Regulatory Decision Summary for Segluromet
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 (NDS) was filed to obtain marketing authorization for the use of Segluromet (ertugliflozin and metformin hydrochloride) fixed dose combination (FDC) tablets, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes mellitus 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?
Ertugliflozin (Steglatro) and metformin (Glucophage) are both antihyperglycemic medications for adults with type 2 diabetes mellitus (T2DM). In the current Canadian clinical treatment paradigm, patients with T2DM are first treated with metformin and if they are inadequately controlled, additional therapeutic options are prescribed to control blood glucose levels, as measured by glycated hemoglobin (Hb) A1c levels. Ertugliflozin is one of many therapeutic options that can be added to metformin to improve glycemic control in T2DM.
The current application proposes a fixed dose combination (FDC) of ertugliflozin and metformin hydrochloride tablets (Segluromet) at four different dosage strengths: 2.5 mg/500 mg, 2.5 mg/1,000 mg, 7.5 mg/500 mg and 7.5 mg/1,000 mg. The proposed Segluromet FDC tablets were not used in Phase III clinical studies. However, the bioavailability of Segluromet was comparable to individual ertugliflozin and metformin hydrochloride tablets administered together at the same respective doses.
The efficacy of ertugliflozin was adequately supported across the clinical trials, which 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. Ertugliflozin 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 the percentage of HbA1c ranging 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 with background metformin therapy, non-inferiority was shown only for ertugliflozin 15 mg dose compared to glimepiride (mean daily dose 3 mg) 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 ertugliflozin.
The safety of ertugliflozin was adequately supported based on the data from 3,409 patients exposed to ertugliflozin (alone or with metformin) 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 ertugliflozin 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.
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. Segluromet 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. Additional safety data will be available following completion of the companys ongoing cardiovascular clinical trial.
The overall safety profile of Segluromet was comparable to that of the currently approved sodium-glucose co-transporter 2 (SGLT2) inhibitor / biguanide combination products, and no new or synergistic adverse reaction was observed relative to what has been observed with each mono component of Segluromet.
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, Segluromet was considered to have significant benefits on glycemic control in patients with T2DM with acceptable risk.
The overall benefit-harm-uncertainty profile of Segluromet is considered favourable.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.