Alnylam Pharmaceuticals, Inc. announced positive topline results from the ILLUMINATE-C Phase 3 open-label study of lumasiran in patients of all ages with advanced primary hyperoxaluria type 1 (PH1) associated with progressive decline in renal function. Lumasiran is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – that is being investigated for the treatment of adult and pediatric patients with advanced PH1. Results of the primary analysis at six months demonstrated substantial reduction in plasma oxalate from baseline in patients (N=21) with advanced disease, including those on hemodialysis. Elevated plasma oxalate is directly related to the pathophysiology of oxalosis and results in systemic deposition of oxalate in extra-renal tissues, potentially leading to bone fractures, cardiomyopathy, impaired erythropoiesis, vision loss, skin ulcers, and other serious manifestations1. The safety and tolerability profile of lumasiran following six months of treatment is encouraging across all ages, with no drug related serious adverse events (SAEs) and injection site reactions (ISRs) as the most common adverse event (AE). ILLUMINATE-C (NCT04152200) is a single arm, open-label, multinational Phase 3 study evaluating the safety and efficacy of lumasiran in PH1 patients of all ages with severe renal impairment (eGFR = 45 mL/min/1.73m2 or elevated serum creatinine for patients <12 months of age), and conducted at 13 study sites across 10 countries around the world. Cohort A enrolled six patients with advanced PH1 who do not yet require dialysis, and Cohort B enrolled 15 patients who are hemodialysis-dependent. The dosing regimen is based on weight with three monthly starting doses followed by ongoing monthly or quarterly doses. The primary efficacy endpoint for Cohort A was the percent change in plasma oxalate from baseline to month six, and the primary endpoint for Cohort B was the percent change in pre-dialysis plasma oxalate from baseline to month six. Key secondary endpoints are designed to evaluate additional measures of plasma oxalate and changes in urinary oxalate. Renal function, frequency and mode of dialysis, frequency of renal stone events, and measures of systemic oxalosis, including clinical manifestations, will also be evaluated in the extension period of the study. At six months, treatment with lumasiran resulted in a substantial reduction in plasma oxalate from baseline in both dialysis-independent and -dependent patients. Lumasiran also demonstrated positive results across key secondary endpoints, including measures of urinary oxalate (for patients in Cohort A) and additional measures of plasma oxalate. There were no deaths and no drug related SAEs among enrolled patients. There were two treatment discontinuations due to adverse events in the extension period of the study, neither of which was drug related. The most common drug related AEs (occurring in 10% or more of patients) were ISRs reported in five patients (23.8%), all of which were mild. Based on these results, the Company plans to submit a Supplemental New Drug Application (sNDA) for lumasiran with the U.S. Food and Drug Administration (FDA) and a Type II Variation with the European Medicines Agency (EMA) in late 2021. In November 2020, lumasiran was approved by the FDA for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients and by the EMA for the treatment of PH1 in all age groups. Lumasiran is marketed in the U.S. and EU as OXLUMO®. ILLUMINATE-C topline results will be discussed during Alnylam’s Second Quarter Earnings Conference Call on August 3rd at 8:30 am ET, and full results are expected to be presented at a medical meeting later this year.