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Abstract: TH-PO721

Safety and Efficacy Study of Lumasiran (ALN-GO1), an Investigational RNA Interference (RNAi) Therapeutic, in Patients with Primary Hyperoxaluria Type 1

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Hulton, Sally, Birmingham Childrens'' Hospital, Birmingham, United Kingdom
  • Frishberg, Yaacov, Shaare Zedek Medical Center, Jerusalem, Israel
  • Deschênes, Georges, Hospital Robert Debre/Pediatric Nephrology, Paris, France
  • Cochat, Pierre, Université ClaudeBernard Lyon1-, Bron, France
  • Magen, Daniella, Rambam Health Care Campus, Haifa, Israel
  • Groothoff, Jaap Willem, Emma Children's Hospital AMC, Amsterdam, Netherlands
  • Harambat, Jerome, Bordeaux University Hospital, Bordeaux, France
  • van't Hoff, William, Great Ormond Street Hospital, Lond, United Kingdom
  • Hoppe, Bernd, University Hospital Bonn, Bonn, Germany
  • Lieske, John C., Mayo Clinic , Rochester, Minnesota, United States
  • McGregor, Tracy, Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States
  • Haslett, Patrick, Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States
  • Erbe, David V., Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States
  • Milliner, Dawn S., Mayo Clinic , Rochester, Minnesota, United States
Background

In Primary Hyperoxaluria Type 1 (PH1), defective alanine:glyoxylate aminotransferase leads to excessive hepatic oxalate production, leading to progressive renal impairment and multi-organ damage from systemic oxalosis. Lumasiran, an investigational RNAi therapeutic suppresses hepatic glycolate oxidase, decreases the conversion of glycolate to glyoxylate, and results in reduced oxalate production.

Methods

ALN-GO1-001 is a randomized, placebo-controlled, single-blind, multicenter trial, evaluating lumasiran in patients with PH1 ≥6 years of age with urinary oxalate (UOx) ≥0.7 mmol/1.73m2/day and eGFR >45 mL/min/1.73m2. One of four patients in each dosing cohort was randomized to placebo prior to subcutaneous lumasiran. Cohorts 1 & 2 received 3 monthly doses of 1 mg/kg or 3 mg/kg, respectively; cohort 3 received 2 quarterly doses of 3 mg/kg lumasiran. An additional 4 patients received lumasiran in expansions of each of the first 2 cohorts. The primary endpoint is safety; secondary endpoints include change in 24-hour UOx from baseline. Eligible patients may continue dosing in the open-label extension (OLE) study.

Results

Patients in cohorts 1-3 had a mean age of 13.1 years (range 6-43), 7 (58%) female, and baseline UOx was 1.58 mmol/1.73m2/day (range 0.63-2.37). Lumasiran has demonstrated acceptable preliminary safety and tolerability with no treatment related serious adverse events or discontinuations; majority of adverse events were mild/moderate and unrelated to study drug. All patients treated with lumasiran in cohorts 1-3 experienced UOx lowering below 0.7 mmol/1.73m2/day, with a mean maximal decrease of 65%. Data available 85 days after initial dosing in the first 3 cohorts (n=9) showed a mean UOx reduction of 63% (range 49-73%). Data from patients in all cohorts (n=20), including quarterly dosing, expansions and OLE will be presented.

Conclusion

Preliminary results demonstrate acceptable safety data and lowering of UOx in patients with PH1 supporting the continued development of lumasiran as a potential therapeutic to alleviate pathologic overproduction and consequences of excess oxalate in this devastating disease.

Funding

  • Commercial Support