Long-Term Safety and Efficacy Evaluation of Donidalorsen in Hereditary Angioedema Prophylaxis: An Open-Label Study

The primary objective of this study is to evaluate the **safety** of long-term dosing with donidalorsen in patients with **Hereditary Angioedema** (HAE). This is clinically relevant as ensuring the safety of prolonged treatment is crucial for the management of chronic conditions like HAE, where ongoing prophylactic treatment is necessary to prevent attacks.

Secondary objectives include:

• Evaluating the long-term efficacy of donidalorsen in reducing the number of HAE attacks.
• Assessing the impact of donidalorsen on the quality of life (QoL) of patients with HAE.

The clinical trial involves participants diagnosed with **Hereditary Angioedema** (HAE), specifically types HAE-1 and HAE-2. The study population includes both male and female subjects aged 12 years and older. Participants are required to have a stable dose of prophylaxis treatment with lanadelumab, berotralstat, or C1-esterase inhibitor for at least 12 weeks prior to the screening period. The trial population was selected based on their satisfactory completion of a previous study or their ability to exit the study per protocol with an acceptable safety and tolerability profile. The sponsor has not provided the total number of participants. The study includes a vulnerable population, and participants must have access to acute medications to manage angioedema attacks. The trial aims to evaluate the safety of long-term dosing with donidalorsen in patients with HAE.

The clinical trial is designed to evaluate the long-term safety and efficacy of **donidalorsen** in the prophylactic treatment of **Hereditary Angioedema** (HAE). This study is an open-label, long-term investigation, focusing on the safety of extended dosing with donidalorsen. The trial is structured as a Phase 3 study, which is not categorized as low intervention. The trial is expected to run from November 15, 2022, to November 6, 2026, with a total duration of approximately four years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age (≥ 12 years), documented diagnosis of HAE-1/HAE-2, and stable prophylaxis treatment. The trial will include follow-up visits to monitor the incidence and severity of treatment-emergent adverse events (TEAEs) and to assess secondary endpoints, such as the time-normalized number of HAE attacks and the percentage of attack-free patients over a 53-week period. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected.

Participants are expected to be involved in the study for a maximum treatment period of 157 weeks. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or failure to adhere to the study protocol. The investigational product, ISIS 721744, is administered via subcutaneous injection, with a maximum daily dose of 80 mg and a total dose not exceeding 960 mg. The study aims to provide comprehensive data on the long-term use of donidalorsen, contributing to the understanding of its safety profile in managing hereditary angioedema.

The clinical trial involves the administration of the experimental medication **ISIS 721744**, which contains the active substance **donidalorsen**. This medication is formulated as an **injection** and is classified as an **antisense oligonucleotide**. The pharmaceutical form is specifically designed for **subcutaneous** administration. The dosing regimen for this trial specifies a maximum daily dose of 80 mg, with a cumulative maximum total dose of 960 mg over the treatment period. The maximum treatment duration is set at 157 days. The medication is delivered using a prefilled injector, although it does not possess a CE mark. The active substance, donidalorsen, is derived from **nucleic acid** and is developed by Ionis Pharmaceuticals, Inc.

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 long-term dosing with donidalorsen in patients diagnosed with **hereditary angioedema** (HAE). Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial evaluating **Donidalorsen** for the prophylactic treatment of Hereditary Angioedema (HAE) will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the incidence and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints include several measures: the time-normalized number of Investigator-confirmed HAE attacks per month from Week 1 to Week 53, the time-normalized number of such attacks from Week 5 to Week 53, and the percentage of patients who remain free from HAE attacks from Week 5 to Week 53. Additionally, the trial will assess the time-normalized number of moderate or severe HAE attacks per month from Week 5 to Week 53, the number of HAE attacks requiring acute therapy from Week 5 to Week 53, and the Angioedema Quality of Life (AE-QoL) questionnaire total score over 53 weeks.

These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, which extends up to 53 weeks. The use of validated scales and questionnaires, such as the AE-QoL, will ensure the reliability and accuracy of patient-reported outcomes. The trial is designed to provide comprehensive data on the long-term efficacy of Donidalorsen in reducing the frequency and severity of HAE attacks, as well as its impact on patients' quality of life.