Presentation Authors: Yaacov Frishberg, Jerusalem, Israel, Georges Deschenes, Paris, France, Pierre Cochat, Lyon, France, Daniella Magen, Haifa, Israel, Jaap Groothoff, Amsterdam, Netherlands, Sally A. Hulton, Birmingham, United Kingdom, Jérôme Harambat, Bordeaux, France, William vant Hoff, London, United Kingdom, Bernd Hoppe, Bonn, Germany, John C Lieske*, Rochester, MN, Tracy L McGregor, Patrick Haslett, Sandeep Talamudupula, David V Erbe, Cambridge, MA, Dawn S Milliner, Rochester, MN
Introduction: PH1 is a genetic disorder characterized by hepatic overproduction of oxalate, which crystalizes 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 â‰¥6 years of age with urinary oxalate (UOx) â‰¥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.
Source of Funding: Study sponsored and funded by Alnylam Pharmaceuticals.