Garrelfs, Sander F.

Abstract 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.

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic oxalate overproduction. Excess oxalate is excreted by the kidneys, leading to recurrent kidney stones, nephrocalcinosis, and progressive kidney disease. Patients with PH1 generally experience a slow decline in kidney function over time that can be punctuated by abrupt worsening precipitated by infection, obstructing stones, or dehydration. Approximately half of patients with PH1 progress to kidney failure by early adulthood, and nearly all by 60 years of age. Lumasiran is an RNAi therapeutic indicated for the treatment of PH1 in all age groups. In clinical trials, treatment with lumasiran resulted in substantial reductions in urinary and plasma oxalate in pediatric and adult patients, with an acceptable safety profile. This analysis evaluates the change in kidney function of patients with PH1 with an eGFR of ≥30 mL/min/1.73m2 enrolled in clinical trials of lumasiran. Method We analyzed kidney function from 75 patients with PH1, age ≥12 months old, eGFR ≥30 mL/min/1.73m2, enrolled in 3 clinical trials of lumasiran (Phase 2 open-label extension, and Phase 3 ILLUMINATE-A and ILLUMINATE-B). In these trials, eGFR was calculated with the Modification of Diet in Renal Disease (MDRD) Study equation in adults or the bedside Schwartz equation in children. The effect of lumasiran on eGFR was assessed by baseline eGFR subgroup: ≥90, <90, 60 to <90, 45 to <60, and 30 to <45 mL/min/1.73m2. Results Of 75 patients available for analysis, 46 were treated with lumasiran from the start of the study through the Month 12 visit. eGFR remained stable in all eGFR subgroups. Patients with eGFR ≥90 mL/min/1.73m2 at baseline (N=16) demonstrated fluctuations in mean values by timepoint, with a mean change (95% CI) from baseline of -1 (-8, 6) mL/min/1.73m2 at Month 12. In patients with eGFR <90 mL/min/1.73m2 (N=30), no change in mean eGFR from baseline was observed at Month 12; the mean change (95% CI) was 0 (-3, 3). When evaluating subgroups with impaired kidney function, variations in the mean change were observed at Month 12 due to small sample sizes. For patients with eGFR 60 to <90 mL/min/1.73m2 (N=22), the mean change (95% CI) was -2 (-5, 1). For patients with eGFR 45 to <60 mL/min/1.73m2 (N=5), the mean change (95% CI) was 3 (-8, 14). For patients with eGFR 30 to <45 mL/min/1.73m2 (N=3), the mean change (95% CI) was 9 (7, 11). Conclusion Patients with PH1 had stable kidney function over time with lumasiran treatment, regardless of kidney function at baseline. Given the progressive kidney function decline that is characteristic of PH1, the eGFR stability observed during 12 months of treatment with lumasiran is encouraging. Kidney function will continue to be monitored for the duration of the lumasiran clinical trials.

Background and objectives In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. Design, setting, participants, & measurements This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3–6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. Results Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. Conclusions Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. Clinical Trial registry name and registration number: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886

Abstract Background and Aims PH1 is a rare genetic disorder characterized by hepatic oxalate overproduction, leading to recurrent kidney stones, nephrocalcinosis, progressive kidney failure, and multiorgan damage from systemic oxalosis. There are no approved pharmacologic therapies for PH1. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic that targets glycolate oxidase to reduce hepatic oxalate production. We report the first results from the six-month, double-blind period of ILLUMINATE-A, a randomized, placebo-controlled Phase 3 study to evaluate lumasiran in patients with PH1. Method Key inclusion criteria: age≥6 years, 24hr urinary oxalate (UOx)≥0.70 mmol/24hr/1.73m2, confirmed PH1 diagnosis, eGFR≥30 mL/min/1.73m2. Randomization: 2:1; lumasiran (n=26), placebo (n=13). Dosing: 3 mg/kg monthly×3, then quarterly. Primary endpoint: percent change in 24hr UOx excretion from baseline to month (M) 6. Primary comparison: least square (LS) mean treatment difference in percent change from baseline (average of M3-6). Results Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline to M6 (average of M3-6) was −65.4% with lumasiran and −11.8% with placebo (LS mean difference: −53.5%; p=1.7 × 10−14). Subgroup analyses of the primary endpoint showed a consistent effect of lumasiran across age, baseline UOx, eGFR, and concomitant pyridoxine use. Lumasiran led to statistically significant improvements in all hierarchically tested secondary endpoints, including: proportion of lumasiran-treated patients that achieved normalization or near-normalization of 24hr UOx at M6 (84% vs 0% of placebo-treated patients, p=8.3 × 10−7), and percent change in plasma oxalate from baseline to M6 (average of months 3-6) (-39.5%, p=2.9 × 10−8). There were no serious or severe adverse events. The most common adverse events related to lumasiran were mild, transient injection site reactions. Conclusion Lumasiran resulted in clinically meaningful, rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels compared to placebo during the six-month double-blind period. Lumasiran has a favorable safety profile.