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PHILADELPHIA -- A low-dose, investigational endothelin A receptor antagonist paired with an SGLT2 inhibitor reduced albuminuria in patients with chronic kidney disease (CKD) in the phase IIb ZENITH-CKD trial.

By week 12 of treatment, patients on zibotentan 1.5 mg plus dapagliflozin had a -33.7% (90% CI -42.5 to -23.5) difference in urinary albumin-to-creatinine ratio (UACR) compared with dapagliflozin (Farxiga) added onto placebo, reported Hiddo Heerspink, PhD, of the University Medical Center Groningen in the Netherlands, at the American Society of Nephrology (ASN) Kidney Week.

An even lower dose of zibotentan -- 0.25 mg -- was also effective at reducing albuminuria, as patients on this dose plus dapagliflozin saw a -27.0% (90% CI -38.4 to -13.6) difference in UACR compared with dapagliflozin alone, according to the trial that was simultaneously published in .

"Zibotentan in combination with dapagliflozin reduced albuminuria more than dapagliflozin alone and this effect was apparent already after 3 weeks of treatment and was sustained over time," Heerspink said in the ASN presentation. "During the [2-week] washout period, we see that albuminuria returned to baseline."

The trial was originally designed as part A and part B. Participants randomized in part A were slated to receive a higher dose of zibotentan, with one group only receiving 5 mg of zibotentan and another receiving 5 mg plus dapagliflozin 10 mg/day. However, this part of the trial was stopped during due to increased rates of fluid retention.

After that, Heerspink's group only continued with part B of the trial: zibotentan 1.5 mg plus dapagliflozin 10 mg/day and zibotentan 0.25 mg plus dapagliflozin 10 mg/day.

Here, fluid-retention events were observed in 18% (33/179) of participants in the zibotentan 1.5-mg group, 9% (8/91) of the zibotentan 0.25-mg group, and 18% (14/177) of the dapagliflozin plus placebo group. This was defined as an increase in body weight of at least 3% -- at least 2.5% must have been from total body water -- from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL, if without atrial fibrillation, or BNP greater than 400 pg/mL if with atrial fibrillation.

The researchers described zibotentan as "the most potent and selective endothelin A receptor antagonist developed to date." But endothelin A receptor antagonists (ERAs) cause fluid retention and edema, so it was paired with an SGLT2 inhibitor, which has both diuretic effects and renoprotective properties. Other ERAs in development or on the market today include atrasentan and sparsentan.

"The fluid retention profile of a low-dose combination supports further clinical trials," Heerspink added. "Results of these larger and longer studies in a high-risk CKD populations are awaited."

In an in The Lancet, Neeraj Dhaun, MBChB, PhD, and Gavin Brian Chapman , both of the University of Edinburgh, called the low rates of fluid retention with these lower zibotentan doses "encouraging." However, they also pointed out that "caution is needed when interpreting this finding," given the disproportionate number of patients with heart failure at baseline across the three groups: 10% with dapagliflozin monotherapy, 3% with low-dose zibotentan and dapagliflozin, and 6% with high-dose zibotentan and dapagliflozin.

"Additionally, participants with an increased circulating [BNP] concentration -- an indirect marker of left ventricular stretch -- and, therefore, those most likely to develop fluid overload with endothelin antagonists, were excluded from the study," they added.

BNP increase, fluid retention, peripheral edema, and hypotension were the most common adverse events (AEs) leading to drug discontinuation, but occurred in less than 3% of participants. Rates of other AEs were generally low, including headache (≤5% on zibotentan), metabolic acidosis (≤4%), BNP increase (≤5%), and hypertension (≤5%).

This 170-site trial was conducted across 18 countries with adults with an eGFR of 20 mL/min per 1.73 m² or more and a UACR of 150-5000 mg/g. All patients were already on maximally tolerated RAAS inhibition. The average age of patients was around 62, 69% were male, and 62%-71% were white. Baseline eGFR was 46.7 mL/min per 1.73 m² and median UACR was 565.6 mg/g.

Throughout the trial, all groups also saw a significant drop from baseline in systolic blood pressure, one of the secondary efficacy endpoints. Heerspink pointed out that this decline in systolic blood pressure was not correlated to the change in UACR:

• Zibotentan/dapagliflozin 0.25 mg/10 mg: -7.1 mmHg (90% CI -10.0 to -4.1)
• Zibotentan/dapagliflozin 1.5 mg/10 mg: -11.0 (mmHg 90% CI -13.5 to -8.4)
• Dapagliflozin 10 mg: -3.4 mmHg (90% CI -5.8 to -1.0)

The secondary endpoint of change in eGFR took a dive within the first week of treatment, and didn't rebound to baseline levels until the washout period:

• Zibo/dapa 0.25 mg/10 mg: -3.1 (90% CI -4.7 to -1.5)
• Zibo/dapa 1.5 mg/10 mg: -3.0 (90% CI -4.4 to -1.6)
• Dapa 10 mg: -1.9 (90% CI -3.3 to -0.6)

The researchers reported that all groups saw a significant drop in average body weight, with the dapagliflozin-only group seeing the biggest drop. BNP numerically increased in all groups, but was only significant in the zibotentan 1.5-mg group.

Heerspink said his group started work on the phase III outcome trial, which will include patients with an eGFR between 20 to 90 mL/min per 1.73 m² and UACR above 700 mg/g or a urine protein creatinine ratio above 1,000 mg/g.