On October 2, 2023, the FDA approved nedosiran (Rivfloza; Novo Nordisk), a once-monthly, subcutaneous ribonucleic acid interference (RNAi) therapy, to lower urinary oxalate (UOX) levels in children aged ≥9 years and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function (eg, estimated glomerular filtration rate [eGFR] of ≥30 mL/min/1.73 m2).
Primary hyperoxaluria is a rare genetic disease that causes the liver to overproduce oxalate. Patients with PH1, a subtype of primary hyperoxaluria, can have progressive kidney damage. Nedosiran was designed to inhibit the expression of lactate dehydrogenase, a liver enzyme that catalyzes the final step in the glyoxylate metabolism pathway that leads to the overproduction of oxalate in patients with PH1.
“RNA interference is a proven treatment approach for individuals with PH1. With the approval of Rivfloza, we now have a novel treatment that lowers oxalate production safely and effectively. Using the GalXC RNAi platform, Rivfloza targets the liver-specific lactate dehydrogenase enzyme, which is the final step of oxalate production in PH1,” stated David S. Goldfarb, MD, Clinical Chief, Nephrology Division, NYU Langone Medical Center, and Professor of Medicine and Physiology, NYU Grossman School of Medicine, in a press release.
The approval of nedosiran was based on the results from the phase 2 PHYOXTM2 trial (NCT03847909), a randomized, double-blind clinical study that compared nedosiran with placebo in patients aged ≥6 years who have PH1 or PH2 and an eGFR of ≥30 mL/min/1.73 m2, as well as interim data from the ongoing phase 3 trial extension study, PHYOXTM3 (NCT04042402).
The primary efficacy end point of PHYOXTM2 was the area under the curve (AUC), from days 90 to 180, of the percent change from baseline in 24-hour UOX excretion (AUC24-hour UOX). PHYOXTM2 demonstrated that patients who received nedosiran achieved a marked reduction from baseline in 24-hour UOX excretion from day 90 to day 180. The least-squares (LS) mean between the group difference of AUC24-hour UOX was 4976 (95% confidence interval [CI], 2803-7149; P<.0001). The LS mean percent change from baseline in 24-hour UOX excretion (corrected for body surface area in patients aged <18 years) averaged over days 90, 120, 150, and 180 was –37% (95% CI, –53 to –21) in the nedosiran group and 12% (95% CI, –12 to 36) in the placebo group, for a between-group difference of 49% (95% CI, 26-72). Among patients with PH1, the between-group difference was 56% (95% CI, 33-80).
The interim results from the PHYOXTM3 extension study showed that reductions in 24-hour UOX excretion were maintained in 13 patients with PH1 who received an additional 6 months of treatment with nedosiran.
The most common (≥20%) adverse reaction with nedosiran was injection-site reaction, including reddening, pain, bruising, rash, or dimpling at the site of injection.
“We…welcome the addition of Rivfloza as a new treatment option that provides those 9 and older living with PH1 and their loved ones with more choices when working with their healthcare professional to select what treatment pathway is best for them,” said Kim Hollander, Executive Director, Oxalosis & Hyperoxaluria Foundation, in a press release.
Nedosiran is administered subcutaneously once monthly, and the recommended dose of nedosiran varies based on age and weight, as described in the prescribing information.