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

In the small single-arm trial of 21 patients with a genetically confirmed diagnosis of PH1, treatment with lumasiran resulted in a mean least squares reduction of 33.33% (95% CI -15.16 to 81.82) plasma oxalate (POx) after 6 months for patients who did not need dialysis or kidney transplantation initially, reported Mini Michael, MD, of Baylor College of Medicine in Houston.

This equates to an absolute drop in plasma oxalate of 35.28% between baseline and month 6, Michael said during a presentation at the American Society of Nephrology Virtual Kidney Week.

Among these patients, lumasiran also caused a decrease in urinary oxalate. This was marked by a 10.56% change in urinary oxalate over 24 hours from baseline through month 6, as well as an almost 40% change in localized urinary oxalate / creatinine ratio. during this treatment period.

For patients on hemodialysis at the start of the study, lumasiran resulted in a mean least-squares reduction in plasma oxalate of 42.43% (95% CI 34.15-50.71) – in average over months 3 to 6 of treatment. Associated with this, there was an absolute drop of approximately 48% in plasma oxalate between baseline and month 6.

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

For all patients – on or off hemodialysis – the drops in plasma oxalate were only noticeable during the first month of treatment.

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

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

The treatment was also safe and generally well tolerated, with the majority of adverse events (AEs) only mild or moderate. The most frequently reported AEs included pyrexia (29%) and injection site reactions (24%). No patient withdrew from the study or discontinued treatment prematurely, 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 start of the study (baseline mean POx 64.7) while 15 patients were on hemodialysis (mean POx of base 108.4). For inclusion in the study, all patients had to have a genetically confirmed diagnosis of PH1, an eGFR of 45 ml / min / 1.73 m² or younger if they were older than 1 year (stages 3b-5 chronic kidney disease), or elevated serum creatinine if they were younger than 12 months. All patients also required plasma oxalate levels of 20 μmol / L or greater.

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

“PH1 is characterized by an excessive production of hepatic oxalate due to a deficiency of the hepatic peroxisomal enzyme AGT,” explained Michael. “Too much oxalate leads to recurrent kidney stones, nephrocalcinosis, progressive kidney disease and ultimately kidney failure. As renal function decreases, oxalate elimination is compromised and plasma oxalate increases, resulting in systemic oxalosis and multiple organ damage. “

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

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