Evaluation of the Safety and Efficacy of Nedosiran in Patients with Primary Hyperoxaluria Type 1 and Severe Renal Impairment, Including Dialysis

The primary objective of this study is to evaluate the **efficacy** of DCR-PHXC in reducing plasma oxalate (Pox) levels in participants with Primary Hyperoxaluria Type 1 (PH1) and severe renal impairment, with or without the need for hemodialysis or peritoneal dialysis. This is clinically relevant as elevated Pox levels are a hallmark of PH1, leading to systemic oxalosis and significant renal damage, thus reducing Pox can potentially mitigate disease progression and improve patient outcomes.

Secondary objectives include:

• Assessing the efficacy of DCR-PHXC in lowering Pox in participants with PH1 and severe renal impairment, with or without dialysis.
• Characterizing the safety profile of DCR-PHXC in this patient population.
• Evaluating the pharmacokinetics (PK) of multiple doses of DCR-PHXC.
• Assessing the impact of DCR-PHXC on the dialysis regimen of participants undergoing hemodialysis or peritoneal dialysis.
• Evaluating the effect of DCR-PHXC on stone burden and nephrocalcinosis score.
• Assessing the effect of DCR-PHXC on cardiac oxalosis.

The clinical trial involves a total of **18 participants** diagnosed with **Primary Hyperoxaluria** type 1 (PH1) and severe renal impairment. The study population includes both male and female subjects, spanning four distinct age groups: adults and adolescents aged 12 years and older, children aged 6 to 11 years, children aged 2 to 5 years, and infants and newborns from birth to less than 2 years of age. Participants were selected based on specific criteria, including a documented diagnosis of PH1 confirmed by genotyping and an estimated glomerular filtration rate (GFR) at screening of less than 30 mL/min normalized to 1.73 m² body surface area. The trial also considers lifestyle factors such as the stability of hemodialysis or peritoneal dialysis regimens, which must have been stable for at least two weeks prior to screening. The study population is characterized by its inclusion of a vulnerable population, with participants required to be affiliated with or beneficiaries of a health insurance system, where applicable. The trial does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is designed to evaluate the **efficacy** and safety of **nedosiran** in patients with **Primary Hyperoxaluria** Type 1 and severe renal impairment, with or without dialysis. This is a Phase 2, open-label study, which means that both the researchers and participants know which treatment is being administered. The trial is expected to run from February 2021 to January 2026, with the primary objective being the assessment of the reduction in plasma oxalate levels from baseline to Day 180. Secondary endpoints include changes in dialysis regimen, stone burden, nephrocalcinosis score, and cardiac oxalosis.

Participants will be enrolled across four age groups: adults and adolescents (aged 12 years and older), children aged 6 to 11 years, children aged 2 to 5 years, and infants and newborns from birth to less than 2 years. The inclusion criteria require a documented diagnosis of Primary Hyperoxaluria Type 1 confirmed by genotyping, an estimated glomerular filtration rate (GFR) at screening of less than 30 mL/min/1.73 m², and specific plasma oxalate levels. Participants receiving dialysis must have a stable regimen for at least two weeks prior to screening.

The study involves several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The expected length of participant involvement is up to 60 days, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The investigational product, nedosiran, is administered as a subcutaneous injection, with a maximum daily dose of 170 mg. The trial is not categorized as low intervention, and it is not a pediatric formulation. The study is sponsored by Novo Nordisk A/S, and the investigational product is classified as an orphan drug, indicating its use in treating a rare disease.

The clinical trial involves the administration of **Nedosiran**, an experimental medication developed by Novo Nordisk A/S. Nedosiran is formulated as a **solution for injection** and is administered via the **subcutaneous route**. The active substance is a synthetic double-stranded RNA oligonucleotide conjugated to N-acetyl-D-galactosamine (GalNAc), which is derived from nucleic acid. The maximum daily dose of Nedosiran is 170 mg, with a total maximum dose of 170 mg over the treatment period. The treatment duration is set for a maximum of 60 days. This medication is not a pediatric formulation and has been designated as an orphan drug under the designation number EU/3/18/2052.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety and efficacy of Nedosiran in patients with Primary Hyperoxaluria Type 1 and severe renal impairment, with or without dialysis. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of DCR-PHXC in patients with Primary Hyperoxaluria Type 1 (PH1) and severe renal impairment will be assessed through several key endpoints. The primary endpoint is the absolute and percent change in plasma oxalate (**Pox**) levels from Baseline to Day 180. Secondary endpoints include the absolute and percent change in Pox from Baseline to the maximum reduction through Day 180, changes in the hemodialysis or peritoneal dialysis regimen, changes in stone burden as identified via ultrasound from Baseline to Day 180, changes in nephrocalcinosis score, and changes in cardiac oxalosis.

Measurements of Pox levels will be conducted at specified timepoints, with the primary focus on the change from Baseline to Day 180. The study will utilize validated laboratory tests to ensure accurate and reliable data collection. The analysis will involve comparing the baseline values to those obtained at subsequent timepoints to determine the efficacy of the treatment. The study is designed to provide comprehensive data on the impact of DCR-PHXC on Pox levels and related clinical parameters in the target patient population.