Abstract
Original language | English |
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Pages (from-to) | 1025-1036 |
Number of pages | 12 |
Journal | Clinical journal of the American Society of Nephrology |
Volume | 16 |
Issue number | 7 |
DOIs | |
Publication status | Published - 1 Jul 2021 |
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In: Clinical journal of the American Society of Nephrology, Vol. 16, No. 7, 01.07.2021, p. 1025-1036.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Phase 1/2 study of lumasiran for treatment of primary hyperoxaluria type 1 a placebo-controlled randomized clinical trial
AU - Frishberg, Yaacov
AU - Deschenes, Georges
AU - Groothoff, Jaap W.
AU - Hulton, Sally-Anne
AU - Magen, Daniella
AU - Harambat, Jerome
AU - van’t Hoff, William G.
AU - Lorch, Ulrike
AU - Milliner, Dawn S.
AU - Lieske, John C.
AU - Haslett, Patrick
AU - Garg, Pushkal P.
AU - Vaishnaw, Akshay K.
AU - Talamudupula, Sandeep
AU - Lu, Jiandong
AU - Habtemariam, Bahru A.
AU - Erbe, David V.
AU - McGregor, Tracy L.
AU - study collaborators
AU - Cochat, Pierre
N1 - Funding Information: in Alnylam Pharmaceuticals. Y. Frishberg reports employment with Shaare Zedek Medical Center, consultancy fees from Alnylam Pharmaceuticals, serving as a member of the Safety Review Committee for Alnylam Pharmaceuticals, and serving as a Data Monitoring Committee member for Alexion Pharmaceuticals. P. P. Garg reports employment with Alnylam Pharmaceuticals, holding stock in Alny-lam Pharmaceuticals, and serving as a scientific advisor or membership of SQZ Biotech. J. W. Groothoff reports employment with Amsterdam University Medical Center (Academic Medical Center); consultancy agreements with Alnylam Pharmaceuticals, Dicerna Pharmaceuticals, and UniQure Pharmaceuticals; receiving research funding from Alnylam Pharmaceuticals, Dicerna Pharmaceuticals, and UniQure Pharmaceuticals; and serving as a scientific advisor or member of Alnylam Pharmaceuticals. B. A. Habtemarian reports employment with and holds stock in Alnylam Pharmaceuticals. J. Harambat reports employment with Bordeaux University Hospital, France; consultancy agreements with Alnylam Pharmaceuticals and Chiesi; receiving research funding from Advicenne, Alnylam Pharmaceuticals, and GSK; receiving honoraria from Alnylam Pharmaceuticals and Chiesi; and serving as European Society for Paediatric Nephrology/ European Renal Association - European Dialysis and Transplant Association Chairman, International Pediatric Nephrology Association member, European Society for Paediatric Nephrology member, European Dialysis and Transplant Association member, and on the Pediatric Nephrology editorial board. P. Haslett is a full-time employee of and holds stock in Alnylam Pharmaceuticals, the sponsor of the study reported in the article. S.-A. Hulton reports employment with Birmingham Women’s and Children’s Hospital NHS Foundation Trust; consultancy agreements with Alnylam Pharmaceuticals, Chiesi, and Dicerna; receiving research funding from Alnylam Pharmaceuticals and Dicerna; receiving honoraria from Alnylam Pharmaceuticals, Chiesi, and Dicerna; serving as president of the British Association for Paediatric Nephrology, vice president of the Renal Association, and a scientific advisor or member of the OxalEurope Committee; and speakers bureau for Alnylam Pharmaceuticals, Chiesi, and Dicerna. S.-A. Hulton also reports travel expenses to participate in clinical research meetings and consultancy fees paid to Birmingham Children’s Hospital Renal Research Fund from Alnylam Pharmaceuticals during the conduct of the study. J. C. Lieske reports employment with Mayo Clinic; consultancy agreements with Allena, Alnylam Pharmaceuticals, the American Board of Internal Medicine, Dicerna, Novobiome, Orfan, OxThera, Siemens, and Synlogic; receiving research funding from Allena, Alny-lam Pharmaceuticals, Dicerna, OxThera, Retrophin, Siemens, and Synlogic; grants from Alnylam Pharmaceuticals during the conduct of the study; grants from Dicerna, Retrophin, OxThera, and Siemens outside the submitted work; other from Orfan-Bridgebio outside the submitted work; grants and other from Allena outside the submitted work; receiving honoraria from the American Board of Internal Medicine and UpToDate; and serving as a scientific advisor or member of American Board of Internal Medicine, Kidney International, and the Oxalosis & Hyperoxaluria Foundation. U. Lorch reports employment with Richmond Pharmacology Ltd., which is a clinical research organization that provides clinical research services to coauthor colleagues. J. Lu reports employment with and ownership interest in Alnylam Pharmaceuticals. D. Magen reports employment with Rambam Health Care Campus, Haifa, Israel and Technion–Israeli Institute of Technology, Haifa, Israel; consultancy agreements with Alnylam Pharmaceuticals; and receiving research funding and honoraria from Alnylam Pharmaceuticals. T. L. McGre-gor reports employment with and holds stock in Alnylam Pharmaceuticals. D. S. Milliner reports employment with the Mayo Clinic; receiving honoraria from Alnylam Pharmaceuticals and Synlogic Medical Advisory Committee personal honorarium; and serving on the advisory committee for Alnylam Pharmaceuticals, the data safety and monitoring committee for a clinical trial conducted by Dicerna, the data safety monitoring board for a clinical trial conducted by OxThera, and the editorial board for Urolithiasis.D. S. Milliner reports consultancy agreements with Allena Pharmaceutical Company, Alnylam Pharmaceuticals, Dicerna Pharmaceutical Company, and OxThera Pharmaceutical Company, with all consulting fees paid directly to the Mayo Clinic; she received no personal compensation for this work. D. S. Milliner also reports receiving research funding from Alnylam Pharmaceuticals, Dicerna, and OxThera, with all research funding provided to the Mayo Clinic and not to her personally. D. S. Milliner reports ongoing work with the Oxalosis and Hyperoxaluria Foundation, a nonprofit private foundation. This includes some research funding; there is no personal compensation. Additionally, D. S. Milliner reports ongoing work with the Kidney Health Initiative and Oxalosis & Hyperoxaluria Foundation for a KHI-sponsored project. S. Talamudupula reports employment with and ownership interest in Alnylam Pharmaceuticals. A. K. Vaishnaw is a full-time employee and stockholder of Alnylam Pharmaceuticals. W. G. van’t Hoff reports employment with the National Institute for Health Research Clinical Research Network; receiving research funding from Alnylam Pharmaceuticals with contract research income to the previous employing organization and travel/accommodation for investigator meeting; and receiving research funding from Ultragenyx with contract research income to the previous employing organization. W. G. van’t Hoff also reports travel expenses to participate in clinical research meetings and financial recompense for clinical trial participation, which was paid to his institute during the conduct of the study, and travel expenses for attending investigator meetings from Kyowa Kirin Pharmaceuticals outside of the published work. Funding Information: This work was supported by Alnylam Pharmaceuticals. Publisher Copyright: © 2021 by the American Society of Nephrology.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Background and objectives In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. Design, setting, participants, & measurements This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. Results Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels #1.5 times the upper limit of normal. Conclusions Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. Clinical Trial registry name and registration number: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
AB - Background and objectives In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. Design, setting, participants, & measurements This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. Results Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels #1.5 times the upper limit of normal. Conclusions Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. Clinical Trial registry name and registration number: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
UR - http://www.scopus.com/inward/record.url?scp=85111321221&partnerID=8YFLogxK
U2 - https://doi.org/10.2215/CJN.14730920
DO - https://doi.org/10.2215/CJN.14730920
M3 - Article
C2 - 33985991
SN - 1555-9041
VL - 16
SP - 1025
EP - 1036
JO - Clinical journal of the American Society of Nephrology
JF - Clinical journal of the American Society of Nephrology
IS - 7
ER -