scholarly journals Case Report: Sustained Efficacy of Lumasiran at 18 Months in Primary Hyperoxaluria Type 1

2022 ◽  
Vol 9 ◽  
Author(s):  
Benedetta Chiodini ◽  
Nathalie Tram ◽  
Brigitte Adams ◽  
Elise Hennaut ◽  
Ksenija Lolin ◽  
...  

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, ultimately responsible for kidney stones, kidney failure and systemic oxalosis. Lumasiran, is a liver-directed RNA interference therapeutic agent. It has been shown to reduce hepatic oxalate production by targeting glycolate oxidase, and to dramatically reduce oxalate excretion.Care Report: We present the case of a teenager patient affected by PH1, who entered in the lumasiran compassionate use program. The patient had a rapid and sustained decrease in urinary oxalate/creatinine ratio, with a mean reduction after lumasiran administration of about 70%. During the 18 months long follow-up, urinary oxalate remained low, reaching nearly normal values. Plasma oxalate also decreased dramatically. Normal levels were reached immediately after the first dose and remained consistently low thereafter. During the same follow-up period, eGFR remained stable at about 60 ml/min/1.73 m2, but no new kidney stones were observed. Existing kidney stones did not increase in size. The patient did not suffer renal colic events and did not require further urological interventions.Conclusion: In our severely affected PH1 patient, lumasiran proved to be very effective in rapidly and consistently reducing plasma oxalate and urinary excretion to normal and near-normal levels, respectively. In the 18 months long follow-up post-lumasiran, the eGFR remained stable and the patient showed clinical improvements. As far as we know, this report covers the longest observation period after initiation of this novel RNAi therapy.

Author(s):  
Yaacov Frishberg ◽  
Georges Deschênes ◽  
Jaap W. Groothoff ◽  
Sally-Anne Hulton ◽  
Daniella Magen ◽  
...  

Background and objectivesIn 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, & measurementsThis 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.ResultsThirty-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.ConclusionsLumasiran 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


2016 ◽  
Vol 24 (4) ◽  
pp. 770-778 ◽  
Author(s):  
Chaitali Dutta ◽  
Nicole Avitahl-Curtis ◽  
Natalie Pursell ◽  
Marita Larsson Cohen ◽  
Benjamin Holmes ◽  
...  

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