Summary Basis of Decision for Steglatro

Clinical Pharmacology

Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2 reversibly, ertugliflozin (the active ingredient of Steglatro) reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

In this New Drug Submission, the clinical pharmacology included reports on human pharmacokinetic and pharmacodynamic studies.

Pharmacokinetics

The pharmacokinetics of ertugliflozin is similar in healthy subjects and patients with type 2 diabetes mellitus. In healthy subjects administered multiple dose once-daily ertugliflozin, the steady state mean plasma (area under the concentration time curve; AUC) and maximum plasma concentration (C_max) were 398 ng^.hr/mL and 81.3 ng/mL, respectively, with 5 mg ertugliflozin once daily treatment, and 1,193 ng^.hr/mL and 268 ng/mL, respectively, with 15 mg ertugliflozin once daily treatment. Steady state is reached after 4 to 6 days of once-daily dosing with ertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up to 10% to 40% following multiple dose administration. Plasma C_max and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg to 300 mg and following multiple doses from 1 mg to 100 mg once daily. The apparent steady state volume of distribution of ertugliflozin was 85.5 L with a plasma protein binding of 93.6%.

Pharmacodynamics

Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following single and multiple dose administration of ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion. Urinary glucose excretion with ertugliflozin also results in increases in urinary volume.

Cardiac electrophysiology

In a double-blind, randomized, placebo- and positive-controlled, crossover study (P010/1025) conducted in 42 healthy subjects, there was no evidence of a treatment-related effect on the QTcF (corrected using Fridericia's formula) interval, the QRS duration, the PR interval, or ventricular heart rate with a single supratherapeutic oral dose of ertugliflozin 100 mg (6.7 times the maximum recommended dose). Ertugliflozin was however associated with postural hypotension in some subjects. This effect is likely to be a result of volume depletion secondary to the osmotic diuresis produced by ertugliflozin.

In patients with a history of both type 2 diabetes mellitus and mild to moderate hypertension with inadequate glycemic and blood pressure control, there was a statistically significant decrease from baseline in blood pressure. The blood pressure-lowering effect of ertugliflozin is expected to be beneficial in many patients, but it does raise concerns regarding postural hypotension and syncope in some recipients. A pronounced diuretic effect was observed with all doses of ertugliflozin. The magnitude of the diuretic effect was greater with all doses of ertugliflozin than with hydrochlorothiazide.

Renal impairment

The efficacy of Steglatro was assessed separately in a dedicated study (Study P001/1016) of diabetic patients with moderate renal impairment (468 patients with estimated glomerular filtration rate [eGFR] ≥30 to <60 mL/min/1.73 m²).

In this study, 202 patients exposed to Steglatro (5 mg or 15 mg) had an eGFR between 45 and less than 60 mL/min/1.73 m² and 111 patients exposed to Steglatro (5 mg or 15 mg) had an eGFR between 30 and less than 45 mL/min/1.73 m².

Steglatro did not show efficacy in this study. In patients with moderate renal impairment, the HbA1c reductions from baseline to Week 26 were not significantly different between placebo and Steglatro 5 mg or 15 mg. Therefore, Steglatro should not be initiated in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² and should be discontinued if eGFR falls below 45 mL/min/1.73 m². Steglatro is contraindicated in patients with eGFR less than 45 mL/min/1.73 m².

For further details, please refer to the Steglatro Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Steglatro was established primarily on the basis of seven Phase III multicentre, randomized, double-blind, placebo- or active comparator-controlled, clinical trials involving 4,863 patients with type 2 diabetes mellitus. Of these seven Phase III placebo- and active-controlled efficacy and safety trials, only four were considered pivotal by Health Canada to support the indications sought. Therefore, market authorization was based on these four trials which included three placebo-controlled trials (P003/1022, P007/1017, and P006/1015) and one active comparator-controlled trial (P002/1013). The remaining clinical trials were considered by Health Canada as supportive trials.

In all three Phase III placebo-controlled trials, the main treatment period was 26 weeks. For the active-controlled trial, the treatment period was 52 weeks. The placebo-controlled trials (i.e., 26-week treatment periods [Phase A]) were completed for the evaluation of efficacy. However, long-term safety extensions (i.e., 26-78 week treatment periods [Phase B]) were either ongoing or completed without final analyses available at the time of this submission.

Across all four pivotal Phase III trials, the mean age of the study population ranged from approximately 56 to 59 years. Proportions of patients aged ≥65 years ranged from 16% to 30%. The proportion of males ranged from 46% to 57%. The proportion of Caucasian patients ranged from 66% to 84% across studies, Asian patients from 9% to 20%, and Black patients from 2% to 10%. Mean baseline body mass index ranged from 31 kg/m2 to 33 kg/m². The mean baseline estimated glomerular filtration rate (eGFR) was similar across these Phase III trials, ranging from 87 to 91 mL/min/1.73 m².

In the monotherapy trial (P003/1022), a total of 461 treatment-naïve patients with inadequately controlled type 2 diabetes mellitus and (HbA1c between 7% and 10.5%) were randomized (1:1:1) to receive either Steglatro 5 mg, Steglatro15 mg, or a placebo administered once daily over 26 weeks. In this trial, mean duration of diabetes at screening was five years.

In the add-on to metformin trial (P007/1017), a total of 621 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 10.5%) on metformin monotherapy (≥1500 mg/day for ≥8 weeks) were evaluated for efficacy of Steglatro in combination with metformin. In this trial, patients were randomized (1:1:1) to receive Steglatro 5 mg, Steglatro 15 mg, or a placebo administered once daily in addition to continuation of background metformin therapy over 26 weeks. Mean duration of diabetes at screening was eight years.

In the add-on to metformin plus sitagliptin trial (P006/1015), a total of 463 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 10.5%) on metformin (≥1500 mg/day for ≥8 weeks) and sitagliptin 100 mg once daily were evaluated for efficacy of Steglatro in combination with metformin and sitagliptin. In this trial, patients were randomized (1:1:1) to receive Steglatro 5 mg, Steglatro 15 mg, or a placebo administered once daily in addition to continuation of background metformin and sitagliptin therapy over 26 weeks. Mean duration of diabetes at screening was 9.5 years.

The primary efficacy endpoint for all three Phase III trials (P003/1022, P007/1017, and P006/1015) was the difference in HbA1c between baseline and week 26. A consistent and clinically meaningful mean reduction from baseline HbA1c at endpoint was observed across the three Phase III trials. Mean reductions from baseline HbA1c varied from -0.73% to -0.79% and from -0.86% to -0.96% for Steglatro 5 mg and Steglatro 15 mg, respectively. The reductions were statistically significantly greater than placebo (p<0.001), with placebo adjusted changes ranging from -0.69% to -0.99% for Steglatro 5 mg and from -0.76% to -1.16% for Steglatro 15 mg. Decreases in HbA1c were generally paralleled by the proportions of patients achieving a target HbA1c of <7.0%, which ranged from 28% to 40%. Overall, effect sizes were considered modest and similar to other products in this class of antidiabetic agent. The robustness of these results was supported by sensitivity and subgroup analyses.

In the active-controlled trial (P002/1013), a total of 1,326 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 9%) on metformin monotherapy was evaluated for efficacy of Steglatro in combination with metformin. In this trial, patients were randomized (1:1:1) to receive Steglatro 5 mg, Steglatro 15 mg, or glimepiride administered once daily in addition to continuation of background metformin therapy. Glimepiride was initiated at 1 mg/day and titrated up to a maximum dose of 6 or 8 mg/day or a maximum tolerated dose or down-titrated to avoid or manage hypoglycemia. The mean daily dose of glimepiride was 3 mg. Total duration was 52 weeks. In the study, mean duration of diabetes at screening was 7.5 years.

In the active-controlled trial, only the Steglatro 15 mg treatment arm was non-inferior to the glimepiride arm as the difference fell within the prespecified non-inferiority margin of 0.3%. The long-term data provided by this study was considered sufficient to evaluate the long-term efficacy of Steglatro as both doses demonstrated a clinically meaningful and persistent reduction in HbA1c over 52 weeks.

Secondary endpoints for glycemic control, including reduction from baseline in fasting plasma glucose and post-prandial plasma glucose, were generally consistent and support the primary efficacy results. The effect of Steglatro on reduction in body weight was also a secondary endpoint and patients treated with Steglatro experienced modest placebo adjusted reductions in body weight from baseline ranging from -1.60 kg to -2.16 kg. Change from baseline in sitting systolic blood pressure was also measured in all trials as a secondary efficacy endpoint and generally consistent trend of reduction from baseline was observed with Steglatro 15 mg and 5 mg across the studies regardless of between-study differences in background medication and clinical trial designs.

Indication

The New Drug Submission for Steglatro was filed by the sponsor with the following indication:

Steglatro as monotherapy is indicated for use as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus for whom metformin is inappropriate due to contraindications or intolerance; and as add-on combination with metformin, or with sitagliptin (alone or with metformin) to improve glycemic control in adult patients with type 2 diabetes mellitus when metformin alone or the existing therapy listed above, along with diet and exercise, does not provide adequate glycemic control.

Health Canada approved the following indication:

Steglatro is favourable as monotherapy, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes mellitus for whom metformin is inappropriate due to contraindications or intolerance; and as add-on combination with metformin, or with metformin and sitagliptin to improve glycemic control in adult patients with type 2 diabetes mellitus when the therapy listed above, along with diet and exercise, does not provide adequate glycemic control.

For more information, refer to the Steglatro Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A total of 3,409 patients with type 2 diabetes mellitus were exposed to Steglatro in seven Phase III clinical trials to evaluate the safety of Steglatro alone or in combination with other antidiabetic agents.

The primary assessment of safety and tolerability was conducted in a pooled analysis of three Phase III placebo-controlled clinical trials (see Clinical Efficacy) where 1,544 patients were randomized and received at least one dose of study medication.

In the placebo-controlled trials, adverse events reported in ≥2% of patients and more frequently in Steglatro-treated patients than placebo-treated patients included female and male genital mycotic infections, urinary tract infections, headache, increased urination, nasopharyngitis, back pain, and decreased weight. The occurrence of hypoglycemia events when Steglatro was administered as monotherapy was relatively low (2.6%), with higher rates reported in combination with metformin (≤7.8%), and sitagliptin plus metformin (≤4.5%). The incidence of severe hypoglycemia was relatively low and similar between treatment arms.

The most common adverse events leading to discontinuation in Steglatro-treated patients were genital mycotic infections. There were numerically more patients in the combined Steglatro treatment arms that discontinued due to events related to renal and urinary disorders. The proportions of patients with severe adverse events, adverse events resulting in discontinuation, and serious adverse events were of low and comparable incidence between treatment arms.

With regard to adverse events of special interest, there were generally no differences between treatment groups, and there were no unexpected findings. The adverse events of genital mycotic infection were higher in the Steglatro-containing treatment groups. Female patients experienced more adverse events than males, especially vulvovaginal mycotic infections. There was no clinically relevant difference in the frequencies of patients with decreased renal function, hypersensitivity reactions or hepatic adverse events across treatment groups. Across the Steglatro clinical program, events of ketoacidosis were identified in 3 of 3,409 (0.1%) Steglatro-treated patients, with no events occurring in the non-Steglatro treatment arm. The incidence of volume depletion events was low (<2%) and not notably different across the Steglatro and placebo groups. However, patients with eGFR <60 mL/min/1.73 m², patients ≥65 years of age and patients on diuretics had a higher incidence of volume depletion. The frequency of marked laboratory abnormalities was low and comparable between the treatment groups. Total cholesterol, low-density lipoprotein cholesterol, hemoglobin and serum phosphate were elevated in patients treated with Steglatro relative to placebo.

Patients with moderate renal impairment treated with Steglatro showed increased serum creatinine and decreased eGFR compared to placebo. The proportions of patients with >30% decrease in eGFR from baseline were higher in the Steglatro 5 mg and 15 mg groups compared with the placebo group. A higher incidence of renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure) was seen in patients with moderate renal impairment; events were reported by 2.5%, 1.3%, and 0.6% of patients treated with Steglatro 5 mg, 15 mg, and placebo, respectively. Most of the patients with renal-related adverse events are from Stage 3B stratum, suggesting that patients with an eGFR ≥30 and <45 mL/min/1.73 m² have a higher risk of developing renal-related adverse events when treated with Steglatro. Additionally, the frequency of patients with eGFR decreases >30% from baseline are higher in the Stage B stratum compared to the Stage A stratum.

One concerning safety finding was identified across the Steglatro clinical program. A numerical imbalance in the number of patients who experienced lower limb amputations was observed in the Steglatro arm compared to the non-Steglatro arm. These events were reported in 1 of 1,450 (0.1%) patients in the non-Steglatro arm, 3 of 1,716 (0.2%) in the Steglatro 5 mg arm, and 8 of 1,693 (0.5%) in the Steglatro 15 mg arm. The most frequently reported procedure was toe amputation, which was the surgical procedure for 8 of the 11 Steglatro-treated patients, while the remaining 3 patients had lower limb amputations. All patients had pre-existing risk factors, such as peripheral neuropathy, peripheral artery disease, diabetic foot, and/or current or past smoking history. The most common precipitating medical events included those related to limb infection, peripheral artery disease, and gangrene. An increased risk for lower limb amputations has been seen with another SGLT2 inhibitor and carries a boxed warning for the risk of lower limb amputations in patients with established cardiovascular disease or at risk for cardiovascular disease. The basis for that comes from findings of increased risk based on a larger database, cardiovascular outcomes trial (CVOT). Although the event rate is relatively low, the data are sufficiently concerning to include this potential risk as a warning and precaution for Steglatro-containing products to inform prescribers and patients of this risk and recommend monitoring for associated signs and symptoms. The available data are not sufficient to warrant a Serious Boxed Warning but additional data from the ongoing CVOT will inform whether further labeling would be appropriate in the future. The product monograph was updated accordingly.

In accordance with the 2008 Food and Drug Agency (FDA) Guidance Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, the sponsor has conducted a program-wide cardiovascular meta-analysis to support the cardiovascular safety of Steglatro. Given the importance of maintaining the integrity of the ongoing CVOT, neither the detailed results of the cardiovascular meta-analysis report nor any other results from the CVOT have been included in this new drug submission. In lieu of the detailed cardiovascular meta-analysis report, an attestation from the external data monitoring committee was submitted to Health Canada. Based on data from nine clinical trials (including interim data from Trial P004/1021, their dedicated CVOT), the upper bound of the adjusted 95% confidence interval for the hazard ratio for the composite MACEplus endpoint was <1.8. Per agreement with the FDA and the European Medicines Agency (EMA), this cardiovascular outcomes trial will remain blinded until its completion. The completion of the CVOT is planned for the end of 2019 with a prespecified interim analysis at approximately the end of 2018. In order to assess the cardiovascular safety of Steglatro, results of the ongoing cardiovascular outcomes study have been requested as they become available.

The remaining safety concerns and uncertainties are considered to be adequately addressed through warnings and restrictions in the Steglatro Product Monograph.

A risk management plan was deemed acceptable by Health Canada. Risk minimization measures include ongoing post-marketing surveillance and adequate labelling of all identified safety issues.

For more information, refer to the Steglatro Product Monograph, approved by Health Canada and available through the Drug Product Database.