Long-Term Safety Evaluation of NTLA-2002 in Patients with Hereditary Angioedema: A Follow-Up Study on Ziclumeran and Lonvoguran

The primary objective of this study is to evaluate the long-term **safety** of NTLA-2002 in subjects previously treated for **Hereditary Angioedema**. This is clinically relevant as it aims to ensure that the therapeutic intervention remains safe over an extended period, which is crucial for chronic conditions requiring ongoing management.

Secondary objectives include:

• Evaluating the long-term efficacy of NTLA-2002 in previously treated subjects, which is important for understanding the sustained therapeutic benefits of the treatment.
• Assessing disease-related outcomes in these subjects to determine the impact of NTLA-2002 on the progression or stabilization of Hereditary Angioedema.
• Evaluating patient-reported outcomes to gain insights into the subjective experiences and quality of life of patients undergoing treatment with NTLA-2002.

The clinical trial involves a total of **13 participants** diagnosed with **Hereditary Angioedema**. The study population includes both male and female subjects, with an age range encompassing adults and adolescents. Participants were selected based on their prior involvement in an Intellia-sponsored or -supported treatment protocol where they received a complete or partial dose of NTLA-2002. The trial aims to evaluate the long-term safety of NTLA-2002 in these previously treated subjects. The study population includes a vulnerable group, indicating special considerations in the trial design. Participants are required to have provided informed consent and demonstrate willingness to attend study visits and comply with the follow-up schedule. The trial does not specify particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the long-term safety of **NTLA-2002** in subjects previously treated for **Hereditary Angioedema**. This study is a follow-up to prior treatment protocols and is structured as a non-randomized, open-label trial. The trial will span approximately 15 years, with an estimated end date in February 2038. Participants are required to have completed or discontinued from a prior Intellia-sponsored or supported treatment protocol involving NTLA-2002 and must provide informed consent to participate in this long-term follow-up (LTFU) study.

Study visits are sequenced to ensure comprehensive monitoring and data collection. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on the completion of prior treatment and consent. Follow-up visits will occur at regular intervals to assess the incidence of treatment-related adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). Secondary endpoints include the rate of **Hereditary Angioedema** attacks, changes in plasma kallikrein protein levels, and quality of life (QoL) assessments using validated instruments such as the MOXIE Angioedema QoL instrument, EQ-5D-5L, and WPAI:GH. The end-of-study visit will conclude the participant's involvement, summarizing the long-term safety data collected.

Participant involvement is expected to last until the study's conclusion in 2038, unless early termination is warranted. Conditions for early termination include withdrawal of consent, non-compliance with study requirements, or any safety concerns that may arise during the trial. The study aims to provide valuable insights into the long-term safety profile of NTLA-2002, contributing to the understanding of its effects in managing **Hereditary Angioedema**.

The clinical trial involves the administration of **NTLA-2002**, an experimental medication developed by Intellia Therapeutics Inc. **NTLA-2002** is formulated as a **dispersion for infusion** and is administered via the **intravenous route**. The active substances in NTLA-2002 are **ziclumeran** and **lonvoguran**, both of which are nucleic acids. Ziclumeran is a messenger RNA encoding the Cas9 protein, also known as mRNA000042. Lonvoguran is a single guide RNA targeting the human kallikrein B1 gene (KLKB1), also referred to as hu-G012267. The medication is designed as a chemical advanced therapy investigational medicinal product (IMP) and is not classified as a pediatric formulation or an orphan drug. The trial aims to evaluate the long-term safety of NTLA-2002 in subjects who have been previously treated with this therapy.

In this study, NTLA-2002 is delivered in the form of lipid nanoparticles containing the two active ingredients: a human KLKB1 gene-specific single guide RNA (sgRNA) and a codon-optimized mRNA encoding for the Cas9 protein. The administration schedule, dosage, and frequency are determined based on the study protocol, although specific dosing details are not provided in the available data. Participant compliance with the treatment regimen is monitored throughout the trial to ensure adherence to the prescribed dosing schedule.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the provided data. The focus of the trial is solely on the long-term follow-up of subjects treated with NTLA-2002, assessing its safety profile over an extended period. The trial does not involve any genetically modified organisms (GMOs) and is conducted in vivo, emphasizing the direct application of the therapy in human subjects.

Efficacy in the clinical trial of NTLA-2002 will be assessed using both primary and secondary endpoints. The primary endpoints focus on the safety profile of the treatment, specifically the incidence of treatment-related adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) as defined by the protocol. These safety-related endpoints are crucial for evaluating the long-term safety of NTLA-2002 in subjects who have previously received the treatment.

The secondary endpoints are designed to measure the therapeutic efficacy of NTLA-2002 in managing **Hereditary Angioedema (HAE)**. These include the overall rate of HAE attacks and the rate of attacks requiring acute therapy. Additionally, the trial will assess changes from baseline in total plasma kallikrein protein levels, consumption of on-demand HAE medications, and healthcare utilization for HAE attacks. Quality of life (QoL) parameters will also be evaluated using validated instruments such as the MOXIE Angioedema QoL instrument, EQ-5D-5L, and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH).