#2388 Long-term efficacy and safety in the 60-month, Phase 3 ILLUMINATE-B trial of lumasiran in infants and young children with primary hyperoxaluria type 1

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Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a genetic disorder resulting in excess hepatic oxalate production, potentially leading to urolithiasis, nephrocalcinosis (NC), and ultimately, chronic kidney disease, kidney failure, and systemic oxalosis. Lumasiran, the first liver-directed RNA interference therapeutic administered to infants and toddlers, is approved in several countries, including those of the European Union and the United States, for treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate (POx) levels in pediatric and adult patients. Lumasiran demonstrated sustained efficacy with an acceptable safety profile over 30 months in infants and young children age <6 years with PH1 participating in ILLUMINATE-B (NCT03905694). We evaluated efficacy and safety outcomes through Month (M) 60 of ILLUMINATE-B. Method ILLUMINATE-B was a Phase 3, multinational, open-label, single-arm study. Eligibility included a confirmed PH1 diagnosis, age <6 years at study entry, an estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2 if age ≥12 months or normal serum creatinine if age <12 months, and a UOx:creatinine ratio (UOx:Cr) greater than the upper limit of normal (ULN). Lumasiran was administered subcutaneously using weight-based dosing. An extension period (EP) of up to 54 months followed the 6-month primary analysis. The primary endpoint was percentage change in spot UOx:Cr from baseline to M6. Secondary endpoints included change from baseline in UOx excretion, proportion of patients with UOx excretion ≤ULN and ≤1.5 × ULN for age, and changes from baseline in POx and in eGFR. Exploratory endpoints included changes in NC and kidney stone event rates. Results All 18 patients who enrolled in ILLUMINATE-B entered the EP and completed the study at M60. At consent, the median (range) age was 50.1 (3–72) months; the median age at diagnosis was 16.3 months. The median (range) exposure to lumasiran was 55.5 (54.5–56.1) months. The mean spot UOx:Cr actual values were 0.63 mmol/mmol at baseline and 0.11 mmol/mmol at M60 (Fig. 1A); the mean percentage change from baseline in the spot UOx:Cr was −74% at M60 (Fig. 1B). Overall, 100% of patients had a spot UOx:Cr value that was ≤ULN at ≥1 post-baseline visit. The mean POx decreased from 13.24 μmol/L at baseline to 8.21 μmol/L at M60 (ULN: 12.11 μmol/L), a mean percentage change from baseline of −25%. The eGFR remained stable over time, with a mean (SEM) of 112.8 (6.9) mL/min/1.73 m2 at baseline and 109.8 (5.7) mL/min/1.73 m2 at M60 (Fig. 2). The mean (SEM) annual rate of change in eGFR was 0.26 (0.8) mL/min/1.73 m²/y, calculated using simple linear regression. In the 2 patients who had CKD stage 2 at baseline, the mean (SEM) eGFR was 70.2 (5.6) mL/min/1.73 m2 at baseline and mean (SEM) change from baseline at M60 was −3.5 (4.3) mL/min/1.73 m2. Among 14 patients with medullary NC at baseline, NC grade was improved at M60 in 12 (86%; 10 had complete resolution and 2 did not), stable in 1 (7%), and indeterminate in 1 (7%). The 4 patients without NC at baseline remained stable, with no NC at M60. During the study, the rate of kidney stone events per person-year was 0.11 (95% confidence interval, 0.06–0.21); 14 (78%) patients had 0 kidney stone events. Overall, 5 (28%) patients had adverse events (AEs) considered related to lumasiran by the investigator. The most common lumasiran-related AEs were mild, transient injection site reactions, which affected 3 patients (17%; 7 events in 410 total administered doses); symptoms included erythema, discoloration, hematoma, urticaria, and pain at the injection site. There were no AEs leading to treatment discontinuation or study withdrawal, and no deaths. Conclusion In this final analysis of long-term data from ILLUMINATE-B, infants and young children with PH1 had reductions in UOx and POx that were sustained over 60 months of lumasiran treatment. Kidney function was stable throughout long-term treatment. Medullary NC grade improved in most patients, and kidney stone event rates were low. The safety profile remained acceptable; the most common lumasiran-related AEs were mild, transient injection site reactions. Source of Funding Alnylam Pharmaceuticals.

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