Dicerna Reports Mixed Results for Study of Nedosiran in Primary Hyperoxaluria Type 3
October 19, 2021
Dicerna Pharmaceuticals reported top-line results from its late stage PHYOX4 study of experimental RNAi therapeutic nedosiran for patients with primary hyperoxaluria type 3 met the primary safety endpoint, but failed to meet the prespecified secondary efficacy endpoint.
The company said the data nevertheless showed encouraging trends in urinary oxalate reduction with treatment. Dicerna plans to submit an application for to market nedosiran to the U.S. Food and Drug Administration for the treatment of primary hyperoxaluria type 1 (PH1) in the fourth quarter of 2021.
“The favorable safety and tolerability results, coupled with the encouraging trends in Uox reduction observed in the first clinical trial of any investigational therapy in patients with PH3, provide important initial data for nedosiran in PH3,” said Shreeram Aradhye, executive vice president and chief medical officer at Dicerna. “While we have refined our near-term nedosiran strategy primarily to focus on the treatment of PH1, there is a significant unmet medical need in PH3, and we plan to analyze these data further as part of our discussions to out-license the commercialization of nedosiran.”
Primary hyperoxaluria (PH) is a family of ultra-rare, life-threatening genetic disorders that initially manifest with complications in the kidneys. There are three known subtypes of PH (PH1, PH2 and PH3), each resulting from a mutation in one of three different genes. These genetic mutations cause enzyme deficiencies that result in the overproduction of oxalate, which is an end-product of metabolism. Excess production and accumulation of oxalate leads to recurrent kidney stones, nephrocalcinosis, and chronic kidney disease that may progress to end-stage renal disease requiring intensive dialysis.
Compromised renal function eventually results in the accumulation of oxalate in a wide range of organs including the skin, bones, eyes and heart. In the most severe cases, symptoms start in the first year of life. A combined liver-kidney transplant may be undertaken to resolve PH1 or PH2, but it is an invasive solution with limited availability and high morbidity that requires lifelong immune suppression to prevent organ rejection. Genetic studies suggest approximately 8,500 people in the United States are affected by PH, and researchers estimate that more than 80 percent of patients remain undiagnosed. There is currently only one approved therapy available that is limited to the treatment of patients with PH1.
Nedosiran is part of the PHYOX clinical development program and is Dicerna’s most advanced RNAi drug candidate utilizing its proprietary GalXC RNAi technology. Nedosiran is designed to inhibit production of the hepatic lactate dehydrogenase (LDH) enzyme—an enzyme that catalyzes the final step in the glyoxylate metabolism pathway that can lead to oxalate overproduction in patients with PH.
The PHYOX4 trial was a randomized, placebo-controlled, double-blind, multicenter study evaluating the safety and tolerability of a single subcutaneous dose of nedosiran compared to placebo in patients with PH3 who had at least one kidney stone event in the prior 12 months (nedosiran n=4; placebo n=2). All reported adverse events (AEs) were mild and unrelated to nedosiran treatment. The most commonly reported AE was back pain. No serious AEs were reported in the study.
No subjects in either group achieved the prespecified secondary efficacy endpoint, which was a greater than 30 percent decrease from baseline in 24-hour Uox excretion on at least two consecutive visits over the three-month observation period. However, all patients administered a single dose of nedosiran demonstrated Uox reductions relative to baseline at one or more time points during the three-month period.
Author: Rare Daily Staff
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