Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. Methods: This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m 2 , if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. Results: All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. Conclusion: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial

“…Lumasiran demonstrated an acceptable safety profile in the 6-month primary analysis period of ILLUMINATE-C. Consistent with what was previously reported in patients with preserved kidney function, 19,20 the most common AEs related to lumasiran treatment were injection-site reactions, all of which were mild and transient.…”

“…24,[27][28][29] In previous studies, treatment with lumasiran was shown to achieve substantial and sustained reductions in UOx with an acceptable safety profile in patients with relatively J o u r n a l P r e -p r o o f preserved kidney function. 19,20 Treatment with lumasiran also led to rapid and sustained reductions in UOx in Cohort A in ILLUMINATE-C. As expected, anuria in Cohort B was nearly universal, precluding meaningful analysis of UOx. The post-baseline increase in plasma glycolate observed in ILLUMINATE-C was consistent with the mechanism of action of lumasiran and with previous findings in patients with relatively preserved kidney function, 19,20 suggesting comparable liver uptake of lumasiran and target suppression with the recommended weight-based dosing regimen in patients with advanced PH1.…”

“…19,20 Treatment with lumasiran also led to rapid and sustained reductions in UOx in Cohort A in ILLUMINATE-C. As expected, anuria in Cohort B was nearly universal, precluding meaningful analysis of UOx. The post-baseline increase in plasma glycolate observed in ILLUMINATE-C was consistent with the mechanism of action of lumasiran and with previous findings in patients with relatively preserved kidney function, 19,20 suggesting comparable liver uptake of lumasiran and target suppression with the recommended weight-based dosing regimen in patients with advanced PH1. In case reports of patients with GO deficiency, elevated plasma and urinary glycolate concentrations have been reported without apparent adverse clinical consequences.…”

“…[16][17][18] In the Phase 3 ILLUMINATE-A (ClinicalTrials.gov: NCT03681184; EudraCT: 2018-001981-40) and ILLUMINATE-B (ClinicalTrials.gov: NCT03905694; EudraCT: 2018-004014-17) studies, lumasiran resulted in substantial reductions in UOx and POx levels, with an acceptable safety profile in patients with PH1 whose kidney function was relatively preserved. 19,20 J o u r n a l P r e -p r o o f…”

Infantile Primary Hyperoxaluria Type 1 Treated With Lumasiran in Twin Males

“…A double-blinded randomized trial in PH1 patients aged six years or older has demonstrated a 53.5% reduction in 24-hour urinary oxalate excretion and a substantial decrease in plasma oxalate levels [4]. An open-label trial of patients <6 years with PH1 has demonstrated a 72% reduction in spot urine oxalatecreatinine ratio [6].…”