Regulatory Decision Summary for Kerendia

The purpose of this Supplement to a New Drug Submission filed by Bayer Inc. was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Kerendia (finerenone) for a new indication for the treatment of heart failure with left ventricular ejection fraction (LVEF) ≥40% to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits. The submission also intended to seek authorization for a new dosage strength of 40 mg.

The submission was reviewed using the international review work-sharing model with the Access Consortium. Health Canada reviewed the clinical module of the submission, Swissmedic reviewed the non-clinical module, and the Australian Therapeutic Goods Administration reviewed the quality portion of the submission. Health Canada peer-reviewed non-clinical and quality modules.

The sponsor consented to information sharing between Health Canada and the health technology assessment organizations as part of an aligned review pathway.

The effect of Kerendia in patients with Heart Failure (HF) with Left Ventricular Ejection Fraction (LVEF) greater than or equal to 40% was evaluated in one randomized, double-blind, placebo controlled, multicenter, Phase 3 trial, FINEARTS-HF. A total of 6001 patients were treated with placebo or Kerendia (10 milligram [mg], 20 mg, or 40 mg) once daily in addition to the standard of care therapy for congestion and comorbidities (loop diuretics, an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, or an angiotensin receptor/neprilysin inhibitor, and sodium-glucose cotransporter 2 inhibitor). The trial population included male and female patients 40 years of age and above with a diagnosis of HF with LVEF greater than or equal to 40%. In addition, patients had estimated glomerular filtration rate (eGFR) greater than or equal to 25 milliliters per minute per 1.73 square metres (mL/min/1.73 m²) and serum potassium less than or equal to ≤ 5.0 millimoles per litre (mmol/L) at screening and randomization. The demographics and baseline characteristics were balanced. Overall study duration was 45 months with a median treatment duration of 28 months.

The starting dose of Kerendia was based on the patient’s renal function at the initiation of the treatment. Patients with an eGFR between 25 to less than 60 mL/min/1.73 m² were given a starting dose of 10 mg once daily, whereas patients with eGFR greater than or equal to 60 mL/min/1.73 m² were given a starting dose of 20 mg once daily. Both of the groups were up-titrated to a higher daily dose (20 mg and 40 mg, respectively) after 4 weeks depending on their serum potassium level and eGFR. Periodic monitoring of serum potassium levels and eGFR were conducted for dose adjustment or treatment interruption.

Kerendia demonstrated superiority to placebo by significantly reducing the risk of the primary composite endpoint of cardiovascular (CV) death and total (first and recurrent) heart failure events (hospitalization for heart failure and urgent heart failure visits) up to 45 months of treatment (risk ratio [RR] 0.84, 95% Confidence Interval [CI] 0.74-0.95, probability-value [p] = 0.0072). The effect was observed early with the curves separating from the first month and continuing to diverge throughout the study period. This was mostly driven by the HF events component. The treatment effect was consistent across prespecified subgroups, including subgroups with eGFR, LVEF, New York Heart Association class, weight, age, sex, race, or region at baseline.

The overall safety profile of Kerendia is considered acceptable for use in the patient population studied. The safety profile of Kerendia in patients with HF with LVEF greater than or equal to 40% in FINEARTS-HF trial was similar to the previously reported safety profile in patients with chronic kidney disease and type 2 diabetes in FIGARO-DKD and FIDELIO-DKD trials. No new adverse events (AEs) other than the previously established AEs were noted in the FINEARTS-HF study. Hyperkalemia (9.7% Kerendia versus [vs.] 4.2% placebo), hypotension (7.6% Kerendia vs. 4.7% placebo) and decreased eGFR (5.2% Kerendia vs. 3.6% placebo) were commonly observed treatment related adverse effects. Higher frequencies of treatment-emergent adverse events (TEAEs) related to worsening of renal function were observed in the Kerendia group (17.7%) compared to placebo (10.9%) group. These included renal function impairment (6.6% vs. 3.9%), glomerular filtration rate decreased (5.2% vs. 3.6%), acute kidney injury (3.7% vs. 2.1%), renal failure (2.6% vs. 1.6%), blood creatinine increased (1.2% vs. 0.8%). Most of the TEAEs related to worsening of renal function in the Kerendia group were non-serious, mild to moderate in severity and had resolved or were resolving under Kerendia continuation. The frequencies of renal function TEAEs of clinical consequences, i.e., leading to hospitalization, were low and comparable to placebo (2.0% Kerendia vs. 1.3% placebo). Additionally, frequencies of these TEAEs leading to permanent discontinuation of study drug (0.3% Kerendia vs. 0.3% placebo) were low. Precautionary statements and risk minimization measures have been included in the Product Monograph to address safety issues and uncertainties.

The information submitted and reviewed with respect to chemistry and manufacturing was considered acceptable and in accordance with the Health Canada Guidance Document: Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) requirement. The new dosage strength of 40 mg was acceptable.

Comparative bioavailability data was reviewed and demonstrated that administration of a single Kerendia 40 mg tablet with a high-fat, high-calorie meal to healthy volunteers did not have an effect on the total exposure, area under the curve, of Kerendia relative to fasting conditions.

A Risk Management Plan (RMP) was submitted. Upon review, the RMP was acceptable in order to ensure that the benefit of Kerendia continues to outweigh any risk after authorization.

Overall, the benefit-harm-uncertainty profile was favorable for Kerendia 10 mg, 20 mg, and 40 mg when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

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