Diabetics could boost Daiichi's nascent heart asset

Daiichi Sankyo has revealed a phase III win with esaxerenone in hypertension, a project that many years ago emerged from the labs of Exelixis. If all goes well the asset could develop into a helpful revenue generator for both groups – the Japanese giant is struggling with patent expiries, and the US developer is in the midst of launching its oncology franchise.

Esaxerenone works in a similar way to Pfizer’s long-expired Inspra, although presumably it has some pharmacological advantages – the pivotal trial pitted the two agents head to head. At the same time Daiichi announced a move into diabetic nephropathy, where Bayer is already active with another similar compound, and representing an area that arguably holds greater commercial potential.

That Bayer project is finerenone, which like esaxerenone prevents binding of aldosterone by blocking the mineralocorticoid receptor and helping to control a rise in blood pressure. Like other next-generation antagonists in development it is described as non-steroidal, and has been designed for greater selectivity towards the mineralocorticoid receptor than Inspra plus stronger binding affinity.

As such, it is hoped that these newer agents will be more tolerable than earlier compounds like eplerenone, Inspra's active ingredient. Fear of hyperkalaemia, caused by very high potassium levels, has severely restricted the use of Inspra, despite evidence that the drug can reduce mortality and morbidity in patients with heart failure.

That potential remains to be proven, however, and limited detail released by Daiichi on the Esax-HTN study leaves the question unanswered for now. The trial recruited 1,000 Japanese patients with hypertension and dosed them with one of two doses of esaxerenone or Inspra, measuring blood pressure change from baseline as the primary endpoint. The company said the primary endpoint had been achieved, with no significant safety concerns.

Targeting the mineralocorticoid receptor
Product Company Notes
Inspra (eplerenone) Pfizer Launched in 2003; sales peaked at $233m in 2013.
Aldactone (spironolactone) Pharmacia Active ingredient first launched in 1961; sales of Aldactone peaked at $224m.
Finerenone Bayer Currently in phase III.
CS-3150 (esaxerenone) Daiichi Sankyo Currently in phase III.
MT-3995 Mitsubishi Tanabe Only in active development for Nash, in phase II.
LY2623091 Eli Lilly Presumed abandoned in 2015 in phase II.
PF‐03882845 Pfizer   Presumed abandoned in 2013 in phase I.
Source:   EvaluatePharma    

The incidence of hyperkalaemia will be crucial to determining the potential of esaxerenone, assuming that it is also at least as effective at controlling blood pressure as Inspra.

Bayer’s work with finerenone has also so far failed to prove its agent’s benefits over Inspra, although signals of greater potential can possibly be found in a large phase IIb study presented in 2015.

Arts-HF, in patients hospitalised for worsening heart failure, found no difference between finerenone and Inspra on the primary endpoint, change in a measure of cardiac stress. Secondary endpoints pointed to a numerical benefit for the Bayer project on measures such as the incidence of death or cardiovascular hospitalisation.

The trial, which was criticised at the time for being underpowered, was not designed for statistical analysis on the secondary endpoints, while rates of hyperkalaemia were similar between the two arms.

Still, this did not stop Bayer from proclaiming a move into a large pivotal finerenone programme, comprising three studies – two in diabetic nephropathy and one in chronic heart failure - although the latter indication was dropped in 2016.

Any bigger?

With nothing available to specifically treat nephropathy, and growing rates of diabetes, this is arguably a more attractive area for these agents anyway - around 40% of diabetics are estimated to suffer kidney damage.

It is hoped that this mechansim will promote an improvement in kidney function; aldosterone, which is active in the nephrons, is considered a potent mediator of organ damage.

Bayer’s two huge kidney disease studies, which are seeking to recruit 11,200 patients, should provide an answer, though data are unlikely to emerge before 2020. And it should be remembered that there have been several dropouts from this space: despite running fairly recent trials Mitsubishi Tanabe does not seem to be pushing on with its MRA antagonist MT-3995 in diabetes patients, while Pfizer canned PF‐03882845 about five years ago.

In the meantime Morgan Stanley analysts reckon Daiichi could build esaxerenone to a ¥10-20bn ($89-179m) franchise in Japan, but that development costs are likely to curtail international ambitions. Strong signals in diabetes patients could prompt the company to think bigger.

Late stage diabetic nephropathy pipeline (novel agents)
Product Company Pharma class Trials Data 
Atrasentan AbbVie Endothelin A receptor antagonist Sonar: NCT01858532 2018
Finerenone Bayer Mineralocorticoid receptor   antagonist Fidelio-DKD: NCT02540993;   Figaro-DKD: NCT02545049 2019/2020
Invokana Johnson & Johnson SGLT 2 inhibitor Credence: NCT02065791 2019
Farxiga AstraZeneca SGLT 2 inhibitor Dapa-CKD: NCT03036150 2020
Esaxerenone   (CS-3150) Daiichi Sankyo Mineralocorticoid receptor antagonist Exas-DN: JapicCTI-173695 2019?

This story has been corrected to state that Bayer has dropped development of finerenone in heart failure.

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @ByAmyBrown on Twitter

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