Kerendia finerenone 20 mg Tablet, Film Coated, 90-count — NDC 50419-541-02 (Billing 50419-0541-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor (MR), which is activated by aldosterone and cortisol and regulates gene transcription. Finerenone blocks MR mediated sodium reabsorption and MR overactivation in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, and blood vessels) tissues. MR overactivation is thought to contribute to fibrosis and inflammation.

Finerenone has a high potency and selectivity for the MR and has no relevant affinity for androgen, progesterone, estrogen, and glucocorticoid receptors.

12.2Pharmacodynamics In FIDELIO-DKD and FIGARO-DKD, randomized, double-blind, placebo-controlled, multicenter studies in adult patients with chronic kidney disease associated with type 2 diabetes, the placebo-corrected relative reduction in urinary albumin-to-creatinine ratio (UACR) in patients randomized to finerenone was 31% (95% CI 29-34%), and 32% (95% CI 30-35%) respectively at Month 4 and remained stable for the duration of the trial. In ARTS DN, a randomized, double-blind, placebo-controlled, multicenter phase IIb dose finding study in adults with CKD and T2DM, the placebo-corrected relative reduction in UACR at Day 90 was 25% and 38% in patients treated with finerenone 10 mg and 20 mg once daily, respectively.

In patients treated with Kerendia, the mean systolic blood pressure decreased by 3 mmHg and the mean diastolic blood pressure decreased by 1-2 mmHg at month 1, remaining stable thereafter. Cardiac Electrophysiology At a dose 2 times the maximum approved recommended dose, finerenone does not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics Finerenone exposure increased proportionally over a dose range of 1.25 to 80 mg (0.06 to 4 times the maximum approved recommended dosage). Steady state of finerenone was achieved after 2 days of dosing. The estimated steady-state geometric mean C max,md was 166 µg/L and steady-state geometric mean AUC τ,md was 718 µg.h/L following administration of finerenone 20 mg to patients.

Absorption Finerenone is completely absorbed after oral administration but undergoes metabolism resulting in absolute bioavailability of 44%. Finerenone C max was achieved between 0.5 and 1.25 hours after dosing. Effect of Food There was no clinically significant effect on finerenone AUC following administration with high fat, high calorie food.

Distribution The volume of distribution at steady-state (Vss) of finerenone is

52.6L. Plasma protein binding of finerenone is 92%, primarily to serum albumin, in vitro. Elimination The terminal half-life of finerenone is about 2 to 3 hours, and the systemic blood clearance is about 25 L/h.

Metabolism Finerenone is primarily metabolized by CYP3A4 (90%) and to a lesser extent by CYP2C8 (10%) to inactive metabolites. Excretion About 80% of the administered dose is excreted in urine (<1% as unchanged) and approximately 20% in feces (< 0.2% as unchanged). Specific Populations There are no clinically significant effects of age (18 to 86 years), sex, race/ethnicity (White, Asian, Black, and Hispanic), or weight (54 to 126 kg) on the pharmacokinetics of finerenone.

Renal Impairment There were no clinically relevant differences in finerenone AUC or C max values in patients with eGFR 15 to < 90 mL/min/1.73m 2 compared to eGFR ≥ 90 mL/min/1.73 m 2 . For dosing recommendations based on eGFR and serum potassium levels see Dosage and Administration (2) . Hepatic Impairment There was no clinically significant effect on finerenone exposure in cirrhotic patients with mild hepatic impairment (Child Pugh A).

Finerenone mean AUC was increased by 38% and C max was unchanged in cirrhotic patients with moderate hepatic impairment (Child Pugh B) compared to healthy control subjects. The effect of severe hepatic impairment (Child Pugh C) on finerenone exposure was not studied . Drug Interaction Studies Clinical Studies and Model-Informed Approaches Str… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor (MR), which is activated by aldosterone and cortisol and regulates gene transcription. Finerenone blocks MR mediated sodium reabsorption and MR overactivation in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, and blood vessels) tissues. MR overactivation is thought to contribute to fibrosis and inflammation.

Finerenone has a high potency and selectivity for the MR and has no relevant affinity for androgen, progesterone, estrogen, and glucocorticoid receptors.

12.3Pharmacokinetics Finerenone exposure increased proportionally over a dose range of 1.25 to 80 mg (0.06 to 4 times the maximum approved recommended dosage). Steady state of finerenone was achieved after 2 days of dosing. The estimated steady-state geometric mean C max,md was 166 µg/L and steady-state geometric mean AUC τ,md was 718 µg.h/L following administration of finerenone 20 mg to patients.

Absorption Finerenone is completely absorbed after oral administration but undergoes metabolism resulting in absolute bioavailability of 44%. Finerenone C max was achieved between 0.5 and 1.25 hours after dosing. Effect of Food There was no clinically significant effect on finerenone AUC following administration with high fat, high calorie food.

Distribution The volume of distribution at steady-state (Vss) of finerenone is

52.6L. Plasma protein binding of finerenone is 92%, primarily to serum albumin, in vitro. Elimination The terminal half-life of finerenone is about 2 to 3 hours, and the systemic blood clearance is about 25 L/h.

Metabolism Finerenone is primarily metabolized by CYP3A4 (90%) and to a lesser extent by CYP2C8 (10%) to inactive metabolites. Excretion About 80% of the administered dose is excreted in urine (<1% as unchanged) and approximately 20% in feces (< 0.2% as unchanged). Specific Populations There are no clinically significant effects of age (18 to 86 years), sex, race/ethnicity (White, Asian, Black, and Hispanic), or weight (54 to 126 kg) on the pharmacokinetics of finerenone.

Renal Impairment There were no clinically relevant differences in finerenone AUC or C max values in patients with eGFR 15 to < 90 mL/min/1.73m 2 compared to eGFR ≥ 90 mL/min/1.73 m 2 . For dosing recommendations based on eGFR and serum potassium levels see Dosage and Administration (2) . Hepatic Impairment There was no clinically significant effect on finerenone exposure in cirrhotic patients with mild hepatic impairment (Child Pugh A).

Finerenone mean AUC was increased by 38% and C max was unchanged in cirrhotic patients with moderate hepatic impairment (Child Pugh B) compared to healthy control subjects. The effect of severe hepatic impairment (Child Pugh C) on finerenone exposure was not studied . Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors : Concomitant use of itraconazole (strong CYP3A4 inhibitor) was predicted to increase finerenone AUC by >400%.

Moderate CYP3A Inhibitors : Concomitant use of erythromycin (moderate CYP3A4 inhibitor) increased finerenone mean AUC and C max by 248% and 88%, respectively. Concomitant use of verapamil (moderate CYP3A4 inhibitor) increased finerenone mean AUC and C max by 170% and 122%, respectively. Weak CYP3A Inhibitors : Concomitant use of amiodarone (weak CYP3A4 inhibitor) increased finerenone AUC by 21%.

Strong or Moderate CYP3A Inducers : Concomitant use of efavirenz (moderate CYP3A4 inducer) and rifampicin (strong CYP3A4 inducer) was predicted to decrease finerenone AUC by 80% and 90%, respectively. CYP3A4 Substrates: Concomitant use of multiple finerenone 40 mg doses once daily with midazolam (sensitive CYP3A4 substrate) increased the mean AUC by 31% with no effect on C max . There were no clinically significant differences in the pharmacokinetics of midazolam when used concomitantly with multiple finerenone 20 mg doses once daily.

CYP2C8 Substrates: Concomitant use of multiple finerenone 40 mg doses once daily with repaglinide (sensitive CYP2C8 substrate) increased the mean AUC and C max of repaglinide by 59% and 30%, respectively. There were no clinically significant differences in the pharmacokinetics of repaglinide when used concomitantly with multiple finerenone 20 mg doses once daily. Other Drugs : No clinically significant differences in the pharmacokinetics of the following drugs were observed or predicted when used concomitantly with finerenone: S-warfarin (CYP2C9 substrate), digoxin (P-gp substrate), and rosuvastatin (BCRP and OATP s… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In FIDELIO-DKD and FIGARO-DKD, randomized, double-blind, placebo-controlled, multicenter studies in adult patients with chronic kidney disease associated with type 2 diabetes, the placebo-corrected relative reduction in urinary albumin-to-creatinine ratio (UACR) in patients randomized to finerenone was 31% (95% CI 29-34%), and 32% (95% CI 30-35%) respectively at Month 4 and remained stable for the duration of the trial. In ARTS DN, a randomized, double-blind, placebo-controlled, multicenter phase IIb dose finding study in adults with CKD and T2DM, the placebo-corrected relative reduction in UACR at Day 90 was 25% and 38% in patients treated with finerenone 10 mg and 20 mg once daily, respectively.

In patients treated with Kerendia, the mean systolic blood pressure decreased by 3 mmHg and the mean diastolic blood pressure decreased by 1-2 mmHg at month 1, remaining stable thereafter. Cardiac Electrophysiology At a dose 2 times the maximum approved recommended dose, finerenone does not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES

14.1CKD associated with T2DM FIDELIO-DKD (NCT: 02540993) and FIGARO-DKD (NCT: 02545049) studies were randomized, double-blind, placebo-controlled, multicenter studies in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2DM). In FIDELIO-DKD, patients needed to either have an UACR of 30 to < 300 mg/g, eGFR 25 to < 60 mL/min/1.73 m 2 and diabetic retinopathy, or an UACR of ≥ 300 mg/g and an eGFR of 25 to < 75 mL/min/1.73 m 2 to qualify for enrollment. In FIGARO-DKD, patients needed to have an UACR of 30 mg/g to < 300 mg/g and an eGFR of 25 to 90 mL/min/1.73m 2 , or an UACR ≥ 300 mg/g and an eGFR ≥ 60 mL/min/1.73m 2 .

Both trials excluded patients with known significant non-diabetic kidney disease. All patients were to have a serum potassium ≤ 4.8 mEq/L at screening and be receiving standard of care background therapy, including a maximum tolerated labeled dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients with a clinical diagnosis of chronic heart failure with reduced ejection fraction and persistent symptoms (New York Heart Association class II to IV) were excluded.

The starting dose of Kerendia was based on screening eGFR (10 mg once daily in patients with an eGFR of 25 to < 60 mL/min/1.73 m 2 and 20 mg once daily in patients with an eGFR ≥ 60 mL/min/1.73 m 2 ). The dose of Kerendia could be titrated during the study, with a target dose of 20 mg daily. The primary objective of the FIDELIO-DKD study was to determine whether Kerendia reduced the incidence of a sustained decline in eGFR of ≥ 40%, kidney failure (defined as chronic dialysis, kidney transplantation, or a sustained decrease in eGFR to < 15 mL/min/1.73 m 2 ), or renal death.

The secondary outcome was a composite of time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure. The primary objective of the FIGARO-DKD study was to determine whether Kerendia reduced the time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure. The secondary outcome was a composite of time to kidney failure, a sustained decline in eGFR of 40% or more compared to baseline over at least 4 weeks, or renal death.

In FIDELIO-DKD, a total of 5674 patients were randomized to receive Kerendia (N=2833) or placebo (N=2841) and were followed for a median of 2.6 years. The mean age of the study population was 66 years, and 70% of patients were male. This global trial population was 63% White, 25% Asian, and 5% Black.

At baseline, the mean eGFR was 44 mL/min/1.73m 2 , with 55% of patients having an eGFR < 45 mL/min/1.73m 2 . Median urine albumin-to-creatinine ratio (UACR) was 852 mg/g, mean glycated hemoglobin A1c (HbA1c) was 7.7%, and the mean blood pressure was 138/76 mmHg. Approximately 46% of patients had a history of atherosclerotic cardiovascular disease and 8% had a history of heart failure.

At baseline, 99.8% of patients were treated with an ACEi or ARB. Approximately 97% were on an antidiabetic agent (insulin [64.1%], biguanides [44%], glucagon-like peptide-1 [GLP-1] receptor agonists [7%], sodium-glucose cotransporter 2 [SGLT2] inhibitors [5%]), 74% were on a statin, and 57% were on an antiplatelet agent. In FIGARO-DKD, a total of 7352 patients were randomized to receive Kerendia (N=3686) or placebo (N=3666) and were followed for 3.4 years.

As compared to FIDELIO-DKD, baseline eGFR was higher in FIGARO-DKD (mean eGFR 68, with 62% of patients having an eGFR ≥ 60 mL/min/1.73 m 2 ) and median UACR was lower (308 mg/g). Otherwise, baseline patient characteristics and background therapies were similar in the two trials. In FIDELIO-DKD, Kerendia reduced the incidence of the primary composite endpoint of a sustained decline in eGFR of ≥ 40%, kidney failure, or renal death (HR 0.82, 95% CI 0.73-0.93, p=0.001) as shown in Table 5 and Figure 1.

The treatment effect reflected a reduction in a sustained… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Finerenone was non-genotoxic in an in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in cultured Chinese hamster V79 cells, or the in vivo micronucleus assay in mice. In 2-year carcinogenicity studies, finerenone did not show a statistically significant increase in tumor response in Wistar rats or in CD1 mice. In male mice, Leydig cell adenoma was numerically increased at a dose representing 10 times the AUC unbound in humans and is not considered clinically relevant.

Finerenone did not impair fertility in male rats but impaired fertility in female rats at 9 times AUC to the maximum human exposure.