Regulatory Decision Summary for Jardiance
Review decision
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.
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What was the purpose of this submission?
At the time of submission, Jardiance was indicated in adults with type-2 diabetes mellitus (T2DM) as an adjunct to diet and exercise, to improve glycemic control with or without metformin, and along with standard of care therapy, to reduce the incidence of cardiovascular death. It was also indicated in adults as an adjunct to standard of care therapy for the treatment of heart failure with reduced ejection fraction (HFrEF) - left ventricular ejection fraction (LVEF) ≤40%. This Supplemental New Drug Submission (SNDS) was filed to expand the heart failure (HF) indication, in order to include adult HF patients who have preserved ejection fraction (HFpEF) – LVEF >40%, thereby targeting all chronic HF patients.
Why was the decision issued?
The pivotal study in the Supplemental New Drug Submission (SNDS), EMPEROR-Preserved, evaluated the efficacy and safety of empagliflozin 10 milligrams (mg) as an add-on to standard of care treatment in adult patients with chronic HFpEF - LVEF >40%. This was a randomized, double-blind, placebo-controlled, event-driven, multinational phase 3 trial, with a median exposure period of 23 months.
A total of 5,988 patients were randomized to be given empagliflozin (2,997) or placebo (2,991). The mean age was 72 years: 45% were women, 76% were Caucasian, and 14% Asian. The mean LVEF was 54% ([LVEF <50%; 33%], [50 to <60%; 34%], [≥60%; 33%]), 81.5% of patients were in the New York Heart Association (NYHA) class II HF, 18.1% were in NYHA class III and 0.3% were in NYHA class IV, and 49% had T2DM. The mean estimated glomerular filtration rate (eGFR) was 60.6 millilitres (mL)/minute (min)/1.73 metres squared (m2), ≥60 mL/min/1.73 m2 (50.1%), <60 mL/min/1.73 m2 (49.9%), and <30 mL/min/1.73 m2 (5.2%). The main cause of HFpEF was ischemic (35.4%), hypertensive (36.5%), idiopathic (9.2%), and valvular heart disease (5.9%). At study baseline, 86% of patients were treated with beta-blockers, 81% with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors, 38% with mineralocorticoid receptor antagonists, and 86% with diuretics.
The primary composite endpoint, incidence of cardiovascular (CV) death or first hospitalisation for heart failure (HHF), occurred in a lower proportion of patients in the empagliflozin group (415 patients; 13.8%) than in the placebo group (511 patients; 17.1%), with a hazard ratio (HR) of 0.79 (95% confidence interval [CI]: 0.69, 0.90, p = 0.0003). The separation of the estimated cumulative incidence of primary endpoint between empagliflozin and placebo started within 2 months of randomization, and was maintained throughout the trial. The primary endpoint results were driven by a decrease in the incidence of first HHF, 8.6% for the empagliflozin group versus (vs.) 11.8% for placebo group, while incidence of CV death as first event was similar, 5.2% vs. 5.3%. The beneficial effect of empagliflozin on the primary endpoint was generally consistent across pre-specified patient subgroups, with interaction p-values >0.05 for all analysed subgroups (for example [e.g.], non-T2DM/T2DM, LVEF, age <70 or older, male/female, body mass index [BMI], eGFR <60 or more).
Treatment with empagliflozin during the trial revealed no new safety signals and was overall consistent with its known safety profile in patients with T2DM or HFrEF. There were similar proportions of patients between treatment groups with adverse events (AEs), AEs leading to premature discontinuation, and AEs leading to death. Serious AEs were less commonly reported for the empagliflozin group (47.9%) compared to the placebo group (51.6%). For specific AEs and of special interest, acute renal failure, ketoacidosis, hypoglycemic events, bone fractures, urinary tract malignancies, and hepatic injuries occurred at similar or lower frequencies in the empagliflozin group compared to the placebo group. More patients in the empagliflozin group vs. placebo group had urinary tract infections (7.9% vs. 6.1%), genital infections (2.2% vs. 0.7%), volume depletion (11.9% vs. 9.6%), and hypotension (7.7% vs. 6.3%). These are known AEs of empagliflozin, and treatment discontinuation for these events were infrequent. Adverse events in subgroups by demographics, baseline characteristics, and concomitant renin-angiotensin-aldosterone system blockers or diuretics showed trends generally consistent with the overall AE profile in the trial.
Overall, the benefit-risk assessment of Jardiance was considered favorable for use as an adjunct to standard of care therapy for the treatment of chronic HFpEF. Along with the approved HFrEF indication, Jardiance can be used for the treatment of chronic HF across the entire LVEF spectrum. A Notice of Compliance, pursuant to section C.08.004 of the Food and Drug Regulations was recommended.
Decision issued
Authorized; issued a Notice of Compliance (NOC) in accordance with the Food and Drug Regulations.