By Manasi Vaidya, Reporter, New York
Biopharmaceutical Report II
Sodium-glucose cotransporter-2 (SGLT2) inhibitors’ growing prominence in diabetic kidney disease (DKD) will likely impede uptake for Bayer’s (ETR:BAYN) Phase III mineralocorticoid receptor antagonist (MRA), finerenone, experts noted. While finerenone will likely have an advantage over older drugs within its class, payers are likely to also scrutinize its value-add when combined with SGLT2 inhibitors and may still prefer the less expensive existing versions, they explained. Nonetheless, they added, the lack of standard SGLT2 use and the class being contraindicated for some patients will aid market traction.
SGLT2 inhibitors were not an option for DKD patients when Phase III development started in September 2015 for finerenone, experts acknowledged. Prominent among the SGLT2 inhibitor class is Johnson & Johnson’s (NYSE:JNJ) Invokana (canagliflozin), which won FDA approval for DKD on 30 September. Because finerenone will likely not be directly compared to SGLT2 inhibitors, the choice between the two in deciding a patient’s regimen will become a factor of cost and payer coverage, two experts said.
Ongoing finerenone studies do not compare the drug to Invokana or any other SGLT2 inhibitor, but subgroup data on the combination of an SGLT2 inhibitor and finerenone will give an indication of the duo’s additive efficacy, some experts noted. Yet, they added, a separate randomized trial will likely be required to spur use in this fashion.
Results from Phase III FIDELIO-DKD(NCT02540993), which has a kidney function-focused primary endpoint, are expected in 2Q20, as per an analyst report. The Phase III FIGARO-DKD(NCT02545049), focused on cardiovascular risk analysis, has a primary completion date in June 2021, according to ClinicalTrials.gov. This news service reported earlier today that experts are cautiously optimistic about the chances of FIDELIO and FIGARO achieving success due to encouraging Phase II data.
A second analyst estimated peak sales of USD 1bn for finerenone with a 50% probability of commercial success. Bayer’s market cap is EUR 65.84bn (USD 71.17bn). Bayer did not respond to a request for comment.
SGLT2 inhibitors claim space in kidney disease
The new environment for kidney disease is more complicated than when the finerenone trials started, said Dr Mark Cooper, head, Department of Diabetes, Monash University, Melbourne, Australia. Johnson & Johnson won approval for Invokana on the back of the
Phase III CREDENCE study (NCT02065791), which was stopped early after an interim analysis indicated the risk of kidney failure and cardiovascular events was lower when patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) received Invokana
compared to placebo (Perkovic et al N Engl J Med 2019; 380:2295-2306).
Renal outcomes and cardiovascular mortality data with other SGLT2 inhibitors like AstraZeneca’s (LON:AZN) Farxiga (dapagliflozin) and Boehringer Ingelheim’s Jardiance (empagliflozin) are expected, but both drugs have been shown to be renoprotective in T2D studies. The Phase III DAPA-CKD trial with Farxiga will complete in November 2020, and Phase III EMPAKIDNEY with the latter completes in 2022. While FIDELIO and FIGARO were being performed, the renoprotective qualities of Farxiga, Jardiance and Invokana became apparent, along with their ability to target albuminuria, said a FIGARO investigator.
"Because finerenone will likely not be directly compared to SGLT2 inhibitors, the choice between the two in deciding a patient’s regimen will become a factor of cost and payer coverage"
CREDENCE trial results are practice-changing, experts noted. More patients should be treated with SGLT2 inhibitors, and in fact, they should not be used exclusively in diabetic patients where they were first approved, said Dr Jay Wish, professor of Clinical Medicine, Division of Nephrology, Indiana University, Indianapolis. SGLT2 inhibitors are effective regardless of whether a patient has diabetes at least from the cardiovascular risk point of view, agreed a FIDELIO investigator.
However, despite SGLT2 inhibitor efficacy in patients with diabetes and kidney disease or even kidney disease alone, some patients continue to have residual disease, said a second FIGARO investigator and the FIDELIO investigator. Also, while CREDENCE results were significant, SGLT2 inhibitors are still not used in most countries, and the class is contraindicated for some patients, albeit a relatively small part of the population, said Cooper. Invokana is not yet approved in the EU, but in a 22 August press release, Cambridge, UK-based Mundipharma—Invokana’s European distributor—said the drug’s license extension to treat Stage 2 and 3 CKD patients was accepted by the
EMA. Invokana is contraindicated for patients with severe renal impairment, end-stage renal disease or on dialysis and those with a serious hypersensitivity reaction to Invokana.
Hence, there is room for finerenone as a therapy for renal disease, said the second FIGARO investigator. Moreover both classes act by distinct pathways, he added. SGLT2 inhibitors lower blood sugar by causing its excretion through urine, and MRAs block
the hormone aldosterone, which regulates sodium and potassium transport, thus impacting the heart and kidneys. While effective, SGLT2 inhibitors still do not counteract the effects of aldosterone, said the first FIGARO investigator.
Yet, it is hard to predict the efficacy of finerenone combined with an SGLT2 inhibitor, said the second FIGARO investigator. If patients are on SGLT2 inhibitors, their kidney disease progression will have slowed, making it tougher to show an extra benefit with a new drug, Cooper added. Also, MRAs and SGLT2s are both diuretics, and it is not known whether this will have an additive effect when used long-term, he noted.
Since the FIDELIO and FIGARO studies have patients who were on SGLT2 inhibitors, data from this patient subgroup receiving both drugs will give an indication of their interaction, said the second FIGARO investigator. A preplanned analysis will evaluate the impact of patients on SGLT2 inhibitors in addition to finerenone, added the FIDELIO and first FIGARO investigator. The timing of this analysis has not been stated in trial-related publications. In FIDELIO and FIGARO, 4.5% and 8.3% of patients are on SGLT2 inhibitors, respectively (Bakris et al; Am J Nephrol. 2019 Oct 25:1-12 and Ruilope et al; Am J Nephrol. 2019 Oct 30:1-12.).
While the FIDELIO and FIGARO studies will give an idea about finerenone’s additional benefit on top of SGLT2 inhibitors or angiotensin-converting enzyme (ACE) inhibitors, a separate trial would still be needed to establish use of such a combination, said the FIDELIO investigator. Cooper agreed that data from FIDELIO and FIGARO will not be enough to drive the use of a finerenone/SGLT2 inhibitor combination.
Payer considerations for finerenone use
The MRA class is a cornerstone of renal protection, and physicians could likely accept finerenone as a first choice between drugs of that class, said Wish. If the finerenone studies are positive, the drug would be preferred over other MRAs, since it is expected that finerenone will have lower rates of hyperkalemia compared to other MRAs based on the Phase II studies, added Cooper.
Yet, since finerenone will likely be more expensive than other MRAs, physicians may mainly want to use it in CKD patients who receive MRAs but develop side effects, noted Wish. Payers as well may demand that finerenone be an option only after patients have either
failed spironolactone or been treated with potassium binders for the hyperkalemia, he added. Physicians are very comfortable using MRAs for kidney disease and they have also been widely used for heart failure, added Cooper.
And while combination data is needed for finerenone/ SGLT2 inhibitor use, expense will also be a factor. The challenge is that newer drugs like finerenone and the T2D therapies are expensive, and using the two classes together would be very expensive compared to an older drug like metformin, said the first FIGARO investigator. Ideally, a patient still suffering from albuminuria despite metformin and an SGLT2 inhibitor would benefit from finerenone being added to those two, but the high cost would mean physicians may have to choose between finerenone and an SGLT2 inhibitor, he added. The magnitude of positive data in the finerenone trials compared to CREDENCE may help with the selection, said the first FIGARO investigator.
Manasi Vaidya joined as a reporter in New York in February 2015 and has covered the drug development space across a number of therapeutic areas, and built an expertise in writing about oncology. While focusing on analysis pieces about ongoing clinical trials, her coverage has also branched out to regulatory issues, pricing and reimbursement and patent litigation. She has covered practice-changing developments from high profile conferences like ASCO and SABC, in addition to FDA regulatory meetings. She previously covered the Asian biotechnology industry for BioSpectrum, a monthly magazine in India,
for two years. She has a Masters degree in Science, Health and Environmental Reporting from New York University, and a Masters degree in Biotechnology from Dr. D. Y. Patil University. Her work has appeared in Nature Medicine, Nautilus and Technology Review India.