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

doi:10.1016/j.ekir.2021.12.001

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

Kidney Int Rep. 2021 Dec 11;7(3):494-506. doi: 10.1016/j.ekir.2021.12.001. eCollection 2022 Mar.

Authors

Sally A Hulton¹, Jaap W Groothoff², Yaacov Frishberg³, Michael J Koren⁴, J Scott Overcash⁵, Anne-Laure Sellier-Leclerc⁶, Hadas Shasha-Lavsky⁷, Jeffrey M Saland⁸, Wesley Hayes⁹, Daniella Magen¹⁰, Shabbir H Moochhala¹¹, Martin Coenen¹², Eva Simkova¹³, Sander F Garrelfs², David J Sas¹⁴, Kristin A Meliambro⁸, Taylor Ngo¹⁵, Marianne T Sweetser¹⁵, Bahru A Habtemariam¹⁵, John M Gansner¹⁵, Tracy L McGregor¹⁵, John C Lieske¹⁶

Affiliations

¹ Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham, UK.
² Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³ Division of Pediatric Nephrology, Shaare Zedek Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
⁴ Jacksonville Center for Clinical Research, Jacksonville, Florida, USA.
⁵ Velocity Clinical Research, San Diego, California, USA.
⁶ Hôpital Femme Mère Enfant and Centre d'Investigation Clinique Institut National de la Santé et de la Recherche Médicale, Hospices Civils de Lyon, ERKnet, Bron, France.
⁷ Pediatric Nephrology Unit, Galilee Medical Center and Azrieli Faculty of Medicine, Bar-Ilan University, Nahariya, Israel.
⁸ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁹ Department of Pediatric Nephrology, Great Ormond Street Hospital, London, UK.
¹⁰ Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel.
¹¹ UCL Department of Renal Medicine, Royal Free Hospital, London, UK.
¹² Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
¹³ Al Jalila Children's Hospital, Dubai, United Arabs Emirates.
¹⁴ Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
¹⁶ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

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.

Keywords: RNA interference; lumasiran; nephrocalcinosis; phase 3 clinical trial; primary hyperoxaluria type 1; urinary oxalate.