast-feeding patients, and patients with severe hepatic or renal impairment. Limited data were available for patients over 75 years of age.
Safety concerns and uncertainties were considered to be adequately addressed through warnings and restrictions in the Canadian Product Monograph. A risk management plan was deemed acceptable by the Marketed Health Products Directorate. Risk mitigation was achieved by including standard ongoing post-marketing surveillance and adequate labelling of all identified safety issues. Based on the available data, Steglatro was considered to have significant benefits on glycemic control in patients with T2DM with acceptable risk.
The overall benefit-harm-uncertainty profile of Steglatro is considered favourable.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.