Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children

• Published in: Genetics in medicine Vol. 24; no. 3; pp. 654 - 662
• Main Authors: Sas, David J., Magen, Daniella, Hayes, Wesley, Shasha-Lavsky, Hadas, Michael, Mini, Schulte, Indra, Sellier-Leclerc, Anne-Laure, Lu, Jiandong, Seddighzadeh, Ali, Habtemariam, Bahru, McGregor, Tracy L., Fujita, Kenji P., Frishberg, Yaacov, Bacchetta, Justine, Baudouin, Véronique, Becker-Cohen, Rachel, Tzvi Behr, Shimrit, Ben-Shalom, Efrat, Berdaguer, Maria, Bockenhauer, Detlef, Cochat, Pierre, Coenen, Martin, Cramer, Carl H., Deschênes, Georges, Dossier, Claire, Doye, Emilie, Feldman, Liat Feraru, Hohenadel, Maximilian, Kaguelidou, Florentia, Zebegret, Irina Libinson, Lieske, John C., Maisin, Anne, Milliner, Dawn S., Plonsky Toder, Moran, Pollack, Shirley, Portefaix, Aurélie, Ranchin, Bruno, Rinat, Choni, Safdar, Adnan, Schalk, Gesa, Srivaths, Poyyapakkam R., Tran, Cheryl L., Van't Hoff, William, Weinbrand-Goichberg, Jenny, Weissman, Irith
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2022
• Subjects: Child, Preschool; Humans; Hyperoxaluria, Primary - complications; Hyperoxaluria, Primary - genetics; Hyperoxaluria, Primary - therapy; Infant; Infants; Lumasiran; PH1; RNA Interference; RNA, Small Interfering; RNAi; RNAi Therapeutics; Young children; PH1; Lumasiran; RNAi; Young children; Infants
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1016/j.gim.2021.10.024

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. 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. 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. 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. [Display omitted]