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Alnylam Initiates Pivotal Study of RNAi Therapeutic for PH1; Reports Positive Extension Study Results

November 12, 2019

Alnylam Pharmaceuticals said it has initiated a new global phase 3 study of lumasiran, an experimental subcutaneously administered RNAi therapeutic in development for the 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.

The ILLUMINATE-C study, a single-arm, open-label, global study to evaluate the efficacy and safety of lumasiran, will enroll patients of all ages with advanced renal disease, and the primary study endpoint is the percent reduction in plasma oxalate from baseline to six months. Alnylam expects to report initial study results in late 2020.

“This study complements our comprehensive clinical development plan for lumasiran, led by our ILLUMINATE-A pivotal study with results expected later this year and our ILLUMINATE-B study in young pediatric patients. Given the heterogeneity of the PH1 population, the ILLUMINATE trials collectively address PH1 patients across the spectrum of age and disease onset and severity,” said Pritesh Gandhi, vice president and general manager of the lumasiran program at Alnylam. “We are also pleased to report new results from our Phase 2 OLE study, and are encouraged by the sustained reductions in urinary oxalate and by the overall safety profile of lumasiran observed to date.”

Alnylam also reported new positive efficacy results from the ongoing phase 2 open-label extension study of lumasiran, which were just presented at the American Society of Nephrology 2019 Annual Meeting.

The results, based on a median study duration of 10.4 months, demonstrated a 76 percent mean maximal reduction in urinary oxalate excretion relative to phase 1/2 baseline values in all cohorts (N=19). In the study, all patients achieved a urinary oxalate level at or below 1.5 times the upper limit of normal, and 68 percent of patients achieved a urinary oxalate level within the normal range. Patients also experienced an 82 percent mean maximal reduction in urinary oxalate:creatinine ratio after lumasiran dosing across all cohorts (N=20). While adverse events were reported in 95 percent of patients in the study, most were mild and assessed as unrelated to the study drug.

Lumasiran has received both U.S. and EU Orphan Drug designations, a Breakthrough Therapy designation from the U.S. Food and Drug Administration, and a Priority Medicines (PRIME) designation from the European Medicines Agency.

Photo: Pritesh Gandhi, vice president and general manager of the lumasiran program

Author: Rare Daily Staff

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