Non-steroidal MRAs for Chronic Kidney Disease

What to know in terms of the mechanism of action of non-steroidal MRA finerenone compared with other therapies used to treat patients with chronic kidney disease and type 2 diabetes.

Neil B. Minkoff, MD: You were saying that finerenone isn’t a brother or a cousin, but maybe a second cousin or second cousin twice removed. But to somebody like me, is it a different mechanism of action? We talked a little about the pharmacodynamics of it. But is it working?

George L. Bakris, MD: Let’s face it. If it’s a mineralocorticoid receptor antagonist [MRA], its goal is to block aldosterone. It’s affecting aldosterone. There’s nothing different about that. It’s how it’s doing it that’s different. The chemistry of the molecule is totally different. If anything, it looks a little like nifedipine. It looks like a calcium blocker. When it interacts with the molecule, it doesn’t just bind, it changes a lot of the properties of the receptor in a different way than spironolactone does. It’s maybe more similar to eplerenone, but different from eplerenone. It’s not affecting it the same way. And as Rajiv says, the half-life is much shorter. As a result, some of the effects are much shorter; not just because you don’t have metabolites, but because of the duration of action.

Rajiv Agarwal, MD: Neil, George explained it really well. And I want to emphasize what George just said. This is a designer drug. This isn’t an accidental discovery.

Neil B. Minkoff, MD: Right.

Rajiv Agarwal, MD: This drug was discovered after screening one million molecules in Bayer’s library and discovering one that blocked the MR [mineralocorticoid receptor] very effectively and spared the androgen and progesterone receptors. It was also clarified by asking, “Is this the molecule that can cause toxicity?” We’re concerned about things like hepatotoxicity and skin necrosis. They cleared it with the molecular modeling and said that this drug appears safe. So not only do you have a drug that gets a small amount of hyperkalemia, but it also has no off-target effects. It’s doesn’t have any liver necrosis or skin necrosis. There’s absolutely nothing off target.

What George said is very important. The mineralocorticoid receptor is not a surface receptor, it’s a nuclear receptor. For the nuclear receptor, it will bind to the ligand, the MR. Basically, the complex is being transported to the nucleus and you have what’s called a cofactor recruitment. Finerenone is like an orchestra conductor and it’s telling who’s playing the violin, who’s playing the drums, etc, and it’s a very different song that it’s playing compared with spironolactone. Spironolactone has a completely different cofactor recruitment pattern. More than that, if you look at the animal models and compare eplerenone, which is a newer generation MRA, head-to-head with finerenone, you’ll find that it blocks inflammation and fibrosis more effectively in both the heart and kidneys.

Obviously, we can study this in a phase 3 trial and look at fibrosis and do serial biopsies and all that. But if you look at the animal models and compare it head-to-head with eplerenone, it’s doing something quite different, which is supporting the basic science of being a nuclear receptor antagonist and recruiting cofactors, which are quite different. There’s a lot of rich basic science to it. We probably can’t go into too much detail on that, but it’s a designer molecule.

Transcript edited for clarity.

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