Atrasentan Back on the SONAR for Diabetes and Kidney Disease

Maureen Salamon

April 15, 2019

MELBOURNE, Australia — The addition of atrasentan to standard-of-care drugs cuts the odds of progression to end-stage renal disease by more than one-third in patients with type 2 diabetes and chronic kidney disease, according to results from a phase 3 multinational trial that took an unusual turn.

"In short, the trial was highly positive, highly significant, and showed a 35% reduction in the primary combined end point," said investigator Dick de Zeeuw, MD, PhD, from University Medical Center Groningen in the Netherlands.

But "the caveat is, this was a stopped trial," he told Medscape Medical News. "The statistical power of the whole study was less robust, but the effect we see is clearly really impressive."

SONAR (NCT01858532) was one of two late-breaking clinical trials presented here at the International Society of Nephrology: 2019 World Congress that focused on what investigators agree is an especially vulnerable patient population: those with diabetes and chronic kidney disease.

Unlike the CREDENCE trial of canagliflozin (Invokana, Janssen), which suggested sizable benefits for these patients, SONAR was stopped in 2017 by AbbVie, the study's sponsor, because 4 years after its launch, only about half of the end points had been met.

Despite the setback, when de Zeeuw and his colleagues gathered more data, with AbbVie's limited agreement, they found that there were benefits. Those findings were published online in the Lancet to coincide with their presentation.

The caveat is, this was a stopped trial.

"We advised the company to continue," de Zeeuw explained, "because there may be a huge effect of the drug, which would lower the events." If so, he added, "when combined with placebo, this would still produce a low event rate."

In the double-blind, randomized, placebo-controlled trial, investigators initially screened more than 11,000 patients from 689 sites in 41 countries.

All participants were adults with type 2 diabetes and chronic kidney disease, with an estimated glomerular filtration rate (eGFR) of 25 to 75 mL/min per 1.73 m² and a urine albumin-to-creatinine ratio of 300 to 5000 mg/g. They had also received a maximum labeled or tolerated dose of a renin-angiotensin system inhibitor, which is standard of care, for at least 4 weeks.

More than 4700 patients completed a 6-week "enrichment period" to assess responses to once-daily atrasentan 0.75 mg.

After the enrichment period, the 2648 patients who responded and met the predefined criteria continued on to randomization, in which either atrasentan, a selective endothelin-receptor antagonist, or placebo was added to standard of care.

Use of the enrichment design — a first in a trial of patients with diabetes — improves safety, de Zeeuw reported. Although all study participants received the drug initially, only patients with a reduction in albumin-to-creatinine ratio of at least 30% moved on to randomization.

And patients who responded with signs of fluid retention were removed from the trial to eliminate their exposure to harm.

Holding Water

Fluid retention — a notable adverse effect of atrasentan — "leads eventually to an increased risk of heart failure," said de Zeeuw. But a lower dose of the drug created a more "balanced" risk–benefit ratio, he added.

The primary end point was a composite of a doubling of serum creatinine sustained for at least 30 days or end-stage kidney disease — defined as eGFR below 15 mL/min per 1.73 m² sustained for at least 90 days, chronic dialysis for at least 90 days, kidney transplantation, or death from kidney failure — in the intention-to-treat population of all responders.

At a median follow-up of 2.2 years, the primary end point was 35% lower in responders in the atrasentan group than in the placebo group (95% confidence interval [CI], 0.49 - 0.88; P = .0047). The rate of hospitalization for heart failure was similar in the atrasentan and placebo groups (3.5% vs 2.6%; 95% CI, 0.85 - 2.07; P = .208).

Members of the SONAR steering committee might try to interest another sponsor in developing atrasentan or another drug in the class on the basis of these data, de Zeeuw said.

"We want to make sure what we did together will benefit the patients in the end," he said.

In the Backdrop of the Positive CREDENCE Trial

Atrasentan could potentially be combined with a sodium-glucose cotransporter (SLGT) inhibitor, such as canagliflozin, to maximize patient benefits, de Zeeuw suggested.

"Because of the positive CREDENCE trial result, we've got to consider" where atrasentan fits into the treatment strategies for patients with diabetes and chronic kidney disease, said Mark Cooper, MD, PhD, from Monash Medical Centre in Clayton, Australia, who attended the presentation.

"If it's combined with an SGLT inhibitor, it could be a new way to use this drug with a major side effect of fluid retention," he pointed out.

"I think SONAR confirms that the endothelium plays a critical role in kidney disease and showed that atrasentan is indeed a renal protective strategy," Cooper told Medscape Medical News. "The big issue is whether it will be developed further."

The study was funded by AbbVie. de Zeeuw is cochair of the SONAR study steering committee and serves on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi-Tanabe; and serves on steering committees and/or as a speaker for AbbVie and Janssen; and is a member of data safety and monitoring committees for Bayer. Cooper reports financial relationships with Boehringer Ingelheim and AstraZeneca.

International Society of Nephrology (ISN): 2019 World Congress: Abstract O-353. Presented April 15, 2019.

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