Summary Basis of Decision for Kerendia

As described above, the clinical review of the New Drug Submission for Kerendia was conducted using various methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Finerenone, the medicinal ingredient in Kerendia, is a nonsteroidal, selective antagonist of the mineralocorticoid receptor (MR). Finerenone binds to the MR and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone system (RAAS). Aldosterone plays a central role in the homeostatic regulation of blood pressure and plasma sodium and potassium levels. The mechanisms of action of Kerendia which contribute to the reduction of renal and cardiovascular events are not completely understood and may be due to multi-factorial effects in different tissues. Potential mechanisms of action which have been reported under certain experimental conditions include:

• attenuation of inflammation and fibrosis that are thought to be mediated by MR overactivation,
• in vitro, inhibition of MR interaction with transcriptional coactivators implicated in the expression of pro‑inflammatory and pro‑fibrotic mediators in a dose‑dependent manner,
• blocking of MR by finerenone in vivo, which counteracts sodium retention in the kidneys and hypertrophic processes in the kidneys, heart, and blood vessels.

Finerenone has no relevant affinity for androgen, progesterone, estrogen and glucocorticoid receptors and therefore is unlikely to cause sex hormone‑related adverse events (e.g., gynecomastia).

The pharmacokinetics and pharmacodynamics of finerenone were evaluated in a series of Phase I, II and III studies. The absolute oral bioavailability of finerenone is estimated as 43.5%. Finerenone is eliminated almost exclusively in the form of metabolites, with approximately 80% and 20% of the administered dose excreted in urine and feces, respectively. The pharmacokinetic parameters of finerenone are linear across the investigated dose range of 1.25 mg to 20 mg.

An increase in finerenone exposure was observed in special populations of interest, including elderly subjects, subjects with moderate and severe renal impairment (defined as an estimated glomerular filtration rate [eGFR] of 15 to <60 mL/min/1.73 m²), and subjects with moderate hepatic impairment (Child Pugh B). As the dosage of finerenone is based on multiple factors, including levels of serum potassium, eGFR, and pre‑existing conditions, dose adjustment is not necessary for elderly subjects and subjects with moderate hepatic impairment. Subjects with moderate to severe renal impairment should initiate finerenone treatment at a lower dose (10 mg) compared to subjects with mild renal impairment and normal kidney function (20 mg), depending on baseline eGFR. There was no clinical experience with subjects with end‑stage renal disease (eGFR of <15 mL/min/1.73 m²) or severe hepatic impairment (Child Pugh C) in the Phase I studies.

Cytochrome P450 (CYP) 3A4 is a major contributor to the metabolic clearance of finerenone. Therefore, CYP3A4 inhibitors or inducers were identified as potentially relevant extrinsic factors. Concomitant use of finerenone with strong CYP3A4 inhibitors is contraindicated due to an expected increase in finerenone exposure (as measured by the area under the concentration‑time curve [AUC]) by more than 350%. Interactions between finerenone and the moderate CYP3A4 inhibitors erythromycin and verapamil were identified through clinical drug‑drug interaction studies. Caution and additional monitoring of potassium levels are advised when finerenone is administered concomitantly with moderate CYP3A4 inhibitors, as an increase in finerenone exposure (as measured by the AUC) of 170‑248% has been observed. Due to an expected decrease in finerenone exposure by more than 80%, concomitant use of finerenone with moderate and strong CYP3A4 inducers should be avoided.

Pharmacodynamics studies evaluated the effects of finerenone on healthy subjects, patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), and on the QT interval.

In healthy subjects, multiple dose regimens of finerenone (daily doses of 20 mg or 40 mg over 10 days) led to activation of the RAAS. This was based on reversible increases of plasma renin activity and serum aldosterone concentrations, which returned to baseline values within 48 hours after the last dose. Following activation of the MR with the agonist fludrocortisone, single doses of finerenone up to 20 mg showed natriuretic effects while decreasing urinary potassium excretion compared to placebo. The highest single dose of 80 mg and the highest multiple dose of 40 mg of finerenone did not affect vital signs parameters in healthy participants.

Based on data from the Phase III studies in adult patients with CKD and T2D (described in the Clinical Efficacy section), the placebo‑corrected relative reduction in urinary albumin‑to‑creatinine ratio (UACR) in patients randomized to finerenone at Month 4 were 31% and 32% for the FIDELIO‑DKD and FIGARO‑DKD studies, respectively. In both studies, the reduction in UACR was maintained for at least 48 months. In a Phase IIb dose‑finding study in adult patients with CKD and T2D, the placebo‑corrected relative reductions in the UACR at Day 90 were 25% and 38% in patients treated once daily with finerenone 10 mg and 20 mg, respectively.

In a dedicated QT study in 57 healthy participants, there was no indication of a clinically relevant prolonging effect of finerenone on the QT/corrected QT (QTc) interval after single doses of 20 mg (therapeutic) or 80 mg (supratherapeutic).

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

Clinical Efficacy

The clinical efficacy of Kerendia was evaluated in two randomized, double‑blind, placebo‑controlled, multicenter pivotal Phase III studies, FIDELIO‑DKD and FIGARO‑DKD. In both studies, the effect of Kerendia (a once‑daily 10 mg or 20 mg dose) on kidney and cardiovascular outcomes was evaluated in adults with chronic kidney disease (CKD) and type 2 diabetes (T2D) as compared to treatment with placebo. The results from these two studies provided sufficient evidence to support the safe and efficacious use of Kerendia in the target population.

FIDELIO‑DKD Study

The FIDELIO‑DKD study was conducted in adult patients with CKD and T2D, with either a UACR of 30 to <300 mg/g, an eGFR of 25 to <60 mL/min/1.73 m² and diabetic retinopathy, or a UACR of ≥300 mg/g and an eGFR of 25 to <75 mL/min/1.73 m², and a serum potassium concentration of ≤4.8 mmol/L at screening. Additionally, patients were required to be receiving standard of care, including a maximum tolerated labeled dose of an angiotensin‑converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). Patients with diagnosed heart failure with reduced ejection fraction and persistent symptoms (New York Heart Association II‑IV) were excluded.

In total, 5,674 patients were randomized to receive either 10 mg or 20 mg Kerendia (2,833 patients in total for both doses) or placebo (2,841 patients) once daily for a mean duration of treatment of 2.2 years, with a median study follow‑up time of 2.6 years.

The primary endpoint was a composite of time to first occurrence of one of the following:

• kidney failure (defined as chronic dialysis or kidney transplantation, or a sustained decrease in eGFR to <15 mL/min/1.73 m² over at least 4 weeks),
• a sustained decline in eGFR of 40% or more compared to baseline over at least 4 weeks, or
• renal death.

Kerendia was found to be superior to placebo, as it significantly reduced the risk of the primary composite endpoint compared to placebo in a time‑to‑event analysis using the Cox proportional hazards model and log‑rank test (hazard ratio [HR] 0.82; 95% confidence interval [CI]: 0.73, 0.93; p = 0.0014).

The key secondary endpoint was a composite of time to first occurrence of cardiovascular death, non‑fatal myocardial infarction, non‑fatal stroke, or hospitalization for heart failure. Kerendia significantly reduced the risk of the key secondary composite endpoint compared to placebo (HR 0.86; 95% CI: 0.75, 0.99; p = 0.0339).

The treatment effect for the primary kidney and key secondary cardiovascular endpoints was generally consistent across subgroups regardless of baseline characteristics. The treatment effect for the primary endpoint was mainly driven by an effect on a reduction in sustained decrease in eGFR, though kidney failure also contributed to the treatment effect. There were too few renal deaths during the study to allow for statistical inference, and the incidence observed was the same in the Kerendia and placebo groups (two events each).

FIGARO‑DKD Study

The FIGARO‑DKD was conducted in adult patients with CKD and T2D, with either a UACR of 30 to <300 mg/g and an eGFR of 25 to 90 mL/min/1.73 m², or a UACR of ≥300 mg/g and an eGFR of ≥60 mL/min/1.73 m² at screening. Additionally, patients were required to have a serum potassium concentration of ≤4.8 mmol/L at screening and had received standard of care background therapy, including a maximum tolerated labeled dose of a renin angiotensin system (RAS) inhibitor (either an ACEi or an ARB). Patients with diagnosed heart failure with reduced ejection fraction and persistent symptoms (New York Heart Association II‑IV) were excluded.

In total, 7,352 patients were randomized to receive either 10 mg or 20 mg Kerendia (3,686 patients in total for both doses) or placebo (3,666 patients) once daily for a mean duration of treatment of 2.9 years, with a median study follow‑up time of 3.4 years.

The primary endpoint was a composite of time to first occurrence of one of the following: cardiovascular death, non‑fatal myocardial infarction, non‑fatal stroke, or hospitalization for heart failure.

Kerendia significantly reduced the risk of the primary composite endpoint compared to placebo in a time‑to‑event analysis using the Cox proportional hazards model and log‑rank test (hazard ratio [HR] 0.87; 95% CI: 0.76, 0.98; p = 0.0264).

Among the components of the composite primary endpoint, hospitalization for heart failure was the major driver for the results, though cardiovascular death also contributed to the treatment effect. The other components were not statistically significant. There was a substantial number of events in each component of the primary composite, including 408 cardiovascular deaths in total and 280 total hospitalizations for heart failure across both treatment groups. The treatment effect for the primary endpoint was consistent across subgroups (regardless of baseline characteristics).

The key secondary endpoint was a composite of time to first occurrence of kidney failure, a sustained decline in eGFR of 40% or more compared to baseline over at least 4 weeks, or renal death. Although a lower incidence rate was also observed of the secondary composite outcome compared to placebo, this difference did not achieve statistical significance (HR 0.87, 95% CI: 0.76, 1.01; p = 0.0689).

Indication

For more information, refer to the Kerendia Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Kerendia in patients with CKD and T2D was evaluated in the Phase III FIDELIO‑DKD and FIGARO‑DKD studies, described in the Clinical Efficacy section. In the FIDELIO‑DKD study, 2,827 patients received Kerendia with a mean treatment duration of 2.2 years. In the FIGARO‑DKD study, 3,683 patients received Kerendia with a mean treatment duration of 2.9 years.

Serious adverse reactions were reported in both the FIDELIO‑DKD study (32% of Kerendia‑treated patients versus [vs.] 34% of placebo‑treated patients) and in the FIGARO‑DKD study (31% of Kerendia‑treated patients vs. 33% of placebo‑treated patients). Adverse reactions led to permanent discontinuation in 7% of patients receiving Kerendia and 6% of patients receiving placebo in the FIDELIO‑DKD study, and 6% of patients receiving Kerendia and 5% of patients receiving placebo in the FIGARO‑DKD study.

Adverse reactions that were reported at a higher frequency in Kerendia‑treated patients and that occurred in 5% or more of patients receiving Kerendia were:

• FIDELIO‑DKD study:
  • hyperkalemia (18.3% ‑ Kerendia vs 9.0% ‑ placebo)
  • decreased eGFR (6.3% ‑ Kerendia vs. 4.7% ‑ placebo)
• FIGARO‑DKD study:
  • hyperkalemia (10.8% ‑ Kerendia vs. 5.3% ‑ placebo).

Adverse reactions that were reported in 1% or more of patients receiving Kerendia in the Phase III studies (pooled FIDELIO‑DKD and FIGARO‑DKD) and that were reported more frequently in patients receiving Kerendia than in patients receiving placebo included anemia (6.5% vs. 6.1%), hyperuricemia (5.1% vs. 3.9%), hyponatremia (1.3% vs. 0.7%), hypotension (4.6% vs. 3.9%), and pruritus (2.9% vs. 2.2%).

The safety of Kerendia during pregnancy and breastfeeding and in patients with severe hepatic impairment or end‑stage kidney failure is uncertain, since these populations were excluded from clinical studies. Patients with severe renal impairment (<25 mL/min/1.73 m²) were under‑represented. The long‑term safety of Kerendia is also uncertain. Appropriate cautionary statements, additional patient monitoring, dosage adjustments or interruptions, and descriptions of the findings and safety concerns are in place in the Kerendia Product Monograph to guide health professionals and patients on the safe and efficacious use of Kerendia.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Kerendia, and to support its safe and effective use. Overall, the safety profile of Kerendia was found to be acceptable for the approved indication.

For more information, refer to the Kerendia Product Monograph, approved by Health Canada and available through the Drug Product Database.