Regulatory Decision Summary for Forxiga

The purpose of this Supplemental New Drug Submission was to expand the indication for Forxiga to include the treatment of heart failure in patients with a left ventricular ejection fraction over 40%; that is, patients having Heart Failure with Preserved Ejection Fraction, and to update the Product Monograph with new information related to a drug-drug interaction with lithium.

This submission was based on the single pivotal trial “Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure” (DELIVER). DELIVER was an international, multi-centre, parallel-group, event-driven, randomised, double-blind, placebo-controlled Phase III study. It was designed to evaluate the effect of dapagliflozin 10 milligrams (mg) compared with placebo, given once daily, in reducing the time to the composite outcome of cardiovascular (CV) death, hospitalization for heart failure (HHF) or an urgent heart failure (HF) visit (HHF and urgent HF visit were also referred to as an ‘HF event’) in adult patients having HF with preserved ejection fraction (HFpEF); left ventricular ejection fraction [LVEF] over40%).

A total of 6,263 patients were randomized to Forxiga 10 mg (number of patients [n] = 3,131) or placebo (n = 3,132) once daily, on top of standard of care, and followed for a median of 28 months. At baseline, 97.8% of patients were treated with a diuretic, 82.7% with a beta-blocker, 77.2% with a renin-angiotensin system modifier, and 42.6% with a mineralocorticoid receptor antagonist.

Treatment with dapagliflozin, as compared to placebo, led to a statistically significant reduction in the incidence of the primary composite endpoint of time to CV death or an HF event (hazard ratio [HR] 0.82 [95% Confidence interval (CI) 0.73, 0.92; p-value (p) = 0.0008]). The treatment effect was mainly driven by a reduction in HHF (p = 0.0004). Based on time-to-event analysis, the frequencies of CV death (3.3% dapagliflozin and 3.8% placebo, p = 0.1678) and urgent HF visit (0.9% dapagliflozin and 1.1% placebo, p = 0.1159) were similar between groups and the differences were not statistically significant. The effect of Forxiga on the primary composite endpoint was generally consistent across various prespecified patient subgroups. An analysis of pooled data from DELIVER and a previous study (DAPA-HF) in patients having heart failure with reduced ejection fraction (HFrEF) demonstrated that Forxiga had a significantly beneficial effect on time to CV death as well as HHF, and confirmed that there was a benefit in the primary composite endpoint across the full range of LVEF values studied.

The DELIVER trial excluded patients with a history of infiltrative cardiomyopathy (for example cardiac amyloidosis) and patients having a baseline value for the HF biomarker N-terminal pro b-type natriuretic peptide (NT-proBNP) that was below 300 picograms per milliliter (pg/mL). Therefore, the efficacy of Forxiga in these patient subgroups remains unknown.

The safety results from DELIVER were generally consistent with the established safety profile of Forxiga in patients with type 2 diabetes mellitus (T2DM), chronic kidney disease and HFrEF. Treatment with dapagliflozin was generally well-tolerated. The rates of serious adverse events (SAE) (46.5% dapagliflozin, 48.2% placebo) and adverse events (AE) with a fatal outcome (16.2% dapagliflozin, 16.9% placebo) were balanced between treatment groups. Rates for serious renal AE or renal AE leading to discontinuation (DAE), major hypoglycemic events and amputations were also balanced between groups. There were two patients with diabetic ketoacidosis, a known risk with dapagliflozin. Both were T2DM patients in the dapagliflozin group. The overall frequency of patients with any DAE was 5.8% in each group, but there was a numeric trend toward increased DAE suggestive of volume depletion and related to the investigational product in the dapagliflozin group (8 patients on dapagliflozin, 1 patient on placebo). Overall, no new safety signals were identified.

To investigate the possibility of a drug-drug interaction (DDI) between dapagliflozin and lithium, the sponsor created and validated a simulated pharmacokinetic model, and showed that co-treatment of dapagliflozin with lithium leads to an increase (from 13% to 38%) in the proportion of virtual patients having serum lithium concentrations that were below therapeutic level at trough. Based on these findings, the sponsor added information regarding a potential DDI with lithium in the Drug Interactions section of the Product Monograph (PM).

An updated risk management plan for Forxiga, with a Canadian addendum, was also submitted by the sponsor. The RMP was reviewed by the Marketed Health Products Directorate and judged to be acceptable.

Following review and requested revisions, the final labelling and PM were considered to be acceptable.

Overall, the benefit-risk assessment of Forxiga was considered favourable for the treatment of HFpEF in adults. A Notice of Compliance was issued.

Together with the previously approved HFrEF indication, Forxiga can be recommended for treatment of adult HF patients across the full range of LVEF values.

For further details about Forxiga, please refer to the PM, approved by Health Canada and available through the Drug Product Database.