CADTH Reimbursement Review

Finerenone (Kerendia)

Sponsor: Bayer Inc.

Therapeutic area: Chronic kidney disease

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Diabetes is the most common cause of kidney disease in Canada, and it is estimated by the sponsor that there are more than 1 million people in Canada living with chronic kidney disease (CKD) and type 2 diabetes (T2D) in 2022.^1-3 Older age, low socioeconomic status, obesity, smoking, poor glycemic and blood pressure control, and genetic factors are known risk factors for diabetic kidney disease.⁴ CKD is the leading cause of kidney failure (previously termed end-stage renal disease [ESRD]), necessitating dialysis or renal transplant; CKD is also associated with cardiovascular complications, leading to decreased quality of life and premature death.^1,4,5 In a US survey that evaluated 15,000 patients with diabetes and kidney disease, 10-year mortality was 4-fold and 2.7-fold higher and cardiovascular mortality was 3-fold and 6-fold higher in patients with both CKD and T2D than in patients with, respectively, CKD alone or T2D alone.⁶ Patients with both CKD and T2D also reported lower health-related quality of life (HRQoL) scores than those with CKD alone or T2D alone.^7,8 CKD is clinically diagnosed in patients who are diabetic based on the presence of albuminuria (> 30 mg/g) and/or a decreased estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m²) in at least 2 out of 3 samples in a 3-month period.^4,5 These are also 2 important indicators of disease progression: High urinary albumin-creatinine ratio (UACR) and low eGFR values indicate more severe disease.^5,9

According to the clinical experts consulted by CADTH, the primary goal of treatment is to reduce the risk of progression of CKD to ESRD by the application of pharmacologic and lifestyle strategies. The general approach to management of patients with CKD and T2D includes optimization of blood pressure, proteinuria, and glycemic control; dietary changes; and lowering of lipid levels with statins.¹⁰ In addition, for several decades, patients with CKD have been treated with either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) that inhibits the renin-angiotensin-aldosterone system (RAAS).¹⁰ Recently, guidelines have been revised to encourage the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with CKD and T2D, particularly for patients with severely increased albuminuria (> 300 mg/g).^10-12 Some patients may be intolerant of SGLT2 inhibitors, including patients with poor glycemic control, patients at high risk of genital infections or lower limb amputation, and patients with acute kidney injury.¹⁰ According to the clinical experts consulted by CADTH, there is limited access to SGLT2 inhibitors in Canada and access varies by jurisdictions, although access and subsequent use are expected to increase with time. In this review, the sponsor identifies SGLT2 inhibitors, in addition to ACE inhibitors or ARBs, as standard of care (SOC). Despite the application of pharmacologic and lifestyle strategies, the clinical experts indicated that a number of patients with both CKD and T2D continue to progress to kidney failure or develop cardiovascular events and that patients with CKD and T2D could benefit from additional pharmacologic therapies.

The reimbursement request submitted by the sponsor for review by CADTH for finerenone is as an adjunct to SOC therapy to reduce the risk of end-stage kidney disease and a sustained decrease in eGFR, as well as of cardiovascular death, nonfatal myocardial infarction (MI), and hospitalization for heart failure, where SOC includes an ACE inhibitor or ARB, and an SGLT2 inhibitor, unless contraindicated or not tolerated. Finerenone underwent review by Health Canada through the standard review pathway and received a Notice of Compliance (NOC) on October 14, 2022. Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist (MRA) that reduces inflammation and fibrosis caused by mineralocorticoid receptor overactivation by selectively binding to these receptors.¹³ Finerenone has not been previously reviewed by CADTH. Finerenone is available as oral tablets (10 mg and 20 mg). The recommended starting dosage of finerenone is 20 mg once daily for patients with an eGFR greater than or equal to 60 mL/min/1.73 m² or 10 mg once daily for patients with an eGFR greater than or equal to 25 mL/min/1.73 m² to less than 60 mL/min/1.73 m². Four weeks after initiation, restart, or up-titration of finerenone treatment, serum potassium and eGFR should be remeasured to determine continuation of finerenone treatment and dose adjustment. Thereafter, serum potassium should be remeasured periodically and as needed based on patient characteristics and serum potassium levels. Initiation of finerenone treatment is not recommended in patients with an eGFR less than 25 mL/min/1.73 m² or in patients with serum potassium greater than 5.0 mmol/L. Treatment should be discontinued in patients with ESRD (eGFR < 15 mL/min/1.73 m²).

The objective of this review is to perform a systematic review of the beneficial and harmful effects of finerenone 10 mg and 20 mg tablets to delay the progression of kidney disease and to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke) and hospitalization for heart failure in adult patients with CKD and T2D.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Patient input for the review of finerenone was provided as a joint submission from the Kidney Foundation of Canada and Diabetes Canada. They conducted an online survey of patients with CKD and T2D, and their caregivers, residing across Canada in May 2022 (n = 24; 9 completed and 15 partially completed the survey). Eight respondents identified as patients with CKD, 1 respondent identified as a caregiver of a patient with CKD, and 6 respondents identified as patients with T2D.

Survey respondents who identified themselves as living with both CKD and diabetes reported challenges with fatigue and anemia as well as adhering to dietary restrictions due to the high costs associated with those restrictions and inconvenience when dining with others. Patients with CKD may often present with comorbidities; 7 respondents reported high blood pressure, 3 reported high cholesterol, 1 reported high potassium levels, 1 reported heart disease, and 1 reported having had a heart attack. One survey respondent stated feeling tired and unable to focus on certain tasks due to living with multiple medical conditions. Five respondents reported worsening of their CKD, and 6 respondents indicated they had taken a medication to reduce the risk of worsening kidney disease, of which 3 reported experience with ACE inhibitors and 2 reported experience with ARBs. Respondents also indicated experience with diuretics, tacrolimus, erythropoietin, and dapagliflozin (SGLT2 inhibitor). Of the 6 survey respondents who indicated their level of satisfaction with their current medication(s), 3 were satisfied, 1 was very satisfied, and 2 were neutral.

Survey respondents identified the following factors as the most important considerations for new treatment options in CKD: “Does it make me feel tired?” “Does it interfere with my other medications?” and “How much does it cost?” Survey respondents identified the following outcomes as important for new treatment options for CKD both with or without diabetes: “limiting or arresting the progression of both diseases,” “make kidneys better,” “a longer life span,” and “maintain and improve quality of life overall.”

Finally, the Kidney Foundation of Canada and Diabetes Canada indicated that patients living with CKD may experience significant financial challenges due to reduced income (e.g., missed time from work as a result of their symptoms) and increased expenses (e.g., high costs associated with treatment, frequent visits to the health care team, and hospitalization). According to the organizations, equitable access to medications that slow the progression of kidney disease and reduce the risk of cardiovascular events, such as finerenone, may help relieve the financial burden of CKD and T2D on patients and the health care system.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

The clinical experts mentioned that, despite available therapies for patients with CKD and T2D, there is a need for additional treatment options that reduce the risk of progression to kidney failure or cardiovascular events. There are still patients who progress to these outcomes and who could benefit from additional therapies such as finerenone. The clinical experts noted that the current paradigm aims to reduce progression of CKD to ESRD (kidney failure requiring dialysis or renal transplant). Treatment measures include blood pressure control, RAAS inhibition (ACE inhibitors and/or ARBs), and the use of SGLT2 inhibitors, in addition to lifestyle changes, the use of statins, and glycemic control. The clinical expert noted that finerenone may be combined with SGLT2 inhibitors to reduce cardiorenal risk as they protect kidney function through distinct and complementary pathways.¹⁴

According to the clinical experts, finerenone should be considered for patients who retain significant residual proteinuria despite being on a maximum tolerated dose of ACE inhibitor or ARB and SGLT2 inhibitor and noted, based on clinical experience, that finerenone can be added to these therapies 3 months after initiating SGLT2 inhibitor. They also mentioned that patients who are unable to tolerate SGLT2 inhibitor (e.g., due to hypotension or acute kidney injury) should be considered for finerenone. In the opinion of the clinical experts, treatment response can be assessed using surrogate measures such as changes in proteinuria over time and stability of renal function (eGFR). Intervals for monitoring should follow the current guidelines (twice annually according to the American Diabetes Association).¹⁵

According to the clinical experts, finerenone is better initiated as an add-on therapy in a specialist setting or in a community setting with specialist guidance and support. The clinical experts noted that finerenone should be discontinued if the patient is unable to tolerate the drug because of adverse events (AEs) such as hyperkalemia that are not amenable to management (e.g., dietary changes and/or diuretic use) or such as hypotension.

Clinician Group Input

The views of the clinician groups were consistent with the views of the clinical experts consulted by CADTH. Clinician group input for the review of finerenone was prepared and submitted by clinicians representing LMC Diabetes and Endocrinology, a single-specialty group endocrinology practice with 13 clinics across 3 provinces (Ontario, Quebec, and Alberta).

The clinician group recognized that there is an unmet need for a medication that will address significant decline in kidney function and cardiovascular disease in patients with T2D despite the availability of RAAS blockers and SGLT2 inhibitors and in patients who experience intolerance to and side effects with the currently available treatment options. The clinician group indicated finerenone would be used as an add-on therapy to RAAS blockers with or without SGLT2 inhibitors in patients with T2D and an ongoing risk of kidney disease progression and cardiovascular disease. Alternatively, finerenone would be used as the first add-on therapy for patients who were unable to tolerate or who developed side effects with RAAS blockers or SGLT2 inhibitors.

With respect to the patient population that will most likely benefit from finerenone, the clinician group identified patients with an eGFR greater than or equal to 25 mL/min/1.73 m² and a UACR greater than or equal to 34 mg/mmol or patients with an eGFR of 25 mL/min/1.73 m² to 90 mL/min/1.73 m² and a UACR of 3.4 mg/mmol to 33.9 mg/mmol. The patient population identified to be the least suitable for treatment with finerenone was patients with a history of clinically significant hyperkalemia. Outcomes used in clinical practice would be preservation of eGFR over time, reduction in UACR, improved symptoms of heart failure or prevention of heart failure, and reduced emergency department visits or hospitalizations.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators in the randomized controlled trials (RCTs); considerations for initiation of therapy, for prescribing of therapy, and for discontinuation of therapy; and system and economic issues. The clinical experts consulted by CADTH weighed evidence from the FIDELIO and FIGARO studies and other clinical considerations to provide responses to the drug program implementation questions. Refer to Table 5 for more details.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

FIDELIO (N = 5,734) and FIGARO (N = 7,437) are phase III, randomized, double-blind, placebo-controlled, parallel-group, multicentre, event-driven studies of finerenone compared with placebo in patients with CKD and T2D. The 2 studies differed in their primary objective: The primary objective in FIDELIO was time to first occurrence of a renal composite end point in both the finerenone and placebo groups, while the primary objective of FIGARO was time to first occurrence of a cardiovascular composite end point in both the finerenone and placebo groups. Secondary objectives in each study included the primary objective of the other study, as well as time to first occurrence of a more severe renal composite end point, time to all-cause mortality, time to all-cause hospitalization, and change in UACR from baseline to month 4. The studies were sponsored by Bayer and included 30 (FIDELIO) and 31 (FIGARO) study centres in Canada.

After a run-in period of up to 16 weeks and a screening period of up to 2 weeks, eligible patients were randomized in a 1:1 ratio to the finerenone (10 mg or 20 mg) or placebo treatment arm, and stratified by region, eGFR category at screening, and albuminuria interval at screening. Randomization occurred at visit 1, and then there were 3 more planned monthly visits, followed by a visit every 4 months until the end of the study. The finerenone dose could be up-titrated or down-titrated at any point following the start of treatment at visit 1. If patients stopped the study drug prematurely, they remained in the trial and were followed up with until the end of the study.

Patient demographic characteristics and key disease characteristics were balanced between the finerenone and placebo groups in both trials. The mean age in both groups in both studies was approximately 65 years old. Most patients in both trials were male (69.8%) and white (68.1%). The mean baseline body mass index across all groups was 31.3 (standard deviation [SD] = 6.0), 47.5% of patients had never smoked, and 59.8% were alcohol abstinent. In the FIDELIO trial, the mean baseline eGFR was approximately 44 mL/min/1.73 m² (SD = 12.5) in both groups, and the mean baseline UACR was 798.8 mg/g (SD = 2.7) and 814.7 mg/g (SD = 2.7) in the finerenone and placebo groups, respectively. In FIGARO, the mean baseline eGFR was approximately 68 mL/min/1.73 m² (SD = 21.7) in both groups, and the mean baseline UACR was 284.3 mg/g (SD = 3.6) and 288.9 mg/g (SD = 3.5) in the finerenone and placebo groups, respectively. Regarding medication use at baseline, 66% of patients in FIDELIO and 57% of patients in FIGARO were on ARBs, and 34% of patients in FIDELIO and 43% of patients in FIGARO were on ACE inhibitors. Across the 2 trials, 97.7% of patients were also on antidiabetic treatment, including 6.7% of patients who were on SGLT2 inhibitors.

Efficacy Results

Key efficacy results of the FIDELIO and FIGARO trials for all randomized patients are summarized in Table 2. In FIDELIO, the primary and key secondary end points met the preplanned criteria for significance, and all-cause mortality (the next secondary end point) was tested hierarchically. It did not reach statistical significance, and so the remaining secondary end points were tested in an exploratory manner. In FIGARO, the primary end point met the preplanned criteria for significance, and the key secondary end point did not; therefore, the remaining secondary end points were tested in an exploratory manner.

The primary outcome in the FIDELIO study was time to first occurrence of the 40% renal composite end point, which comprises onset of kidney failure, a sustained decrease of eGFR greater than or equal to 40% from baseline over at least 4 weeks, or renal death. The 40% renal composite end point was a key secondary end point in FIGARO. In FIDELIO, this composite outcome occurred in 504 patients (17.8%) and 600 patients (21.1%) in the finerenone and placebo groups, respectively, and the hazard ratio (HR) was 0.825 (95% confidence interval [CI], 0.73 to 0.93; P = 0.0014) in favour of finerenone. In FIGARO, this end point occurred in 350 patients (9.5%) and 395 patients (10.8%) in the finerenone and placebo groups, respectively, and the HR was 0.87 (95% CI, 0.76 to 1.01; P = 0.0689), which was not statistically significant. In the pooled analysis of FIDELIO and FIGARO, the HR was 0.85 (95% CI, 0.77 to 0.93) and 0.77 (95% CI, 0.67 to 0.88) for the 40% and 57% renal composite end points, respectively, in favour of finerenone.

The 57% renal composite end point was a secondary end point in both studies. In FIDELIO, it occurred in 252 patients (8.9%) and 326 patients (11.5%) in the finerenone and placebo groups, respectively, and the HR was 0.76 (95% CI, 0.65 to 0.90) in favour of finerenone. In FIGARO, it occurred in 108 patients (2.9%) and 139 patients (3.8%) in the finerenone and placebo groups, respectively, and the HR was 0.77 (95% CI, 0.60 to 0.99) in favour of finerenone. In FIDELIO, the individual components of sustained decrease in eGFR greater than or equal to 40% or of greater than or equal to 57% (relative to baseline) had HRs of 0.815 (95% CI, 0.722 to 0.920) and 0.68 (95% CI, 0.55 to 0.82), respectively, and were the main drivers of the composite outcome results. The treatment effect of finerenone was assessed across the following subgroups of patients: history of cardiovascular disease, eGFR category at baseline, type of albuminuria at baseline, and SGLT2 inhibitor treatment at baseline. In general, the treatment effect of finerenone on the primary end point (time to first occurrence of the 40% renal composite end point) was consistent with the primary analysis across patient subgroups, with the following exception: In FIDELIO, the HR was greater than 1 in patients who were treated with SGLT2 inhibitors at baseline, favouring placebo over finerenone, yet the small sample size and wide CIs in this subgroup reflect uncertainty in the effect estimates. In FIGARO, the HR was also greater than 1 in patients with an eGFR of 45 mL/min/1.73 m² to less than 60 mL/min/1.73 m² at baseline and in patients with high albuminuria (30 mg/g to < 300 mg/g) at baseline.

Baseline values of UACR were comparable between the treatment groups but differed between trials according to the inclusion criteria, with higher values in the FIDELIO trial population. Nevertheless, in both trials, the change in UACR from baseline to month 4 was larger in the finerenone group than in the placebo group, with a ratio of least squares (LS) mean change from baseline (95% CI) of 0.69 (0.66 to 0.72) and 0.68 (0.65 to 0.70) in FIDELIO and FIGARO, respectively, with a P value less than 0.0001.

Baseline values of eGFR were comparable between the treatment groups but differed between trials according to the inclusion criteria, with lower values in the FIDELIO trial population. There was a larger acute reduction in eGFR in the finerenone group than in the placebo group, with an LS mean difference between groups at month 4 of –2.38 (95% CI, –2.77 to –1.98) and –2.24 (95% CI, –2.67 to –1.80) in FIDELIO and FIGARO, respectively, with a P value of less than 0.0001. The decrease in eGFR in the finerenone group then slows down, until the difference between both groups becomes positive, indicating a slower rate in eGFR decline in the finerenone group than in the placebo group at month 28 in the FIDELIO trial and month 36 in the FIGARO trial.

The primary outcome in the FIGARO study was time to first occurrence of the cardiovascular composite end point, which comprises cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure. The cardiovascular composite end point was a key secondary end point in FIDELIO. In FIDELIO, this composite outcome occurred in 367 patients (13%) and 420 patients (14.8%) in the finerenone and placebo groups, respectively, and the HR was 0.86 (95% CI, 0.75 to 0.99; P = 0.0339) in favour of finerenone. In FIGARO, this end point occurred in 458 patients (12.4%) and 519 patients (14.2%) in the finerenone and placebo groups, respectively, and the HR was 0.87 (95% CI, 0.76 to 0.98; P = 0.0264) in favour of finerenone. In the pooled analysis of both trials, the HR was 0.86 (95% CI, 0.78 to 0.95) with a P value of 0.0018 in favour of finerenone. In FIGARO, the only individual component of statistical significance was hospitalization for heart failure, which had an HR of 0.71 (95% CI, 0.56 to 0.90) in favour of finerenone. In both trials, there was almost no difference in the risk of nonfatal stroke, with an HR of 0.97 (95% CI, 0.74 to 1.26) in FIDELIO and of 1.03 (95% CI, 0.77 to 1.38) in FIGARO. The treatment effect of finerenone on time to first occurrence of the cardiovascular composite end point was assessed across the following subgroups of patients: history of cardiovascular disease, eGFR category at baseline, type of albuminuria at baseline, and SGLT2 inhibitor treatment at baseline. In general, the treatment effect of finerenone was consistent with the primary analysis across patient subgroups, with the following exception: The HR was approximately 1 in patients who were treated with SGLT2 inhibitors at baseline in FIDELIO, while the HR was 0.49 (95% CI, 0.28 to 0.86) in FIGARO. However, the small sample size of this patient group in both trials reflects uncertainty in the effect estimates.

Incidence of all-cause mortality was similar between both groups in both trials, with 552 deaths (8.5% of patients) and 614 deaths (9.4% of patients) from any cause in the finerenone and placebo groups, respectively. Comparing the finerenone group with the placebo group, the HR was 0.90 (95% CI, 0.75 to 1.07) in FIDELIO and 0.89 (95% CI, 0.77 to 1.04) in FIGARO.

Incidence of all-cause hospitalization was similar between both groups in both trials, with 2,836 patients (43.5%) and 2,926 patients (45.0%) hospitalized for any cause in the finerenone and placebo groups, respectively. More hospitalizations were non–cardiovascular related (35%) than cardiovascular related (19%). Comparing the finerenone group with the placebo group, the HR was 0.95 (95% CI, 0.88 to 1.02) in FIDELIO and 0.97 (95% CI, 0.90 to 1.04) in FIGARO.

At baseline, the mean Kidney Disease Quality of Life survey (KDQOL-36) summary scores in all domains were comparable between treatment groups in each trial, and between both trials, except for the “burden of kidney disease” domain, where patients in the FIGARO group scored higher than those in the FIDELIO group. The quality of life decreased over time for all patients, consistently in all domains, assessed until month 36 in FIDELIO and month 48 in FIGARO. The physical component summary showed a sustained difference in favour of finerenone in FIDELIO at month 12 (LS mean difference = ███ ████ ███ ███ ██ ████ ███████ █ █████) and month 24 (LS mean difference = ███ ████ ███ ███ ██ ████ █████████████), and in FIGARO at month 36 (██ ████ ██████████ ████ ████ ███ ███ ██ ████ ███████ ██████).

Table 2: Summary of Key Results From Pivotal and Protocol-Selected Studies (FAS)

CI = confidence interval; eGFR = estimated glomerular filtration rate; FAS = full analysis set; HR = hazard ratio; LS = least squares; SD = standard deviation; UACR = urinary albumin-creatinine ratio.

^aRenal composite end point comprises onset of kidney failure, sustained decrease of eGFR greater than or equal to 40% or of greater than or equal to 57% from baseline over at least 4 weeks, or renal death. For composite outcomes and each component, the first event after randomization is considered. Subsequent events of the same type are not shown. The incidence rate is estimated as the number of patients with events divided by the cumulative at-risk time in the reference population, where a patient was no longer at risk once an event occurred. Incidence rates, HRs, and P values were only calculated for predefined efficacy end points.

^bTwo-sided P value from log-rank test, stratified. Adjusted for multiplicity for the primary 40% renal composite outcome and the key secondary cardiovascular composite outcome in FIDELIO, and only for the primary cardiovascular composite outcome in FIGARO.

^cCardiovascular composite end point comprises cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Events were adjudicated by an independent adjudication committee and considered from randomization until the end-of-study visit. For composite outcomes and each component, the first event after randomization is considered. Subsequent events of the same type are not shown. The incidence rate is estimated as the number of patients with events divided by the cumulative at-risk time in the reference population, where a patient was no longer at risk once an incident event occurred.

^dUACR was determined 3 times at each visit from first morning void urine samples collected on 3 consecutive days and summarized according to the statistical analysis plan. For baseline, only samples with two-thirds of measurements taken on or before the day of randomization were used.

^eMonth 4 is the visit closest to day 120 within a time window of 120 ± 30 days after randomization. If no measurements are available in this time window, the patient is excluded from this analysis.

^fAnalysis of covariance with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, and log-transformed baseline value as covariate nested within type of albuminuria.

^gF test of equal means between the following additional factor levels: region, eGFR category at screening, and type of albuminuria at screening.

^hFor the statistical evaluation, a mixed model was applied with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, time, treatment × time, baseline value nested within type of albuminuria, and baseline value × time as covariate.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Harms Results

A summary of harms in the pooled analysis of FIDELIO and FIGARO is presented in Table 3. A total of 5,602 patients (86.1%) in the finerenone group and 5,607 patients (86.4%) in the placebo group experienced at least 1 AE. The most common AE in the finerenone group was hyperkalemia (14% versus 6.9% in the placebo group), and the most common AEs in the placebo group were hypertension (9% versus 6.4% in the finerenone group) and peripheral edema (5.9% versus 9% in the finerenone group). A total of 2,060 patients (31.6%) in the finerenone group and 2,186 patients (33.7%) in the placebo group experienced at least 1 serious AE (SAE). The most commonly reported SAE was pneumonia (2.2% in the finerenone group versus 3.3% in the placebo group).

A total of 414 patients (6.4%) in the finerenone group and 351 patients (5.4%) in the placebo group stopped treatment due to AEs. There were 110 deaths (1.7% of patients) and 151 deaths (2.3% of patients) due to treatment-emergent AEs in the finerenone and placebo groups, respectively.

In terms of notable harms, more patients reported hypotension in the finerenone group than in the placebo group (4.3% versus 2.7%). The number of patients who experienced atrial flutter and atrial fibrillation was less than 1% in each treatment group and comparable between groups. The number of patients who experienced hospitalization due to hyperkalemia was higher in the finerenone group than in the placebo group (0.9% versus 0.2%).

Table 3: Summary of Key Harms Results From the Pooled Analysis (Safety Analysis Set)

SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Source: FIDELITY pooled analysis.¹⁸

Critical Appraisal

Key baseline demographic and disease characteristics and past history of medication used appear to be balanced between the finerenone and placebo groups in both trials. There were important protocol deviations, balanced between treatment groups, reported in 53% and 58.5% of patients in FIDELIO and FIGARO, respectively. Due to study timelines, more protocol deviations associated with the COVID-19 pandemic were reported in FIGARO than in FIDELIO; however, deviations were balanced between treatment groups, and supportive analyses did not uncover any notable effect of the COVID-19 pandemic on the treatment effect of finerenone. The interpretation of results for the HRQoL instruments (i.e., the ability to assess trends over time and to make comparisons across treatment groups) is limited by the significant decline in patients available to provide assessment over time as well as lack of evidence of validity or minimal important difference (MID) of the HRQoL questionnaires used in the trials in patients with CKD and T2D. In the prespecified FIDELITY pooled analysis combining both trials, patients in FIDELIO had a lower eGFR at baseline than those in FIGARO, and the mean treatment duration was longer in FIGARO (approximately 35 months) than in FIDELIO (approximately 27 months). The statistical analysis in FIDELITY was exploratory and descriptive in nature with no adjustment for multiplicity; however, pooling is considered appropriate.

According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of both study populations were generally reflective of the patients with CKD and T2D living in Canada. They agreed that there was an overrepresentation of male patients (70% male to 30% female) and noted there should be a more proportionate representation of patients, given potential differences in treatment efficacy and safety. The product monograph indicates that patients with an eGFR less than or equal to 25 mL/min/1.73 m² should not start finerenone; however, 2.4% of patients in FIDELIO reported a baseline eGFR less than or equal to 25 mL/min/1.73 m² (potentially due to decline in eGFR between screening and randomization). While the trials were under way, the SOC for patients with CKD and T2D evolved to include SGLT2 inhibitor. Therefore, only 6.7% of patients in both trials (n = 877) were on an SGLT2 inhibitor at baseline, and patients were not stratified by SGLT2 inhibitor use; however, use at baseline was balanced between the 2 treatment groups in both trials. In addition, the proportion of patients using glucagon-like peptide-1 (GLP-1) agonists with and without SGLT2 inhibitor at baseline was not balanced (18.5% versus 6.4%). This may have confounded the subgroup findings as GLP-1 agonists may also improve cardiorenal outcomes in patients with CKD and T2D.^19,20 The clinical experts consulted by CADTH agreed that placebo plus SOC was an appropriate comparator in Canadian clinical practice for patients with CKD and T2D. The clinical experts agreed with the sponsor’s definition of SOC as including an ACE inhibitor or ARB, and ideally an SGLT2 inhibitor, which is still not widely accessible to patients with CKD and T2D living in Canada. The clinical experts pointed out that a combination therapy with the 2 drugs together makes physiologic sense as SGLT2 inhibitors are linked to reductions in the risk of hyperkalemic episodes (serum potassium ≥ 6.0 mmol/L), and finerenone has hyperkalemia as a side effect. There is, however, limited evidence on the positioning of finerenone in relation to SGLT2 inhibitors, and the evidence available for the addition of finerenone to ACE inhibitor or ARB, and an SGLT2 inhibitor, is limited. A non-sponsor-submitted reimbursement review assessing the use of SGLT2 inhibitor in patients with CKD and T2D is currently ongoing. A phase II RCT that will compare finerenone plus placebo, SGLT2 inhibitors plus placebo, and finerenone plus SGLT2 inhibitors (CONFIDENCE trial)²¹ will begin in 2022, and results may provide more insight into this comparison and the place of finerenone in therapy. Finally, the trials included composite renal and cardiovascular outcomes and were only powered for their respective primary composite outcomes and not for the components of the primary outcome, which include a sustained decrease in eGFR and initiation of ESRD in FIDELIO, and hospitalization for heart failure in FIGARO; hence, the impact of finerenone on each of the components of the composite outcomes is uncertain.

Indirect Comparisons

Indirect evidence from 1 published network meta-analysis (NMA) by Zhao et al. (2022)²² evaluated the effectiveness of finerenone compared to SGLT2 inhibitors in the treatment of CKD and T2D. SGLT2 inhibitors are currently part of the SOC for patients with diabetic kidney disease; however, only 6.7% of patients (877 out of 13,026) in the pivotal trials were concurrently taking SGLT2 inhibitors in the FIDELIO and FIGARO trials. This NMA, therefore, provides an indirect comparison of efficacy outcomes between finerenone and SGLT2 inhibitors.

Description of Studies

The authors include 14 articles reporting 8 placebo-controlled RCTs comprising 30,661 patients. Seven studies involved an assessment of SGLT2 inhibitor (13,246 patients receiving gliflozin versus 11,741 receiving placebo): EMPA-REG OUTCOME,^23,24 CANVAS Program,^25,26 CREDENCE,^27,28 DECLARE–TIMI 58,²⁹ DAPA-CKD,³⁰ VERTIS CV,^31,32 and SCORED.³³ One study (the pivotal FIDELIO trial)^34,35 assessed finerenone (2,833 patients receiving finerenone versus 2,841 receiving placebo). According to risk of bias assessment, there was low risk of bias in all 8 studies.

Major adverse cardiovascular events were defined consistently across the included studies. Kidney function progression, however, was defined differently across the included studies, with composite end points that included ESRD, renal death, and a sustained decrease in eGFR that ranged from 40% to 50%. One trial (EMPA-REG OUTCOME) included patients who had initiated renal replacement therapy, and 2 trials (DAPA-CKD and SCORED) included patients with kidney transplants. One trial (VERTIS CV) did not report a renal composite end point. The authors considered these definitions similar enough to be used in the meta-analysis.

Efficacy Results

NMA results showed that, compared to finerenone, SGLT2 inhibitors significantly reduced the risks of kidney function progression (HR = 0.78; 95% CI, 0.67 to 0.90) and hospitalization for heart failure (HR = 0.71; 95% CI, 0.55 to 0.92). No treatment was favoured when finerenone was compared to SGLT2 inhibitors for the outcomes of major adverse cardiovascular events (HR = 0.95; 95% CI, 0.71 to 1.27), nonfatal MI (HR = 0.91; 95% CI, 0.64 to 1.30), nonfatal stroke (HR = 0.70; 95% CI, 0.35 to 1.39), cardiovascular death (HR = 1.00; 95% CI, 0.78 to 1.29), and all-cause death (HR = 0.96; 95% CI, 0.75 to 1.23). No network plot for any outcome had a closed loop, suggesting a lack of direct evidence between finerenone and SGLT inhibitors, so an inconsistency test was not performed.

Harms Results

The safety outcomes of the treatments were not assessed in this NMA.

Critical Appraisal

This NMA included a limited number of studies, with some heterogeneity in the definition of a key renal outcome across the studies. Only 1 study assessed finerenone, while the other 7 assessed an SGLT2 inhibitor, which limited the statistical power of this NMA. The second pivotal RCT on finerenone from this review (FIGARO) was not included in this NMA; its inclusion may have strengthened this analysis. The authors did not explore the baseline demographic characteristics of the patient populations across the trials and reported that “the cardiorenal risk of participants was possibly different among included trials.”²² The durations of the trials were not reported and may have differed between studies. Moreover, the safety outcomes of the treatments were not assessed in this NMA. The CADTH review team was unable to rigorously assess the methods in this article because insufficient details on the methods were provided (e.g., no details on the retrieved number of records in the systematic review), and there was no discussion on possible adjustments for potential effect modifiers or feasibility assessment. A small proportion of patients in the included FIDELIO trial were using SGLT2 inhibitor at baseline, but no additional analysis including and excluding this subgroup was conducted.

Conclusions

Two RCTs informed the systematic review of finerenone as an adjunct therapy for the treatment of patients with CKD and T2D. The trials demonstrated that treatment with finerenone was associated with a clinically meaningful reduction in the renal composite outcome and the cardiovascular composite outcome, driven by the outcome components of a sustained decrease in eGFR greater than or equal to 40% or greater than or equal to 57% and incidence of hospitalization for heart failure. The trials also demonstrated that finerenone was associated with a significant reduction in UACR from baseline, which the clinical experts referred to as an important marker for reduced risk of progression of CKD to ESRD. The impact of finerenone on HRQoL is uncertain due to difficulty interpreting results from the HRQoL instruments. All patients in both trials were on a maximum tolerated dose of ACE inhibitor or ARB as SOC, but only a small proportion in both trials were on SGLT2 inhibitor at baseline; hence, available evidence on the efficacy and safety of the addition of finerenone to ACE inhibitor or ARB, and an SGLT2 inhibitor, is limited. No significant difference was reported when comparing patients who were on an SGLT2 inhibitor at baseline with patients who were not. Furthermore, although the included NMA favoured SGLT2 inhibitor over finerenone in improving cardiorenal outcomes, this NMA had several limitations that preclude any definitive conclusion.

The safety profile of finerenone in these trials was consistent with the known safety profile of other nonsteroidal MRAs in terms of hyperkalemia and hypotension. No additional safety signals were identified with finerenone in this study.

Introduction

Disease Background

Diabetes is the most common cause of kidney disease in Canada, and it is estimated by the sponsor (applying prevalence estimates) that there are more than 1 million people in Canada living with CKD and T2D in 2022.^1-3 Diabetic kidney disease has “numerous overlapping etiologic pathways” where changes in glomerular hemodynamics, inflammation, and fibrosis mediate kidney tissue damage.⁴ However, the only way to differentiate between CKD caused directly by diabetes (diabetic nephropathy) and CKD from other causes in patients who are diabetic is a kidney biopsy, which is rarely performed, and so the term “diabetic kidney disease” with no pathological phenotype is most commonly used.⁴ Older age, low socioeconomic status, obesity, smoking, poor glycemic and blood pressure control, and genetic factors are known risk factors for diabetic kidney disease.⁴ T2D linked to obesity is now common in younger populations, resulting in an earlier and more rapid rate of progression of CKD complications.⁴

CKD is the leading cause of ESRD, requiring dialysis or renal transplant. CKD is also associated with cardiovascular complications leading to decreased quality of life and premature death.^1,4,5 In a US survey that evaluated 15,000 patients with diabetes and kidney disease, 10-year mortality was 4-fold and 2.7-fold higher and cardiovascular mortality was 3-fold and 6-fold higher in patients with both CKD and T2D than in patients with, respectively, CKD alone or T2D alone.⁶ Patients with both CKD and T2D also reported lower HRQoL scores than those with CKD alone or T2D alone.^7,8

CKD is clinically diagnosed in patients who are diabetic based on the presence of albuminuria (> 30 mg/g) and/or decreased eGFR (eGFR < 60 mL/min/1.73 m²) in at least 2 out of 3 samples in a 3-month period.^4,5 These are also 2 important indicators of disease progression: High UACR and low eGFR values indicate more severe disease.^5,9 In some cases, patients with T2D and CKD may present with only reduced eGFR and normal urine albumin levels (UACR ≤ 30 mg/mmol), referred to as nonproteinuric diabetic CKD.⁴

Standards of Therapy

According to the clinical experts consulted by CADTH, the primary goal of treatment is to reduce the risk of progression of CKD to ESRD by the application of pharmacologic and lifestyle strategies. The general approach to management of patients with CKD and T2D includes optimization of blood pressure, proteinuria, and glycemic control; dietary changes; and lowering of lipid levels with statins.¹⁰ In addition, for several decades, patients with CKD have been treated with either an ACE inhibitor or an ARB that inhibits the RAAS.¹⁰ RAAS inhibiters are antihypertensive drugs and have also been linked to decreasing the risk of progression of albuminuria from normal to mildly increased (30 mg/g to 300 mg/g) and from mildly increased to severely increased (> 300 mg/g).¹⁰ Assessment of serum creatinine and potassium soon after starting or intensifying RAAS inhibitors is recommended due to their serum creatinine and potassium–elevating effects.^10,12

Recently, guidelines have been revised to encourage the use of SGLT2 inhibitors in patients with CKD and T2D, particularly for patients with severely increased albuminuria (> 300 mg/g).^10-12 SGLT2 inhibitors can prevent renal disease progression, including the development of ESRD, as well as the incidence of cardiovascular disease in patients with diabetic kidney disease, as demonstrated in 2 large RCTs: CREDENCE and DAPA-CKD.^27,32,36 Some patients may be intolerant of SGLT2 inhibitors, including patients with poor glycemic control, patients at high risk of genital infections or lower limb amputation, and patients with acute kidney injury.¹⁰ According to the clinical experts consulted by CADTH, there is limited access to SGLT2 inhibitors in Canada, and access varies by jurisdictions, although access and subsequent use are expected to increase with time. In this review, the sponsor identifies SGLT2 inhibitors, in addition to ACE inhibitors or ARBs, as SOC.

In spite of the application of the pharmacologic and lifestyle strategies, the clinical experts indicated that there are patients with CKD and T2D who continue to progress to renal failure or develop cardiovascular events and who could benefit from additional pharmacologic therapies.

According to the clinical experts consulted by CADTH and clinical management guidelines, patients with CKD and T2D should ideally be monitored every 3 months to 6 months to assess blood pressure, glycated hemoglobin, volume status, eGFR based on serum creatinine, serum potassium, and albuminuria.¹⁰

Drug

The initial reimbursement request submitted by the sponsor for review by CADTH for finerenone is as an adjunct to SOC therapy to delay progression of kidney disease and to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke) and hospitalization for heart failure in adults with CKD and T2D, where SOC includes an ACE inhibitor or ARB, and an SGLT2 inhibitor, unless contraindicated or not tolerated.³⁷ Finerenone underwent review by Health Canada through the standard review pathway and received an NOC on October 14, 2022. The approved indication is as adjunct to SOC therapy in adults with CKD and T2D to reduce the risk of end-stage kidney disease and a sustained decrease in eGFR, as well as of cardiovascular death, nonfatal MI, and hospitalization for heart failure.¹³ The CADTH review team agreed with the sponsor’s assessment that this revision to the indication does not meaningfully impact the CADTH clinical review, and the reimbursement request was subsequently revised to this approved indication. Finerenone was approved by the FDA on July 9, 2021, to be used to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, nonfatal MI, and hospitalization for heart failure in adult patients with CKD associated with T2D.¹¹ It was approved by the Australian Therapeutic Goods Administration on November 18, 2021, to delay progressive decline of kidney function in adults with CKD associated with T2D (with albuminuria), in addition to SOC.³⁸ Finally, finerenone was approved by the European Medicines Agency on December 16, 2021, for the treatment of CKD (stage 3 and 4 with albuminuria) associated with T2D in adults.³⁹ The sponsor noted that the European Medicines Agency review was based only on the FIDELIO clinical trial and that a European Medicines Agency review based on the FIGARO trial is ongoing. In its draft guidance issued in May 2022, the National Institute for Health and Care Excellence (NICE) was minded not to recommend finerenone as an option for treating stage 3 and 4 CKD with albuminuria associated with T2D in adults.⁴⁰ The sponsor noted that the institute’s process is ongoing, with a second appraisal committee meeting to be held after requested clarification and analyses are provided. Finerenone is currently under review at the Scottish Medicines Consortium.

Mineralocorticoid receptors are expressed in the kidneys, heart, and blood vessels. Finerenone is a nonsteroidal, selective MRA that reduces inflammation and fibrosis caused by mineralocorticoid receptor overactivation by selectively binding to mineralocorticoid receptors.¹³ This binding leads to a “specific receptor ligand complex that blocks recruitment of transcriptional coactivators implicated in the expression of proinflammatory and profibrotic mediators.”¹³ Due to its nonsteroidal structure, finerenone has no relevant affinity for androgen, progesterone, estrogen, or glucocorticoid receptors and therefore does not cause sex hormone–related AEs such as gynecomastia (as is common with other MRAs, such as spironolactone). Finerenone has not been previously reviewed by CADTH.

Key characteristics of finerenone are shown in Table 4. Finerenone is available as oral tablets (10 mg and 20 mg). The recommended starting dosage of finerenone is 20 mg once daily for patients with eGFR greater than or equal to 60 mL/min/1.73 m² or 10 mg once daily for patients with eGFR greater than or equal to 25 mL/min/1.73 m² to less than 60 mL/min/1.73 m². Four weeks after initiation, restart, or up-titration of finerenone treatment, serum potassium and eGFR should be remeasured to determine continuation of finerenone treatment and dose adjustment. Thereafter, serum potassium should be remeasured periodically and as needed based on patient characteristics and serum potassium levels. Initiation of finerenone treatment is not recommended in patients with eGFR less than 25 mL/min/1.73 m² and for patients with serum potassium greater than 5.0 mmol/L. Treatment with finerenone should be discontinued in patients with ESRD (eGFR < 15 mL/min/1.73 m²).¹³

Table 4: Key Characteristics of Finerenone and SGLT2 Inhibitors for CKD and T2D

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; SGLT2 = sodium-glucose cotransporter-2; T2D = type 2 diabetes.

^aHealth Canada–approved indication.

Source: Finerenone product monograph;¹³ Perkovic et al. (2022).¹⁰

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.

Patient input for the review of finerenone was provided as a joint submission from the Kidney Foundation of Canada and Diabetes Canada. The Kidney Foundation of Canada and Diabetes Canada are charities committed to eliminating the burden of kidney disease and leading the fight against diabetes, respectively, through research, education, and advocacy.

The Kidney Foundation of Canada and Diabetes Canada conducted an online survey of patients with CKD and T2D, and their caregivers, residing across Canada in May 2022 (n = 24; 9 completed and 15 partially completed the survey). Eight respondents identified as patients with CKD, 1 respondent identified as a caregiver of a patient with CKD, and 6 respondents identified as patients with T2D. Of the 8 respondents who reported their current age, or the age of the patient they cared for, 2 patients were aged between 40 years and 54 years, 2 patients were aged between 55 years and 69 years, and 4 patients were 70 years old or older.

Survey respondents who identified themselves as living with both CKD and diabetes reported challenges with fatigue and anemia as well as adhering to dietary restrictions due to the high costs associated with those restrictions and inconvenience when dining with others. Patients with CKD may often present with comorbidities; 7 respondents reported high blood pressure, 3 reported high cholesterol, 1 reported high potassium levels, 1 reported heart disease, and 1 reported having had a heart attack. One survey respondent stated feeling tired and unable to focus on certain tasks due to living with multiple medical conditions.

Five respondents reported worsening of their CKD, and 6 respondents indicated they had taken a medication to reduce the risk of worsening kidney disease, of which 3 reported experience with ACE inhibitors and 2 reported experience with ARBs. Respondents also indicated experience with diuretics, tacrolimus, erythropoietin, and dapagliflozin (SGLT2 inhibitor). Of the 6 survey respondents who indicated their level of satisfaction with their current medication(s), 3 were satisfied, 1 was very satisfied, and 2 were neutral. One respondent reported side effects with tacrolimus (nausea, heartburn, and flushing), while other respondents reported the benefits of their current medication (e.g., controlled the itch and burning sensation in the feet and legs with excess fluid and achieved lab values within acceptable ranges).

Survey respondents identified the following factors as the most important considerations for new treatment options in CKD: “Does it make me feel tired?” “Does it interfere with my other medications?” and “How much does it cost?” Survey respondents identified the following outcomes as important for new treatment options for CKD with or without diabetes: “limiting or arresting the progression of both diseases,” “make kidneys better,” “a longer life span,” and “maintain and improve quality of life overall.”

Finally, the Kidney Foundation of Canada and Diabetes Canada indicated that patients living with CKD may experience significant financial challenges due to reduced income (e.g., missed time from work as a result of their symptoms) and increased expenses (e.g., high costs associated with treatment, frequent visits to the health care team, and hospitalization). According to the organizations, equitable access to medications that slow the progression of kidney disease and reduce the risk of cardiovascular events, such as finerenone, may help relieve the financial burden of CKD and T2D on patients and the health care system.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of CKD with T2D and in cardiovascular conditions subsequent to CKD.

Unmet Needs

The clinical experts mentioned that in spite of available therapies for patients with CKD and T2D, there is a need for additional treatment options that reduce the risk of progression to kidney failure or cardiovascular events. There are patients who continue to progress to these outcomes and who could benefit from additional therapies such as finerenone.

Place in Therapy

The clinical experts noted that the current paradigm aims to reduce progression of CKD to ESRD (kidney failure requiring dialysis or renal transplant). Treatment measures include blood pressure control, RAAS inhibition (ACE inhibitors and/or ARBs), and the use of SGLT2 inhibitors, in addition to lifestyle changes, the use of statins, and glycemic control. The clinical experts noted that finerenone may be combined with SGLT2 inhibitors to reduce cardiorenal risk as they protect kidney function through distinct and complementary pathways.¹⁴

The clinical experts also mentioned that steroidal MRAs, such as spironolactone and pelerine, are currently used in conjunction with ACE inhibitors (or ARBs) and beta-blockers in the treatment of heart failure with reduced ejection fraction. Replacing steroidal MRAs with nonsteroidal MRAs such as finerenone may have a better safety profile and produce better outcomes for patients (citing a phase II tolerability and safety trial comparing both drugs).⁴¹

Patient Population

According to the clinical experts, finerenone should be considered for patients who retain significant residual proteinuria despite being on ACE inhibitor or ARB and SGLT2 inhibitor and noted that finerenone can be added to these therapies 3 months after initiating the SGLT2 inhibitor. They also mentioned that patients who are unable to tolerate SGLT2 inhibitor (e.g., due to hypotension or acute kidney injury) should be considered for finerenone.

Assessing Response to Treatment

In the opinion of the clinical experts, treatment response can be assessed using surrogate measures such as changes in proteinuria over time and stability of renal function (eGFR). Intervals for monitoring should follow the current guidelines (twice annually according to the American Diabetes Association).¹⁵

Discontinuing Treatment

The clinical experts noted that finerenone should be discontinued if the patient is unable to tolerate the drug because of AEs such as hyperkalemia that are not amenable to management (e.g., dietary changes and/or diuretic use) or such as hypotension.

Prescribing Conditions

According to the clinical experts, finerenone is better initiated as an add-on therapy in a specialist setting or in a community setting with specialist guidance and support.

Additional Considerations

One clinical expert (a cardiologist) noted that the use of finerenone may be more cost-effective than a combination of steroidal MRAs and potassium binders.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group input(s) received by CADTH have been included in the stakeholder section at the end of this report.

Clinician group input for the review of finerenone was prepared and submitted by 2 clinicians representing LMC Diabetes and Endocrinology, a single-specialty group endocrinology practice with 13 clinics across 3 provinces (Ontario, Quebec, and Alberta).

The clinician group recognized that there is an unmet need for a medication that will address significant decline in kidney function and cardiovascular disease in patients with T2D despite the availability of RAAS blockers and SGLT2 inhibitors and in patients who experience intolerance to and side effects with the currently available treatment options.

The clinician group indicated finerenone would be used as an add-on therapy to RAAS blockers with or without SGLT2 inhibitors in patients with T2D and an ongoing risk of kidney disease progression and cardiovascular disease. Alternatively, finerenone would be used as the first add-on therapy for patients who were unable to tolerate or who developed side effects with RAAS blockers or SGLT2 inhibitors.

With respect to the patient population that will most likely benefit from finerenone, the clinician group identified patients with an eGFR greater than or equal to 25 mL/min/1.73 m² and a UACR greater than or equal to 34 mg/mmol or patients with an eGFR of 25 mL/min/1.73 m² to 90 mL/min/1.73 m² and a UACR of 3.4 mg/mmol to 33.9 mg/mmol. The patient population identified to be the least suitable for treatment with finerenone was patients with a history of clinically significant hyperkalemia. Outcomes used in clinical practice would be preservation of eGFR over time, reduction in UACR, improved symptoms of heart failure or prevention of heart failure, and reduced emergency department visits or hospitalizations.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CDEC = CADTH Canadian Drug Expert Committee; CKD = chronic kidney disease; CV = cardiovascular; GP = general practitioner; HF = heart failure; MRA = mineralocorticoid receptor antagonist; SGLT2 = sodium-glucose cotransporter-2; SOC = standard of care; T2D = type 2 diabetes.

Clinical Evidence

The clinical evidence included in the review of Kerendia (finerenone) is presented in 2 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence selected from the literature that met the selection criteria specified in the review (no indirect evidence was submitted by the sponsor).

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of finerenone 10 mg and 20 mg tablets, used to delay progression of kidney disease and to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke) and hospitalization for heart failure in adult patients with CKD and T2D.

Methods

Studies selected for inclusion in the systematic review will include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans. Of note, the systematic review protocol presented in the following was established before the granting of an NOC from Health Canada.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.⁴²

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) via Ovid and Embase (1974—) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were finerenone and CKD. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on June 15, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on October 26, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist.⁴³ Included in this search were the websites of regulatory agencies (FDA and the European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

A focused literature search for indirect treatment comparisons (ITCs) dealing with diabetes and CKD was run in MEDLINE All (1946–) on June 15, 2022. No search limits were applied.

Findings From the Literature

Fifteen studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 7: Details of Included Studies

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; CV = cardiovascular; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; EQ-5D-5L = 5-level EQ-5D; ESRD = end-stage renal disease; HRQoL = health-related quality of life; KDQOL-36 = Kidney Disease Quality of Life survey; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; SBP = systolic blood pressure; UACR = urinary albumin-creatinine ratio.

Note: Three additional reports were included: sponsor-submitted Clinical Study Reports for FIDELIO and FIGARO and the FIDELITY pooled analysis.^16-18

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Description of Studies

FIDELIO (N = 5,734) and FIGARO (N = 7,437) are phase III, randomized, double-blind, add-on, parallel-group, multicentre, event-driven studies on the efficacy and safety of finerenone 10 mg or 20 mg once daily compared with placebo in patients with CKD and T2D. The 2 trials were conducted in 48 countries in Europe, Asia, North America, and South America during 2015 to 2021. The study design was completely identical despite some differences in patient inclusion criteria, through which FIDELIO likely included more severe CKD in terms of eGFR than FIGARO.

The primary end point for FIDELIO was time to first occurrence of the 40% renal composite end point: onset of kidney failure, a sustained decrease of eGFR greater than or equal to 40% from baseline over at least 4 weeks, or renal death. The primary end point for FIGARO was time to first occurrence of the cardiovascular composite end point: cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure. Secondary end points in each study included the primary objective of the other study, as well as time to first occurrence of a more severe renal composite end point, time to all-cause mortality, time to all-cause hospitalization, and change in UACR from baseline to month 4. The studies were sponsored by Bayer and included 30 (FIDELIO) and 31 (FIGARO) study centres in Canada.

After a run-in period of up to 16 weeks and a screening period of up to 2 weeks, eligible patients were randomized 1:1 to the finerenone (10 mg or 20 mg) or placebo treatment arm, and stratified by region, eGFR category at screening, and albuminuria interval at screening. Randomization occurred at visit 1, and then there were 3 more planned monthly visits, followed by a visit every 4 months until the end of the study. The finerenone dose could be up-titrated or down-titrated at any point following the start of treatment at visit 1. If patients stopped the study drug prematurely, they remained in the trial and were followed up with until the end of the study.

A summary of the study designs for FIDELIO and FIGARO is shown in Figure 2.

Figure 2: FIDELIO and FIGARO Study Design

eGFR = estimated glomerular filtration rate; EOS = end of study; OD = once daily; PD = permanent discontinuation; Post Trt = posttreatment; V = visit.

* Scheduled visits continued even if treatment with study drug was discontinued.

† PD visit conducted only after permanent withdrawal from treatment.

†† EOS visit conducted after notification of end of study by the sponsor.

‡ Posttreatment visit for all patients on study drug treatment at end of study.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Populations

Inclusion and Exclusion Criteria

Key inclusion and exclusion criteria for FIDELIO and FIGARO are shown in Table 7. Adult patients with T2D mellitus, a diagnosis of CKD, prior treatment with ACE inhibitors or ARBs, and serum potassium levels less than or equal to 4.8 mmol/L were included in both trials. The criteria for CKD severity differed between trials: In FIDELIO, patients had persistent high albuminuria (UACR ≥ 30 mg/g to < 300 mg/g) and eGFR greater than or equal to 25 mL/min/1.73 m² but less than 60 mL/min/1.73 m² with the presence of diabetic retinopathy or persistent very high albuminuria (UACR ≥ 300 mg/g) and eGFR greater than or equal to 25 mL/min/1.73 m² to less than 75 mL/min/1.73 m², while in FIGARO patients had less severe CKD with persistent high albuminuria and eGFR greater than or equal to 25 mL/min/1.73 m² but less than or equal to 90 mL/min/1.73 m² or persistent very high albuminuria and eGFR greater than or equal to 60 mL/min/1.73 m². Patients were excluded from the studies if they had a known significant nondiabetic renal disease, uncontrolled hypertension or hypotension, cardiovascular events (e.g., stroke) in the 30 days before the screening visit, chronic heart failure, dialysis for acute renal failure within 12 weeks of run-in visit, or renal allograft or planned renal transplant within 12 months.

Baseline Characteristics

The baseline demographic and disease characteristics of all patients in the full analysis set (FAS) are presented in Table 8. The mean age in both groups in both studies was approximately 65 years old, with 58.1% and 52.5% of patients aged 65 years and older in the FIDELIO and FIGARO trials, respectively. Most patients in both trials were male (69.8%) and white (68.1%), and 287 patients (2.2%) were in Canada. The mean baseline body mass index across all groups was 31.3 (SD = 6.0), 47.5% of patients had never smoked, and 59.8% were alcohol abstinent.

In the FIDELIO trial, the mean baseline eGFR was approximately 44 mL/min/1.73 m² (SD = 12.5) in both groups, and the mean baseline UACR was 798.8 mg/g (SD = 2.7) and 814.7 mg/g (SD = 2.7) in the finerenone and placebo groups, respectively. In FIGARO, the mean baseline eGFR was approximately 68 mL/min/1.73 m² (SD = 21.7) in both groups, and the mean baseline UACR was 284.3 mg/g (SD = 3.6) and 288.9 mg/g (SD = 3.5) in the finerenone and placebo groups, respectively. Approximately 88% of patients in FIDELIO and 51% of patients in FIGARO had very high albuminuria. Across both trials, the mean baseline serum potassium was 4.35 mmol/L (SD = 0.44), the mean baseline systolic blood pressure was 136.7 mm Hg (SD = 14.2), and the baseline hemoglobin A1C was 7.7% (SD = 1.4). Regarding medication use at baseline, 65.7% of patients (n = 3,725) in FIDELIO and 57% of patients (n = 4,212) in FIGARO were on ARBs, and 34% of patients (n = 1,942) in FIDELIO and 43% of patients (n = 3,137) in FIGARO were on ACE inhibitors. Across the 2 trials, patients were also on statins (72%), diuretics (51.5%), beta-blockers (50%), and antidiabetic treatment (97.7%), including 6.7% (n = 877) of patients who were on SGLT2 inhibitors. Across both trials, 45.6% of patients (n = 5,935) had a history of cardiovascular disease and 96.5% of patients (n = 12,566) had a history of hypertension.

Table 8: Summary of Baseline Characteristics (FAS)

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BMI = body mass index; CV = cardiovascular; eGFR = estimated glomerular filtration rate; FAS = full analysis set; GLP-1 = glucagon-like peptide-1; NR = not reported; Q = quartile; SD = standard deviation; SGLT2 = sodium-glucose cotransporter-2; UACR = urinary albumin-creatinine ratio.

^aArithmetic mean and arithmetic SD.

^bGeometric mean and geometric SD.

^cBelow median and above median (851.9 mg/g in FIDELIO and 308.2 mg/g in FIDELIO) in the FAS.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Interventions

The patients received 1 of the following: finerenone 10 mg tablet once daily (starting dose for patients with an eGFR between 25 mL/min/1.73 m² and < 60 mL/min/1.73 m² at the screening visit) or 20 mg tablet once daily (starting dose for patients with an eGFR ≥ 60 mL/min/1.73 m² at the screening visit), or a matching placebo tablet once daily. Patients were instructed to take 1 tablet once daily, preferably in the morning.

Dose Modifications

Patients starting at 10 mg would be up-titrated to 20 mg at any visit if they had been on a stable dose for over 4 weeks, provided the potassium concentration was less than or equal to 4.8 mmol/L and eGFR decrease was less than 30% below the value at the previous visit. Patients at 20 mg could be down-titrated to 10 mg at any point during the study if required for safety reasons.

Concomitant Medications

The conditions of prior therapy with ACE inhibitors and ARBs during the time leading up to the screening visit are depicted in Figure 3. For at least 4 weeks before run-in, patients are treated with ACE inhibitors and/or ARBs but then only treated with the maximum tolerated labelled dose of an ACE inhibitor or an ARB starting from the run-in visit for at least 4 weeks before the screening visit. Concomitant therapies not permitted during either study included eplerenone, spironolactone, any renin inhibitor or potassium-sparing diuretic, a combination of ACE inhibitor and an ARB, and potent cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors or inducers.

Figure 3: Background Therapy With RAS Blockade

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; RAS = renin-angiotensin system.

^‡ If applicable.

* During the maintenance phase, there should preferably be no adjustments to dose of ACEI or ARB or to any other antihypertensive or antiglycemic treatment.

Source: FIDELIO Clinical Study Report protocol.¹⁶

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials is provided in Table 9. These end points are summarized in the following text. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

The primary outcome in the FIDELIO study was time to first occurrence of the 40% renal composite end point, which comprises onset of kidney failure, a sustained decrease of eGFR greater than or equal to 40% from baseline over at least 4 weeks, or renal death. Kidney failure was defined as either ESRD (initiation of chronic dialysis for at least 90 days or renal transplant) or 2 measurements of eGFR of less than 15 mL/min/1.73 m² (KDIGO 2013)⁵³ that were 4 weeks apart. Renal death included deaths where renal replacement therapy was indicated but not started and there were no other likely causes of death. Events were included from visit 1 (randomization day) until the end-of-study visit, or the last visit in cases where there was premature discontinuation. Randomized patients without an event of the renal composite end point at the time of analysis were censored at the date of their last visit when complete information on all components of the composite renal end point was available, up to and including the end of study visit, or date of nonrenal death. Patients without any information about the primary composite end point after baseline were censored at day 1.

The primary outcome in the FIGARO study was time to first occurrence of the cardiovascular composite end point, which comprises cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure. Cardiovascular death included any death resulting from an acute MI, sudden cardiac death, sudden death, death due to heart failure, death due to stroke, and death due to cardiovascular procedures and other cardiovascular causes such as pulmonary embolism. Randomized patients without an event of the primary composite end point at the time of analysis were censored at the date of their last contact up to and including the end of study visit or date of non-CV death. Patients without any information about the primary composite end point after baseline were censored at day 1. All events qualifying for the primary outcome were adjudicated by an independent adjudication committee.

The primary outcome in each trial was a key secondary outcome in the other trial. Additional secondary outcomes in both trials included time to all-cause mortality, time to all-cause hospitalization, change in UACR from baseline to month 4, and time to first occurrence of the second renal composite end point (comprising onset of kidney failure, a sustained decrease in eGFR of ≥ 57% from baseline over at least 4 weeks, or renal death), hereafter referred to as the 57% renal composite end point. Patients were censored on day 1 if there was no subsequent information about the secondary composite end point, or if patients were without an event at the date of noncardiovascular death (in FIDELIO) or nonrenal death (in FIGARO) or at the date of their last visit if they did not experience an event of the secondary composite end point at the time of analysis. Hospitalization events were counted as withdrawal or death, and all-cause mortality was counted as the last visit. Randomized patients without such an event at the time of analysis were censored at the last date vital status could be obtained.

Exploratory outcomes of interest included the components of the renal and cardiovascular composite end points, new diagnosis of atrial fibrillation or atrial flutter, time to noncardiovascular or nonrenal death, change in eGFR and UACR from baseline, and change in HRQoL summary scores.

HRQoL was assessed using the KDQOL-36 and the 5-level EQ-5D (EQ-5D-5L) questionnaires. KDQOL-36 assesses the HRQoL of patients with CKD and consists of generic and disease-specific sections, with higher scores indicating a more favourable HRQoL. EQ-5D-5L comprises a descriptive system and the visual analogue scale, and a higher score indicates better HRQoL. The questionnaires were completed by the patient at visit 1 (baseline) and then completed before other visit procedures every 12 months (visits 5, 8, 11, and so on) and at the last visit (end of study or after permanent discontinuation). The MID in both questionnaires was not identified in the literature in the setting of diabetic CKD. A detailed discussion and critical appraisal of the HRQoL measures is provided in Appendix 4.

Safety and tolerability were assessed using the incidence of AEs and SAEs coded using the Medical Dictionary for Regulatory Activities. Serum potassium concentration was assessed at all visits, and change from baseline and incidence of hyperkalemia and hyperkalemia-related events were reported. In this report, the term hyperkalemia refers to the combined Medical Dictionary for Regulatory Activities preferred terms “blood potassium increased” and “hyperkalemia.”

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

CV = cardiovascular; eGFR = estimated glomerular filtration rate; EQ-5D-5L = 5-Level EQ-5D; ESRD = end-stage renal disease; HRQoL = health-related quality of life; KDQOL-36 = Kidney Disease Quality of Life survey; MI = myocardial infarction; UACR = urinary albumin-creatinine ratio.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Statistical Analysis

Statistical analysis of all efficacy outcomes (specified in the protocol for the systematic literature review) is summarized in Table 10.

Power Calculation

Both event-driven trials were designed to achieve 90% power using a log-rank test (at a 2-sided significance level of 3.33% in FIDELIO and 5% in FIGARO) to detect 20% relative risk reduction in the events of the primary end point with finerenone compared with placebo. In FIDELIO, the total number of primary end point events needed was 1,068 across both treatment groups, and in FIGARO it was 976.

The following assumptions were made: study duration of approximately 44 months, annual placebo event rate of 12% in FIDELIO and 8% in FIGARO, annual loss to follow-up rate of 0.7%, and annual finerenone treatment discontinuation rate of 5%. A slower-than-assumed event rate was observed during the study, so the required number of randomized patients was 5,800 and 7,400 in FIDELIO and FIGARO, respectively.

Statistical Model

Neither study was stopped early in the interim analysis; therefore, the final primary analysis was performed as specified in the studies’ protocols. The statistical analyses followed the intention-to-treat principle and were based primarily on the FAS. Events for inclusion in the primary analysis were counted from randomization at visit 1 until the end-of-study visit or until end-of-study notification ( + 4 weeks).

A group sequential design was used in each study with a single interim analysis when two-thirds of the information was available, with a stopping rule of 2-sided P of less than 0.00270, which required a small adjustment to the significance level of the final analysis to maintain the overall significance level at 5%. To account for multiplicity, a weighted Bonferroni-Holm procedure was used for the primary and key secondary end points, followed by hierarchical testing of the remaining efficacy end points at the adjusted 2-sided significance level of 0.04967388, as shown in Figure 4 and Figure 5. If the testing strategy stopped at 1 point due to a nonsignificant result, the remaining secondary efficacy variables were tested in an exploratory manner.

In FIDELIO, the primary and key secondary end points met the preplanned criteria for significance, and all-cause mortality (the next secondary end point) was tested hierarchically. It did not reach statistical significance, and so the remaining secondary end points were tested in an exploratory manner. In FIGARO, the primary end point met the preplanned criteria for significance, and the key secondary end point did not; therefore, the remaining secondary end points were tested in an exploratory manner.

The primary and secondary time-to-event end points were analyzed using stratified log-rank testing, and a stratified Cox proportional hazard regression model was used to provide a point estimate of the HR and a corresponding 2-sided 95% CI. Kaplan-Meier curves were provided for the cumulative incidence risk of outcome events by treatment group. Stratification factors included region (North America, Latin America, Europe, Asia, other), eGFR category at screening (25 mL/min/1.73 m² to < 45 mL/min/1.73 m², 45 mL/min/1.73 m² to < 60 mL/min/1.73 m², ≥ 60 mL/min/1.73 m²) type of albuminuria at screening (high albuminuria, very high albuminuria), and — only in FIGARO — history of cardiovascular disease.

An analysis of covariance model was fitted to the logarithmized ratios of UACR at month 4 to UACR at baseline, including the factor treatment group; the stratification factors region, type of albuminuria, and eGFR category; and the logarithmized baseline UACR as covariates. All other exploratory variables were analyzed in the FAS and the per-protocol set (in the per-protocol set only data points and events up to 30 days after stopping of study drug were considered). The eGFR was summarized descriptively by treatment group and visit, including absolute and relative changes from baseline. The absolute change of eGFR from baseline at each visit was analyzed by a mixed model with the factors treatment group, visit, treatment-by-visit interaction, factors for the stratification levels, baseline value as covariate (nested within eGFR category), and baseline by visit interaction. HRQoL analyzed based on KDQOL-36 and EQ-5D, with absolute change of the patient-related outcome from baseline at each visit up to the last visit analyzed by a mixed model.

Subgroup Analyses

Descriptive statistics, graphical display of estimated treatment effects with 95% CIs in a forest plot, and a statistical test for interaction were completed for exploratory subgroup analysis for the primary and secondary efficacy end points. The following subgroups, planned a priori in the statistical analyses plan, aligned with the subgroups prespecified in the protocol for this CADTH review: history of cardiovascular disease, eGFR category at baseline, type of albuminuria at baseline, and SGLT2 inhibitor use at baseline.

Sensitivity Analyses

For the primary end point, the analysis was repeated in the per-protocol set, and patients with a censoring or event date more than 30 days after last study drug intake were censored at the date of last study drug intake ( + 30 days). Additional analyses included an on-treatment analysis (FAS only) — repeating the inferential statistics, the log-rank test, and the Cox regression model without including stratification factors — and a tipping point analysis based on the intention-to-treat approach (FAS only). For the secondary time-to-event end points, the same additional analyses were conducted except for the on-treatment and tipping point analyses, which were only performed for the key secondary end points.

Figure 4: Hierarchical Testing Strategy in FIDELIO Study

CV = cardiovascular; UACR = urinary albumin-creatinine ratio.

Note: H_x refers to the null hypothesis of no treatment effect for each end point, and w_x denotes the weight allocated to the test of H_x, which in case of rejection is passed on to the next test as indicated by the arrows.

Figure 5: Hierarchical Testing Strategy in FIGARO Study

CV = cardiovascular; UACR = urinary albumin-creatinine ratio.

Note: H_x refers to the null hypothesis of no treatment effect for each end point, and w_x denotes the weight allocated to the test of H_x, which in case of rejection is passed on to the next test as indicated by the arrows.

Protocol Changes

The major changes to the study protocol are:

• In Amendment 3, study duration and site numbers were increased, rescreening rules were amended, an exclusion criterion was modified to allow randomization of patients with a recent cardiovascular disease episode, and the definition of the end point “kidney failure” was added.

• In Amendment 4, the posttreatment visit could be performed as a telephone contact, baseline values for patients who did not immediately start with study drug treatment were specified, the time window after last study drug administration was increased from 3 days to 30 days for on-treatment analyses, and the definition of treatment-emergent AEs and interruptions of study treatment were specified.

Table 10: Statistical Analysis of Primary and Secondary Efficacy End Points

ANCOVA = analysis of covariance; BOCF = baseline observation carried forward; CI = confidence interval; CV = cardiovascular; eGFR = estimated glomerular filtration rate; FAS = full analysis set; ITT = intention to treat; LOCF = last observation carried forward; PPS = per-protocol set; UACR = urinary albumin-creatinine ratio.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Analysis Populations

The analysis populations are presented in detail in Table 11. The FAS population was used in all efficacy analyses and included all randomized patients without good clinical practice (GCP) violations. The safety analysis set included only patients who took at least 1 dose of the study drug. Per-protocol patients comprised FAS patients without validity findings, such as being younger than 18 years old or not having T2D.

FIDELITY Pooled Analysis

FIDELITY is a prespecified pooled efficacy and safety analysis combining data from FIDELIO and FIGARO, with a prespecified formal statistical analysis plan. Statistical analyses were exploratory and descriptive in nature with no adjustment for multiplicity. Only the primary or secondary outcomes from the complementary studies were included in this pooled analysis.

End points were analyzed using stratified Cox proportional hazards models (stratification factors described earlier) as HRs with corresponding 95% CIs. P values for the comparison of treatment groups were presented based on a stratified log-rank test. For the cardiovascular composite outcome and the key renal composite outcome, cumulative incidences were calculated based on Aalen-Johansen accounting for mortality as competing risk, and corresponding numbers needed to treat were calculated in 6-month intervals. For all-cause mortality, cumulative incidences were calculated based on Kaplan-Meier methods. An on-treatment sensitivity analysis was performed for outcomes, considering only events occurring up to 30 days after study drug discontinuation in the FAS.

Results

Patient Disposition

Patient disposition for the FIDELIO and FIGARO studies is presented in Table 11.

Of the 13,911 patients screened in the FIDELIO study, 5,734 (41%) were randomized and, after excluding 60 patients due to GCP violations, the FAS included 5,674 patients randomized to receive finerenone (n = 2,833) or placebo (n = 2,841). By the end of the study, 1,623 patients (28.6%) had discontinued treatment, most commonly due to an adverse or outcome event (10.9% in the finerenone group and 10.3% in the placebo group). The safety population included 2,827 patients in the finerenone group and 2,831 patients in the placebo group.

Of the 19,381 patients screened in the FIGARO study, 7,437 (38%) were randomized and, after excluding 85 patients due to GCP violations, the FAS included 7,352 patients randomized to receive finerenone (n = 3,686) or placebo (n = 3,666). By the end of the study, a total of 2,023 patients (27.5%) had discontinued treatment, most commonly due to an adverse or outcome event (7.5% in the finerenone group and 7.4% in the placebo group). The safety population included 3,682 patients in the finerenone group and 3,659 patients in the placebo group.

Table 11: Patient Disposition

GCP = good clinical practice; FAS = full analysis set; PP = per protocol.

^aPatients who were found to be ineligible for a study during the run-in and screening periods (due to variations in estimated glomerular filtration rate and urinary albumin-creatinine ratio) were permitted to switch from either study to the other only once.

^bA patient is considered as having completed the study if there was contact with the patient after the end-of study notification or if the patient died.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Protocol Violations

In FIDELIO, important protocol deviations in the FAS were reported in ████ ███████ patients and ████ ███████ ████████ in the finerenone and placebo groups, respectively. The most frequently reported deviations in the finerenone and placebo groups were up-titration visit not done ██████ ███ ███████; SAE not submitted within 24 hours after initial flagging of event as serious in the electronic case report form ██████ ███ ███████; and up-titration visit not performed in time ██████ ███ ███████. Deviations associated with the COVID-19 pandemic included end-of-study visit not conducted as per protocol ███ ███ █████ and end point not assessable (████ ███ █████).

In FIGARO, important protocol deviations in the FAS were reported in ████ ███████ patients and ████ ███████ patients in the finerenone and placebo groups, respectively. The most frequently reported deviations in the finerenone and placebo groups were COVID-19 — visit not conducted as outlined in the CSP due to logistical reasons; ██████ ███ ███████ up-titration visit not done ██████ ███ ███████; and SAE not submitted within 24 hours after initial flagging of event as serious in the electronic case report form ██████ ███ ███████. Approximately ███ of patients were assigned to the incorrect stratification group. Deviations associated with the COVID-19 pandemic were reported in █████ ███ █████ of patients, specifically a visit was not conducted as outlined in the clinical study protocol due to logistical reasons (█████ ███ ███████ due to patient decision ███ ███ ██████ or physician decision █████ ███ ████).

Table 12: Important Protocol Deviations

^aCOVID-19-related important protocol deviations were categorized under “other protocol deviations.”

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Exposure to Study Treatments

A summary of exposure to study treatments is provided in Table 13. Overall, the mean duration of treatment was similar between treatment groups but differed between both studies. In FIDELIO, the mean duration of treatment in the FAS was 26.9 months (range = 0 months to 51.5 months) in the finerenone group and 27.2 months (range = 0 months to 51.5 months) in the placebo group. In FIGARO, the mean duration of treatment in the FAS was longer, at 35.2 months (range = 0 months to 61 months) in the finerenone group and 35.3 months (range = 0 months to 61.4 months) in the placebo group. In FIDELIO, 58% and 1.8% of patients took the study treatment for at least 24 months and 48 months, respectively, while in FIGARO this corresponded to 81% and 22.6% of patients, respectively.

At the start of the trials, ███ of the patients in FIDELIO (█ ██████) and ███ of patients in FIGARO (█ ██████) were on the 10 mg dose of finerenone; by month 48, the percentage of patients on 10 mg of finerenone was ███ ██ ████ and ███ ██ ██ ███, respectively. Details on the finerenone doses are presented in Table 14.

Table 13: Exposure in FIGARO and FIDELIO (FAS)

FAS = full analysis set; NA = not applicable; SD = standard deviation.

^aTreatment duration was from first to last intake of study drug.

^bStudy duration refers to total observation time from randomization until end-of-study visit or until last contact date if no end-of-study visit took place.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Table 14: Number of Patients on Doses of Finerenone Over Time (FAS)

FAS = full analysis set; N = number of patients who have not yet permanently discontinued study drug up until the respective time point; NA = not applicable.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported as follows.

In FIDELIO, the primary and key secondary end points met the preplanned criteria for statistical significance, and all-cause mortality (the next secondary end point) was tested hierarchically. It did not reach statistical significance, and so the remaining secondary end points were tested in an exploratory manner. In FIGARO, the primary end point met the preplanned criteria for statistical significance, and the key secondary end point did not; therefore, the secondary end points were tested in an exploratory manner.

Renal Outcomes

Renal end points were assessed at every visit up to and including the last visit after premature discontinuation and the end-of-study visit. Results are presented in detail in Table 15. The 40% renal composite end point was the primary end point in FIDELIO and a key secondary end point in FIGARO. In FIDELIO, the composite events occurred in 504 patients (17.8%) and 600 patients (21.1%) in the finerenone and placebo groups, respectively, and the HR was 0.83 (95% CI, 0.73 to 0.93; P = 0.0014), representing a 17% reduction in risk in favour of finerenone. In FIGARO, this event occurred in 350 patients (9.5%) and 395 patients (10.8%) in the finerenone and placebo groups, respectively, and the HR was 0.87 (95% CI, 0.76 to 1.01; P = 0.0689); this end point was not statistically significant.

The 57% renal composite end point was a secondary end point in both studies. In FIDELIO, it occurred in 252 patients (8.9%) and 326 patients (11.5%) in the finerenone and placebo groups, respectively, and the HR was 0.76 (95% CI, 0.65 to 0.90) in favour of finerenone. In FIGARO, it occurred in 108 patients (2.9%) and 139 patients (3.8%) in the finerenone and placebo groups, respectively, and the HR was 0.77 (95% CI, 0.60 to 0.99).

In FIDELIO, the individual components of a sustained decrease in eGFR greater than or equal to 40% and eGFR greater than or equal to 57% (relative to baseline) had HRs of 0.815 (95% CI, 0.722 to 0.920) and 0.68 (95% CI, 0.55 to 0.82), respectively, in favour of finerenone. The HRs of the other individual components of kidney failure, ESRD, and sustained decrease in eGFR to less than 15 mL/min/1.73 m² were 0.87 (95% CI, 0.72 to 1.05), 0.86 (95% CI, 0.67 to 1.10), and 0.82 (95% CI, 0.67 to 1.01), respectively.

In FIGARO, the individual components of sustained decrease in eGFR greater than or equal to 40% and eGFR greater than or equal to 57% (relative to baseline) had HRs of 0.87 (95% CI, 0.75 to 1.00) and 0.76 (95% CI, 0.58 to 1.00), respectively. The HRs of the other individual components of kidney failure, ESRD, and a sustained decrease in eGFR to less than 15 mL/min/1.73 m² were 0.72 (95% CI, 0.49 to 1.05), 0.64 (95% CI, 0.41 to 1.00), and 0.71 (95% CI, 0.43 to 1.16), respectively.

In the pooled analysis of FIDELIO and FIGARO, the HR was 0.85 (95% CI, 0.77 to 0.93) and 0.77 (95% CI, 0.67 to 0.88) for the 40% and 57% renal composite end points, respectively, in favour of finerenone. The cumulative incidences based on Aalen-Johansen estimates are presented in Figure 6.

Table 15: Renal Composite End Point (FAS)

CI = confidence interval; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; FAS = full analysis set; HR = hazard ratio; NR = not reported.

^aRenal composite end point comprises the onset of kidney failure, sustained decrease of eGFR greater than or equal to 40% from baseline over at least 4 weeks, or renal death. For composite outcomes and each component, the first event after randomization is considered. Subsequent events of the same type are not shown. The incidence rate is estimated as the number of patients with events divided by the cumulative at-risk time in the reference population, where a patient was no longer at risk once an event occurred. Incidence rates, HRs, and P values were only calculated for predefined efficacy end points.

^bP value: 2-sided P value from log-rank test, stratified. Only adjusted for multiple testing in the FIDELIO 40% renal composite end point.

^cRenal composite end point comprises the onset of kidney failure, sustained decrease of eGFR greater than or equal to 57% from baseline over at least 4 weeks, or renal death.

^dIn the pooled analysis, statistical analyses were prespecified exploratory evaluations, and no adjustment for multiplicity was performed.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report;¹⁷ FIDELITY pooled analysis.¹⁸

Figure 6: Time to Renal Outcomes From Pooled Analysis

CI = confidence interval; eGFR = estimated glomerular filtration rate.

Source: Agarwal et al. (2021). Copyright © 2021 Oxford University Press. Reprinted in accordance with Creative Commons Attribution License CC BY-NC 4.0.⁵²

Subgroup Analysis

The renal composite results by subgroups of interest, as specified a priori in the protocol for this CADTH review, are summarized in Table 16. In FIDELIO, the HR was greater than 1 in patients who were treated with SGLT2 inhibitors at baseline, favouring placebo over finerenone, yet the small sample size and wide CIs in this subgroup reflect uncertainty in the effect estimates. In FIGARO, the HR was also greater than 1 in patients with an eGFR of 45 mL/min/1.73 m² to < 60 mL/min/1.73 m² at baseline and in patients with high albuminuria (30 mg/g to < 300 mg/g) at baseline.

Table 16: Forty Percent Renal Composite Outcomes by Subgroups (FAS)

CI = confidence interval; CV = cardiovascular; eGFR = estimated glomerular filtration rate; FAS = full analysis set; HR = hazard ratio; NC = not calculated; SGLT2 = sodium-glucose cotransporter-2; UACR = urinary albumin-creatinine ratio.

^aHRs, 95% CIs, and interaction P values (2-sided) are based on stratified Cox proportional models including treatment, subgroup, and a subgroup by treatment interaction term as fixed effects.

Change in UACR From Baseline to Month 48

Baseline values of UACR were comparable between the treatment groups but differed between trials according to the inclusion criteria, with higher values in the FIDELIO trial population. Nevertheless, in both trials, the change in UACR from baseline to month 4 was larger in the finerenone group than in the placebo group, with an LS mean ratio to baseline of 0.69 (95% CI, 0.66 to 0.72) and 0.68 (95% CI, 0.65 to 0.70) in FIDELIO and FIGARO, respectively. This effect was sustained for the duration of the study up to month 36 in FIDELIO and month 48 in FIGARO, as shown in Figure 7 and Figure 8. Further details are provided in Table 17.

Table 17: Change in UACR From Baseline to Month 48 (FAS)

CI = confidence interval; eGFR = estimated glomerular filtration rate; FAS = full analysis set; LS = least squares; NA = not available; SD = standard deviation; UACR = urinary albumin-creatinine ratio.

^aUACR was determined 3 times at each visit from first morning void urine samples collected on 3 consecutive days and summarized according to the statistical analysis plan. For baseline, only samples with two-thirds of measurements taken on or before the day of randomization were used.

^bMonth 4 is the visit closest to day 120 within a time window of 120 ± 30 days after randomization. If no measurements are available in this time window, the patient is excluded from this analysis.

^cAnalysis of covariance with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, and log-transformed baseline value as covariate nested within type of albuminuria.

^dF test of equal means between the following additional factor levels: region, eGFR category at screening, and type of albuminuria at screening. Not adjusted for multiplicity.

^eFor the statistical evaluation, a mixed model was applied with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, time, treatment × time, log-transformed baseline value nested within type of albuminuria at screening, and log-transformed baseline value × time as covariate. Separate unstructured covariance patterns were estimated for each treatment group. Values after the onset date of end-stage renal disease were excluded from this analysis.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report;¹⁷ FIDELITY pooled analysis.¹⁸

Figure 7: FIDELIO — Least Squares Means of Ratio to Baseline for UACR Values by Visit (FAS)

FAS = full analysis set; LS = least squares; UACR = urinary albumin-creatinine ratio.

Note: LS means result from a mixed model with factors treatment group, region, estimated glomerular filtration rate category at screening, type of albuminuria at screening, cardiovascular disease history, time, treatment × time, log-transformed baseline value nested within type of albuminuria at screening, and log-transformed baseline value × time as covariate. Separate unstructured covariance patterns were estimated for each treatment group. Values after the onset date of end-stage renal disease are excluded from this analysis.

Source: FIDELIO Clinical Study Report.¹⁶

Figure 8: FIGARO — Least Squares Means of Ratio to Baseline for UACR Values by Visit (FAS)

FAS = full analysis set; LS = least squares; UACR = urinary albumin-creatinine ratio.

Note: LS means result from a mixed model with factors treatment group, region, estimated glomerular filtration rate category at screening, type of albuminuria at screening, cardiovascular disease history, time, treatment × time, log-transformed baseline value nested within type of albuminuria at screening, and log-transformed baseline value × time as covariate. Separate unstructured covariance patterns were estimated for each treatment group. Values after the onset date of end-stage renal disease are excluded from this analysis.

Source: FIGARO Clinical Study Report.¹⁷

Change in eGFR From Baseline to 48 Months

Baseline values of eGFR were comparable between the treatment groups but differed between trials according to the inclusion criteria, with lower values in the FIDELIO trial population (44.4 mL/min/1.73 m² and 44.3 mL/min/1.73 m² in the finerenone and placebo groups, respectively) compared to the FIGARO trial population (67.6 mL/min/1.73 m² and 68.0 mL/min/1.73 m² in the finerenone and placebo groups, respectively). Results from the mixed model analysis are presented in Table 18. After baseline, there was a larger acute reduction in eGFR in the finerenone group than in the placebo group, with an LS mean difference at month 4 of –2.38 (95% CI, –2.77 to –1.98) and –2.24 (95% CI, –2.67 to –1.80) in FIDELIO and FIGARO, respectively. The decrease in eGFR in the finerenone group then slows down, as shown in Figure 9 and Figure 10, until the difference becomes positive at month 28 in the FIDELIO trial and month 36 in the FIGARO trial.

Table 18: Mixed Model Analysis of eGFR (FAS)

CI = confidence interval; eGFR = estimated glomerular filtration rate; FAS = full analysis set; LS = least squares; NA = not applicable.

^aLS mean difference of finerenone minus placebo. For the statistical evaluation, a mixed model was applied, with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, time, treatment × time, baseline value nested within type of albuminuria, and baseline value × time as covariate.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

Figure 9: FIDELIO — Least Squares Means of eGFR Absolute Changes From Baseline by Visit (FAS)

eGFR = estimated glomerular filtration rate; FAS = full analysis set; LS = least squares.

Note: LS means result from a mixed model with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, time, treatment × time, baseline value nested within eGFR category at screening, and baseline value × time as covariate. Separate unstructured covariance patterns were estimated for each treatment group. Values after the onset date of end-stage renal disease are excluded from this analysis.

Source: FIDELIO Clinical Study Report.¹⁶

Figure 10: FIGARO — Least Squares Means of eGFR Absolute Changes From Baseline by Visit (FAS)

eGFR = estimated glomerular filtration rate; FAS = full analysis set; LS = least squares.

Note: LS means result from a mixed model with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, cardiovascular disease history, time, treatment × time, baseline value nested within eGFR category at screening, and baseline value × time as covariate. Separate unstructured covariance patterns were estimated for each treatment group. Values after the onset date of end-stage renal disease are excluded from this analysis.

Source: FIGARO Clinical Study Report.¹⁷

Cardiovascular Outcomes

Cardiovascular end points were assessed at every visit up to and including the last visit after premature discontinuation and the end-of-study visit. Results are presented in detail in Table 19. The cardiovascular composite end point was the primary end point in FIGARO and a key secondary end point in FIDELIO. In FIDELIO, the composite events occurred in 367 patients (13%) and 420 patients (14.8%) in the finerenone and placebo groups, respectively, and the HR was 0.86 (95% CI, 0.75 to 0.99; P = 0.0339), representing a 14% reduction in risk in favour of finerenone. In FIGARO, this end point occurred in 458 patients (12.4%) and 519 patients (14.2%) in the finerenone and placebo groups, respectively, and the HR was 0.87 (95% CI, 0.76 to 0.98; P = 0.0264), representing a 13% reduction in risk in favour of finerenone.

In FIGARO, the only individual component of statistical significance was hospitalization for heart failure, which had an HR of 0.71 (95% CI, 0.56 to 0.90) in favour of finerenone. The individual components of cardiovascular death and nonfatal MI had HRs of 0.90 (95% CI, 0.74 to 1.09) and 0.99 (95% CI, 0.76 to 1.31), respectively. In FIDELIO, the individual components of cardiovascular death, nonfatal MI, and hospitalization for heart failure had HRs of 0.86 (95% CI, 0.68 to 1.08), 0.80 (95% CI, 0.58 to 1.09), and 0.86 (95% CI, 0.68 to 1.08), respectively. In both trials, there was almost no difference in risk of nonfatal stroke, with an HR of 0.97 (95% CI, 0.74 to 1.26) in FIDELIO and of 1.03 (95% CI, 0.77 to 1.38) in FIGARO.

In the pooled analysis of FIDELIO and FIGARO, the HR was 0.86 (95% CI, 0.78 to 0.95) in favour of finerenone. The cumulative incidences based on Aalen-Johansen estimates are presented in Figure 11.

Table 19: Cardiovascular Composite End Point (FAS)

CI = confidence interval; CV = cardiovascular; FAS = full analysis set; HR = hazard ratio; MI = myocardial infarction.

^aCV composite end point comprises CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure. Events were adjudicated by an independent adjudication committee and considered from randomization until the end-of-study visit. For composite outcomes and each component, the first event after randomization is considered. Subsequent events of the same type are not shown. The incidence rate is estimated as the number of patients with events divided by the cumulative at-risk time in the reference population, where a patient was no longer at risk once an incident event occurred.

^bTwo-sided P value from log-rank test, stratified. Adjusted for multiplicity in composite outcome in both trials. Not powered for individual components of the composite outcome.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report;¹⁷ and FIDELITY pooled analysis.¹⁸

Figure 11: Time to Cardiovascular Outcome From Pooled FIDELITY Analysis

Source: Agarwal et al. (2021). Copyright © 2021 Oxford University Press. Reprinted in accordance with Creative Commons Attribution License CC BY-NC 4.0.⁵²

Subgroup Analysis

The cardiovascular composite results by subgroups of interest, as specified a priori in the protocol for this CADTH review, are summarized in Table 20. The HR was approximately 1 in patients who were treated with SGLT2 inhibitors at baseline in FIDELIO, while the HR was 0.49 (95% CI, 0.28 to 0.86) in FIGARO. However, the small sample size of this patient group in both trials reflects uncertainty in the effect estimates.

Table 20: Cardiovascular Composite Outcome by Subgroups (FAS)

CI = confidence interval; CV = cardiovascular; eGFR = estimated glomerular filtration rate; FAS = full analysis set; HR = hazard ratio; NC = not calculated; SGLT2 = sodium-glucose cotransporter-2; UACR = urinary albumin-creatinine ratio.

^aHRs, 95% CIs, and interaction P values (2-sided) are based on stratified Cox proportional hazards models, including treatment, subgroup, and a subgroup by treatment interaction term as fixed effects.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report.¹⁷

All-Cause Mortality

All-cause mortality was assessed throughout the study and counted up to the last date a vital status could be obtained. Incidence of all-cause mortality was similar between both groups in both trials, with 552 deaths (8.5% of patients) and 614 deaths (9.4% of patients) from any cause in the finerenone and placebo groups, respectively. Comparing the finerenone group with the placebo group, the HR was 0.90 (95% CI, 0.75 to 1.07) in FIDELIO and 0.89 (95% CI, 0.77 to 1.04) in FIGARO. All-cause mortality results are presented in Table 21.

Table 21: All-Cause Mortality (FAS)

CI = confidence interval; CV = cardiovascular; FAS = full analysis set; HR = hazard ratio.

^aEvents were adjudicated by an independent adjudication committee and considered from randomization until the end-of-study visit. For composite outcomes and each component, the first event after randomization is considered. Subsequent events of the same type are not shown. The incidence rate is estimated as the number of patients with events divided by the cumulative at-risk time in the reference population, where a patient was no longer at risk once an incident event occurred.

^bTwo-sided P value from log-rank test, stratified. Not adjusted for multiplicity.

^cInteraction P value displays the study treatment interaction based on a stratified model including study, treatment, and study treatment as covariates and removing study as a stratification factor.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report;¹⁷ and FIDELITY pooled analysis.¹⁸

All-Cause Hospitalization

All-cause hospitalization was assessed throughout the studies up to the day of withdrawal from the study, death, or the end-of-study visit. Incidence of all-cause hospitalization was similar between both groups in both trials, with 2,836 patients (43.5%) and 2,926 patients (45.0%) hospitalized for any cause in the finerenone and placebo groups, respectively. More hospitalizations were noncardiovascular related (35%) than cardiovascular related (19%). Comparing the finerenone group with the placebo group, the HR was 0.95 (95% CI, 0.88 to 1.02) in FIDELIO and 0.97 (95% CI, 0.90 to 1.04) in FIGARO. While cardiovascular hospitalizations overall were comparable between both groups in both trials, the risk of hospitalization for heart failure was lower in the finerenone group than in the placebo group in the FIGARO trial, with an HR of 0.71 (95% CI, 0.56 to 0.90). The incidence of other hospitalizations and all-cause hospitalization results are presented in Table 22.

Table 22: All-Cause Hospitalization (FAS)

CI = confidence interval; CV = cardiovascular; FAS = full analysis set; HR = hazard ratio.

^aEvents were adjudicated by an independent adjudication committee and considered from randomization until the end-of-study visit. For composite outcomes and each component, the first event after randomization is considered. Subsequent events of the same type are not shown. The incidence rate is estimated as the number of patients with events divided by the cumulative at-risk time in the reference population, where a patient was no longer at risk once an incident event occurred.

^bTwo-sided P value from log-rank test, stratified. Not adjusted for multiplicity.

^cInteraction P value displays the study treatment interaction based on a stratified model including study, treatment, and study treatment as covariates and removing study as a stratification factor.

Source: FIDELIO Clinical Study Report;¹⁶ FIGARO Clinical Study Report;¹⁷ FIDELITY pooled analysis.¹⁸

Health-Related Quality of Life

Kidney Disease Quality of Life Survey

At baseline, mean KDQOL-36 summary scores in all domains were comparable between treatment groups in each trial, and between both trials, except for the “burden of kidney disease” domain, where patients in the FIGARO group scored higher than those in the FIDELIO group. The quality of life decreased over time in all patients, consistently in all domains, assessed until month 36 in FIDELIO and month 48 in FIGARO. The physical component summary showed a sustained difference in favour of finerenone in FIDELIO at month 12 (LS mean difference = ███ ████ ███ ███ ██ ███) and month 24 (LS mean difference = ███ ████ ███ ███ ██ ███, and in FIGARO at month 36 (LS mean difference = ███ ████ ███ ███ ██ ███. Detailed results are presented in Table 27 in Appendix 3.

EQ-5D-5L Visual Analogue Scale

At baseline, mean EQ-5D-5L visual analogue scale summary scores were comparable between treatment groups in each trial, and between both trials. Quality of life decreased over time in all patients; however, the decrease appears to be more rapid in FIDELIO than in FIGARO. Detailed results are presented in Table 28 in Appendix 3.

Harms

Only those harms identified in the review protocol are reported in the following. Refer to Table 23 for detailed harms data. Results from the FIDELITY pooled analysis are reported.

Adverse Events

A total of 5,602 patients (86.1%) in the finerenone group and 5,607 patients (86.4%) in the placebo group experienced at least 1 AE. The most common AE in the finerenone group was hyperkalemia (14% versus 6.9% in the placebo group) and the most common AEs in the placebo group were hypertension (9% versus 6.4% in the finerenone group) and peripheral edema (9% versus 5.9% in the finerenone group).

Serious AEs

A total of 2,060 patients (31.6%) in the finerenone group and 2,186 patients (33.7%) in the placebo group experienced at least 1 SAE. The most commonly reported SAE was pneumonia (2.2% in the finerenone group versus 3.3% in the placebo group).

Withdrawals due to AEs

A total of 414 patients (6.4%) in the finerenone group and 351 patients (5.4%) in the placebo group stopped treatment due to AEs.

Mortality

There was a total of 110 deaths (1.7% of patients) and 151 deaths (2.3% of patients) due to treatment-emergent AEs in the finerenone and placebo groups, respectively.

Notable Harms

More patients reported hypotension in the finerenone group than in the placebo group (4.3% versus 2.7%). The number of patients who experienced atrial flutter and atrial fibrillation was less than 1% in each treatment group and comparable between groups. The number of patients who experienced hospitalization due to hyperkalemia was higher in the finerenone group than in the placebo group (0.9% versus 0.2%).

Table 23: Summary of Harms (Safety Analysis Set)

GFR = glomerular filtration rate; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aFrequency greater than 5% in either group.

^bFrequency greater than 2% in either group.

^cThe number of patients who died as a result of a treatment-emergent event.

Source: FIDELITY pooled analysis.¹⁸

Critical Appraisal

Internal Validity

The included pivotal studies FIDELIO and FIGARO were phase III, randomized, double-blind, placebo-controlled studies of finerenone in adult patients with CKD and T2D. Identical finerenone and placebo tablets were designed to maintain blinding with packaging and labelling; however, it is unclear if unblinding could have occurred due to a difference in the taste of the tablets or due to additional investigations following SAEs (such as hyperkalemia). Randomization codes were broken for ██ patients by the sponsor’s pharmacovigilance department ██████ or by the investigator due to a safety concern ██████ but all patients were included in the FAS and safety analysis set. Randomization was stratified by region, eGFR category at screening, type of albuminuria at screening, and — only in FIGARO — history of cardiovascular disease. Key baseline demographic and disease characteristics, and past history of medication used, appear to be balanced between the finerenone and placebo groups in both trials. Dietary changes, such as reduced sodium intake, are important in the management of patients with CKD and T2D;¹⁰ however, there is no mention of diet management in the trials, how closely dietary changes were followed by patients in both trials, and whether there were any differences in diet between patients in the 2 treatment groups.

There were important protocol deviations, balanced between treatment groups, reported in ███ ███ ████% of patients in FIDELIO and FIGARO, respectively. In FIDELIO, more procedure deviations were reported in the finerenone group than in the placebo group. In FIGARO, approximately 10% of patients were assigned to the incorrect stratification group. Due to study timelines, more protocol deviations associated with the COVID-19 pandemic were reported in FIGARO than in FIDELIO; however, deviations were balanced between treatment groups. In FIGARO, supportive analyses were conducted to account for pandemic-related disruptions, and deviations associated with the COVID-19 pandemic had no notable effect on the treatment effect of finerenone. For ███ ██████ ███ ███ ██████ patients in FIDELIO and FIGARO, respectively, the first drug intake was not on the day of randomization; however, for the majority, the difference was 1 day, and no significant impact on the comparative clinical efficacy of finerenone versus placebo would be expected.

Almost all the patients completed the studies; however, a high proportion of patients discontinued treatment in both studies (approximately 28%). This may have biased the studies, although the direction of bias is unknown as the timing of discontinuation is not reported in the clinical study reports.

Maintaining and improving quality of life overall was rated as an important outcome by patients, yet interpretation of the results for the HRQoL instruments (i.e., the ability to assess trends over time and to make comparisons across treatment groups) is limited by the significant decline in patients available to provide assessment over time. The CADTH review team conducted an assessment on the validity of outcome measures and did not find evidence of validity or the MID of the KDQOL-36 or EQ-5D-5L in patients with CKD and T2D. The clinical experts consulted by CADTH pointed out that HRQoL instruments were not used routinely in clinical practice and that more weight is placed on clinical outcomes, which, if improved, would likely improve HRQoL.

In the prespecified FIDELITY pooled analysis, data from both trials were combined. Based on the individual study’s inclusion criteria, patients in FIDELIO had a worse diagnosis of CKD at baseline than those in FIGARO. However, the clinical experts agreed that the pooling of patient data from both trials was appropriate as they represent the wide range of patients with CKD and T2D seen in clinical practice. In addition, the mean treatment duration was longer in FIGARO (approximately 35 months) than in FIDELIO (approximately 27 months). Other than those differences, the study design of both trials was completely identical, and pooling is considered appropriate.

External Validity

According to the clinical experts CADTH consulted for this review, the FIDELIO and FIGARO study population is considered reflective of the requested reimbursement population. The following considerations are of importance regarding the external validity of the study.

Population: According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of both study populations were generally reflective of patients with CKD and T2D living in Canada. They agreed that there was an overrepresentation of male patients (70% male to 30% female), and they noted there should be a more proportionate representation of patients, given potential differences in treatment efficacy and safety. The mean age of patients was 65 years old, which they agreed was consistent with the population of patients who develop CKD due to T2D in clinical practice. Most participants were white; however, the clinical experts did not think this would limit generalizability to patients in Canadian clinical practice. The product monograph indicates that patients with an eGFR less than or equal to 25 mL/min/1.73 m² should not start finerenone; however, 2.4% of patients in FIDELIO reported a baseline eGFR less than or equal to 25 mL/min/1.73 m² (potentially due to deterioration between screening and randomization). Only patients with persistent high or very high albuminuria were included in the trials; however, approximately 3% of the patients in the FIGARO trial had normal albuminuria levels at baseline. While the trials were under way, the SOC for patients with CKD and T2D evolved to include SGLT2 inhibitor. Therefore, only 6.7% of patients in both trials (n = 877) were on an SGLT2 inhibitor at baseline, and patients were not stratified by SGLT2 inhibitor use; however, use at baseline was balanced between the 2 treatment groups in both trials. The clinical experts agreed that future trials would ideally include a larger population of patients treated with SGLT2 inhibitor. In addition, the proportion of patients using GLP-1 agonists with and without SGLT2 inhibitor at baseline was not balanced (18.5% versus 6.4%). This may have confounded the subgroup findings as GLP-1 agonists may also improve cardiorenal outcomes in patients with CKD and T2D.^19,20

Appropriateness of comparator: The clinical experts consulted by CADTH agreed that placebo plus SOC was an appropriate comparator in Canadian clinical practice for patients with CKD and T2D. The clinical experts agreed with the sponsor’s definition of SOC as including an ACE inhibitor or ARB, and ideally an SGLT2 inhibitor, which is still not widely accessible to patients with CKD and T2D living in Canada. The clinical experts pointed out that a combination therapy with the 2 drugs together makes physiologic sense as SGLT2 inhibitors are linked to reductions in the risk of hyperkalemic episodes (serum potassium ≥ 6.0 mmol/L), and finerenone has hyperkalemia as a side effect. There is, however, limited evidence on the positioning of finerenone in relation to SGLT2 inhibitors, and the evidence available for the addition of finerenone to ACE inhibitor or ARB, and an SGLT2 inhibitor, is limited. It is uncertain if results from the pivotal studies would be generalizable for patients who would receive finerenone as an add on to ACE inhibitor or ARB, and an SGLT2 inhibitor. A non-sponsor-submitted reimbursement review assessing the use of SGLT2 inhibitor in patients with CKD and T2D is currently ongoing. A phase II RCT that will compare finerenone plus placebo, SGLT2 inhibitors plus placebo, and finerenone plus SGLT2 inhibitors (CONFIDENCE trial)²¹ will begin in 2022, and results may provide more insight into this comparison and the place of finerenone in therapy.

Relevance of end points: The clinical experts consulted by CADTH and clinician groups providing input agreed that reducing progression of CKD to ESRD is the most meaningful end point in the treatment of patients with CKD and T2D, since ESRD signifies kidney failure and the need for dialysis or renal transplant. The clinical experts agreed that the most important surrogate marker is reduction in albuminuria and stability of eGFR. The clinician groups also added improved symptoms of or prevention of heart failure and reduced emergency department visits or hospitalizations as important outcomes in clinical practice. The trials included 2 composite renal outcomes that differed in 1 component: sustained decrease in eGFR of 40% or 57% from baseline. The clinical experts mentioned that both end points were clinically meaningful, as any significant decline in eGFR indicates the patient is likely to develop kidney failure. Both studies were only powered for their respective primary composite outcomes and not for the components of the primary outcome; thus, there is some uncertainty about the impact of finerenone on each of the components of the composite outcomes. In the FIDELIO trial, the statistically significant improvement in the composite primary renal outcome was only reproduced for a sustained decrease greater than or equal to 40% in eGFR from baseline. In the FIGARO trial, the statistically significant improvement in the composite primary cardiovascular outcome was only reproduced for hospitalization for heart failure. It is, therefore, not possible to conclude that the treatment has a clinically relevant effect on the composite end points as a whole. Moreover, the sponsor defined ESRD as the initiation of chronic dialysis for at least 90 days or renal transplant but only provided the number of patients who experienced each individual event; therefore, it is not possible to conclude the potential risk of dialysis and renal transplant separately.

Setting: This study was a multinational, multicentre trial. The study population was drawn from a wide variety of sites across the globe, with 13.3% of patients in the US and 2.2% in Canada. The clinical experts indicated that there is no concern in generalizing the findings from the pivotal study to the Canadian clinical setting due to the use of homogenized global management guidelines for CKD with T2D.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to critically appraise available indirect evidence comparing finerenone to relevant comparators for the treatment of diabetic kidney disease. SGLT2 inhibitors are currently part of SOC for patients with diabetic kidney disease; however, only 6.7% of patients (877 out of 13,026) in the FIDELIO and FIGARO trials were concurrently taking SGLT2 inhibitors. Therefore, the focus of this section is on ITCs comparing finerenone and SGLT2 inhibitors.

A focused literature search for ITCs dealing with diabetes and CKD was run in MEDLINE All (1946–) on June 15, 2022. No search limits were applied. In total, 186 articles were retrieved, 10 were potentially relevant, and only 1 published NMA by Zhao et al. (2022)²² was included. This published NMA is summarized in the following.

Methods

Objectives

The objective of this ITC was to assess the relative efficacy of SGLT2 inhibitors versus finerenone on cardiorenal end points in patients with T2D and CKD.

Study Selection Methods

The searches were conducted in March 2021 to capture cardiovascular or renal outcomes in RCTs that compared any SGLT2 inhibitor or finerenone with placebo in patients with CKD and T2D. Two reviewers screened abstracts and full-text articles, conducted data extraction, and assessed the risk of bias of each study. Full details on the study selection methods are presented in Table 24.

Table 24: Study Selection Criteria and Methods

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; MI = myocardial infarction; SGLT2 = sodium-glucose cotransporter-2; T2D = type 2 diabetes.

^aKidney function progression was defined as a composite of a sustained decrease of at least 40% in the eGFR from the baseline or a doubling of the serum creatinine level, kidney failure (a composite of end-stage kidney disease or sustained decrease in eGFR to < 15 mL/min/1.73 m²), or renal death. If this composite outcome was not available, another composite renal outcome was used instead.

^bA major adverse cardiovascular event was defined as a composite of cardiovascular disease, nonfatal MI, or nonfatal stroke. If data on nonfatal MI and nonfatal stroke were not available, data on total MI and stroke were used instead.

Source: Zhao et al. (2022).²²

ITC Analysis Methods

The authors extracted 2 variables from the included study: the number of patients developing events of interest and the total number of patients in the intervention and placebo groups. Treatment effects were presented as risk ratio and 95% CI. The authors first conducted a conventional meta-analysis using the fixed-effects inverse variance method and the random-effects DerSimonian and Laird method (I² was used to measure statistical heterogeneity, and random effects were reported if I² was more than 50%). The authors then conducted an NMA using the restricted maximum likelihood method within the frequentist framework using Stata/MP (version 16.0).

Results

Summary of Included Studies

The authors included 14 articles reporting 8 placebo-controlled RCTs comprising 30,661 patients. Seven studies involved an assessment of SGLT2 inhibitor (13,246 patients receiving gliflozin versus 11,741 receiving placebo): EMPA-REG OUTCOME,^23,24 CANVAS Program,^25,26 CREDENCE,^27,28 DECLARE–TIMI 58,²⁹ DAPA-CKD,³⁰ VERTIS CV,^31,32 and SCORED.³³ One study (the pivotal FIDELIO trial)^34,35 assessed finerenone (2,833 patients receiving finerenone versus 2,841 receiving placebo). According to risk-of-bias assessment, there was low risk of bias in all 8 studies.

Major adverse cardiovascular events were defined consistently across the included studies. Kidney function progression, however, was defined differently across the included studies, with composite end points that included ESRD, renal death, and sustained decrease in eGFR that ranged from 40% to 50%. One trial included patients who had initiated renal replacement therapy (EMPA-REG OUTCOME), and 2 trials included patients with kidney transplants (DAPA-CKD and SCORED). One trial (VERTIS CV) did not report a renal composite end point. The authors considered these definitions similar enough to be used in the meta-analysis.

Results

NMA results showed that, compared to finerenone, SGLT2 inhibitors significantly reduced the risk of kidney function progression (HR = 0.78; 95% CI, 0.67 to 0.90) and hospitalization for heart failure (HR = 0.71; 95% CI, 0.55 to 0.92) as shown in Figure 12. No treatment was favoured when finerenone was compared to SGLT2 inhibitors for the outcomes of major adverse cardiovascular events (HR = 0.95; 95% CI, 0.71 to 1.27), nonfatal MI (HR = 0.91; 95% CI, 0.64 to 1.30), nonfatal stroke (HR = 0.70; 95% CI, 0.35 to 1.39), cardiovascular death (HR = 1.00; 95% CI, 0.78 to 1.29), and all-cause death (HR = 0.96; 95% CI, 0.75 to 1.23). No network plot for any outcome had a closed loop, suggesting a lack of direct evidence between finerenone and SGLT inhibitors, so an inconsistency test was not performed.

Figure 12: NMA Treatment Effects for Kidney Function Progression and Hospitalization for Heart Failure

CI = confidence interval; HHF = hospitalization for heart failure; KFP = kidney function progression; NMA = network meta-analysis; SGLTi = sodium-glucose cotransporter inhibitor; vs = versus.

Source: Zhao et al. (2022). Copyright © 2022 Frontiers. Reprinted in accordance with Creative Commons Attribution License CC BY-NC 4.0.²²

Critical Appraisal of ITC

This NMA included a limited number of studies with some heterogeneity in the definition of a key renal outcome across the studies. Only 1 study assessed finerenone, while the other 7 assessed an SGLT2 inhibitor, which limited the statistical power of this NMA. The second pivotal RCT on finerenone from this review (FIGARO) was not included in this NMA; its inclusion may have strengthened this analysis. The authors did not explore the baseline demographic characteristics of the patient populations across the trials and reported that “the cardiorenal risk of participants was possibly different among included trials.”²² The durations of the trials were not reported and may have differed between studies. Moreover, the safety outcomes of the treatments were not assessed in this NMA.

The CADTH review team was unable to rigorously assess the methods in this article because insufficient details on the methods were provided (e.g., no details on the retrieved number of records in the systematic review), and there was no discussion on possible adjustments for potential effect modifiers or feasibility assessment. A small proportion of patients in the included FIDELIO trial were using SGLT2 inhibitor at baseline, but no additional analysis including and excluding this subgroup was conducted.

Summary

Indirect evidence from the published NMA evaluated the effectiveness of finerenone compared to SGLT2 inhibitor in the management of patients with CKD and T2D. This analysis suggests that SGLT2 inhibitors are more effective than finerenone at reducing kidney function progression and hospitalization for heart failure events in this population. However, only 1 trial out of the included 8 trials assessed finerenone, which limited the statistical power of this NMA and precluded definitive conclusions being drawn about the comparative effectiveness of finerenone versus SGLT2 inhibitor.

Other Relevant Evidence

No long-term extension studies or additional relevant studies were included in the sponsor’s submission to CADTH.

Discussion

Summary of Available Evidence

The CADTH systematic review included 2 pivotal phase III RCTs (FIDELIO and FIGARO). Both trials are completed double-blind, placebo-controlled, multicentre, superiority studies comparing finerenone to placebo in patients with CKD and T2D. Combined, both trials included a total of 13,026 patients randomized in a 1:1 ratio to receive finerenone (n = 6,519) or placebo (n = 6,489), stratified by region, eGFR at baseline, albuminuria at baseline, and — only in FIGARO — history of cardiovascular disease.

The primary outcome in FIDELIO was a renal composite outcome composed of time to onset of kidney failure, a sustained decrease of eGFR greater than or equal to 40% from baseline over at least 4 weeks, or renal death. The primary outcome in FIGARO was a cardiovascular composite outcome composed of time to first occurrence of the cardiovascular composite end point: cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure. The primary outcome in each trial was a key secondary outcome in the other trial. Other secondary outcomes included time to all-cause mortality, time to all-cause hospitalization, change in UACR from baseline to month 4, and time to first occurrence of a second renal composite end point. Exploratory outcomes of interest included the components of the renal and cardiovascular composite end points, new diagnosis of atrial fibrillation or atrial flutter, time to noncardiovascular and nonrenal death, change in eGFR and UACR from baseline, and change in HRQoL summary scores. Both trials enrolled adult patients with T2D and a diagnosis of CKD with persistent high or very high albuminuria and an eGFR greater than or equal to 25 mL/min/1.73 m² (the upper eGFR limit was lower in the FIDELIO inclusion criteria than in those of FIGARO). Patients had to be treated with the maximum tolerated dose of an ACE inhibitor or an ARB for at least 4 weeks before the screening visit. The mean age of the patients in both trials was approximately 65 years old, most patients where white (68%) and male (70%), and approximately 6.7% of patients from both trials were treated with SGLT2 inhibitors.

Indirect evidence from 1 published NMA evaluated the effectiveness of finerenone compared to SGLT2 inhibitors in the treatment of CKD and T2D. This analysis suggests that SGLT2 inhibitors are more effective than finerenone at reducing renal failure and hospitalization for heart failure events in this population. However, only 1 trial out of the included 8 trials assessed finerenone, which limited the statistical power of this NMA and precluded definitive conclusions being drawn about the comparative effectiveness of finerenone versus SGLT2 inhibitor.

Interpretation of Results

Efficacy

Input received from both patient groups and clinicians for the review of finerenone indicated that the most important end point in CKD with T2D is reducing progression of CKD to ESRD. Important surrogate markers included reduction of albuminuria and stability of eGFR. In FIDELIO,¹⁶ where patients had worse characteristics of CKD at baseline (lower eGFR and higher UACR) and the 40% renal composite outcome was the primary outcome, finerenone reduced the risk of 40% renal composite outcome by 17%. In FIGARO,¹⁷ where the cardiovascular composite outcome was the primary outcome, finerenone reduced the risk of the cardiovascular composite outcome by 13%. These effects appeared to be sustained for the duration of the trial. However, the size of the effect on the composite end points is not transferable to the size of the effect on the components, as the trials were not powered for these components. In addition, the statistically significant improvement in the composite primary outcomes was only reproduced for 1 of the disaggregated outcomes in each trial — specifically, a sustained decrease greater than or equal to 40% in eGFR from baseline in the FIDELIO trial and incidence of hospitalization for heart failure in the FIGARO trial.

The clinical experts noted that change in albuminuria has been linked to reduction in incident risk for adverse clinical outcomes of kidney failure,⁵⁴ cardiovascular events,⁵⁵ and mortality.⁵⁶ In both trials, the reduction in UACR from baseline to the end of trial (month 36 in FIDELIO and month 48 in FIGARO) was significantly larger in the finerenone group than in the placebo group, and this between-group difference was considered to be clinically meaningful by the clinical experts.

It is unclear if the benefits of finerenone apply to patients with nonproteinuric diabetic CKD as only 1.8% of the patients in both trials had normal albuminuria levels at baseline and subgroup analysis of baseline albuminuria levels was nonconclusive due to low sample size. However, according to the clinical experts, the management approach and therapeutic targets for this subgroup of patients are similar to those for patients with proteinuric CKD with diabetes.

There was no significant between-group difference in the risk of all-cause mortality and all-cause hospitalization, which the trials were not powered to assess. This lack of difference could be due to the duration of the trials (less than 48 months) or rarity of events (mortality events were less than 10% across all treatment groups in both trials).

The clinical experts consulted by CADTH agreed that finerenone would be an adjunct to SOC therapy that includes ACE inhibitor or ARB, and SGLT2 inhibitor, particularly for patients who cannot tolerate these medications. SGLT2 inhibitor was only added to the management guidelines recently; the trials only included 6.7% of patients who were treated with SGLT2 inhibitor at baseline. Analyses by SGLT2 inhibitor subgroup were not defined before randomization, but use at baseline was balanced between treatment groups in both trials, and there was no significant difference in SGLT2 inhibitor use at baseline across both trials in all primary and secondary outcomes. It is, therefore, uncertain if results from the pivotal studies would be generalizable for patients who would receive finerenone as an add on to ACE inhibitor or ARB, and an SGLT2 inhibitor. A non-sponsor-submitted reimbursement review assessing the use of SGLT2 inhibitor in patients with CKD and T2D is currently ongoing.

The direct comparison of finerenone and SGLT2 inhibitor is limited by the small subpopulation included in the trial. A published NMA was included in this review, comparing finerenone and SGLT2 inhibitor in patients with CKD and T2D, and it concluded that SGLT2 inhibitors are more effective than finerenone at reducing kidney function progression and hospitalization for heart failure events in this population. However, only 1 trial out of the included 8 trials assessed finerenone, which limited the statistical power of this NMA and precluded definitive conclusions being drawn about the comparative effectiveness of finerenone versus SGLT2 inhibitor. A phase II RCT that will compare finerenone plus placebo, SGLT2 inhibitors plus placebo, and finerenone plus SGLT2 inhibitors (CONFIDENCE trial)²¹ will begin in 2022, and results may provide more insight into this comparison and the place of finerenone in therapy.

Maintaining and improving quality of life overall was rated as an important outcome by patients, yet the interpretation of results for the HRQoL instruments is limited by the decline in patients over time and lack evidence of validity or MID of the instruments in patients with CKD and T2D; hence, the impact of finerenone on HRQoL is uncertain. The clinical experts consulted by CADTH pointed out that HRQoL instruments were not used routinely in clinical practice and that more weight is placed on clinical outcomes, which, if improved, would likely improve HRQoL.

Harms

Approximately 86% of patients in both treatment groups in both trials experienced at least 1 treatment-emergent AE, and the proportion of patients discontinuing study treatment due to AEs is only slightly higher in the finerenone group (6.4%) than in the placebo group (5.4%). SAEs were similar in both groups (31.6% in finerenone and 33.7% in placebo). The incidence of hyperkalemia was 2-fold higher in the finerenone group (14%) than in the placebo group (7%), although hyperkalemia leading to hospitalization was less than 1% in both groups. The clinical experts noted that this hyperkalemia would be clinically manageable with routine monitoring of potassium and temporary or permanent discontinuation of finerenone as needed. Hypotension was more common in the finerenone group (4.3%) than in the placebo group (2.7%), and the clinical experts noted that the effect on blood pressure was minimal in the FIDELITY pooled analysis.⁵² Atrial flutter and atrial fibrillation were similar in both groups and less than 1%. Peripheral edema was more common in the placebo group (9%) than in the finerenone group (6%); the clinical experts pointed out that its reduction would be especially valued from the cardiology perspective for patients who had also developed heart failure. In the published NMA, the indirect comparison of safety outcomes of finerenone and SGLT2 inhibitor were not assessed.

Conclusions

Two RCTs informed the systematic review of finerenone as an adjunct therapy for the treatment of patients with CKD and T2D. The trials demonstrated that treatment with finerenone was associated with a clinically meaningful reduction in the renal composite outcome and the cardiovascular composite outcome, driven by the outcome components of a sustained decrease in eGFR greater than or equal to 40% or greater than or equal to 57% and incidence of hospitalization for heart failure. The trials also demonstrated that finerenone was associated with a significant reduction in UACR from baseline, which the clinical experts referred to as an important marker for reduced risk of progression of CKD to ESRD. The impact of finerenone on HRQoL is uncertain due to difficulty interpreting results from the HRQoL instruments. All patients in both trials were on a maximum tolerated dose of ACE inhibitor or ARB as SOC, but only a small proportion in both trials were on SGLT2 inhibitor at baseline; hence, available evidence on the efficacy and safety of the addition of finerenone to ACE inhibitor or ARB, and an SGLT2 inhibitor, is limited. No significant difference was reported when comparing patients who were on an SGLT2 inhibitor at baseline with patients who were not. Furthermore, although the included NMA favoured SGLT2 inhibitor over finerenone in improving cardiorenal outcomes, this NMA had several limitations that preclude any definitive conclusion.

The safety profile of finerenone in these trials was consistent with the known safety profile of other nonsteroidal MRAs in terms of hyperkalemia and hypotension. No additional safety signals were identified with finerenone in this study.

References

1.Tonelli M, Wiebe N, Richard J-F, Klarenbach SW, Hemmelgarn BR. Characteristics of adults with type 2 diabetes mellitus by category of chronic kidney disease and presence of cardiovascular disease in Alberta Canada: a cross-sectional study. Can J Kidney Health Dis. 2019;6:2054358119854113. PubMed

2.LeBlanc AG, Gao YJ, McRae L, Pelletier C. At-a-glance-twenty years of diabetes surveillance using the Canadian Chronic Disease Surveillance System. Health Promot Chronic Dis Prev Can. 2019;39(11):306. PubMed

3.Diabetes Mellitus (types combined), excluding gestational diabetes, crude prevalence, percent, age 1 year and older, Canada. Canadian Chronic Disease Surveillance System (CCDSS). Ottawa (ON): Public Health Agency of Canada (PHAC); 2019: https://health-infobase.canada.ca/CCDSS/data-tool/. Accessed 2022 Aug 3.

4.Mottl AK. Diabetic kidney disease: pathogenesis and epidemiology. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2022: https://www.uptodate.com. Accessed 2022 Aug 3.

5.McFarlane P, Cherney D, Gilbert RE, Senior P. Chronic kidney disease in diabetes. Can J Diabetes. 2018;42:S201-S209. PubMed

6.Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24(2):302-308. PubMed

7.Grandy S, Fox KM, Shield Study Group. Change in health status (EQ-5D) over 5 years among individuals with and without type 2 diabetes mellitus in the SHIELD longitudinal study. Health Qual Life Outcomes. 2012;10(1):99. PubMed

8.Pagels AA, Söderkvist BK, Medin C, Hylander B, Heiwe S. Health-related quality of life in different stages of chronic kidney disease and at initiation of dialysis treatment. Health Qual Life Outcomes. 2012;10(1):1-11. PubMed

9.KDIGO 2020 Clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020;98(4S):S1-S115. PubMed

10.Perkovic V, Badve SV, Bakris G. Treatment of diabetic kidney disease. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2022: https://www.uptodate.com. Accessed 2022 Aug 3.

11.Center for Drug Evaluation Research. Integrated review(s). Kerendia (Finerenone) administration. Company: Bayer Healthcare Pharmaceuticals. Application No.: 215341. Approval date: 07/09/2021 (FDA approval package). Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2021 Jul 9: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/215341Orig1s000IntegratedR.pdf. Accessed 2022 Jul 12.

12.American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, et al. 11. Chronic kidney disease and risk management: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S175-S184. PubMed

13.Kerendia: 10 mg and 20 mg finerenone, oral tablets [product monograph]. Mississauga (ON): Bayer Inc.; 2022.

14.Neuen BL, Jardine MJ. SGLT2 inhibitors and finerenone: one or the other or both? Nephrol Dial Transplant. 2022;37(7):1209-1211. PubMed

15.American Diabetes Association. Standards of medical care in diabetes-2020 abridged for primary care providers. Clin Diabetes. 2020;38(1):10-38. PubMed

16.Clinical Study Report: PH-39746. A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease. [internal sponsor's report]. Whippany (NJ): Bayer Healthcare Pharmaceuticals Inc.; 2020 Sep 22.

17.Clinical Study Report: PH-39747.A randomized, double-blind, placebo-controlled, parallel-group, multicenter, eventdriven phase III study to investigate the efficacy and safety of finerenone on the reduction of cardiovascular morbidity and mortality in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease in addition to standard of care. [internal sponsor's report]. Whippany (NJ): Bayer Healthcare Pharmaceuticals Inc.; 2021 Aug 20.

18.Integrated analysis statistical report: PH-42134. Integrated analysis of FIDELIO-DKD and FIGARO-DKD [internal sponsor's report]. Wuppertal (DE): Bayer AG; 2021 Jul 30.

19.Rossing P, Filippatos G, Agarwal R, et al. Finerenone in predominantly advanced CKD and type 2 diabetes with or without sodium-glucose cotransporter-2 inhibitor therapy. Kidney Int Rep. 2022;7(1):36-45. PubMed

20.Górriz JL, Romera I, Cobo A, O'Brien PD, Merino-Torres JF. Glucagon-like peptide-1 receptor agonist use in people living with type 2 diabetes mellitus and chronic kidney disease: a narrative review of the key evidence with practical considerations. Diabetes Ther. 2022;13(3):389-421. PubMed

21.Green JB, Mottl AK, Bakris G, et al. Design of the COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using an UACR Endpoint study (CONFIDENCE). Nephrol Dial Transplant. 2022. PubMed

22.Zhao LM, Zhan ZL, Ning J, Qiu M. Network meta-analysis on the effects of SGLT2 inhibitors versus finerenone on cardiorenal outcomes in patients with type 2 diabetes and chronic kidney disease. Front Pharmacol. 2022;12:751496. PubMed

23.Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2016;374(11):1094. PubMed

24.Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137(2):119-129. PubMed

25.Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. PubMed

26.Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS program. Circulation. 2018;138(15):1537-1550. PubMed

27.Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation. 2019;140(9):739-750. PubMed

28.Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. PubMed

29.Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. PubMed

30.Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435. PubMed

31.Cherney DZI, McGuire DK, Charbonnel B, et al. Gradient of risk and associations with cardiovascular efficacy of ertugliflozin by measures of kidney function observations from VERTIS CV. Circulation. 2021;143(6):602-605. PubMed

32.Wheeler DC, Stefansson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22-31. PubMed

33.Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129-139. PubMed

34.Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229. PubMed

35.Filippatos G, Anker SD, Agarwal R, et al. Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes. Circulation. 2021;143(6):540-552. PubMed

36.Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2021;372:m4573. PubMed

37.Drug Reimbursement Review sponsor submission: Kerendia® (finerenone) 10 mg, and 20 mg tablets [internal sponsor's package]. Mississauga (ON): Bayer Inc.; 2022 Jun 3.

38.Australian public assessment report for finerenone. Canberra (AU): Australian Department of Health; 2022: https://www.tga.gov.au/sites/default/files/2022-07/auspar-finerenone-220519.pdf. Accessed 2022 Aug 16.

39.Kerendia: EPAR - Public Assessment Report. Amsterdam (NL): European Medicines Agency; 2021 Dec 16: https://www.ema.europa.eu/en/documents/assessment-report/kerendia-epar-public-assessment-report_en.pdf. Accessed 2022 Aug 16.

40.Finerenone for treating chronic kidney disease in type 2 diabetes. NICE appraisal consultation document. London (UK): National Institute For Health And Care Excellence (NICE); 2022: https://www.nice.org.uk/guidance/gid-ta10820/documents/129. Accessed 2022 Aug 16.

41.Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016;37(27):2105-2114. PubMed

42.McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40-46. PubMed

43.Grey matters: a practical tool for searching health-related grey literature. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/grey-matters. Accessed 2022 Jun 30.

44.Agarwal R, Joseph A, Anker SD, et al. Hyperkalemia risk with finerenone: results from the FIDELIO-DKD trial. J Am Soc Nephrol. 2022;33(1):225-237. PubMed

45.Bakris GL, Agarwal R, Anker SD, et al. Design and baseline characteristics of the finerenone in reducing kidney failure and disease progression in diabetic kidney disease trial. Am J Nephrol. 2019;50(5):333-344. PubMed

46.Filippatos G, Pitt B, Agarwal R, et al. Finerenone in patients with chronic kidney disease and type 2 diabetes with and without heart failure: a prespecified subgroup analysis of the FIDELIO-DKD trial. Eur J Heart Fail. 2022;03:03.

47.Filippatos G, Anker SD, Agarwal R, et al. Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial. Circulation. 2022;145(6):437-447. PubMed

48.Filippatos G, Bakris GL, Pitt B, et al. Finerenone reduces new-onset atrial fibrillation in patients with chronic kidney disease and type 2 diabetes. J Am Coll Cardiol. 2021;78(2):142-152. PubMed

49.Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385(24):2252-2263. PubMed

50.Ruilope LM, Agarwal R, Anker SD, et al. Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial. Am J Nephrol. 2019;50(5):345-356. PubMed

51.Ruilope LM, Pitt B, Anker SD, et al. Kidney outcomes with finerenone: an analysis from the FIGARO-DKD study. Nephrol Dial Transplant. 2022;22:22. PubMed

52.Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2021;43(6):474-484. PubMed