George Bakris, MD, takes part in a Q&A with Endocrinology Network staff to explore the design of the upcoming FIND-CKD trial and potential research priorities surrounding finerenone moving forward.
Backed by a pair of phase 3 clinical trials and FDA approval in July 2021, finerenone is well-positioned to make a meaningful impact on the lives of patients with chronic kidney disease and type 2 diabetes. Demonstrating significant cardiorenal protective benefits in both FIDELIO-DKD and FIGARO-DKD, trial data reflect a potential role for finerenone in the treatment algorithms for a large patient group.
Although the results from the phase 3 program may have been enough to satisfy clinicians and researchers in recent years, the revelation of SGLT2 inhibitors' effects in patients with and without diabetes seem to have raised the bar for stepping into the spotlight. Now, after demonstrating its safety and efficacy in patients with type 2 diabetes, Bayer is sponsoring the FIND-CKD trial, which will explore the effects of finerenone in patients with chronic kidney disease without diabetes.
In a presentation at the American Society of Nephrology Kidney Week 2021, clinicians were offered their most comprehensive view of the design of the upcoming FIND-CKD trial. The primer end point of the trial is rate of change in eGFR over time from baseline to end of treatment, which is planned to be approximately 32 months, and secondary outcomes include a composite renal end point similar to that used in FIGARO-DKD.
For more into the design of this study and future research priorities surrounding finerenone, Endocrinology Network reached out to George Bakris, MD, professor of medicine at the University of Chicago and principal investigator of FIGARO-DKD and FIDELIO-DKD, and that conversation has been transcribed as a Q&A below.
Endocrinology Network: Can you describe FIND-CKD and the impetus behind its design?
George Bakris, MD: Well, FIND-CKD came out of the finding that okay, we've got a clear impact in diabetes, but what about people without diabetes? To be honest with you, it really emanated from the results of the DAPA-CKD study, where they populated a third of the group with nondiabetics and were shocked to find out that they got really positive results, especially in IGA nephropathy and to a lesser extent in hypertension and other types of nephropathies. The question became why, and, to this day, we don't know why.
Now, if you look at a mineralocorticoid receptor antagonist, you can make a stronger argument for a mechanism because in hypertension, especially in obesity, mineralocorticoid receptors, at least at the basic science level, are more occupied and there is more interaction with aldosterone at those levels. Not that you've got high aldosterone levels, but that the impact on inflammation is greater because the fat cells in the abdomen, these visceral adipocytes, actually produce aldosterone.
So, the exploration here is to say, "Well, if SGLT2s are doing something, there's a stronger theoretical basis for blocking mineralocorticoid to be doing something". So, why not look at that?
So that's really where the impetus is coming from for this. I mean, the choices were to do or to look at type 1 diabetes. In fact, in type 1 diabetes, finerenone would be absolutely amazing. There's no data, at any level, in type one diabetes for the last 20 years on renal outcomes. So, this would have been a welcome change, but that was vetoed, and I think people wanted to expand the denominator in terms of people that would benefit.
That's where FIND-CKD is going. The design of the study is similar to what we did with FIDELIO and FIGARO in the sense that people are going to be maximized on ACEs and ARBS and then, they'll get randomized to finerenone or placebo. They are going to look at SGLT2 use and they're going to look at some other factors. Obviously, they're excluding people with diabetes, but they're not excluding obesity. So, it's going to be interesting to see how this all turns out, but we won't know the answer to that question until about 2025. But you got to start somewhere.
Endocrinology Network: Beyond FIND-CKD, what are the next steps in research for finerenone?
George Bakris, MD: Well, that's a that's a very good question. I think one of the unique things about finerenone is it's doing all of this with almost no blood pressure effects. I mean, it has blood pressure effects, let's be clear, but they're half of what you get with SGLT2 inhibitors, and it's not considered to be a blood pressure effect. So, this is independent, I would say, or relatively independent of blood pressure lowering.
Now, that's kind of a big deal and I think that when you look at this, we need what we're missing and we're missing some mechanistic studies. We're missing more of a deeper dive into renal hemodynamics. I published a paper in 2014 in the Seminars of Nephrology that basically identified, very simply, 2 factors that predict hyperkalemia—independent of diseases, independent of everything. The 2 factors: an eGFR, less than 45 or baseline potassium on diuretics of greater than 4.8.
We know that if your GFR is 60 or higher, your hyperkalemia rate was less than half of what you got if it was less than 60. So, in people with good eGFRs—meaning 60,70, 80—that have a lot of albuminuria, those people did very well and tolerated it far better than people with eGFRs of 30. Now, if you tell a nephrologist that, they will never be surprised because that is what you'd expect, but I'm just making the point that in FIND-CKD it's going to be interesting because you're going to tend to have lower levels of albuminuria than you did in the diabetes studies. So, you'll be able to see it in the cross-section of the population with different diseases.
The issue is going to be to get other physicians to use it and the major stumbling block is hyperkalemia. So, what can you do to assure people? Well, you can show them data that makes physiologic sense that is actually known by specialists but maybe not generalists. I think FIND-CKD is one way to expand that. But, when I think of the data that we have, one of the things we don't know, is: what are the changes?
There's a drop in GFR. Now, why is there a drop in GFR when you first give the drug? it's not a big drop, but you're dropping one to two to three and mL/L per minute within the first week. Now, things that happen that can affect that are either: Number 1, internal hemodynamic effect, like you get from ACE inhibitors or ARBs. Number 2, the big glucose load that you get from SGLT2s with sodium or, number 3, some type of internal hemodynamic effect that you're getting from blocking of aldosterone. This is also seen with spironolactone. So, it's really something that requires some better understanding, and we really don't have that. We have the observations, but we don't know why.
What's really disturbing is a lot of physicians think that if you're on an ACE or an ARB that you blocked aldosterone, which couldn't be further from the truth, and that is stuff that's taught in physiology class and medical school. So, people have either forgotten or they never knew that that's not true. So, everybody's hung up on, you've reduced risk by this much or you've reduced dialysis risk by this much, and this is all good, but if you don't understand really why, then you've only got half the story. It's a good half, but still, you need a better understanding.