Regulatory Decision Summary for XIGDUO

The biopharmaceutics review established bioequivalence between co-administration of individual tablets of dapagliflozin and metformin and the 5 milligrams (mg)/850 mg dapagliflozin/metformin fixed dose combination (FDC) tablets. Bioequivalence was waived for the 5 mg/1,000 mg FDC tablet, based on the quality review which established proportionality between both dosage strengths.

The clinical safety and efficacy program was built upon and supported by the dapagliflozin (Forxiga) development program, which included 12 Phase 3 trials to support the co-administration of dapagliflozin with metformin, with the addition of 4 new Phase 1 trials and one Phase 3 pivotal trial.

Results from the pharmacokinetic and pharmacodynamics study and the bioavailability study support the recommended twice daily dosing regimen (BID) and administration in the fed state.

The pivotal, Phase 3 trial was a 16-week randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of dapaglifozin 2.5 mg BID, 5 mg BID, and 10 mg once daily (QD) as add-on therapy to metformin versus placebo in patients with type 2 diabetes not adequately controlled on metformin therapy. The results of the trial showed statistically significant improvements in the primary efficacy endpoint of glycated hemoglobin (HbA1c) reduction from baseline, and the secondary efficacy endpoints of reduction in fasting plasma glucose (FPG) and body weight.

With respect to the primary endpoint, the study showed a reduction in HbA1c of 0.35% with dapagliflozin 5 mg BID and 0.29% with 10mg QD. A previous placebo-controlled trial of dapagliflozin in add-on combination with metformin showed a statistically significant placebo-adjusted reduction in HbA1c of 0.41% with dapagliflozin 5 mg QD and 0.54% with 10 mg QD. Moreover, the 10 mg QD arm (the currently approved dose for dapagliflozin and the positive control for the study) failed to reach statistical significance against placebo in the analysis of the key secondary efficacy endpoint describing the proportion of subjects with HbA1c <7.0% at week 16.

No new safety concerns regarding co-administration of dapagliflozin and metformin were raised in this trial. Moreover, the sponsor submitted a summary of safety and tolerability from pooled analyses of the dapagliflozin + metformin trials (9 active- and placebo-controlled trials), dapagliflozin + metformin placebo-controlled trials (8 placebo-controlled trials) and all Phase 2b and 3 trials (21 trials from the integrated dapagliflozin database) from the initial dapagliflozin application. The safety profile of dapagliflozin co-administered with metformin as presented from these analyses is consistent with the safety profiles of the individual components. The most commonly reported adverse reactions were hypoglycemia, genital mycotic infections, urinary tract infections and polyuria, and more subjects treated with dapagliflozin experienced events of volume depletion, renal impairment, and polyuria compared to placebo-treated subjects.

Risk management is addressed through the existing Risk Management Plan, labelling, and limiting the indication to patients already achieving glycemic control with separate dosing of dapagliflozin and metformin. Given the totality of the evidence provided, the benefit risk is positive.