FC 013LUMASIRAN DEMONSTRATED COMPARABLE OXALATE REDUCTION AND SAFETY IN CHILDREN AND ADULTS WITH PRIMARY HYPEROXALURIA TYPE 1

Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic overproduction of oxalate. Excretion of oxalate via the kidneys leads to recurrent kidney stones, nephrocalcinosis, progressive kidney disease, and multiorgan damage from systemic oxalosis. Lumasiran, a subcutaneously administered RNAi therapeutic indicated for the treatment of PH1 in all age groups, has multiple ongoing phase 3 studies including ILLUMINATE-A, which enrolled 39 patients ≥6 years of age with eGFR ≥30 mL/min/1.73m2, and ILLUMINATE-B, which enrolled 18 patients <6 years of age with eGFR >45 mL/min/1.73m2 if ≥12 months of age or normal serum creatinine if <12 months of age. Here we present a comparison of the efficacy and safety of lumasiran in children versus adults with PH1 using pooled data from these two phase 3 studies of lumasiran. Method Efficacy and safety data from ILLUMINATE-A and ILLUMINATE-B, including urinary oxalate, plasma oxalate, eGFR, and adverse events were pooled and assessed by age <18 (N=40), or ≥18 years old (N=17). The analysis included all available data from 57 patients with PH1, ages 4 months to 60 years, who completed the initial 6 months of treatment with lumasiran. Results During the initial 6 months of treatment with lumasiran, patients with PH1 had a rapid and sustained decrease in urinary oxalate. The overall mean (SEM) percent reduction in urinary oxalate:creatinine ratios as measured in random spot urine samples from baseline to Month 6 was 63.1% (2.6) across all ages (N=54). A similar time course and magnitude of reduction was seen in patients <18 years at 64.5% (3.3) (N=38), and ≥18 years old at 59.8% (4.4) (N=16). The oxalate reductions observed in random spot urine samples were comparable to those observed from 24-hour urine collections. The overall mean (SEM) percent reduction in urinary oxalate excretion from 24-hour collections was 63.8% (2.6) across all ages (N=40), 63.2% (3.5) in the <18 group (N=23) and 64.8% (3.9) in the ≥18 group (N=17). The overall mean (SEM) percent reduction in plasma oxalate from baseline to Month 6 was 39.5% (3.7) across all ages (N=44), with similar reductions of 39.4% (4.6) and 39.7% (6.5) in patients <18 (N=30) and ≥18 (N=14) years of age, respectively. eGFR was calculated for all patients ≥12 months of age and remained stable in both age groups during the 6 months of treatment with lumasiran. The 57 patients had a cumulative exposure of 27.1 patient-years and 227 doses were given. Adverse events were reported in 86% of all patients, 88% of patients <18, and 82% of patients ≥18 years of age. All adverse events were graded as mild or moderate in severity by the investigator. One patient had a serious adverse event of viral infection that was not related to lumasiran. In all patients, the most common adverse events related to lumasiran were mild, transient, injection site reactions, experienced by 30% of all patients, 23% of patients <18 and 47% of patients ≥18 years of age. No treatment interruptions or discontinuations related to lumasiran or deaths occurred. Conclusion Lumasiran reduced urinary and plasma oxalate to a similar degree in pediatric and adult patients with PH1 enrolled in the Phase 3 studies ILLUMINATE-A and ILLUMINATE-B. Reductions in urinary oxalate were similar between random spot urine samples and valid 24-hour urine collections. Overall safety was comparable between pediatric and adult patients.