Regulatory Decision Summary for Forxiga

Heart failure (HF) is a severe, chronic syndrome where the ability of the cardiac ventricle to fill with or eject blood is impaired. It is associated with a progressive worsening of cardiac function and symptoms. HF is frequently classified according to the ejection fraction (EF), commonly measured by echocardiography. When the EF is ≤40% it is classified as HF with reduced ejection fraction (HFrEF). Primary manifestations of HF are dyspnea, fatigue, and fluid retention. As HF progresses, patients will develop symptoms such as light-headedness, shortness of breath, exercise intolerance, cachexia and peripheral edema.

This SNDS evaluated the efficacy and safety of Forxiga (dapagliflozin) as an add-on treatment for HF with reduced ejection fraction, based on a single, double-blind placebo-controlled Phase 3 trial, DAPA-HF. A total of 4,744 patients with HFrEF were randomised 1:1 to dapagliflozin 10 milligrams (mg) (n = 2,373) or placebo (n = 2,371); randomization was stratified according to type 2 diabetes mellitus (T2DM) status. Patients were predominantly male, with an average age of 66.3 years and most were classified as New York Heart Association (NYHA) class II at enrolment. In the study, a total of 2,600 (54.9%) patients did not have a T2DM diagnosis at baseline. All patients were receiving standard of care (SoC) HF treatment.

When added to SoC, dapagliflozin was shown to be effective in reducing cardiovascular (CV) death or HF events. The primary efficacy endpoint, a composite of CV death or HF events requiring hospitalization or urgent intervention, showed a statistically significant 26% relative risk reduction over a median follow-up of 18 months for the dapagliflozin-treated patients, relative to the placebo-treated patients (386 of 2,373 patients [16.3%] in the dapagliflozin group and in 502 of 2371 patients [21.2%] in the placebo group [hazard ratio, 0.74; 95% confidence interval (CI) 0.65 to 0.85; p<0.001]).

No new safety signal was identified during the clinical trial. The safety profile of dapagliflozin in the DAPA-HF study was comparable to placebo and did not differ from the established safety profile of dapagliflozin. No new potential risks were identified. Dapagliflozin was well tolerated, with a low number of adverse events (AEs) leading to discontinuations.

In the pre-specified subgroup analysis by diabetic status, results of the primary efficacy endpoint were similar in patients with and without T2DM. The safety profile of dapagliflozin also did not differ substantially in the patients without T2DM at baseline compared to those with T2DM, other than the known increased risk of diabetic ketoacidosis in T2DM patients receiving dapagliflozin, which is not seen in non-diabetic patients.

A Risk Management Plan (RMP) for the new Forxiga indication, now including non-diabetic patients, was submitted and reviewed by the Marketed Health Products Directorate (MHPD) and was considered acceptable.

Overall, the benefit risk assessment of Forxiga is considered favorable for use in adults, as an adjunct to standard of care therapy, for the treatment of heart failure with reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular (CV) death, hospitalization for heart failure and urgent heart failure visit.