Rare Daily Staff
Alnylam Pharmaceuticals reported that its experimental subcutaneously administered RNAi therapeutic lumasiran met its primary efficacy endpoint and all tested secondary endpoints in a phase 3 study as a treatment of primary hyperoxaluria type 1.
Primary hyperoxaluria type 1 (PH1) is an ultra-rare disease in which excessive oxalate production results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. Compromised kidney function results in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Current treatment options include frequent renal dialysis or combined organ transplantation of liver and kidney. Although a small minority of patients respond to Vitamin B6 therapy, there are no approved pharmaceutical therapies for PH1.
Lumasiran targets hydroxyacid oxidase 1 (HAO1), which encodes glycolate oxidase (GO). By silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1.
“Patients living with PH1 and their families are faced with the burden of recurrent and painful stone events and a progressive and unpredictable decline in kidney function that ultimately results in end-stage renal disease and the need for intensive dialysis as a bridge to dual liver/kidney transplantation,” said Akshay Vaishnaw, president of R&D at Alnylam. “The results from ILLUMINATE-A demonstrate that lumasiran can significantly reduce the hepatic production of oxalate, which we believe can thereby address the underlying pathophysiology of PH1.”
ILLUMINATE-A is a randomized, double-blind, placebo-controlled trial, designed to enroll approximately 30 patients with PH1 ages six and above, at 16 study sites, in eight countries around the world. It is the largest interventional study conducted specifically in PH1. Patients were randomized 2:1 to lumasiran or placebo, with lumasiran administered at 3 mg/kg monthly for three months followed by quarterly maintenance doses. The primary endpoint for the study was the percent change from baseline in 24-hour urinary oxalate excretion averaged across months 3 to 6 in patients treated with lumasiran as compared to placebo. At six months, lumasiran met the primary endpoint in patients with PH1 and achieved statistically significant results for all six hierarchically-tested secondary endpoints, including the proportion of lumasiran patients that achieved near-normalization or normalization of urinary oxalate levels, relative to placebo.
There were no serious or severe adverse events in the study, and results showed that lumasiran was generally well tolerated with an overall profile generally consistent with that observed in phase 1/2 and open-label extension studies of lumasiran. Based on these results, Alnylam plans to submit a New Drug Application (NDA) and file a Marketing Authorization Application (MAA) for lumasiran in early 2020.
“These patients live with the angst of not knowing when that next kidney stone will come or for how long their kidneys will keep working, and they grapple with the possibility of needing new organs. said Kim Hollander, executive director of the Oxalosis and Hyperoxaluria Foundation. “We have lived with the hope that someday patients living with PH1 and their families would finally have a treatment with the potential to have a positive impact on their health and alleviate some of that angst. Today we are hopeful that we are much closer to that day than we have ever been.”
Alnylam is also conducting ILLUMINATE-B – a global phase 3 study of lumasiran in PH1 patients less than six years of age, with results expected in mid-2020, and ILLUMINATE-C – a global phase 3 study of lumasiran in PH1 patients of all ages with advanced renal disease, with results expected in 2021.
Lumasiran has received U.S. and E.U. Orphan Drug designations, Breakthrough Therapy designation from the U.S. Food and Drug Administration, and a Priority Medicines (PRIME) designation from the European Medicines Agency. The full study results will be presented in March 2020 at the OxalEurope International Congress in Amsterdam, Netherlands.
Photo: Akshay Vaishnaw, president of R&D at Alnylam