BACKGROUND:Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder of hepatic oxalate overproduction leading to kidney failure and systemic oxalosis. Lumasiran is an RNA interference therapeutic approved for lowering urinary oxalate (UOx) and plasma oxalate (POx) in PH1. This Phase 2 open-label extension (OLE) study evaluated the safety and efficacy of long-term lumasiran treatment (up to 54 months) in patients with PH1 who had completed the Phase 1/2 parent study. METHODS:The Phase 2 OLE (NCT03350451) included patients with PH1 6 to 64 years of age, 24-hour UOx excretion >0.7 mmol/1.73 m2/day, and estimated glomerular filtration rate (eGFR >45 ml/min/1.73 m2) who enrolled within 12 months of parent study completion. Patients initiated subcutaneous lumasiran at parent study dosage. Endpoints included adverse event (AE) incidence (primary) and change over time in efficacy measures, including 24-hour UOx and eGFR. RESULTS:All 20 patients (median age 11.5 years; 65% female) who completed the parent study entered and completed the Phase 2 OLE. Of 21 treatment-related AEs over 427 doses, 13 were transient injection site reactions (ISRs), affecting 8/20 patients (40%); all ISRs were mild in severity. After Month (M) 18 through M51 (last dosing), no ISRs were reported. No treatment-related severe or serious AEs were reported. Lumasiran treatment led to a substantial mean reduction in 24-hour UOx from baseline to M54 of -1.5 mmol/24 h/1.73 m2. At visits M42 through M54, 24-hour UOx was ≤1.5 × ULN in 89%-94% of patients at each visit. The mean annual change in eGFR was -0.4 ml/min/1.73 m2/year overall; eGFR was also stable in those patients with baseline eGFR <90 ml/min/1.73 m2. CONCLUSION:These data represent the longest published follow-up of lumasiran-treated patients with PH1 (ages 6-43 years) to date. Long-term lumasiran treatment for PH1 had acceptable safety and led to sustained and substantial reduction of UOx with preservation of kidney function.

BACKGROUND & AIMS:Genome-wide association studies have identified loss-of-function variants in the hydroxysteroid 17-beta dehydrogenase 13 gene (HSD17B13) associated with reduced risk of chronic liver disease. In this phase I study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of rapirosiran, an investigational, N-acetylgalactosamine-conjugated small-interfering RNA targeting liver-expressed HSD17B13 mRNA. METHODS:ALN-HSD-001 was a randomized, double-blind, placebo-controlled, multicenter study conducted in two parts. Part A evaluated single ascending subcutaneous doses of rapirosiran or placebo in 58 healthy adults. Part B evaluated two doses, administered 12 weeks apart, in 46 adults with metabolic dysfunction-associated steatohepatitis (MASH). Patients with MASH underwent liver biopsies during screening and once post-randomization for measurement of HSD17B13 mRNA. The primary endpoint was frequency of adverse events (AEs). Rapirosiran plasma and urine pharmacokinetics and change from baseline in liver HSD17B13 mRNA were secondary endpoints. RESULTS:In Part A, the only AE occurring in ≥10% of rapirosiran-treated individuals was injection-site reaction (11%); all occurrences were mild and transient. There were no treatment-related serious AEs. Plasma concentrations of rapirosiran declined rapidly by 24 h post-dose. Across doses, rapirosiran showed 17%-37% excretion in urine. In Part B, the only AE occurring in ≥10% of rapirosiran-treated patients was COVID-19 (14%; 5/36); all occurrences were deemed treatment-unrelated. There was no evidence of drug-induced liver injury in either part of the study. Rapirosiran was associated with a dose-dependent reduction in liver HSD17B13 mRNA in Part B, with a median reduction of 78% at 6 months in the highest-dose (400 mg) group. CONCLUSIONS:Rapirosiran exhibited an encouraging safety and tolerability profile, with a robust reduction in liver HSD17B13 mRNA expression. IMPACT AND IMPLICATIONS:Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent chronic liver disease associated with a high burden of disease. The hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene is implicated in the pathogenesis of MASH. Rapirosiran offers a novel mechanism to treat MASH by directly reducing hepatic HSD17B13 expression. In this phase I study, rapirosiran demonstrated an encouraging safety and tolerability profile and resulted in a robust reduction in liver HSD17B13 mRNA expression following two subcutaneous doses. The data support further development of rapirosiran as a potential treatment option for patients with MASH, a disease for which there is only one approved pharmacological treatment. CLINICAL TRIAL NUMBER:EUDRA-CT: 2020-000847-29; NCT: 04565717.

Rationale & Objective:Characterize the natural history of advanced primary hyperoxaluria type 1 (PH1) in a multinational patient cohort. Study Design:A retrospective chart review. Setting & Participants:Patients, from participating medical centers in North America, Europe, and the Middle East, had ≥ 4 health care visits related to PH1 spanning ≥ 6 months (except deceased patients) on/after January 1, 2000, and ≥ 2 estimated glomerular filtration rate (eGFR) values ≤ 45 mL/min/1.73m2 (if age < 12 months, 2 serum creatinine values elevated for age) were included. Exposure:None (retrospective observational study). Outcomes:Kidney function, liver and/or kidney transplantation, death, plasma oxalate, systemic oxalosis, emergent clinical events, and abnormal clinical laboratory values. Analytical Approach:Patients were categorized as not on dialysis (Cohort A) and receiving hemodialysis (Cohort B). Patients could be in more than one cohort, but not during the same time. Results:Seventy patients were analyzed (up to 21 years of data; Cohort A, n = 54; Cohort B, n = 53). The median age at entry was 11.8 years (Cohort A) and 12.2 years (Cohort B). The eGFR slope was -2.8 mL/min/1.73m2/year (Cohort A). Patients underwent hemodialysis a median of 6 days/week (range, 3-7; Cohort B). Forty-two patients underwent liver and/or kidney transplantation (median age at first transplant, 15.3 years). Nineteen patients died (median age at death, 3.9 years [range, 2.2-34.9]), including 8 who received liver or liver-kidney transplants. Death occurred in 11 of 28 (39.3%) patients without transplant and 8 of 42 (19.0%) patients with transplant. Improvement in skeletal oxalosis after liver-kidney transplantation generally took > 1 year. Limited plasma oxalate and cardiac oxalosis data were available. The most common emergent clinical events were nephrolithiasis (Cohort A [nondialysis]) and fracture (Cohort B [hemodialysis]). The most commonly reported abnormal clinical laboratory values were bicarbonate, creatinine, and eGFR. Limitations:Minimal follow-up in some patients; small sample for some endpoints. Conclusions:Advanced PH1 is associated with high morbidity and mortality rates.

Key Points Primary hyperoxaluria type 1 is a genetic disorder associated with hepatic oxalate overproduction, kidney failure, and systemic oxalosis. Lumasiran treatment for up to 60 months was associated with sustained reductions in urinary and plasma oxalate and encouraging clinical outcomes. Lumasiran's safety profile was acceptable with mild injection site reactions being the most common adverse events. Background Primary hyperoxaluria type 1 (PH1) is characterized by hepatic oxalate overproduction, kidney stones, and progressive kidney disease. Lumasiran is the first approved treatment for PH1. Methods ILLUMINATE-A (NCT03681184) was a 60-month pivotal, phase 3, multinational clinical trial of lumasiran which consisted of a 6-month double-blind, placebo-controlled period (6M DB), followed by a treatment extension period of up to 54 months in which all patients received lumasiran. Eligible patients were aged ≥6 years with genetically confirmed PH1, eGFR ≥30 ml/min per 1.73 m 2 , and mean 24-hour urinary oxalate (UOx) excretion ≥0.70 mmol/24 h per 1.73 m 2 . Results Of 39 patients enrolled, 24 of 26 randomized to lumasiran in the 6M DB (lumasiran/lumasiran group) and 13 of 13 randomized to placebo in the 6M DB (placebo/lumasiran group) completed the study. Sustained reductions in 24-hour UOx were observed in both treatment groups. At month 60 relative to study baseline, the mean (SEM) 24-hour UOx percentage reductions were 54 (6) and 54% (8%) in the lumasiran/lumasiran and placebo/lumasiran groups, respectively, and the mean (SEM) plasma oxalate concentrations had decreased by 35 (5) and 38% (7%). eGFR remained stable through the end of the study in both treatment groups. Kidney stone event rates during the study were 0.47 (95% confidence interval, 0.36 to 0.62) and 0.54 (0.37 to 0.78) per patient-year in the lumasiran/lumasiran group and placebo/lumasiran group, respectively. Medullary nephrocalcinosis grade improved at the end of the study in 21 of 28 (75%) patients with nephrocalcinosis at baseline and an end of study assessment. The safety profile of lumasiran was acceptable. Injection site reactions were the most common adverse events during lumasiran treatment. Most adverse events were mild or moderate in severity. Conclusions Lumasiran treatment for up to 60 months in ILLUMINATE-A was associated with sustained reductions in UOx excretion and plasma oxalate concentration, encouraging clinical outcomes including stable eGFR in a population that would be expected to show eGFR decline, reduced kidney stone event rates, improved medullary nephrocalcinosis, and indications of improved health-related quality of life. Clinical Trial registry name and registration number: ClinicalTrials.gov NCT03681184.

IntroductionPatients with primary hyperoxaluria type 1, a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of primary hyperoxaluria type 1 to lower urinary and plasma oxalate.MethodsILLUMINATE-A (NCT03681184) is a phase III trial in patients aged ≥6 years with primary hyperoxaluria type 1 and estimated glomerular filtration rate ≥30 mL/min/1.73m2. A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through Month 36.ResultsOf 39 patients enrolled, 24/26 (lumasiran/lumasiran group) and 13/13 (placebo/lumasiran group) entered and continue in the extension period. At Month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour urinary oxalate excretion ≤1.5× the upper limit of normal. Estimated glomerular filtration rate remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88, 2.84) per person-year during the 12 months before consent to 0.60 (0.46, 0.77) per person-year during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events were mild, transient injection-site reactions.ConclusionIn patients with primary hyperoxaluria type 1, longer-term lumasiran treatment led to sustained reduction in urinary oxalate excretion, with an acceptable safety profile and encouraging clinical outcomes.

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder in which hepatic oxalate overproduction can lead to kidney failure and life-threatening systemic disease. Lumasiran, an RNA interference (RNAi) therapeutic indicated for treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate (POx) levels, reduces hepatic oxalate production by degrading the mRNA encoding glycolate oxidase. Patients with PH1 who completed a Phase 1/2 study were eligible to enroll in a Phase 2 open-label extension (OLE) study (NCT03350451) within 12 months of completing the Phase 1/2 study. Method Patients enrolled in the 54-month Phase 2 OLE had previously met eligibility criteria for the Phase 1/2 study, including: age 6 to 64 years, PH1 confirmed by genetic criteria, 24-hour (24 h) UOx excretion >0.7 mmol/1.73 m2/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2, and a stable pyridoxine (vitamin B6) regimen for patients taking vitamin B6. In the Phase 2 OLE, patients were to initiate subcutaneous lumasiran 1.0 mg/kg once monthly (qM), 3.0 mg/kg qM, or 3.0 mg/kg every 3 months (q3M) based on their dose/regimen in the Phase 1/2 study. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were change in 24 h UOx corrected for body surface area (BSA) over time, change in 24 h UOx:creatinine ratio (UOx:Cr) over time, and change in estimated glomerular filtration rate (eGFR) over time. Change over time in POx and plasma glycolate, incidence of anti-drug antibodies (ADAs), and rates of kidney stone AEs were also assessed. Results All 20 patients (median age 11.5 years; 65% female) who completed the Phase 1/2 study entered the Phase 2 OLE (Table 1). Most patients (65%) were taking vitamin B6 at baseline. All patients transitioned to the 3.0 mg/kg q3M dose/regimen by month (M) 21, and all patients completed the study. Six patients transitioned to commercially available lumasiran prior to M54 but on or after M45. The most common treatment-related AEs were injection-site reactions (ISRs) with 13 events in 8 patients (40%); all ISRs were graded mild. Of all lumasiran doses administered during the OLE, 3% (13 of 427 total doses of lumasiran) were associated with ISRs. Other than ISRs, the only treatment-related AEs affecting >1 patient were increases in bilirubin (N=3 patients; 15%); all events resolved without lumasiran dosing changes. Severe AEs were reported by 2 patients (10%); serious AEs were reported by 7 patients (35%). No deaths occurred. No severe or serious AEs were related to treatment, and no patients discontinued lumasiran or withdrew due to AEs. Lumasiran treatment led to a substantial reduction in 24 h UOx relative to the Phase 1/2 study-derived baseline (Fig. 1A). At M54, the mean absolute change from baseline in 24 h UOx was −1.5 mmol/24 h/1.73 m2 and the mean percent change was −68%. From M42 through M54, 24 h UOx was ≤1.5×ULN in ≥89% of patients. At M54, the mean percent change from baseline in 24 h UOx:Cr was −77%. Mean eGFR was generally stable over time (Fig. 1B). Mean absolute change from baseline in eGFR at M54 was −1.6 mL/min/1.73 m2. Lumasiran treatment also led to reductions in POx from baseline, and mean post-baseline POx values remained within the normal range through M54. Mean plasma glycolate levels were elevated at the start of the Phase 2 OLE due to persistence of the treatment effect from the Phase 1/2 study. After treatment resumed, levels increased and then plateaued. One patient (5%) had an ADA positive result at M6 but no ADA-related AEs; subsequent tests were negative through M48. Overall, the kidney stone AE rate was low during the Phase 2 OLE (0.17/person-year (PY]); by comparison, the rate of symptomatic kidney stones was 0.45/PY during the 12 months prior to the Phase 1/2 study and the kidney stone AE rate was 0.90/PY during the Phase 1/2 study. Conclusion In the longest follow-up reported to date, lumasiran treatment was well tolerated in patients with PH1 in the Phase 2 OLE. The most common treatment-related AEs were mild, transient ISRs; no severe or serious AEs were treatment related. Mean 24 h UOx reductions were sustained over more than 4.5 years of treatment. Mean eGFR was stable over time.

BackgroundPrimary hyperoxaluria type 1 (PH1) is a genetic disorder resulting in overproduction of hepatic oxalate, potentially leading to recurrent kidney stones, nephrocalcinosis, chronic kidney disease, and kidney failure. Lumasiran, the first RNA interference therapeutic approved for infants and young children, is a liver-directed treatment that reduces hepatic oxalate production. Lumasiran demonstrated sustained efficacy with an acceptable safety profile over 12 months in infants and young children (age <6 years) with PH1 in ILLUMINATE-B (clinicaltrials.gov: NCT03905694), an ongoing, Phase 3, multinational, open-label, single-arm study.MethodsHere, we report interim efficacy and safety findings from ILLUMINATE-B following 30 months of lumasiran treatment. Eligible patients had an estimated glomerular filtration rate (eGFR) >45 ml/min/1.73 m2 if ≥12 months old or normal serum creatinine if <12 months old, and a urinary oxalate to creatinine ratio (UOx:Cr) greater than the upper limit of normal. All 18 patients enrolled in ILLUMINATE-B completed the 6-month primary analysis period, entered an extension period of up to 54 months, and continue to participate in the study.ResultsAt Month 30, mean percent change from baseline in spot UOx:Cr was −76%, and mean percent change in plasma oxalate was −42%. eGFR remained stable through Month 30. In 14 patients (86%) with nephrocalcinosis at baseline, nephrocalcinosis grade improved at Month 24 in 12; no patient worsened. In the 4 patients without baseline nephrocalcinosis, nephrocalcinosis was absent at Month 24. Kidney stone event rates were ≤0.25 per person-year through Month 30. Mild, transient injection site reactions were the most common lumasiran-related adverse events (17% of patients).ConclusionIn infants and young children with PH1, long-term lumasiran treatment resulted in sustained reductions in urinary and plasma oxalate that were sustained for 30 months, with an acceptable safety profile. Kidney function remained stable, low kidney stone event rates were observed through Month 30, and nephrocalcinosis grade improvements were observed through Month 24. Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT03905694.

Background: Measurement of plasma oxalate (POx) is challenging, but critical, for management of patients with primary hyperoxaluria type 1. A novel LC-MS/MS assay was developed, validated and used to quantify POx in patients with primary hyperoxaluria type 1. Methods: Samples (100 μl of plasma in K2EDTA) were spiked with internal standard (13C2-labeled oxalic acid), acidified and cleaned by protein precipitation before analysis using anion HPLC-ESI-MS/MS. The assay was validated with a quantitation range of 0.500-50.0 μg/ml (5.55-555 μmol/l). All parameters successfully met acceptance criteria, including 15% (20% at lower limit of quantification) for accuracy and precision. Conclusion: This assay has advantages over previously published POx quantitation methods, was validated in accordance with regulatory guidelines and accurately determined POx levels in humans.

You have accessJournal of UrologyCME1 Apr 2023MP10-01 EFFICACY AND SAFETY OF LUMASIRAN IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1: 36-MONTH ANALYSIS OF THE ILLUMINATE-A TRIAL John Lieske, Jeffrey Saland, Jaap Groothoff, Yaacov Frishberg, Hadas Shasha-Lavsky, Daniella Magen, Shabbir Moochhala, Eva Simkova, Martin Coenen, Wesley Hayes, Julien Hogan, Anne-Laure Sellier-Leclerc, Yinggu Bao, John Gansner, and Sally-Anne Hulton John Lieske John Lieske More articles by this author , Jeffrey SalandJeffrey Saland More articles by this author , Jaap GroothoffJaap Groothoff More articles by this author , Yaacov FrishbergYaacov Frishberg More articles by this author , Hadas Shasha-LavskyHadas Shasha-Lavsky More articles by this author , Daniella MagenDaniella Magen More articles by this author , Shabbir MoochhalaShabbir Moochhala More articles by this author , Eva SimkovaEva Simkova More articles by this author , Martin CoenenMartin Coenen More articles by this author , Wesley HayesWesley Hayes More articles by this author , Julien HoganJulien Hogan More articles by this author , Anne-Laure Sellier-LeclercAnne-Laure Sellier-Leclerc More articles by this author , Yinggu BaoYinggu Bao More articles by this author , John GansnerJohn Gansner More articles by this author , and Sally-Anne HultonSally-Anne Hulton More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003225.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by hepatic oxalate overproduction leading to kidney stones and progressive kidney disease. Lumasiran is an RNAi therapeutic approved for the treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate levels in pediatric and adult patients. Here, we report data from the 36-month (M) analysis of ILLUMINATE-A, a Phase 3 trial of lumasiran (NCT03681184). METHODS: ILLUMINATE-A is an ongoing Phase 3 trial in patients age ≥6 years with genetically confirmed PH1 and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A 6M double-blind, placebo-controlled primary analysis period is followed by an extension period (up to 54M) in which all patients receive lumasiran. RESULTS: Of 39 patients enrolled, 24/26 in the lumasiran/lumasiran group and 13/13 in the placebo/lumasiran group entered and continue in the extension period. Mean 24-hour UOx reduction at M36 relative to baseline was 63% in the lumasiran/lumasiran group and 55% in the placebo/lumasiran group (M30 post–lumasiran initiation). At M36, the proportion of patients achieving 24-hour UOx excretion ≤1.5× upper limit of normal was 76% in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group. Mean baseline-to-M36 reductions in plasma oxalate were 36% and 37% in the lumasiran/lumasiran and placebo/lumasiran groups, respectively. In both groups, eGFR remained stable through M36. Kidney stone event rates decreased from 3.19/person-year during the 12M before consent to 0.70/person-year in the lumasiran/lumasiran group and from 0.54/person-year to 0.39/person-year in the placebo/lumasiran group. Medullary nephrocalcinosis generally remained stable or improved. The most common lumasiran-related adverse events were mild injection-site reactions (36% of patients). CONCLUSIONS: Long-term treatment with lumasiran led to sustained UOx reduction through M36, with an acceptable safety profile in patients with PH1 and encouraging clinical outcomes data. Source of Funding: Alnylam Pharmaceuticals © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e114 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Lieske More articles by this author Jeffrey Saland More articles by this author Jaap Groothoff More articles by this author Yaacov Frishberg More articles by this author Hadas Shasha-Lavsky More articles by this author Daniella Magen More articles by this author Shabbir Moochhala More articles by this author Eva Simkova More articles by this author Martin Coenen More articles by this author Wesley Hayes More articles by this author Julien Hogan More articles by this author Anne-Laure Sellier-Leclerc More articles by this author Yinggu Bao More articles by this author John Gansner More articles by this author Sally-Anne Hulton More articles by this author Expand All Advertisement PDF downloadLoading ...

Rationale & Objective: Lumasiran reduces uri-nary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease.Study Design: Phase 3, open-label, single-arm trial.Setting & Participants: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate <= 45 mL/min/1.73 m2 (if age >= 12 months) or increased serum creatinine level (if age <12 months), and POx >= 20 mu mol/ L at screening, including patients with or without systemic oxalosis.Intervention: Lumasiran administered subcuta-neously; 3 monthly doses followed by monthly or quarterly weight-based dosing.Outcome: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enroll-ment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); abso-lute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. Results: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient.Limitations: Single-arm study without placebo control.Conclusions: Lumasiran resulted in substantial reductions in POx with acceptable safety in pa-tients with PH1 who have advanced kidney dis-ease, supporting its efficacy and safety in this patient population.Funding: Alnylam Pharmaceuticals.Trial Registration: Registered at Clinical-Trials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17.

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disease in which hepatic oxalate overproduction can lead to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis, a condition in which calcium oxalate is deposited in various tissues, including bone [1]. Radiological signs of bone oxalosis include findings such as dense metaphyseal bands and coarse trabeculation [2]. No scale exists to grade bone oxalosis severity using X-rays. Method An X-ray grading scale to evaluate systemic oxalosis in specific bones was developed based on expert opinion. Scores on individual items ranged from 0–4, except for ribs and spine, which ranged from 0–2. Higher values represent more advanced oxalosis. To validate the scale, 85 X-ray images from 5 pediatric patients with PH1 who had developed bone oxalosis were collected from charts at Shaare Zedek Medical Center and de-identified [2]. Two blinded, independent raters evaluated each X-ray twice and assigned a grade to each applicable item on the scale. Inter-rater and intra-rater reliability analyses were conducted using the weighted Cohen's kappa with asymptotic 95% confidence intervals (CIs) of the estimate and interpreted as proposed in the literature [3]. Total weighted kappa estimates were generated by pooling all observed ratings across all items. Results Total overall inter-rater (0.83 [95% CI: 0.79, 0.87]) and intra-rater (0.95 [0.93, 0.97]) kappa estimates demonstrated almost perfect agreement. Overall inter-rater kappa estimates were >0.8 to 1.0 (almost perfect agreement) for the left hand/wrist, left hip, left knee (femur), and left humerus; >0.6 to 0.8 (substantial agreement) for the right hip, right knee (tibia), right humerus, spine, and ribs; and >0.4 to 0.6 (moderate agreement) for the right knee (femur) and right knee (fibula). The overall inter-rater kappa estimate for the left knee (fibula) demonstrated poor agreement (−0.08 [−0.27, 0.10]). Overall inter-rater kappa estimates for the right hand/wrist and left knee (tibia) were considered unreliable due to lack of variability in the data, and the standard errors were not estimable. Calculable overall intra-rater kappa estimates were >0.8 to 1.0 (almost perfect agreement) for the spine and >0.6 to 0.8 (substantial agreement) for the right knee (femur) and right knee (fibula). Most other overall intra-rater kappa estimates could not be calculated because the kappas for one or both raters lacked variability. In these instances, intra-rater kappa estimates for the first and second raters demonstrated moderate to almost perfect agreement (>0.4 to 1.0; left hand/wrist, right hip, left hip, left knee [femur], right knee [tibia], left knee [tibia], right humerus, left humerus, and ribs). For the left knee (fibula), intra-rater kappa estimates for the first and second raters were −0.14 (−0.34, 0.05) and 1.00, respectively, and for the right hand/wrist, they were 1.00 and 0.00. Conclusion We developed a novel X-ray–based bone oxalosis grading scale for patients with PH1. Total overall weighted kappa estimates for inter-rater and intra-rater reliability demonstrated almost perfect strength of agreement. Most individual items demonstrated reliable kappa estimates. The right and left knee (fibula) were removed from the scale due to poor reliability.

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018–004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here. Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7–20.5) months). Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)). Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic oxalate overproduction that leads to progressive kidney disease. As kidney function declines, oxalate elimination is compromised and plasma oxalate (POx) increases, leading to systemic oxalosis. Lumasiran, an RNA interference therapeutic designed to reduce hepatic oxalate production, is indicated for the treatment of PH1 in all age groups. We describe lumasiran pharmacokinetics (PK) and pharmacodynamics (PD) in patients with PH1 from four clinical studies. METHOD Data from a Phase 1/2 study and three Phase 3 studies of lumasiran (ILLUMINATE-A, B and C) were included in the PK analyses, and data from the ILLUMINATE studies were included in the PD analyses. The studies included patients of all ages with the full spectrum of kidney function, from normal kidney function to patients with severely impaired kidney function or on hemodialysis (HD). Patients received weight-based dosing of subcutaneous lumasiran. PD parameters of efficacy included spot urinary oxalate: creatinine (UOx: Cr) and POx. Target engagement was evaluated using plasma glycolate. RESULTS A total of 90 patients were included, 15 of whom were on HD. Median (range) age was 11 (2‒60) years, median (range) body weight was 34 (5‒121) kg, and median (range) eGFR in patients not on HD was 85 (9‒174) mL/min/1.73 m2. In patients with normal to moderately impaired kidney function, on Day 1, the recommended dose regimen for lumasiran led to comparable plasma concentration and exposure across body weight categories. Median Cmax (ng/mL) was 890, 912, and 446 in the < 10, 10 to < 20, and ≥20 kg weight categories, respectively. Median AUC0-last (h*ng/mL) was 6270, 8110, and 6210 in the same weight categories. Patients weighing <20 kg exhibited faster plasma clearance, consistent with allometric principles. In patients with severely impaired kidney function or on HD, on Day 1, plasma concentrations of lumasiran were slightly increased compared to patients with normal to moderately impaired kidney function. Median Cmax (ng/mL) was 3190, 2670, and 811 in the < 10, 10 to < 20, and ≥20 kg weight categories, respectively. Median AUC0-last (h*ng/mL) was 16 200, 24 800, and 10 100 in the same weight categories. At 24 h postdose, many patients had lumasiran plasma concentrations below the lower limit of quantitation, indicating rapid liver uptake, regardless of kidney function. Mean % reduction in spot UOx: Cr at Month 6 ranged from 44.1 to 71.7% across studies. Mean % reduction in POx at Month 6 ranged from 20.3 to 40.3% across studies. The time course and persistence of reduction in spot UOx: Cr and POx were similar across the studies. Plasma glycolate levels showed an approximately 2-fold elevation at Month 6, consistent with the mechanism of action of lumasiran, suggesting comparable liver exposure and target engagement across studies. CONCLUSION The recommended weight-based dosing regimens of lumasiran achieved comparable target engagement and efficacy for patients of all ages and degrees of kidney function, including patients on HD.