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Abstract: SA-PO414

Interim Results from the Ongoing Phase 2 Open-Label Extension Study of Lumasiran, an Investigational RNA Interference (RNAi) Therapeutic, in Patients with Primary Hyperoxaluria Type 1 (PH1)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

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

PH1 is a rare genetic disorder characterized by persistent hepatic overproduction of oxalate. Oxalate crystalizes with calcium leading to recurrent kidney stones, nephrocalcinosis, progressive renal failure, and multiorgan damage from systemic oxalosis. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic specifically designed to decrease oxalate production. In Phase 1/2, lumasiran demonstrated an acceptable safety profile and clinically significant urinary oxalate (UOx) lowering in patients with PH1. Emerging data from the ongoing Phase 2 open-label extension (OLE) study will be presented.

Methods

Phase 2 OLE includes patients who completed the Phase 1/2 randomized, placebo-controlled, multicenter trial, evaluating lumasiran in patients with PH1 ≥6 years old, UOx ≥0.7mmol/1.73m2/day and eGFR >45mL/min/1.73m2. Patients received 1 of 3 dosing regimens: 1mg/kg or 3mg/kg monthly x3 doses or 3mg/kg every 3 months x2 doses. After completing Phase 1/2, all patients enrolled in OLE, starting at their original dose unless a different dose was approved prior to dosing in OLE. Endpoints include safety and change in 24-hour UOx.

Results

The Phase 1/2 study enrolled 20 patients with PH1 at 9 sites in 5 countries; mean age 14.9 years (range: 6-43), mean baseline UOx 1.69mmol/1.73m2/day (range: 0.83–2.97). As of February 2019, 18 patients were dosed in OLE for median of 4 months (range: 0.03–8.36 ). Continued dosing with lumasiran was well tolerated, with no discontinuations or drug-related serious adverse events. Adverse events were reported in 12/18 (66.7%) patients; majority were mild in severity and assessed as unrelated to study drug. Mean max reduction in UOx relative to Phase 1/2 baseline was 72% (N=9) and mean reduction at day 85 was 69% (N=7); all of these patients achieved normal or near normal levels of UOx.

Conclusion

To date, lumasiran has demonstrated an acceptable safety profile and clinically significant reduction in UOx in patients with PH1. A Phase 3 program evaluating efficacy and safety of lumasiran in patients with PH1 is ongoing.

Funding

  • Commercial Support – Alnylam Pharmaceuticals