Kidney International Reports (Mar 2022)

Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1

  • Sally A. Hulton,
  • Jaap W. Groothoff,
  • Yaacov Frishberg,
  • Michael J. Koren,
  • J. Scott Overcash,
  • Anne-Laure Sellier-Leclerc,
  • Hadas Shasha-Lavsky,
  • Jeffrey M. Saland,
  • Wesley Hayes,
  • Daniella Magen,
  • Shabbir H. Moochhala,
  • Martin Coenen,
  • Eva Simkova,
  • Sander F. Garrelfs,
  • David J. Sas,
  • Kristin A. Meliambro,
  • Taylor Ngo,
  • Marianne T. Sweetser,
  • Bahru A. Habtemariam,
  • John M. Gansner,
  • Tracy L. McGregor,
  • John C. Lieske

Journal volume & issue
Vol. 7, no. 3
pp. 494 – 506

Abstract

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Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels. Methods: We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran). Results: In the lumasiran/lumasiran group (n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group (n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs). Conclusion: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.

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