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Lumasiran (Oxlumo) was both safe and effective in patients with primary hyperoxaluria type 1 (PH1) and advanced kidney disease, according to the phase III ILLUMINATE-C trial.

In the small, single-arm trial of 21 patients with a genetically confirmed PH1 diagnosis, treatment with lumasiran yielded a 33.33% (95% CI -15.16 to 81.82) least-square mean reductions in plasma oxalate (POx) after 6 months for patients who didn't require dialysis or kidney transplantation at baseline, reported Mini Michael, MD, of Baylor College of Medicine in Houston.

This equated to an absolute drop in plasma oxalate from baseline to month 6 of 35.28%, Michael said in a presentation at the American Society of Nephrology virtual Kidney Week.

Among these patients, lumasiran also prompted a drop in urinary oxalate. This was marked by a 10.56% change in 24-hour urinary oxalate from baseline to month 6, as well as a nearly 40% change in spot urinary oxalate-to-creatinine ratio during this treatment period.

As for patients on hemodialysis at the start of the study, lumasiran led to an average least-square mean reductions in plasma oxalate of 42.43% (95% CI 34.15-50.71) -- averaged across months 3 to 6 of treatment. Paired with this, there was about a 48% absolute drop in plasma oxalate from baseline to month 6.

These dialysis patients also saw a 41.4% change in plasma oxalate area under the curve between dialysis session from baseline to month 6.

For all patients -- on or off hemodialysis -- drops in plasma oxalate were notable by only the first month of treatment.

"Changes of this magnitude of plasma oxalate may impact long-term clinical outcomes, including those related to systemic oxalosis, which will be further evaluated in the extension period of the study," Michael pointed out, adding that there is a 54-month extension period beyond this 6-month primary analysis period.

Lumasiran was approved by the FDA in November 2020, and acts as an RNAi therapeutic indicated for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients. The therapy is able to decrease hepatic oxalate production by inhibiting the production of glycolate oxidase. Its administered subcutaneously and is dosed based on weight with three monthly starting doses, then followed by ongoing monthly or quarterly doses.

The treatment was also safe and generally well-tolerated, with the majority of adverse events (AEs) being only mild or moderate. The most commonly reported AEs included pyrexia (29%) and injection-site reactions (24%). No patients withdrew from the study or discontinued treatment early, and no deaths occurred.

This 13-site, 10-country trial included a total of 21 patients, six of whom were not on dialysis at the study start (baseline mean POx 64.7), while 15 patients were on hemodialysis (baseline mean POx 108.4). For study inclusion, all patients had to have genetically confirmed PH1 diagnosis, an eGFR of 45 mL/min/1.73m² or less if they were over age 1 year (stages 3b-5 chronic kidney disease), or elevated serum creatinine if age less than 12 months. All patients also needed a plasma oxalate level of 20 μmol/L or higher.

The median age of the entire cohort was 8 and 43% were female. Among those on dialysis, there was a median of six dialysis therapy sessions per week.

"PH1 is characterized by excessive hepatic oxalate production due to a deficiency in the hepatic peroxisomal enzyme AGT," Michael explained. "Excess oxalate results in recurrent kidney stones, nephrocalcinosis, progressive kidney disease, and ultimately kidney failure. As kidney function declines, oxalate elimination is compromised and plasma oxalate increases, leading to systemic oxalosis and multiorgan damage."

"Patients progressing to, or presenting with kidney failure due to PH1, require intensive hemodialysis, and ultimately require sequential liver and kidney transplantation or combined liver-kidney transplantation," she added.

Developer announced plans to submit the current results to the FDA and European Medicines Agency later in 2021 to support a supplement filing for a label expansion.

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