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Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial

dc.rights.licenseopenen_US
dc.contributor.authorFRISHBERG, Yaacov
dc.contributor.authorDESCHENES, Georges
dc.contributor.authorGROOTHOFF, Jaap W.
dc.contributor.authorHULTON, Sally-Anne
dc.contributor.authorMAGEN, Daniella
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorHARAMBAT, Jerome
dc.contributor.authorVAN'T HOFF, William G.
dc.contributor.authorLORCH, Ulrike
dc.contributor.authorMILLINER, Dawn S.
dc.contributor.authorLIESKE, John C.
dc.contributor.authorHASLETT, Patrick
dc.contributor.authorGARG, Pushkal P.
dc.contributor.authorVAISHNAW, Akshay K.
dc.contributor.authorTALAMUDUPULA, Sandeep
dc.contributor.authorLU, Jiandong
dc.contributor.authorHABTEMARIAM, Bahru A.
dc.contributor.authorERBE, David V.
dc.contributor.authorMCGREGOR, Tracy L.
dc.contributor.authorCOCHAT, Pierre
dc.contributor.authorSTUDY, Collaborators
dc.date.accessioned2021-07-06T14:16:39Z
dc.date.available2021-07-06T14:16:39Z
dc.date.issued2021-05-13
dc.identifier.issn1555-9041en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/95001
dc.description.abstractEnBACKGROUND 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.
dc.language.isoENen_US
dc.subject.enPrimary hyperoxaluria type 1
dc.subject.enRNAi
dc.subject.enLumasiran
dc.subject.enUrinary oxalate
dc.subject.enKidney stones
dc.subject.enNephrocalcinosis
dc.subject.enOxalosis
dc.subject.enPlasma oxalate
dc.subject.enRNAi therapeutics
dc.title.enPhase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial
dc.typeArticle de revueen_US
dc.identifier.doi10.2215/cjn.14730920en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed33985991en_US
bordeaux.journalClinical Journal of the American Society of Nephrologyen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamLEHA_BPH
bordeaux.teamLEHA_BPH
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03279682
hal.version1
hal.date.transferred2021-07-06T14:16:43Z
hal.exporttrue
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