Evaluation of Long-term Safety and Tolerability of Inclisiran in Patients with Heterozygous or Homozygous Familial Hypercholesterolemia Post-ORION-16/13 Studies

The primary objective of this study is to evaluate the long-term **safety** and **tolerability** of inclisiran in participants with heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH). This is clinically relevant as it aims to ensure that inclisiran, a treatment for familial hypercholesterolemia, can be safely administered over an extended period, providing a sustainable therapeutic option for managing this genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels.

Secondary objectives include:

• To evaluate the long-term effect of inclisiran treatment on **LDL-C** levels. This is important for understanding the efficacy of inclisiran in maintaining reduced LDL-C levels over time, which is crucial for reducing cardiovascular risk in patients with familial hypercholesterolemia.

The clinical trial involves a total of **75 participants** diagnosed with **familial hypercholesterolemia** (HeFH or HoFH). The study population includes both male and female subjects who have previously completed the ORION-16 or ORION-13 studies. Participants are required to have derived benefit from treatment with inclisiran in these prior studies, as per the investigator's clinical judgment. The age range of the participants spans from young adults to older adults, as indicated by the age range categories provided. The trial population was selected based on their completion of the previous studies and their ongoing use of lipid-lowering therapies, such as statins and/or ezetimibe, without any planned changes in medication or dosage during the study. The study also includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the long-term safety and tolerability of **inclisiran** in participants with heterozygous or homozygous familial hypercholesterolemia who have completed the adolescent ORION-16 or ORION-13 studies. This is an open-label, single-arm, multicenter extension study. The trial is expected to commence on February 6, 2023, and conclude by February 7, 2028, with a total duration of approximately five years. Participants will be involved in the study for a maximum treatment period of 36 months.

Participants eligible for inclusion are those who have completed the ORION-16 or ORION-13 studies, have derived benefit from treatment with inclisiran, and are continuing their current lipid-lowering therapies without planned changes. The primary endpoint focuses on treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), including their incidence, severity, and relationship to the study drug. Secondary endpoints include the percentage and absolute change in LDL-C from baseline in the feeder study to the end of the study.

The study involves a sequence of visits, starting with a screening visit to confirm eligibility based on the inclusion criteria. Follow-up visits will be scheduled periodically to monitor safety, tolerability, and efficacy parameters. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment. Participants may be terminated early from the study if they experience significant adverse events or if the investigator deems it necessary for their safety.

Throughout the trial, inclisiran will be administered via subcutaneous injection, with a maximum daily dose of 300 mg and a total dose not exceeding 1800 mg. The study will not include any pediatric formulations, and the drug is of chemical origin. The trial is categorized as a Phase 3 study, focusing on the long-term implications of inclisiran treatment in the specified patient population.

The clinical trial involves the administration of **INCLISIRAN**, an experimental medication, to evaluate its long-term safety and tolerability in participants with heterozygous or homozygous familial hypercholesterolemia. **INCLISIRAN** is provided as a **solution for injection** and is administered via **subcutaneous use**. The maximum daily dose is 300 mg, with a total maximum dose of 1800 mg over the treatment period. The treatment duration is set for a maximum of 36 months. **INCLISIRAN** is a nucleic acid-based therapeutic agent, specifically designed to lower cholesterol levels by inhibiting the production of PCSK9, a protein that regulates cholesterol levels in the blood. The drug is not a paediatric formulation and is of chemical origin. The clinical dossier includes alternative packaging sites for clinical trial supplies, and the drug substance has a retest period of 36 months, with a similar shelf life for the drug product.

In addition to the experimental treatment, the study includes a non-experimental treatment categorized under the ATC code C10AA, which corresponds to **HMG CoA reductase inhibitors**. This treatment is administered orally and serves as a comparator or standard-of-care therapy. The pharmaceutical form is denoted as PHF00245MIG, and it is also of chemical origin. The maximum treatment period for this non-experimental therapy is 36 months, aligning with the duration of the experimental treatment. The study does not specify a maximum daily or total dose for this comparator treatment, indicating its role as a background therapy rather than a primary focus of the trial.

The efficacy of inclisiran in the clinical trial will be assessed using specific endpoints. The primary endpoints include the evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), focusing on their incidence, severity, relationship to the study drug, and any discontinuation due to TEAEs. Additionally, vital signs, growth, and laboratory parameters will be monitored. Secondary endpoints will measure the percentage change and absolute change in low-density lipoprotein cholesterol (LDL-C) from baseline in the feeder study to the end of the study (EoS). These parameters will be collected and analyzed to determine the efficacy of inclisiran in participants with heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH) who have completed the ORION-16 or ORION-13 studies.