Long-term Lumasiran Therapy Final Results from a Phase 2 Open-label Extension Study in Primary Hyperoxaluria

Background Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder of hepatic oxalate overproduction leading to kidney failure and systemic oxalosis. Lumasiran is an RNA interference therapeutic approved for lowering urinary oxalate (UOx) and plasma oxalate (POx) in PH1. This Phase 2 open-label extension (OLE) study evaluated the safety and efficacy of long-term lumasiran treatment (up to 54 months) in patients with PH1 who had completed the Phase 1/2 parent study. Methods The Phase 2 OLE (NCT03350451) included patients with PH1 6 to 64 years old, 24-hour UOx excretion > 0.7 mmol/1.73m2/day, and estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73m2 who enrolled within 12 months of parent study completion. Patients initiated subcutaneous lumasiran at parent study dosage. Endpoints included adverse event (AE) incidence (primary) and change over time in efficacy measures, including 24-hour UOx and eGFR. Results All 20 patients (median age 11.5 years; 65% female) who completed the parent study entered and completed the Phase 2 OLE. Of 21 treatment-related AEs over 427 doses, 13 were transient injection site reactions (ISRs), affecting 8/20 patients (40%); all ISRs were mild in severity. After Month (M) 18 through M51 (last dosing), no ISRs were reported. No treatment-related severe or serious AEs were reported. Lumasiran treatment led to a substantial mean reduction in 24 h UOx from baseline to M54 of − 1.5 mmol/24 h/1.73m2. At visits M42 through M54, 24-hour UOx was ≤ 1.5 × ULN in 89–94% of patients at each visit. The mean annual change in eGFR was − 0.4 mL/min/1.73m2/year overall; eGFR was also stable in those patients with baseline eGFR < 90 mL/min/1.73m2. Conclusion These data represent the longest published follow-up of lumasiran-treated patients with PH1 (ages: 6–43 years) to date. Long-term lumasiran treatment for PH1 had acceptable safety and led to sustained and substantial reduction of UOx with preservation of kidney function.