Study results show a significant reduction in 24-hour urine oxalate in treated patients.
Reloxaliase, a nonabsorbed orally administered, recombinant oxalate-degrading enzyme, was associated with a significant reduction from baseline in 24-hour urine oxalate (UOx) levels relative to placebo in patients with enteric hyperoxaluria (EH).
Results from the phase 3 randomized, placebo-controlled URIROX-1 study, presented by Charles Scales Jr, MD, at the 2020 American Urological Association Virtual Experience, represent “an important first step in addressing an unmet need for an effective therapeutic for patients with EH.”
URIROX-1 demonstrated an absolute 14.3% difference between reloxaliase and placebo in the change in UOx from baseline during weeks 1 to 4. In a prespecified subpopulation of study participants who underwent bariatric surgery, “a strong effect of the enzyme on UOx level was also demonstrated,” said Scales, associate professor of surgery (urology) and population health, Duke Clinical Research Institute, Durham, North Carolina.
Enteric hyperoxaluria is a metabolic disorder in which elevated urine oxalate is excreted, resulting in excess gastrointestinal absorption of oxalate and a subsequent increase of renal oxalate excretion, with important clinical sequelae.
To address the unmet need of the EH patient population, reloxaliase was developed as a first-in-class oral therapeutic agent, administered with meals, as a nonabsorbed crystallized enzyme that degrades oxalate in the gut. Reloxaliase produces carbon dioxide and formate that is subsequently excreted.
Previous findings from the phase 2 reloxaliase program showed that patients with EH have a high burden of kidney stones and high levels of urinary oxalate. On average, EH patients had a mean baseline UOx of about 100 mg/24 hr, had experienced a mean of 6 stones prior to enrollment, and had a mean of 3 kidney stones visible by routine computed tomography scan at the time of enrollment.
URIROX-1 enrolled 115 EH patients who had UOx ≥ 50 mg/24 hr despite standard of care. Patients were randomized 1:1 to 7500 U of oral reloxaliase or placebo with a meal or snack 3 to 5 times daily for 28 days. Patients were followed with 24-hour UOx measurements weekly. The primary end point was the percent change from baseline in the 24-hour UOx excretion during weeks 1 to 4. A key secondary end point was the proportion of subjects with a 20% reduction from baseline in 24-hour UOx excretion during weeks 1 to 4.
Mean age at baseline was 59 years and about 48% of the study population was female. The most common cause of EH was bariatric surgery, in approximately two-thirds of the population. Patients had a high burden of disease: their mean baseline UOx was 89.2 mg/day, which is about 3 times the upper limit of normal, Scales said. Participants had an average of 11 stone events in the previous 5 years. In addition, there was a significant burden of chronic kidney disease among the study population, with about one-fourth having stage 3 chronic kidney disease at entry.
A statistically significant reduction in UOx excretion was observed from baseline during weeks 1 to 4 in the reloxaliase arm relative to the placebo arm (22.6% vs 9.7%; P = .004).
“Importantly, the effect of reloxaliase was rapid and sustained over the 4-week follow-up period,” Scales said.
In the subgroup who underwent bariatric surgery prior to entering the study, a reduction in the UOx level of 16.19% was found during weeks 1 to 4 in the active treatment group compared with placebo, which achieved significance (P = .01).
Nearly half (48.3%) of patients randomized to reloxaliase had ≥20% reduction in 24-hour UOx versus baseline compared with 31.6% of the placebo arm, which missed significance (P = .061). In the bariatric surgery subgroup, however, 50% randomized to reloxaliase and 28.9% randomized to placebo achieved a ≥20% reduction in 24-hour UOx from baseline, which was statistically significant (P = 0.036).
Consistently well tolerated
Reloxaliase was consistently well tolerated. There was no substantive difference in the rate of treatment-emergent adverse effects (TEAEs) between the active treatment and placebo arms (69.0 vs 52.6%), with only 1 TEAE leading to study drug withdrawal (in the placebo group).
The data from the trial also confirm that high UOx is associated an increased burden of kidney stones, Scales said. The mean number of kidney stones per patient within 5 years of enrollment was 8.6 in patients with UOx at baseline <90 mg/24 hr compared with 14.7 in those with baseline UOx ≥90 mg/24 hr.
“These data support the important role of 24-hour UOx excretion as a clinically relevant marker for stone disease,” he said.
URIROX-2, an ongoing phase 3 trial, is designed to confirm the clinical benefit of reloxaliase on kidney stone disease progression and kidney function.
Disclosures: Allena Pharmaceuticals funded URIROX-1. Scales also reports funding from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute for scientific studies.