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

Abstract

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.

Keywords: RNAi; RNAi therapeutics; kidney stones; lumasiran; nephrocalcinosis; oxalosis; plasma oxalate; primary hyperoxaluria type 1; urinary oxalate.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Defect in glyoxylate metabolism in hepatocytes of patients with primary hyperoxaluria type 1 and lumasiran therapeutic hypothesis. Patients with primary hyperoxaluria type 1 have reduced or absent alanine-glyoxylate aminotransferase (AGT) function, resulting in increased oxalate and glycolate production by the hepatocyte, both of which are excreted by the kidneys. AGT in the liver peroxisome metabolizes glyoxylate to glycine. When AGT is deficient (black X), glyoxylate cannot be metabolized to glycine. Excess glyoxylate accumulates and is converted to oxalate. Excess hepatic oxalate is then transported to the kidney for excretion in the urine, leading to hyperoxaluria. In the kidneys, excess oxalate combines with calcium, which due to its insolubility, can readily crystallize in the urinary tract and lead to recurrent urolithiasis and nephrocalcinosis, causing progressive kidney damage. As kidney function worsens, there is a reduction in the capacity of the kidneys to clear oxalate from the blood, leading to an increase in plasma oxalate and subsequent deposition of calcium oxalate crystals in tissues and vital organs, including bone, heart, retina, and skin, recognized clinically as systemic oxalosis. Lumasiran targets liver hydroxyacid oxidase 1 mRNA (red X), decreasing production of glycolate oxidase (GO), and hence, reducing hepatic oxalate production and delivery of oxalate to the kidneys for excretion. GR, glyoxylate reductase; LDH, lactate dehydrogenase. Adapted from ref. , with permission.

Figure 2.

Study design part B (patients with primary hyperoxaluria type 1). In this multiple ascending dose part of the study, patients with primary hyperoxaluria type 1 were screened within 45 days prior to study drug administration. Patients were randomized 3:1 to lumasiran (gray boxes) or placebo (blue boxes) between days –1 and 1 into each dosing cohort (1 mg/kg once per month, 3 mg/kg once per month, or 3 mg/kg once every 3 months). All patients received the first dose of lumasiran or placebo on day 1. Patients who received study drug once per month received the remaining two single-blind doses at days 29 and 57. Patients who received study drug once every 3 months received the remaining dose at day 85. Patients initially randomized to placebo received subsequent dosing of lumasiran on day 85 at the same dose administered to the cohort into which they were initially randomized. The 1- and 3-mg/kg monthly dosing cohorts were each expanded by an additional four patients who received three open-label doses of lumasiran. These patients were not randomized or blinded as each patient received open-label lumasiran starting on day 1. The 1-mg/kg once per month expansion cohort was enrolled first, followed by the 3-mg/kg once per month expansion cohort. During the PD follow-up period, patients were monitored for at least 12 weeks (84 days) following the last dose of study drug. N, number of patients; PD, postdose; q28d, every 28 days; q84d, every 84 days; qM, once monthly; q3M, once quarterly; SC, subcutaneous.

Figure 3.

Plasma glycolate levels after a single dose of lumasiran in healthy adult participants (part A).

Figure 4.

Urinary oxalate assessments after multiple doses of lumasiran in patients with primary hyperoxaluria type 1 (part B). (A) 24-hour urinary oxalate excretion (mmol per 24 hours per 1.73 m2). (B) 24-hour urinary oxalate-creatinine ratio. Values for patients during placebo treatment are only shown in (B) because incomplete collections are excluded from quantification of 24-hour urinary oxalate content, resulting in limited data for this measure. BSA, body surface area; N, number of patients with valid collections at each time point; ULN, upper limit of normal. aPatients initially randomized to placebo received their first dose of lumasiran on day 85. For the purpose of this analysis, they are also included in the lumasiran dosing cohort in which they were randomized, with day 1 relative to first dose of lumasiran; the patient randomized to placebo in 3-mg/kg quarterly dosing received a single dose of lumasiran, designated as day 1.