TY - JOUR
T1 - Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1
AU - Hulton, Sally A.
AU - Groothoff, Jaap W.
AU - Frishberg, Yaacov
AU - Koren, Michael J.
AU - Overcash, J. Scott
AU - Sellier-Leclerc, Anne Laure
AU - Shasha-Lavsky, Hadas
AU - Saland, Jeffrey M.
AU - Hayes, Wesley
AU - Magen, Daniella
AU - Moochhala, Shabbir H.
AU - Coenen, Martin
AU - Simkova, Eva
AU - Garrelfs, Sander F.
AU - Sas, David J.
AU - Meliambro, Kristin A.
AU - Ngo, Taylor
AU - Sweetser, Marianne T.
AU - Habtemariam, Bahru A.
AU - Gansner, John M.
AU - McGregor, Tracy L.
AU - Lieske, John C.
N1 - Funding Information:
SAH carried out research through the UK NIHR/Wellcome Trust Birmingham Clinical Research Facility. The views expressed in the manuscript are those of the authors and not necessarily those of the UK National Health Service, the National Institute for Health Research, or the Department of Health. Medical writing and editorial assistance were provided by Ana Camejo, PhD, from Alnylam Pharmaceuticals , and Jinling Wu, MD, PhD, and Stephanie Leinbach, PhD, both from Peloton Advantage, LLC, an OPEN Health company, in accordance with Good Publication Practice (GPP3) guidelines and funded by Alnylam Pharmaceuticals. This study was funded by Alnylam Pharmaceuticals.
Funding Information:
SAH reports receiving travel expenses to participate in clinical research meetings, consultancy fee from serving on the advisory board, and consultancy fees paid to Birmingham Children’s Hospital Renal Research Fund from Alnylam Pharmaceuticals, and other from Dicerna Pharmaceuticals and Chiesi Pharmaceuticals. JWG reports receiving consultancy fees from Alnylam Pharmaceuticals and study grants from Alnylam Pharmaceuticals, Dicerna Pharmaceuticals, and uniQure Pharmaceuticals. YF reports receiving consultancy fees from Alnylam Pharmaceuticals and membership in the safety review committee. MJK is an employee of Jacksonville Center for Clinical Research, which provides research and consulting services to pharmaceutical companies, government, and other industries. JSO reports receiving institutional research funding from Alnylam Pharmaceuticals. ALSL reports receiving consultancy fees from Alnylam Pharmaceuticals and Dicerna Pharmaceuticals and serving as a principal investigator for a research funded by OxThera. HSL is a principal investigator for Alnylam Pharmaceuticals and reports receiving travel and accommodation expenses from Alnylam Pharmaceuticals to attend international investigators’ meetings. JMS reports receiving grants, personal fees, and nonfinancial support from Alnylam Pharmaceuticals. WH reports receiving travel and accommodation expenses from Alnylam Pharmaceuticals to attend an international investigators’ meeting. DM reports receiving research funding, consultancy fees, and nonfinancial support from Alnylam Pharmaceuticals. SHM reports receiving consultancy fees from Allena Pharmaceuticals, Alnylam Pharmaceuticals, and Dicerna Pharmaceuticals and is a principal investigator for a research funded by OxThera. MC is a principal investigator for Alnylam Pharmaceuticals. ES is a principal investigator for Alnylam Pharmaceuticals and reports receiving travel and accommodation expenses from Alnylam Pharmaceuticals to attend international investigators’ meeting. SFG reports receiving nonfinancial support and grants from Alnylam Pharmaceuticals and grants from Dicerna Pharmaceuticals. DJS reports receiving grants and other from Alnylam Pharmaceuticals and personal fees from Advicenne. TN, MTS, and JMG are employees of Alnylam Pharmaceuticals and hold shares in Alnylam Pharmaceuticals. TLM and BAH are former employees of Alnylam Pharmaceuticals and hold shares in Alnylam Pharmaceuticals. JCL reports receiving grants from Alnylam Pharmaceuticals, Dicerna Pharmaceuticals, Retrophin, OxThera, and Siemens; other from Novobiome and Orfan-Bridgebio; and grants and other from Allena and Synlogic. KAM declared no competing interests.
Funding Information:
SAH carried out research through the UK NIHR/Wellcome Trust Birmingham Clinical Research Facility. The views expressed in the manuscript are those of the authors and not necessarily those of the UK National Health Service, the National Institute for Health Research, or the Department of Health. Medical writing and editorial assistance were provided by Ana Camejo, PhD, from Alnylam Pharmaceuticals, and Jinling Wu, MD, PhD, and Stephanie Leinbach, PhD, both from Peloton Advantage, LLC, an OPEN Health company, in accordance with Good Publication Practice (GPP3) guidelines and funded by Alnylam Pharmaceuticals. This study was funded by Alnylam Pharmaceuticals. Because of the sensitive nature of the data collected for this study, the data set will not be made available to other researchers.
Publisher Copyright:
© 2022 International Society of Nephrology
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - RNA interference
KW - lumasiran
KW - nephrocalcinosis
KW - phase 3 clinical trial
KW - primary hyperoxaluria type 1
KW - urinary oxalate
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U2 - 10.1016/j.ekir.2021.12.001
DO - 10.1016/j.ekir.2021.12.001
M3 - Article
AN - SCOPUS:85122986292
SN - 2468-0249
VL - 7
SP - 494
EP - 506
JO - Kidney International Reports
JF - Kidney International Reports
IS - 3
ER -