Rare Daily Staff
Dicerna Pharmaceuticals reported positive top-line results from the PHYOX2 pivotal clinical trial of nedosiran, an experimental once-monthly RNAi treatment for primary hyperoxaluria, which met both primary and secondary endpoints.
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, an end-product of metabolism. Abnormal 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, Alnylam Pharmaceuticals’ Oxlumo, available that is limited to the treatment of patients with PH1.
Nedosiran is Dicerna’s lead RNAi therapeutic candidate and is designed to inhibit 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 PHYOX2 clinical trial included participants with PH subtypes 1 and 2.
Nedosiran achieved the primary endpoint in the PHYOX2 trial, demonstrating a statistically significant reduction from baseline in urinary oxalate (Uox) excretion compared to placebo. The study also achieved the key secondary endpoint, with a significantly higher proportion of patients given nedosiran achieving and sustaining normal or near-normal Uox at two or more consecutive visits after Day 90 compared to placebo. Uox reductions were significant in participants with PH1 while participants with PH2 (5 nedosiran and 1 placebo) showed inconsistent results in this trial. Nedosiran was generally well tolerated in the study with an overall adverse event profile consistent with previously reported data from PHYOX trials.
“We believe the reduction in Uox excretion seen in patients with PH1 showed that nedosiran knocks down LDHA in the liver and reconfirms the ability of Dicerna’s GalXC RNAi technology to silence disease-driving genes, de-risking our growing pipeline of GalXC product candidates,” said Shreeram Aradhye, executive vice president and chief medical officer at Dicerna. “The heterogeneity of Uox response seen in participants with PH2, despite LDHA inhibition in the liver and in contrast to prior clinical experience, suggests more complexity in the PH2 disease biology than has been previously understood and will require further evaluation.”
But investors were not happy with the “inconsistent results” for patients with PH2, which sent shares plummeting. PH2 patients represent a smaller population of patients with PH for whom there is no approved therapy. With Alnylam’s PH1 treatment Oxlumo already on the market, investors had hoped that Dicerna could take a lead in the PH2 population.
Still, the primary endpoint of the study, percent change from baseline in 24-hour urinary oxalate excretion as assessed by area under the curve (AUC) from Day 90 to Day 180, was met, with nedosiran resulting in a statistically significant reduction in Uox of a 57.5 percent greater daily average reduction over Day 90 to Day 180 compared to placebo.
The key secondary endpoint was percentage of patients (PH1 and PH2) achieving normalization (defined as Uox level below 0.46 mmol adjusted per 1.73 m2 body surface area in participants younger than 18 years when collected over 24 hours) or near-normalization (defined as 1.3 times the upper limit of normal) on at least two consecutive visits from Day 90 to Day 180. Nedosiran achieved statistically significant results in the study, with 50 percent of nedosiran-treated patients reaching normal or near-normal Uox on at least two consecutive visits, compared to none for those receiving placebo.
Dicerna intends to present full results from PHYOX2 at an upcoming medical congress, subject to abstract acceptance and expects the results to support marketing authorization applications in the United States and other major markets.
PHYOX2 is part of the broader PHYOX clinical trial program designed to evaluate nedosiran in participants with PH1, PH2 and PH3. Data from PHYOX1, a single-dose phase 1 trial in healthy volunteers and participants with PH1 or PH2; PHYOX2; PHYOX4, a single-dose safety and tolerability study in participants with PH3; and the ongoing PHYOX3 open-label extension study, are expected to support the nedosiran New Drug Application submission, which is planned for the fourth quarter of 2021.
Photo: Shreeram Aradhye, executive vice president and chief medical officer at Dicerna