Evaluation of Long-Term Safety and Efficacy of Nedosiran in Patients with Primary Hyperoxaluria: An Open-Label Roll-Over Study

The primary objective of this study is to evaluate the effect of **DCR-PHXC** on the estimated glomerular filtration rate (**eGFR**) in participants with **Primary Hyperoxaluria** type 1 (**PH1**). This is clinically relevant as eGFR is a critical measure of kidney function, and improving or maintaining eGFR can significantly impact the management and prognosis of patients with PH1.

Secondary objectives include:

• Evaluating the safety and tolerability of DCR-PHXC when administered monthly to patients with PH.
• Identifying the proportion of participants with normalized or near-normalized 24-hour urinary oxalate (Uox).
• Identifying the percentage of participants with a spot urinary oxalate-to-creatinine ratio ≤ the upper limit of normal (ULN) and ≤ 1.5 x ULN.
• Assessing the effect of DCR-PHXC on stone events and stone burden, as well as nephrocalcinosis grade in patients with PH.
• Evaluating the incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in participants with PH.
• Evaluating the effect of DCR-PHXC on quality of life (QoL) assessments in patients with PH.
• Assessing the efficacy of DCR-PHXC in reducing Uox burden in patients with PH, including long-term efficacy.
• Exploratory: Evaluating the effect of DCR-PHXC on eGFR in participants with PH2 and PH3.

The clinical trial involves a total of **46 participants** diagnosed with **Primary Hyperoxaluria**. The study population includes both male and female subjects, with an age range starting from birth. Participants were selected based on a documented diagnosis of Primary Hyperoxaluria, confirmed by genotyping. The trial includes individuals who have successfully completed a previous study of DCR-PHXC or are siblings of such participants. The study population is characterized by a vulnerable group, including pediatric subjects. Key lifestyle considerations such as diet and physical activity are not specified. The trial does not provide specific information on the general health status of participants beyond the inclusion criteria related to estimated glomerular filtration rate and body weight for pediatric siblings. The selection criteria ensure that participants are capable of providing informed consent, with additional provisions for minors and their guardians. The trial does not specify any exclusion criteria beyond those related to the diagnosis and previous study participation.

The clinical trial is designed to evaluate the long-term safety and efficacy of **nedosiran** in patients with **Primary Hyperoxaluria**. This is an open-label, roll-over study, which means that participants who have previously completed a related study of DCR-PHXC or are siblings of such participants are eligible to enroll. The trial is structured to assess the effect of DCR-PHXC on the estimated glomerular filtration rate (eGFR) in participants with PH1. The study is expected to run until March 28, 2031, with recruitment having started on February 1, 2019.

Participants will be involved in the study for a maximum treatment period of 72 months. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The screening visit will involve genotyping to confirm a diagnosis of Primary Hyperoxaluria and other assessments such as eGFR and urinary oxalate levels. Follow-up visits will include evaluations of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and changes in clinical laboratory tests, vital signs, and physical examination findings.

Participants are expected to adhere to the study protocol, including the use of contraception for those of childbearing potential, and compliance with scheduled visits and assessments. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events that compromise participant safety, or withdrawal of consent. The primary endpoint of the study is the annual rate of decline in eGFR in participants with PH1, while secondary endpoints include the incidence and severity of TEAEs and SAEs, changes in ECG, and other clinical parameters.

The clinical trial involves the administration of the experimental medication **Nedosiran**, which is a **solution for injection**. This investigational product is developed by Novo Nordisk A/S and is specifically designed for subcutaneous use. Nedosiran is a synthetic double-stranded RNA oligonucleotide conjugated to a GalNAc aminosugar residue, originating from nucleic acid. The maximum daily dose of Nedosiran is 170 mg, with a total maximum dose of 12,960 mg over the course of the study. The treatment period is set to a maximum of 72 weeks. The primary objective of the trial is to evaluate the effect of Nedosiran on the estimated glomerular filtration rate (eGFR) in participants diagnosed with Primary Hyperoxaluria Type 1 (PH1).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of Nedosiran to assess its long-term safety and efficacy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted as an open-label roll-over study, allowing for the continuous evaluation of the investigational product's impact on the targeted patient population.

Efficacy in this clinical trial will be assessed primarily through the evaluation of the annual rate of decline in **estimated glomerular filtration rate (eGFR)** in participants with Primary Hyperoxaluria Type 1 (PH1). This primary endpoint will provide insight into the long-term impact of the investigational product, DCR-PHXC, on kidney function. Secondary endpoints will include the incidence and severity of treatment-emergent adverse events (TEAE) and serious adverse events (SAE), as well as changes from baseline in 12-lead ECG, physical examination findings, vital signs, and clinical laboratory tests. Additionally, the trial will assess the proportion of participants achieving specific 24-hour urinary oxalate (Uox) levels and changes in the urinary oxalate-to-creatinine ratio at various time points throughout the study.

Further efficacy assessments will involve evaluating changes from baseline in the number of stone events and stone burden, as well as nephrocalcinosis grade over a 12-month period and annually in subsequent years. The trial will also monitor the number of participants with severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), and changes in quality of life measures using the SF-36 and EQ-5D-5L in adults, and the PedsQL in children. The area under the curve (AUC) of 24-hour Uox from Day 90 to Day 180, based on percent change from baseline, will be assessed in specific participant subgroups. These efficacy parameters will be measured and analyzed at designated assessment time points throughout the study to comprehensively evaluate the therapeutic impact of DCR-PHXC on patients with PH1, PH2, and PH3.