SUN-325 SAFETY AND EFFICACY OF LUMASIRAN, AN INVESTIGATIONAL RNA INTERFERENCE (RNAi) THERAPEUTIC, IN ADULT AND PEDIATRIC PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by the hepatic overproduction of oxalate, which forms calcium oxalate crystals in the urinary system. Disease manifestations include recurrent urolithiasis, nephrocalcinosis, progressive renal failure, and multi-organ damage from systemic oxalosis, often resulting in high morbidity and mortality. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic specifically designed to reduce a key substrate thereby decreasing oxalate production. The objective is to the present emerging safety and pharmacodynamic data from the Phase 2 open-label extension (OLE) study of lumasiran. ALN-GO1-001 is a Phase 1/2 randomized, placebo-controlled, single-blind, multicenter trial, evaluating lumasiran in patients with PH1 ≥6 years of age with urinary oxalate (UOx) ≥0.7 mmol/1.73m2/day and eGFR >45 mL/min/1.73m2. The study consists of three dosing regimens: 1 mg/kg monthly for 3 doses, 3 mg/kg monthly for 3 doses, or 3 mg/kg lumasiran every 3 months for 2 doses. Once patients complete follow up in Phase 1/2, eligible patients may enroll in the OLE study for long-term dosing. Endpoints for the OLE study include safety and change in 24-hour UOx from baseline. Patients (N=20; 65% females) in Phase 1/2 had a mean age at enrollment of 14.9 years (range 6-43) and a mean baseline UOx of 1.69 mmol/1.73m2/day (range 0.83–2.97). Previously presented data showed no discontinuations or drug-related serious adverse events (AEs). AEs were reported in 3 (100%) patients during placebo dosing and 19 (95%) patients after lumasiran dosing; the majority of AEs were mild or moderate and deemed unrelated to study drug. Mean maximal reduction in urinary oxalate relative to baseline was 75% after lumasiran dosing; the mean reduction relative to baseline 28 days post last dose of lumasiran was 66%. Among patients receiving lumasiran 3.0 mg/kg monthly or quarterly, 10/12 (83%) achieved urinary oxalate levels within the normal range (<0.46 mmol/1.73m2/day). As of Oct 2018, all patients who have completed follow up in Phase 1/2 have enrolled in the OLE. At the time of data cut off, patients (N=8) have been on the OLE study for 2.7 months (range: 0.03–3.02). Safety data from OLE remains consistent with that observed in the Phase 1/2 study, with no discontinuations or drug related serious adverse events. AEs were reported in 5 (63%) of patients; all AEs were mild or moderate in severity and a majority were unrelated to study drug. The acceptable safety profile and clinically significant reduction in urinary oxalate levels observed in these studies support continued clinical development of lumasiran for patients with PH1. A Phase 3 program to evaluate the efficacy and safety of lumasiran in children and adults with primary hyperoxaluria type 1 is now underway.