Marketed endothelin receptor antagonists (ERAs) have been associated with testicular tubular atrophy and decreases in male animal fertility in chronic toxicity studies in rats and dogs. Consistent with these findings, reduced sperm count has been observed in the clinical setting and is considered a potential class risk with chronic administration of ERAs. In contrast, no such effects on male animal fertility are noted with angiotensin II type 1 receptor blocker (ARB) treatment. Sparsentan (FILSPARI®) is a novel single molecule dual antagonist that antagonizes both the endothelin type A and angiotensin II type 1 receptors. We explored whether the reproductive toxicology profile of this dual endothelin angiotensin antagonist is more like that of marketed ERAs or ARBs. A full package of repeat dose general toxicity, juvenile toxicity, carcinogenicity, and reproductive and developmental toxicity studies was completed with sparsentan. A thorough review of the results from these studies has shown no evidence of effects of sparsentan on spermatogenesis or testicular histopathology. The overall conclusion of this assessment is that sparsentan is not toxic to the testes or the spermatogenic process and is more like ARBs than ERAs in its male fertility toxicity profile.

Atrasentan is a potent and highly selective endothelin A receptor antagonist. In the prespecified 36-week interim analysis (IA) of the Phase 3 global ALIGN clinical trial, atrasentan demonstrated superiority versus placebo with a clinically meaningful and statistically significant reduction in proteinuria (primary endpoint) in patients with IgA Nephropathy (IgAN) receiving supportive care. Here, we report on additional post-hoc analyses from the ALIGN trial. ALIGN is an ongoing Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of atrasentan vs placebo in adults with IgAN at risk of progressive loss of renal function. The main stratum of the ALIGN study included patients with biopsy-proven IgAN and proteinuria of ≥1g/day while on maximum tolerated dose of renin-angiotensin inhibitors. Patients were randomized to receive atrasentan 0.75 mg or placebo orally once daily for 132 weeks while continuing supportive care. These post-hoc analyses assessed the change from baseline in 24-hour UPCR at Week 36 based on baseline proteinuria (<1 or ≥1 g/g), MEST-C scores and baseline hematuria. The analyses were performed on the IA data set which included the first 270 of 340 patients randomized to the main stratum. For the analysis by MEST-C score, 160 of 270 patients from the IA data set were included (i.e. patients with MEST-C scores available at baseline). Atrasentan showed a statistically significant and clinically meaningful proteinuria reduction of 36.1% (95% CI: 26.4%, 44.6%; P < 0.0001) relative to placebo, after 36 weeks of treatment. The reduction in proteinuria in patients with baseline UPCR <1 g/g and ≥1 g/g (LS mean % UPCR change from baseline relative to placebo at Week 36) was −28.7 (95% CI: −47.5, −3.2)​ and −38.3 (95% CI: −47.4, −27.5), respectively (Fig.). In addition, efficacy benefit favoring atrasentan was shown irrespective of MEST-C score and baseline hematuria level (Fig.). Consistent with the primary endpoint findings, atrasentan shows favorable efficacy versus placebo in patients with IgAN regardless of baseline UPCR (<1 g/g and ≥ 1g/g), MEST-C score, and baseline hematuria. These results add to previously presented subgroup analysis data, and further support the efficacy of atrasentan across a broad range of IgAN patients.

Introduction Endothelin A (ETA) receptor activation is a driver of proteinuria, kidney inflammation, and fibrosis in IgA nephropathy (IgAN). Atrasentan, a selective ETA receptor antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. ALIGN (NCT04573478) is a phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss. Methods Eligibility criteria for the ALIGN main stratum included patients with biopsy-proven IgAN, total protein excretion ≥ 1 g/d, estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2, receiving a maximally tolerated stable dose of a renin-angiotensin system (RAS) inhibitor. An exploratory stratum enrolled participants also receiving a stable dose of sodium glucose cotransporter-2 inhibitors (SGLT2i). Participants were randomized to 0.75 mg atrasentan or placebo orally daily for 132 weeks followed by a 4-week wash-out period. The primary outcome is proteinuria change from baseline (24-hour urine protein-to-creatinine ratio [UPCR]) to week 36 in the main stratum. Key secondary end points include eGFR change from baseline to week 136, safety, and tolerability. Results Enrolment occurred across 20 countries; 404 patients were randomized: 340 in the main stratum and 64 in the SGLT2i stratum. At baseline in the main stratum, mean age was 44.7 years, 42.4% were female, mean eGFR and median UPCR were 58.9 ml/min per 1.73 m2 and 1.4 g/g, respectively. Conclusion The ongoing ALIGN trial evaluates the efficacy and safety of atrasentan in a representative global IgAN population at risk for disease progression despite optimized RAS inhibitor therapy and includes an exploratory stratum evaluating atrasentan use in combination with an SGLT2i.

[This corrects the article DOI: 10.1016/j.ekir.2024.10.004.].

In the Study Of diabetic Nephropathy with AtRasentan (SONAR), the endothelin receptor antagonist (ERA) atrasentan slowed progression of chronic kidney disease (CKD) in individuals with type 2 diabetes. Pre-clinical research suggests sex-based differences in the endothelin system might influence the efficacy and safety of atrasentan. We therefore assessed the effects of atrasentan in men and women participating in SONAR. SONAR was a double-blind, placebo-controlled trial that compared atrasentan 0.75 mg/day with placebo in individuals with type 2 diabetes and CKD (eGFR 25–75 ml/min per 1.73 m2, urine albumin/creatinine ratio [UACR] 300–5000 mg/g). The primary endpoint was defined as the time from randomisation to the first occurrence of a doubling in serum creatinine or kidney failure (eGFR <15 ml/min per 1.73 m2, chronic dialysis, kidney transplantation or death from kidney failure). Hospitalisation for heart failure was the secondary endpoint. We performed Cox proportional hazards regression analyses to compare the treatment effect of atrasentan between male and female participants on the risk of the composite kidney outcome as well as hospitalisation for heart failure. Additionally, differences between male and female participants in atrasentan plasma exposure and eGFR change were assessed using, respectively, a t test and linear mixed effect model. Among 3668 randomised participants, 946 (25.8

Endothelin A (ETA) receptor activation drives proteinuria, kidney inflammation and fibrosis in IgA nephropathy (IgAN). Atrasentan, a potent and selective ETA receptor antagonist, is a potential therapy to reduce proteinuria and preserve kidney function in patients with IgAN. Interim results from the IgAN cohort of the open-label AFFINITY study demonstrated atrasentan was well tolerated and resulted in clinically meaningful proteinuria reductions at 12 and 24 weeks. The ongoing ALIGN study (NCT04573478) is a global, phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss.

Simultaneous inhibition of angiotensin II AT 1 and endothelin ET A receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT 1 and ET A receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ET A and AT 1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.

Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ETA receptor and angiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.

BACKGROUND:Patients with IgA nephropathy and severe proteinuria have a high lifetime risk of kidney failure. The efficacy and safety of the selective endothelin type A receptor antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are incompletely understood. METHODS:We are conducting a phase 3, multinational, double-blind, randomized, controlled trial involving adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. Patients were randomly assigned to receive atrasentan (0.75 mg per day) or matched placebo for 132 weeks. The primary outcome, assessed at a prespecified interim analysis of data from the first 270 patients in the main stratum, was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36; the change was estimated with the use of a repeated-measures model. (An exploratory stratum of patients who were receiving a sodium-glucose cotransporter 2 inhibitor were included in a separate analysis.) Safety analyses were based on adverse events across the entire main stratum. RESULTS:A total of 340 patients were recruited into the main stratum. Among the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit, the geometric mean percentage change in the urinary protein-to-creatinine ratio relative to baseline was significantly greater with atrasentan (-38.1%) than with placebo (-3.1%), with a geometric mean between-group difference of -36.1 percentage points (95% confidence interval, -44.6 to -26.4; P<0.001). The percentage of patients with adverse events did not differ substantially between the two groups. Fluid retention was reported by 19 of 169 patients (11.2%) in the atrasentan group and in 14 of 170 (8.2%) in the placebo group but did not lead to discontinuation of the trial regimen. No apparent cases of cardiac failure or severe edema occurred. CONCLUSIONS:In this prespecified interim analysis, atrasentan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Novartis; ALIGN ClinicalTrials.gov number, NCT04573478.).

In the PROTECT study, sparsentan, which targets both the endothelin type A (ETAR) and angiotensin type 1 (AT1R) receptors, reduced proteinuria vs active comparator in immunoglobulin A nephropathy (IgAN), with minimal changes in fluid status. This contrasts with greater fluid retention, including heart failure hospitalization, in studies using agents targeting ETAR alone. This may relate to differences in comorbidities; however, aspects of dual receptor binding by sparsentan may also be a factor.

Some endothelin receptor antagonists (ERAs), whether targeting only the endothelin A receptor or both endothelin A and B receptors, are associated with elevated markers of liver injury.1 The hepatotoxicity has generally been modest; however, one ERA, sitaxsentan, caused serious drug-induced liver injury (DILI), resulting in fatalities.2 The mechanism of ERA hepatotoxicity is not fully understood but probably relates, at least partly, to effects on hepatobiliary transporters and metabolism.3 In addition, ERA chemical structure may be a factor. Bosentan, a sulphonamide-based ERA, is associated with an increased incidence of elevated liver transaminases (> 3 x the upper limit of normal [ULN]).1 By contrast, macitentan, a sulphatide-based ERA, is not associated with elevated markers of liver injury.1 Further, ambrisentan, a carboxylic acid-based ERA, is associated with reduced episodes of elevated liver transaminases.1 Studies using cultured human hepatocytes have corroborated these clinical observations, finding that bosentan > macitentan > ambrisentan reduced hepatobiliary transporter activity (and presumably promoted intracellular bile salt accumulation).3 Atrasentan is a selective endothelin receptor A antagonist that reduces the risk of kidney failure in patients with type 2 diabetes and chronic kidney disease (CKD)4; however, no studies have reported the hepatotoxic effects of atrasentan, a carboxylic acid. Consequently, the current study assessed the effects of atrasentan on markers of liver function and liver-related adverse events. This study constitutes a prespecified analysis of the SONAR trial; the primary results, study design and patient characteristics have been described.4 The trial was conducted at 689 clinical practice sites in 41 countries; the ethics committees from each participating centre approved the study protocol before any study-specific procedures commenced. Inclusion criteria included age 18-85 years, presence of type 2 diabetes, an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73m2, a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g and brain natriuretic peptide (BNP) of less than 200 pg/mL. All patients were on stable doses of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 4 weeks prior to enrolment. Exclusion criteria included alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevated to at least three times ULN, or advanced liver disease with a life expectancy of less than 1 year. All patients initially received 0.75 mg/day atrasentan during a 6-week enrichment period. Patients with 30% or higher (responders, N = 2648) and less than 30% (non-responders, N = 1020) UACR reduction from baseline with no signs of fluid retention (defined as an increase in body weight ≥ 3 kg or increase in BNP ≥ 300 pg/mL) were randomly assigned to 0.75 mg/day atrasentan or placebo. The median total follow-up period was 2.2 years. The effects of atrasentan compared with placebo on the mean change from baseline in ALT, AST, alkaline phosphatase (ALP) and bilirubin were assessed using an ANCOVA model adjusted for the respective baseline values. Data for responders and non-responders were combined. We summarized investigator-reported liver-related treatment-emergent adverse events (TEAEs) by treatment group and searched for potential cases of Hy's law (AST or ALT > 3 x ULN and total bilirubin > 2 x ULN, absence of evidence of cholestasis, and no other explanation for liver injury). The liver-related TEAEs were self-defined by healthcare providers. A total of 3668 subjects were randomized to atrasentan (N = 1834) or placebo (N = 1834). At baseline, the mean (SD) age was 64.5 (9) years, eGFR was 42.3 (14) mL/min/1.73m2 and median UACR was 829 (25th to 75th percentile 457-1556) mg/g. At baseline, 204 (5.6%) and 76 (2.1%) participants reported liver disease (excluding hepatitis) and hepatitis, respectively (the specific aetiologies of liver disease or hepatitis were not reported). There were no differences between atrasentan and placebo groups at baseline in any of the above variables (Table 1). Atrasentan compared with placebo statistically significantly reduced ALT, AST and ALP (Table 2). The numbers of participants with a liver-related TEAE in the atrasentan and placebo groups were not significantly different: 57 (3.1%) and 52 (2.8%), respectively, resulting in an exposure-adjusted incidence rate of 1.6 and 1.4 per 100 person-year follow-up, respectively. No cases meeting Hy's Law or with rare, severe, DILI were observed with atrasentan treatment in SONAR. In this post hoc analysis of the SONAR trial, patients with type 2 diabetes and CKD, who are at high risk of liver disease, had no evidence of liver function abnormalities or liver-related adverse effects during treatment with the endothelin A receptor antagonist atrasentan. Atrasentan treatment was associated with a modest reduction in ALT, AST and ALP levels compared with placebo. Whether this effect is biologically significant is unknown; however, given that activation of liver endothelin A receptors can elicit pleiotropic effects on hepatic vascular smooth muscle and stellate cells, including vasoconstriction, proliferation, inflammation and fibrosis,5 it is possible that atrasentan confers at least a small degree of liver protection in patients with type 2 diabetes and CKD. The current findings raise the possibility that atrasentan treatment will manifest similar liver safety in other forms of CKD. In this regard, ongoing clinical trials are evaluating the effects of atrasentan on kidney outcomes specifically in patients with IgA nephropathy (ALIGN, NCT04573478), and in a basket trial involving patients with IgA nephropathy, focal segmental glomerulosclerosis, Alport syndrome and patients with type 2 diabetes with CKD who are treated with sodium-glucose co-transporter inhibitors (AFFINITY, NCT04573920). Of note, sparsentan, a combined endothelin A and angiotensin AT1 receptor antagonist, was recently given accelerated approval by the US Food and Drug Administration (FDA) for the treatment of IgA nephropathy.6, 7 Importantly, the FDA mandated a Risk Evaluation and Mitigation Strategy for potential hepatotoxicity based on concerns over a class effect of ERAs on liver function, although sparsentan treatment did not alter markers of hepatotoxicity.7 Given that the renoprotective effects of other ERAs are being tested in CKD (e.g. zibotentan in diabetic CKD [ZENITH, NCT04724837]), this issue of ERA-induced hepatoxicity is assuming increasing clinical importance, particularly in the treatment of patients with CKD. The current data from a large international randomized controlled clinical trial provide reassuring evidence that atrasentan does not cause liver injury. Drs. Kohan and Heerspink made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. Drs. Liew, Tang and Barratt made substantial contributions to analysis and interpretation of data. All authors were involved in drafting or revising the manuscript for important intellectual content. DEK has served as a consultant and member of advisory boards for AstraZeneca, Chinook Therapeutics, Idorsia, Janssen, and Travere Therapeutics. AL has served as a consultant and member of advisory boards for Alnylam Pharmaceuticals, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer-Ingelheim, Chinook Therapeutics, Dimerix Limited, Eledon Pharmaceuticals, George Clinical, GlaxoSmithKline, Kira Pharmaceuticals, Prokidney, Otsuka Pharmaceuticals and Visterra Inc, Zai Lab Co. Ltd; has received Speaker's honorarium from AstraZeneca, Baxter Healthcare, Boehringer-Ingelheim, Chinook Therapeutics and Otsuka Pharmaceuticals; and has served as a member of Data Safety and Monitoring Committee for Dimerix Limited and Zai Lab Co. Ltd. SCWT has served as a consultant and advisory board member for Eledon Pharmaceuticals and Travere Therapeutics, and received Speaker's honorarium from AstraZeneca, Baxter Healthcare, Boehringer-Ingelheim, GSK and Novartis. JB has received consultancy fees and grant funding from Travere Therapeutics and Chinook Therapeutics. HJLH has consulting relationships with AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Chinook, Dimerix, Eli-Lilly Gilead, Janssen, Merck, Mitsubishi Tanabe, Mundi Pharma, Novo Nordisk, Novartis and Travere Therapeutics. He has received research support from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk (all payments to his institution). The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15103. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Background Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. Methods We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25–75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. Results In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). Conclusions More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. Trial registration RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25-75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300-5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72-0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71-0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60-0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD.

BACKGROUND:Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS:PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS:Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION:Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING:Travere Therapeutics.

BACKGROUND An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown. METHODS In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated. RESULTS A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m2 with sparsentan and -12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups. CONCLUSIONS Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.).

ABSTRACT Background Endothelin A receptor antagonists (ETARA) slow chronic kidney disease (CKD) progression but their use is limited due to fluid retention and associated clinical risks. Sodium–glucose co-transporter 2 inhibitors (SGLT2i) cause osmotic diuresis and improve clinical outcomes in CKD and heart failure. We hypothesized that co-administration of the SGLT2i dapagliflozin with the ETARA zibotentan would mitigate the fluid retention risk using hematocrit (Hct) and bodyweight as proxies for fluid retention. Methods Experiments were performed in 4% salt fed WKY rats. First, we determined the effect of zibotentan (30, 100 or 300 mg/kg/day) on Hct and bodyweight. Second, we assessed the effect of zibotentan (30 or 100 mg/kg/day) alone or in combination with dapagliflozin (3 mg/kg/day) on Hct and bodyweight. Results Hct at Day 7 was lower in zibotentan versus vehicle groups [zibotentan 30 mg/kg/day, 43% (standard error 1); 100 mg/kg/day, 42% (1); and 300 mg/kg/day, 42% (1); vs vehicle, 46% (1); P < .05], while bodyweight was numerically higher in all zibotentan groups compared with vehicle. Combining zibotentan with dapagliflozin for 7 days prevented the change in Hct [zibotentan 100 mg/kg/day and dapagliflozin, 45% (1); vs vehicle 46% (1); P = .44] and prevented the zibotentan-driven increase in bodyweight (zibotentan 100 mg/kg/day + dapagliflozin 3 mg/kg/day = –3.65 g baseline corrected bodyweight change; P = .15). Conclusions Combining ETARA with SGLT2i prevents ETARA-induced fluid retention, supporting clinical studies to assess the efficacy and safety of combining zibotentan and dapagliflozin in individuals with CKD.