Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 12-month analysis of the phase 3 ILLUMINATE-B trial

Abstract

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here.

Methods: Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months).

Results: Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)).

Conclusions: Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Hyperoxaluria, Primary; Infant; Nephrocalcinosis; RNA interference, Lumasiran.

Conflict of interest statement

Wesley Hayes: travel and accommodation expenses from Alnylam Pharmaceuticals to attend an international investigators’ meeting. David J. Sas: grants and other from Alnylam Pharmaceuticals; personal fees from Advicenne. Daniella Magen: research funding, consultancy fees, and nonfinancial support from Alnylam Pharmaceuticals. Hadas Shasha-Lavsky: travel and accommodation expenses from Alnylam Pharmaceuticals to attend an international investigators’ meeting. Mini Michael: travel and accommodation expenses from Alnylam Pharmaceuticals to attend an international investigators’ meeting. Anne-Laure Sellier-Leclerc: consultancy fees from Alnylam Pharmaceuticals and Dicerna Pharmaceuticals, and principal investigator for research funded by OxThera. Julien Hogan: consultancy fees from Alnylam Pharmaceuticals. Marianne T. Sweetser, John M. Gansner: employment by and shareholders/stock options of Alnylam Pharmaceuticals. Tracy McGregor, Taylor Ngo: previous employment by and shareholders of Alnylam Pharmaceuticals. Yaacov Frishberg: consultancy fees from Alnylam Pharmaceuticals and membership in the Scientific Review Committee.

© 2022. The Author(s).

Figures

Fig. 1

Mean (SEM) spot UOx:Cr. a Percent change from baseline at each visit and b actual values at each visit. Baseline value was the mean of all assessments collected prior to the first dose of lumasiran; 1 mmol/mmol = 0.796 mg/mg; 1 mmol/mmol = 1000 mmol/mol. BL, baseline; M, month; UOx:Cr, urinary oxalate:creatinine ratio

Fig. 2

Actual spot UOx:Cr values by age; 1 mmol/mmol = 0.796 mg/mg; 1 mmol/mmol = 1000 mmol/mol. ULN, upper limit of normal; UOx:Cr, urinary oxalate:creatinine ratio

Fig. 3

Mean (SEM) plasma oxalate. a Percent change from baseline and b actual values at each visit. Baseline value was the mean of all assessments collected prior to the first dose of lumasiran. Dotted line in b represents lower limit of quantitation. Values below this threshold were assigned a value of 5.55 µmol/L. BL, baseline; M, month

Fig. 4

Change from baseline at month 6 and month 12 in nephrocalcinosis grade for patients with nephrocalcinosis at baseline a and without nephrocalcinosis at baseline b. aIndeterminate (one side improves and the other side worsens) is not graphed because there were 0 cases. bUnable to show improvement as patients did not have nephrocalcinosis at baseline. cData not available for one patient in the ≥ 20 kg weight subgroup who did not have kidney ultrasound at month 12. N/A, not available

Fig. 5

Kidney stone events. aHistorical group: patient-reported history of kidney stone events; annualized rate was not calculated for patients < 6 months old