MP12-14 SAFETY AND EFFICACY STUDY OF LUMASIRAN, AN INVESTIGATIONAL RNA INTERFERENCE (RNAI) THERAPEUTIC, IN ADULT AND PEDIATRIC PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1 (PH1)

Abstract

INTRODUCTION AND OBJECTIVES: PH1 is a genetic disorder characterized by hepatic overproduction of oxalate, which crystal-izes with calcium in the urinary system to become toxic; this manifests with recurrent urolithiasis, nephrocalcinosis, progressive renal failure, and multi-organ damage from systemic oxalosis, resulting in high morbidity and mortality. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic specifically designed to reduce the production of oxalate by preventing the formation of a key substrate in the pathway of oxalate production. METHODS: 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. 1 of 4 patients in each dose cohort was randomized to placebo prior to lumasiran. Cohorts 1 & 2 received 3 monthly doses of 1 mg/kg or 3 mg/kg, respectively; cohort 3 received 2 quarterly doses of 3 mg/kg lumasiran. An additional 4 patients received lumasiran in expansions of the first 2 cohorts. Primary endpoint is safety; secondary endpoints include change in 24-hour UOx. Eligible patients may continue dosing in the open-label extension (OLE) study. RESULTS: Patients (N=20) had mean age at enrollment of 14.9 years (range 6-43), 13 (65%) female, and mean baseline UOx of 1.69 mmol/1.73m2/day (range 0.83-2.97). As of 15 Aug 2018, there were no discontinuations or drug related serious adverse events. Adverse events were reported in 3 (100%) patients during placebo dosing and 19 (95%) patients after lumasiran dosing; majority of adverse events were mild or moderate and unrelated to study drug. Mean maximal reduction in UOx relative to baseline was 75% after lumasiran dosing; mean reduction relative to baseline 28 days post last dose of lumasiran was 66%. Among patients receiving 3.0 mg/kg monthly or quarterly doses of lumasiran, 10/12 (83%) achieved UOx levels within the normal range (<0.46 mmol/1.73m2/day). As of 3 Oct 2018, all patients who completed follow up in Phase 1/2 have enrolled to continue dosing in OLE (N=8) and have been on study for 2.7 months (range: 0.03-3.02). Safety data from OLE remains consistent with that observed in Phase 1/2. CONCLUSIONS: The acceptable safety profile and clinically significant reduction in UOx levels observed 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 PH1 is now underway.