What are the benefits of this drug (results of trials used to assess efficacy)?

The primary endpoint of the study was time to first event of a substantial (40%) decline in kidney function (estimated glomerular filtration rate [eGFR]), need for dialysis, or kidney-related death (but there were few of the latter). One of these happened, per year, in 9.1% of patients receiving placebo and 7.6% of patients receiving KERENDIA. Table 1, Figure 1, and Figure 2 are from the approved prescribing information.

Table 1. Analysis of the Primary and Secondary Time-to-Event Endpoints (and Their Individual Components) in Phase 3 Study FIDELIO-DKD

Source: KERENDIA Prescribing Information

Figure 1. Time to First Occurrence of Kidney Failure, Sustained Decline in eGFR ≥40% From Baseline, or Renal Death in the FIDELIO-DKD Study

Source: KERENDIA Prescribing Information
Abbreviations: eGFR, estimated glomerular filtration rate; No., number

A similarly constructed composite endpoint looked at effects on cardiovascular outcomes, and these were also reduced, from 14.8% per year on placebo to 13% on KERENDIA, as shown in Table 1 above and Figure 2 below (also from the approved prescribing information).

Figure 2. Time to First Occurrence of CV Death, Non-Fatal Myocardial Infarction, Non-Fatal Stroke or Hospitalization for Heart Failure in the FIDELIO-DKD Study

Source: KERENDIA Prescribing Information
Abbreviations: CV, cardiovascular

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Treatment effects in various subgroups are shown in Figure 3 below. Figure 3 is from the joint review of KERENDIA posted on the Drugs@FDA website.

Such analyses have limitations. Some subgroups are small, so the confidence limits are wide. Also, these analyses do not take into consideration how different demographic factors might be related.

Figure 3. Primary Efficacy Endpoint by Key Subgroups

Source: Adapted from FDA Review

What are the possible side effects (results of trials used to assess safety)?

Table 2 below (from the KERENDIA prescribing information) shows the only adverse reactions satisfying a criterion of being reported by at least 1% more of patients on KERENDIA than on placebo.

Table 2. Adverse Reactions Reported in ≥1% of Patients on KERENDIA and More Frequently Than Placebo in the Phase 3 Study FIDELIO-DKD

Source: KERENDIA Prescribing Information

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Hyperkalemia is the only common adverse event, but potassium levels increase only weakly with drug exposure (increasing dose, lower body mass, and CYP3A4 impairment). Other demographic factors had little or no impact beyond their relationship to body mass.

Source: adsl.xpt and adae.xpt; Software: R
Analyses performed using safety population, defined as subjects who were randomized and started treatment.

Who participated in the trials?

For a description of the major subgroups studied with KERENDIA, see the forest plot of results by subgroup shown in Figure 3.

How were the trials designed?

The FIDELIO-DKD study was a randomized, double-blind, placebo-controlled, multicenter study in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D), defined as either: having a urine albumin-to-creatinine ratio (UACR) of 30 to 300 mg/g, eGFR of 25 to 60 mL/min/1.73 m², and diabetic retinopathy; or as having an UACR of ≥300 mg/g and an eGFR of 25 to 75 mL/min/1.73 m². The trial 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 m² and 20 mg once daily in patients with an eGFR ≥60 mL/min/1.73 m²). The dose of KERENDIA could be titrated during the study, with a target dose of 20 mg daily.

The primary objective of the 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 m²), or renal death.

A total of 5,674 patients were randomized to receive KERENDIA (N=2,833) or placebo (N=2,841) 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. The trial population was 63% White, 25% Asian, and 5% Black. At baseline, the mean eGFR was 44 mL/min/1.73 m², with 55% of patients having an eGFR <45 mL/min/1.73 m². Median UACR was 852 mg/g and mean glycated hemoglobin A1c (HbA1c) was 7.7%. Approximately 46% of patients had a history of atherosclerotic cardiovascular disease.

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.