Verinurad-febuxostat combo rapidly reduces UACR in T2DM patients

Intensive urate lowering with the combination therapy of verinurad plus febuxostat is successful in lowering the urinary albumin to creatinine ratio (UACR) in patients with type 2 diabetes mellitus (T2DM), albuminuria and hyperuricaemia, according to a study presented at the American Society of Nephrology (ASN) Kidney Week 2019.

“Reduction was rapid, sustained and similar regardless of baseline estimated glomerular filtration rate (eGFR) and degree of albuminuria,” said Austin Stack, study co-author from the Health Services Executive at University of Limerick and a consultant with AstraZeneca.

This phase II, parallel-group, multicentre, randomized, double-blind, placebo-controlled trial included adults with T2DM, albuminuria and hyperuricaemia. Patients were randomly assigned to receive either verinurad 9 mg plus febuxostat 80 mg once daily (n=32) or placebo (n=28) and were then followed for 24 weeks.

Reduction in UACR at 12 weeks compared with baseline was the primary outcome. The researchers assessed changes in UACR as per baseline characteristics including UACR and eGFR.

Baseline UACR was 459±825 mg/g in the verinurad plus febuxostat group and 412±548 mg/g in the placebo group. Patients who received verinurad plus febuxostat had improved UACR, and such improvement was “rapid, sustained over time and met prespecified criteria for significance.” [ASN 2019, abstract SA-OR086]

UACR decreased by 39 percent at week 1, 39 percent at week 12 (90 percent confidence interval, –62 percent to –4 percent; p=0.0747) and 49 percent at week 24 compared with placebo. There was consistent reduction across subgroups, including those based on UACR and eGFR.

“Intensive urate lowering with verinurad plus febuxostat was generally well tolerated,” Stack said.

No treatment-related serious treatment-emergent adverse events occurred in either group, but one patient (3.1 percent) in the verinurad plus febuxostat group had a gout flare. In addition, two patients in each treatment arm had serum creatinine elevations ≥1.5 times the baseline levels.

Furthermore, no clinically relevant changes were observed in vital signs or laboratory safety parameters. There were also no changes detected in eGFR or kidney oxygenation.

“The data suggest that combining URAT1 inhibitor with a xanthine oxidase inhibitor may prevent chronic kidney disease (CKD) progression in T2DM,” the researchers wrote.

Elevated serum urate levels were associated with new-onset microalbuminuria and CKD risk in patients with T2DM. Thus, lowering of serum urate levels could reduce the risk of CKD progression. [PloS One 2013;8:e61450; Clin J Am Soc Nephrol 2015;10:1921-1929; PloS One 2017;12:e0187550; Hypertension 2011;58:2-7]

Verinurad is a novel URAT1 inhibitor in the proximal tubule. In combination with febuxostat, it reduces serum urate levels in healthy volunteers and in patients with gout. [Sci Rep 2017;7:665; Pharmacol Drug Dev 2019;8:179-187; RMD Open 2018;4:e000647]

SAPPHIRE, a phase IIb study, is currently recruiting 725 patients to confirm the findings of the current study and to determine which patient groups might benefit most from the verinurad combination therapy. [https://clinicaltrials.gov/ct2/show/NCT03990363]

Specifically, SAPPHIRE will assess the clinical effect of verinurad plus allopurinol on kidney function in CKD patients with hyperuricaemia and determine if intensive urate lowering confers renoprotection beyond standard of care. Results are expected by 2022. [ASN 2019, abstract INFO12-SA]