Bayer’s big kidney disease readout approaches

Bayer has invested heavily in finerenone in kidney disease, but the window of opportunity has narrowed. Data will soon show whether it has shut completely.

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Putting finerenone into a 12,000-patient pivotal programme in diabetic kidney disease looked like a bold bet back in 2015, when Bayer first started the studies. Five years later, with SGLT2 inhibitors on the way to establishing a beneficial class effect in this very setting, the risk that the move will never pay off is even greater.

All will become clearer as data start to emerge from two phase III trials. Topline results from the first of these, Fidelio-DKD, are due in the second quarter, while Figaro-DKD should read out early next year. Bayer is trying to show that finerenone can reduce these patients’ risk of kidney failure and cardiovascular death; the studies pit the pill against placebo but the results will also be held up against Invokana’s record.

Invokana, Johnson & Johnson’s SGLT2 inhibitor, last year became the first drug of this class to win approval to reduce the risk of end-stage kidney disease and cardiovascular events in diabetics with chronic kidney disease. Around 30% of diabetics develop nephropathy, or progressive destruction of the kidney; these patients are at a very high risk of both cardiac complications and kidney failure.

Differences between the study that won Invokana approval here, Credence, and the finerenone programme complicates a cross-trial comparison. There are certain data points that will be used as yardsticks, however, in particular Invokana’s 32% reduction in the risk of end-stage kidney disease, and 20-30% reduction of various cardiovascular events.

The bar to beat? Invokana in diabetic CKD patients 
Selected endpoints from Credence study Risk reduction: hazard ratio (p value)
Primary composite endpoint* 0.70 (0.0001)
End-stage kidney disease  0.68 (0.002)
Doubling of serum creatinine  0.60 (<0.001)
Cardiovascular death 0.78 (0.05)
Cardiovascular death or hospitalisation for heart failure  0.69 (<0.001)
End-stage kidney disease, doubling of serum creatinine, or renal death 0.66 (<0.001)
Cardiovascular death, myocardial infarction, or stroke 0.80 (0.01)
*Composite of end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death. Source: NEJM 

The Credence findings were considered hugely important not only because of the clear benefit shown, but because Invokana was an established type 2 diabetes treatment with a proven cardiovascular benefit. Trials of other SGLT2 inhibitors are expected to confirm these findings as a class effect: Astrazeneca’s Dapa-CKD study of Farxiga and Lilly’s Empa-Kidney trial of Jardiance are due to report later this year and 2022 respectively.

These studies are recruiting diabetics and non-diabetics, adding another dimension to any attempt to assess the commercial impact that finerenone can hope to achieve. 

Finerenone in numbers
Estimated cost of CKD clinical programme  2024e sales  Product NPV 
$868m  $206m $940m
Source: EvaluatePharma. 

Finerenone is a mineralocorticoid receptor antagonist (MRA), a mechanism already used to control high blood pressure and dampen down the damaging inflammation and fibrosis that are hallmarks of diabetic kidney disease. Safety concerns mean that existing MRAs are only used as a last resort – Pfizer’s Inspra or the older spironolactone are examples – and Bayer is hoping to show that finerenone is an entirely different proposition.

The project’s main differentiators include that it is non-steroidal, with greater selectivity for the MRA receptor. Bayer reckons this should translate into fewer androgen-based side-effects and a decreased risk of hyperkalaemia – very high potassium. Rates of these side effects will be watched closely in the phase III data.

Assuming safety is cleaner, primary endpoints will also have to be met unequivocally. For added complication, the two studies have a different focus.

Fidelio has a composite primary endpoint that includes time to onset of kidney failure, a measure of kidney function and renal death, while the key secondary endpoint is another composite that assesses cardiovascular death and events. Figaro switches these around, with the cardiac endpoints as its primary.

The trials recruited largely same patient population: type 2 diabetics with kidney disease and on maximum dose blood pressure therapy. Some patients will already be on SGLT2 medicines – at the company’s annual results Bayer executives said they were likely to have “in the order of typical market share for SGLT2s in our finerenone population”.

Bernstein analysts note that patients on background SGLT2 inhibitors will form an important cohort, one that Bayer is likely to tease out in future cuts of the data. But, first of all, the company needs these topline readouts to confirm that finerenone even has a chance of competing.

The finerenone pivotal programme, in diabetic CDK patients
Study Trial ID  Primary endpoint
Fidelio-DKD NCT02540993 Composite of onset of kidney failure, eGFR ≥40% decrease over at least 4 weeks or renal death
Figaro-DKD NCT02545049 Composite of cardiovascular death and non-fatal cardiovascular events

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