David J Sas1, Daniella Magen2, Wesley Hayes3, Hadas Shasha-Lavsky4, Mini Michael5, Indra Schulte6, Anne-Laure Sellier-Leclerc7, Jiandong Lu8, Ali Seddighzadeh8, Bahru Habtemariam8, Tracy L McGregor8, Kenji P Fujita8, Yaacov Frishberg9. 1. Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, MN. Electronic address: sas.david@mayo.edu. 2. Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel. 3. Department of Paediatric Nephrology, Great Ormond Street Hospital, London, United Kingdom. 4. Pediatric Nephrology Unit, Galilee Medical Center, Nahariya, Israel. 5. Division of Pediatric Nephrology, Department of Pediatrics, Texas Children's Hospital/Baylor College of Medicine, Houston, TX. 6. Department of Pediatric Nephrology, University of Bonn, Bonn, Germany. 7. Hôpital Femme Mère Enfant and Centre d'Investigation Clinique Inserm, Hospices Civils de Lyon, ERKnet, Bron, France. 8. Alnylam Pharmaceuticals, Cambridge, MA. 9. Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: Yaacovf@ekmd.huji.ac.il.
Abstract
PURPOSE: 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 m2, 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.
PURPOSE: 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 m2, 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.