Finerenone: Another Tool for Diabetic Nephropathy?

Miriam E Tucker

September 01, 2015

The nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (BAY 94-8862, Bayer) improved markers of kidney function when added to a renin-angiotensin system (RAS) blocker in patients with diabetic nephropathy, with lower rates of hyperkalemia than have been seen with other MRAs, a new randomized phase 2 trial finds.

The results were published in the September 1 issue of the Journal of the American Medical Association by George L Bakris, MD, director of the Comprehensive Hypertension Center at the University of Chicago Medicine, Illinois, and colleagues.

The MRAs eplerenone and spironolactone have been shown to further reduce proteinuria in patients with chronic kidney disease as a result of diabetes or other causes who are already taking either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB). But, use of MRAs has been hampered by a three- to eightfold increased risk for hyperkalemia, Dr Bakris and colleagues explain.

Finerenone is a novel nonsteroidal MRA with greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro.

In the current multicenter, randomized, double-blind, placebo-controlled parallel group, phase 2b study entitled Mineralocorticoid Receptor Antagonist Study in Diabetic Nephropathy (ARTS-DN), 821 type 2 diabetes patients with albuminuria who were receiving an ACE inhibitor or an ARB were randomized to receive one of seven finerenone doses or placebo.

The addition of finerenone compared with placebo resulted in an improvement in the primary end point, urinary albumin/creatinine ratio (UACR) at 90 days, while hyperkalemia occurred in just 1.5% of all the patients who received the drug.

"The significant reduction in UACR in patients receiving finerenone, combined with a safety profile similar to that in the placebo group, suggests that longer-term studies investigating clinical end points are warranted," Dr Bakris and colleagues write.

Asked to comment, Robert C Stanton, MD, chief of the nephrology section at the Joslin Diabetes Center and an associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, "Diabetic kidney disease continues to rise at a rapid rate. There's a lack of new [drugs] out there, so if we have another tool that might be useful, I think that would be great."

However, he noted, "It's not a new target. It's basically a [potentially] safer version of a drug that we already have and maybe a more targeted version.

"Whether or not it will allow for higher dosing and [greater efficacy] than with spironolactone, due to the lack of hyperkalemia, remains to be seen. Basically we need a longer-term study to see what happens to glomerular filtration rate [GFR] and albuminuria over time."

Other companies, including Mitsubishi, Daiichi-Sankyo, Eli Lilly, and Pfizer, are also developing nonsteroidal MRAs for the treatment of chronic kidney diseases. "Aldosterone inhibition appears to be a fruitful target at the moment," Dr Stanton commented.

Newer MRAs are also under development for other indications. Results from another phase 2 trial, ARTS-HF, comparing finerenone with eplerenone in worsening heart failure in patients who also have type 2 diabetes and/or chronic kidney disease were reported yesterday at the European Society of Cardiology (ESC) 2015 Congress.

Dose-Dependent Relationship

Patients enrolled in ARTS-DN had type 2 diabetes, albuminuria (UACR 30 mg/g or greater), and an estimated glomerular filtration rate (eGFR) higher than 30 mL/min/1.73 m2; were already taking at least the minimum recommended dosage of a RAS blocker; and had serum potassium levels 4.8 mmol/L or less.

Patients with an eGFR of 30 to 45 mL/min/1.73 m2 must have also been treated with a stable dose of a non–potassium-sparing diuretic prior to the study.

If hyperkalemia occurred during study treatment, the assigned therapy was discontinued and a potassium-lowering agent given.

The 821 patients were randomized to oral, once-daily finerenone at doses of 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg or to matching placebo for 90 days. Of those, 764 patients completed the 90 days of treatment.

There was a dose-response relationship — the primary outcome, UACR at day 90 relative to baseline, was reduced in the higher-dose finerenone groups — for the 7.5-, 10.0-, 15.0- and 20.0-mg/day groups, those values were 0.79 (P = .004), 0.76 (P = .001), 0.67 (P < .001), and 0.62 (P < .001), respectively.

There was no difference in the overall incidence of adverse events or serious adverse events between the finerenone and placebo groups, nor any relevant increases in adverse events across finerenone dosages. Drug-related serious adverse events occurred in 1.5% of patients receiving finerenone.

The prespecified secondary outcome of hyperkalemia (increase in serum potassium of at least 5.6 mmol/L) leading to subsequent discontinuation of study treatment occurred in 12 of 821 patients (1.5%), all of whom were receiving finerenone.

In the 7.5- to 20-mg/day finerenone groups — those doses for which significant changes occurred in the primary end point — the overall hyperkalemia incidence was 1.8%. There were three cases of serum potassium levels above 6.0 mmol/L overall, two in the finerenone 1.25-mg/day group and one in the 15-mg/day group.

Limitations and Next Steps

The study authors noted one drawback of their study, the fact that 60% of patients had an eGFR above 60 mL/min/1.73 m2, thus putting them at lower risk of hyperkalemia.

Dr Stanton agrees this is a limitation. "So whether or not their lower risk for high potassium was due to the fact that they had better kidney function is one question," he noted.

But "a strength is that there was a dose-response effect on the proteinuria.…So it's showing that a newer class of drugs with fewer side effects compared with spironolactone may be promising, but we really don't know in the long run."

Indeed, Bayer expects to begin enrolling patients into phase 3 trials — at least one for diabetic kidney disease, the other for heart failure in patients with type 2 diabetes or chronic kidney disease — by the end of this year, a company spokesperson told Medscape Medical News.

This study was funded by Bayer HealthCare. Dr Bakris has received an investigator-initiated grant/research support from Takeda (direct funding to University of Chicago); has been a principal investigator in national/international clinical trials sponsored by Bayer HealthCare, Medtronic, and Relypsa (direct funding to University of Chicago); and has been an advisor/consultant for AbbVie, Bayer HealthCare , Bristol-Myers Squibb, CVRx, Elcelyx, Eli Lilly/Boehringer Ingelheim, Janssen, Medtronic, Novartis, GlaxoSmithKline, Takeda, Tengion, and ZS Pharma. Disclosures for the coauthors are listed in the article. Dr Stanton is serves on the global renal advisory board for Boehringer Ingelheim.

JAMA. 2015;314:884-894. Abstract

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