Atrasentan: The Difficult Task of Integrating Endothelin A Receptor Antagonists into Current Treatment Paradigm for Diabetic Kidney Disease

CKD will become the fifth global cause of death by 2040, and diabetes is the most common cause of CKD worldwide (¹). This illustrates the global need for optimized early diagnosis and treatment of diabetic kidney disease (DKD). The long-term effect of recently approved kidney protective medications such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the mineralocorticoid receptor antagonist (MRA) finerenone is yet to materialize. Endothelin-1 has long been implicated in the pathogenesis of CKD by preclinical studies. However, clinical development of endothelin receptor antagonists has been marred by safety issues related to sodium retention. Atrasentan is an endothelin A receptor antagonist that met a primary end point of kidney protection in a phase 3 randomized, placebo-controlled trial in DKD, the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial. SONAR enrolled people with diabetes and CKD category G2G4 with eGFR between 25 and 75 ml/min per 1.73 m² and a urinary albumin-creatinine ratio (UACR) category A3 (0.3–5.0 g/g) on maximum tolerated renin angiotensin system (RAS) blockade. After 6 weeks on 0.75 mg/day atrasentan (enrichment period), participants were randomized to continue atrasentan or transition to placebo. The open-label atrasentan enrichment period was designed to limit safety issues related to sodium retention and to categorize the albuminuria response. Of 5117 participants in the enrichment period, 2648 were albuminuria responders (30% decrease in albuminuria) without safety concerns, and were randomized to atrasentan (n=1325) or placebo (n=1323) (²). Additionally, 1020 nonresponders without safety concerns were also randomized to atrasentan or placebo, whereas 1441 patients discontinued atrasentan because of adverse effects (n=258), nonresponder randomization closure (n=796), or other reasons (²). The primary kidney outcome was a composite of sustained serum creatinine doubling or kidney failure (formerly called ESKD). The trial was terminated because of slow recruitment and only reached about half the planned sample size and outcome events. From SONAR, atrasentan emerged as a nephroprotective drug that, despite the enrichment step and contrary to SGLT2i, did not decrease the risk of heart failure or cardiovascular death (^3–5). The decrease in the primary kidney end point (hazard ratio [HR], 0.65; 95% confidence interval [95% CI], 0.49 to 0.88; P=0.005) was in the range found for similar outcomes with SGLT2i (HR, 0.66; 95% CI, 0.53 to 0.81; P<0.001 for canagliflozin in the Canagliflozin and Renal Outcomes in Type 2 Diabetes [CREDENCE] trial and 0.56, 95% CI, 0.45 to 0.68, P<0.001 for dapagliflozin in the Dapagliflozin in Patients with Chronic Kidney Disease [DAPA-CKD] trial) and with the MRA finerenone (HR, 0.82; 95% CI, 0.73 to 0.93; P=0.001 in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease [FIDELIO-DKD] trial) when tested in patients with DKD (^4–6). As has been the case for bardoxolone, a kidney-protective drug with an unfavorable cardiovascular profile, clinical trials are addressing the role of atrasentan in CKD unrelated to diabetes, in which organ damage is for the most part limited to the kidney, such as proteinuric glomerular disease (clinicaltrials.gov NCT04573920; NCT04573478). A complementary approach would be to characterize the effect of atrasentan on diverse subpopulations of persons with DKD to identify subgroups that may benefit most and enrich future clinical trials. Furthermore, because SGLT2i and MRA decrease the risk of heart failure and cardiovascular death, a future strategy may be to combine RAS blockade and SGLT2i or (even “and”) MRA with atrasentan in these enriched populations. The hypothesis would be that the combination of atrasentan (or other endothelin receptor antagonists) with SGLT2i or MRA may add to the kidney-protective effect by adding a different mechanism of kidney protection, while limiting the cardiovascular adverse profile of atrasentan.

In this issue of CJASN, Waijer et al. now report a post hoc analysis of atrasentan effects on the primary kidney outcome and on heart failure hospitalization and cardiovascular death across subgroups of eGFR (G2–G3a, G3b, G4) and of UACR (all within the A3 category: <1.0, 1.0 to <3.0, ≥3.0 g/g) in SONAR, analyzing the overall (n=3688 participants) study population and the responder (n=2648 participants) population (⁷). The key finding was that atrasentan reduced the relative risk of the primary kidney outcome consistently across baseline UACR and eGFR subgroups. The largest absolute risk reduction was observed in persons at the highest risk of CKD progression, namely, those with the lowest eGFR (25–30 ml/min per 1.73 m²) and highest albuminuria (UACR ≥3.0 g/g) (Figure 1, A and B). However, the relative and absolute risks of heart failure hospitalization were similar across subgroups. Thus, the highest absolute benefit:risk ratio was observed for patients with most advanced DKD, defined as either low eGFR or high UACR.

Figure 1.: Subgroup analysis of the effect of clinical trials of SGLT2 inhibitors (canagliflozin: Canagliflozin and Renal Outcomes in Type 2 Diabetes [CREDENCE], dapagliflozin: Dapagliflozin in Patients with Chronic Kidney Disease [DAPA-CKD], and atrasentan: Study of Diabetic Nephropathy with Atrasentan [SONAR]) on a combined kidney end point of doubling of serum creatinine (eGFR decrease >50% for dapagliflozin), kidney failure, or kidney death. (A) Analysis of eGFR category subgroups. Both hazard ratio (HR) and absolute risk differences are shown. (B) Analysis of albuminuria category subgroups. Both HR and absolute risk differences are shown. (C) Residual kidney risk expressed as events/1000 patient-years in the active intervention group. Results shown for eGFR and albuminuria categories. Data from refs. ^7–9. SGLT2, sodium-glucose cotransporter 2.

Analyses along similar lines have been recently published for participants in CKD trials of canagliflozin (⁸) and dapagliflozin (⁹), although these have been limited to either eGFR or albuminuria categories (Figure 1, A and B). In the CREDENCE trial, canagliflozin was associated with a pattern of absolute kidney risk reduction for UACR categories that mimicked the findings for atrasentan (⁸). For dapagliflozin participants in DAPA-CKD, there was no heterogeneity regarding the absolute risk difference of doubling of serum creatinine, kidney failure, or kidney death when comparing the G4 category with G2/G3 (⁹). Unfortunately, we lack similar detailed subgroup analyses for finerenone. A key finding of these subgroup analyses is that there is still a considerable residual risk for CKD progression, despite the recommended management of DKD using RAS blockade plus SGLT2i, and this risk is especially high for patients that demonstrated the highest absolute kidney risk reduction on atrasentan, that is, those with eGFR category G4 and UACR >3.0 g/g (Figure 1C) (^7–9). Thus, these patients with DKD may potentially benefit from adding an endothelin receptor antagonist to either RAS blockade/SGLT2i or RAS blockade/finerenone. Unfortunately, the use of finerenone in SONAR was nonexistent and the use of SGLT2i too low (<2%) to provide insight on what to expect from the RAS blockade/SGLT2i/atrasentan combination on kidney outcomes. However, Heerspink et al. recently analyzed the 14 patients on SGLT2i/atrasentan in SONAR, comparing them to 42 atrasentan-only controls to conclude that 6 weeks of treatment with combined SGLT2i/atrasentan versus atrasentan alone decreased body weight, a surrogate for fluid retention, and further decreased albuminuria (¹⁰). These findings would point to a potential additive effect of SGLT2i and atrasentan on kidney protection while minimizing the adverse effect profile of atrasentan.

In conclusion, the article by Waijer et al. is part of a wider effort to dissect the results of SONAR to improve our understanding of the interaction of atrasentan with DKD that may guide further development of endothelin receptor antagonists for CKD. It identified patients with DKD and eGFR category G4 and UACR >3.0 g/g as those most likely to benefit from add-on atrasentan from a kidney protection point of view, without exposing patients to a higher risk of heart failure and cardiovascular death, as in the analysis, the absolute risks of heart failure hospitalization were similar to subgroups with less advanced DKD. However, findings should be considered hypothesis generating, given the post hoc nature of the analysis, the complex selection and enrichment process that may limit the extrapolation of the results to routine clinical practice, and the low number of patients in the CKD subgroups of interest. In any case, the combination of SGLT2i and endothelin receptor antagonist remains appealing as a theoretical possibility and is indeed already being evaluated in the phase 2 Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD, NCT04724837) trial, testing zibotentan as an add-on to SGLT2i in patients with diabetic or nondiabetic CKD with a primary end point of albuminuria.

Disclosures

A. Ortiz reports being a director of the Catedra Mundipharma UAM of DKD and the Catedra AstraZeneca UAM of CKD and electrolytes, and Editor-in-Chief of Clinical Kidney Journal; reports consultancy agreements with Genzyme Sanofi and Retrophin; reports receiving research funding from AstraZeneca, Mundipharma, and Sanofi-Genzyme; reports receiving honoraria from Advicciene, Alexion, Amicus, Amgen, Astellas, AstraZeneca, Bayer, Chiesi, Fresenius Medical Care, Idorsia, Kyowa Kirin, Menarini, Otsuka, Sanofi-Genzyme, and Vifor Fresenius Medical Care Renal Pharma; reports serving as a scientific advisor or member of Spanish Society of Nephrology, the Journal of Nephrology, JASN, and Peritoneal Dialysis International Editorial Boards, ERA and SOMANE and Councils, Board of Directors of the IIS-Fundacion Jimenez Diaz UAM, and the Dutch Kidney Foundation scientific advisory board; and reports speakers bureau for Advicciene, Alexion, Astellas, AstraZeneca, Amicus, Amgen, Bayer, Chiesi, Fresenius Medical Care, Idorsia, Kyowa Kirin, Menarini, Otsuka, Sanofi-Genzyme, and Vifor Fresenius Medical Care Renal Pharma. B. Fernandez-Fernandez reports consultancy agreements with AstraZeneca, Bayer, Boehringer Ingelheim, Mundipharma, and Novo Nordisk; reports receiving research funding from Esteve and Mundipharma; reports receiving honoraria from Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Esteve, Menarini, Mundipharma, and Novartis; reports serving as a board member of European Renal and Cardiovascular Medicine (EURECA-m European Renal Association and on the Editorial Board of Nefroplus; reports speakers bureau for AstraZeneca, Boehringer Ingelheim, and Mundipharma; reports serving as Professor for Catedra Mundipharma Universidad Autónoma de Madrid (UAM) of DKD; and reports membership with American Society of Nephrology (ASN), European Renal Association (ERA), Spanish Society of Nephrology (SENEFRO), and Madrilenian Society of Nephrology (SOMANE).

Funding

This work is supported by Instituto de Salud Carlos III grants PI20/00744 FIS FEDER funds, ISCIII, Intensificacion IIS-FJD (to B. Fernandez-Fernandez), and FIS/Fondos FEDER (PI18/01366, PI19/00588, PI19/00815, DTS18/00032), ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM (to A. Ortiz).