Bayer has revealed new data from FIDELITY, a pooled analysis from the phase 3 trials FIDELIO-DKD and FIGARO-DKD of Kerendia (Ingredient: finerenone), showing the drug's potential to have positive effects on mortality in patients with chronic kidney disease and type 2 diabetes (T2D).

The FIDELITY trial combines two randomized, double-blinded, and placebo-controlled studies -- the 5,700-patient FIDELIO-DKD and the 7,300-patient FIGARO-DKD.

The analyses from FIDELITY received great attention during the ESC 2022 held in Barcelona, Spain, as it comprises the largest phase 3 cardiorenal outcomes program, with over 13,000 patients with chronic kidney disease and type 2 diabetes patients randomized.

In the overall FIDELITY population, the effect of finerenone on all-cause and CV mortality narrowly missed statistical significance. An analysis of the components of CV mortality in the intention-to-treat population showed that finerenone significantly reduced the incidence of sudden cardiac death. In addition, in a prespecified on-treatment analysis from FIDELITY, finerenone reduced the incidence of all-cause and cardiovascular mortality versus placebo.

The effect on mortality was consistent in patients across baseline estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) values.

Korea Biomedical Review met with Markus Scheerer, Bayer’s vice president of chronic kidney disease (CKD) in global medical affairs, to see the trial results and an in-depth explanation of the study's results.

Question: What is the efficacy of Kerendia that one can confirm from the last published FIDELITY pooled analysis and the newly published analysis regarding fatality? And what is the clinical or socioeconomic value of the data?

Answer: We are proud that we had this hotline session on Monday with Professor Gerasimos Filippatos. And it shows that approximately one-quarter of people with CKD in early stages – stages 1 and 2 – die due to cardiovascular diseases. If we look at the later stages, almost half of the patients die.

We also know that patients with CKD and type 2 diabetes are three times more likely to die from cardiovascular disease than if they have diabetes alone.

I think these two factors together allow us to understand why our analysis is really important.

Finerenone is interesting because the FIDELITY analysis comprises, the largest phase 3 cardiorenal outcomes trial program to date, with 13,000 patients with CKD and type 2 diabetes having been studied across FIDELIO-DKD and FIGARO-DKD.

The FIDELITY analysis showed that finerenone leads to a significant reduction in the renal composite as well as in the cardiovascular composite.

The data we presented on Monday was, in particular, the sudden cardiovascular death component, and we showed a significant 25 percent reduction in the endpoint. On top of that, although we missed the cardiovascular death and all-cause mortality slightly in the intention-to-treat analysis, we were seeing that if patients take finerenone in an on-treatment analysis, the treatment had an 18 percent reduction in cardiovascular death as well as all-cause mortality.

That's very important because this shows that we have a drug that works.

Finerenone is already incorporated into international guidelines, such as the American Diabetes Association for both the CKD and cardiovascular sections, and in the American Heart Association guidelines and statements.

Q: If you could specify a patient group that can benefit the most from using Kerendia, who would it be?

A: That's hard to say because what we looked at was that the benefit is across all stages.

I think that it's really important to mention that we have a wide variety of patients that can benefit from the treatment.

Notably, we would like to stress that finerenone, as a nonsteroidal mineralocorticoid receptor antagonist (MRA), shows benefits in a broad patient population.

Q: The Bayer presentation during the ESC conference emphasized the evaluation of patients' eGFR and UACR to determine which patients would most likely need Kerendia treatment. However, the need to measure UACR may limit patient access to Kerendia. Are UACR measurements essential?

A: That always depends on the label, I would say.

I'm not 100 percent sure what our Korean label will look like, but in general, CKD can be missed by only measuring eGFR as it will only provide a functionality measurement.

UACR is the damage parameter, which is way more sensitive than the function parameter, which is the eGFR.

For us, UACR must be well measured because many patients believe that if they have an eGFR over 60, they are good and don't have CKD.

However, this is not true as many patients with an eGFR over 60 have CKD, and if we measure UACR, these patients have a higher risk of dying, as I said before.

Therefore, I think that measuring UACR is important.

Also, all the guidelines worldwide, including kidney and diabetes guidelines, recommend measuring both eGFR and UACR.

I think it's important to mention that some countries also put in benefit parameters.

For instance, the U.S. recently changed their measurement for Medicare to get reimbursement for physicians to look after these patients.

So, there is a change on the payer side and reimbursement side to look for the damage parameter and identify patients early.

Because if we can identify patients early, we can treat them earlier, and they will have a longer life.

Q: Currently, the efficacy demonstrated by Kerendia is limited to patients with type 2 diabetic kidney disease. Considering that Kerendia has no blood sugar-lowering effect, it is likely that the prescribing priority will be pushed behind the SGLT-2 inhibitor, which has recently demonstrated a cardio-renal protective effect at the same time. What is the company's position on the matter?

A: Kerendia works independently of an SGLT-2 inhibitor.

We have data on 877 patients in a subgroup analysis of FIDELITY which was just recently published in Diabetes Care, and basically, it says the efficacy is irrespective of SGLT-2. So patients benefit from Kerendia, and I think that's important to highlight.

While blood glucose and hemodynamic parameters are important in the treatment paradigm, we also see that inflammation and fibrosis complement the CKD progression.

Also, SGLT-2 inhibitors are not working that well on glucose if you have CKD but they work via hemodynamic parameters, indirectly via ROS, and other postulated mechanisms.

Kerendia works on the over-activation of mineralocorticoid receptor (MR), so a different pathway than SGLT-2 inhibitors, which is thought to contribute to inflammation and fibrosis, as well as via hemodynamic effects.

Thus, many experts are discussing that this mechanism is completely complimentary.

Therefore, you shouldn't have to choose between the two.

We're just here now at ESC, where we have the four fundamental pillars for heart failure.

In the long run, we might see that there will be at least three pillars for treating CKD – ACEi & ARBs, Finerenone and SGLT2 inhibitors.

So I believe in the long run, if I speak to many physicians, the combined therapeutic approach in CKD will take up more and more due to the high residual risk in all CKD studies and the only critical question will be which drug to start first and then escalate quickly.

Q: The company is currently testing and expanding the potential of Kerendia for treating type 1 diabetes and non-diabetic kidney disease. Why do you think Kerendia will function as a kidney drug on its own, regardless of whether you have diabetes or not?

A: As we said, Kerendia doesn't have glucose-lowering potential, which makes the treatment completely independent of glucose.

We are looking into inflammation and fibrosis.

In preclinical models, it was seen that finerenone reduced inflammation and fibrosis, and we also see hemodynamic effects.

We are currently conducting a non-diabetic CKD study called FIND-CKD. This study looks into the hypertension field, the second largest area of CKD after diabetes, including IgA nephropathy and other forms of CKD etiologies.

Due to the mode of action being more hemodynamic and anti-inflammatory as shown in preclinical models, we believe we don't need diabetes as a background therapy to show that Kerendia is working.

FIND-CKD, initiated in Sep. 2021, is a phase 3 study to investigate the efficacy and safety of finerenone in addition to guideline-directed therapy on the progression of CKD in more than 1,500 patients with non-diabetic chronic kidney disease etiologies, including hypertension and chronic glomerulonephritis.

Regarding type 1 diabetes, while we don't have a type 1 diabetes study for adults, we have a pediatric program called Fiona.

FIONA, initiated in November 2021, is a phase 3 study investigating the efficacy, safety, pharmacokinetics, and pharmacodynamics (PK/PD) of finerenone, in addition to standard of care, in approximately 200 pediatric patients with CKD and severely increased proteinuria.

In the study, we are not excluding children with type 1 diabetes.

Q: Lastly, could you explain how far the company expects using Kerendia to expand?

A: Our basis is patients with type 2 diabetes and CKD with data from the phase 3 studies FIDELIO-DKD and FIGARO-DKD, and the pooled analysis FIDELITY.

Then if we look just at the CKD space, we will expand into the non-diabetic CKD space, and we have our pediatric CKD program.

I would also like to mention that we have a study called CONFIDENCE, which is a phase 2 study in type 2 diabetes and CKD, and we are testing the hypothesis that the initial initiation of finerenone and SGLT-2 inhibitor will be superior in UACR reduction after six months in comparison to each of the treatments used as a monotherapy.

In the cardiology field, we are conducting FINEARTS-HF, a study to investigate finerenone vs. placebo in approximately 6,000 patients with symptomatic heart failure with preserved ejection fraction.