Bayer Submits New NDA for Finerenone in Heart Failure with LVEF ≥40% in China

By Yi Wen

On January 12, Bayer's "Finerenone Tablets" Class 2.4 registration application was accepted by the CDE.

Finerenone (finerenone, Kerendia) is a first-in-class non-steroidal, selective mineralocorticoid receptor antagonist (MRA) with higher selective affinity for the mineralocorticoid receptor. Compared with steroidal MRAs (such as spironolactone), finerenone exhibits higher selectivity and stronger affinity for the mineralocorticoid receptor (MR), effectively blocking inflammation, fibrosis, and adverse cardiovascular and renal events mediated by excessive MR activation.

In July 2021, finerenone was approved by the FDA for the treatment of adult patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), reducing the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), cardiovascular death, non-fatal myocardial infarction, and heart failure hospitalization. Its brand name is Kerendia. Notably, Kerendia is the first non-steroidal, selective mineralocorticoid receptor antagonist (MRA) to demonstrate positive renal and cardiovascular outcomes in patients with CKD and T2D.

Kerendia's approval was based on the positive results of the pivotal Phase 3 FIDELIO-DKD study – when combined with standard care, finerenone significantly reduced the risk of the composite primary endpoint of CKD progression, kidney failure, and renal death compared to placebo. Specific data showed that, after a median follow-up of 2.6 years, compared to placebo, finerenone significantly reduced the composite risk of first occurrence of kidney failure, a sustained decline in estimated glomerular filtration rate (eGFR) of ≥40% from baseline for at least four weeks, or renal death by 18%. Moreover, after a median follow-up of 2.6 years, compared to placebo, finerenone also significantly reduced the risk of key secondary endpoints: lowering the composite risk of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure by 14%.

In addition, finerenone is also being developed for the treatment of pediatric patients with chronic kidney disease. In November 2021, Bayer initiated the Phase 3 study FIONA, which evaluates the efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of finerenone in combination with standard care in pediatric patients with chronic kidney disease and severely increased proteinuria. This is a multicenter, randomized, double-blind, placebo-controlled study, with the primary objective of demonstrating that finerenone, when combined with standard care (angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARB]), is superior to placebo in reducing urinary protein excretion in pediatric patients. The primary endpoint is the change in the urine protein-to-creatinine ratio (UPCR) from baseline to 6 months.

In China, according to the Insight database, finerenone has registered five clinical trials (see table below), with indications including diabetic nephropathy and heart failure with left ventricular ejection fraction ≥40%. Among them, Finerenone Film-Coated Tablets were submitted for production in China in February 2021.

The author speculates that the domestic application for the heart failure indication of finerenone tablets is underway. It is reported that in November 2020, Bayer initiated the FINEARTS-HF Phase III multicenter, randomized, double-blind, placebo-controlled study on finerenone for treating symptomatic heart failure (HF) with left ventricular ejection fraction ≥40%. The primary objective of this study is to demonstrate the superiority of finerenone over placebo in reducing the composite endpoint rate of cardiovascular (CV) death and total (first and recurrent) HF events (defined as heart failure or urgent HF visits).

Besides Finerenone, in fact, as early as January 2019, the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan had already approved a new type of mineralocorticoid receptor antagonist, Minnebro (esaxerenone). This drug was initially developed by X-Ceptor Therapeutics (acquired by Exelixis in 2004), licensed to Daiichi Sankyo in 2006, and approved in January 2019 for the treatment of hypertension. Moreover, this drug is also being developed for the treatment of diabetic nephropathy.

In addition, Henry Pharmaceuticals has independently developed a new generation of non-steroidal selective mineralocorticoid receptor antagonist KBP-5074. This drug selectively and competitively binds to human MR, producing antihypertensive, renal protective, and cardiac protective effects. It is being developed for the treatment of moderate to advanced chronic kidney disease with uncontrolled hypertension, heart failure, and chronic kidney disease. The published results of a Phase 2b study of the drug in treating refractory hypertension in patients with moderate to severe (3b/4 stage) chronic kidney disease showed a statistically significant improvement in systolic blood pressure (SBP) from baseline to Day 84. Compared with the placebo group, the average SBP reduction was 10.1 mmHg (p=0.0029) in the 0.5mg KBP-5074 group and 7.0 mmHg (p=0.0399) in the 0.25mg KBP-5074 group. Notably, the trial included patients with Stage 4 renal failure, who are usually contraindicated for MRA drugs. Compared with other similar drugs (MRAs), KBP-5074 did not increase the risk of severe hyperkalemia.