Long-Term Safety Evaluation of NTLA-2001 in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy and Transthyretin Amyloidosis-Related Cardiomyopathy

The primary objective of this study is to evaluate the long-term **safety** of NTLA-2001 in participants who have been previously treated. This is clinically relevant as NTLA-2001 is an advanced gene therapy product targeting **Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)** and **Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)**, conditions that can significantly impact patient quality of life and prognosis. Ensuring the long-term safety of NTLA-2001 is crucial for its potential therapeutic use in these populations.

Secondary objectives include evaluating the long-term pharmacodynamic effects of NTLA-2001 in previously treated participants. Understanding these effects is important for assessing the sustained impact of the therapy on disease progression and patient outcomes.

The clinical trial involves a total of **63 participants** who have been previously treated for **Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)** and **Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)**. The study population includes both male and female subjects, with age categories spanning from adults to older adults. Participants were selected based on their completion or discontinuation from a prior Intellia-sponsored clinical study involving NTLA-2001. The trial includes a vulnerable population, indicating that special considerations are in place for their protection. Participants are expected to adhere to specific lifestyle considerations, such as the use of effective contraceptive methods for a defined period post-study intervention. The selection criteria ensure that participants are capable of attending study visits and complying with follow-up schedules, thereby facilitating the evaluation of the long-term safety of NTLA-2001.

The clinical trial is designed to evaluate the long-term safety of **NTLA-2001** in participants previously treated with this investigational product. The study targets individuals with **Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)** and **Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)**. This trial is a long-term follow-up study, categorized as a Category 2 trial, and is not considered low intervention. The trial is expected to conclude by August 23, 2038, with recruitment having commenced on July 10, 2023.

The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. Participants will be involved in the study for a maximum treatment period of one year, with the possibility of early termination if they fail to comply with study requirements or experience significant adverse events. The study includes several key visits: an inclusion (screening) visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess long-term outcomes.

Inclusion criteria require participants to have completed or discontinued from a previous Intellia-sponsored study involving NTLA-2001, provided informed consent, and agreed to comply with study protocols. Male participants must refrain from sperm donation and use contraception for four months post-treatment, while female participants must use contraception and avoid oocyte retrieval for seven months. The primary endpoints focus on the incidence of treatment-related serious adverse events (SAEs) and protocol-specified adverse events of special interest (AESIs). Secondary endpoints include the evaluation of pharmacodynamic biomarkers such as serum transthyretin (TTR) and serum prealbumin over time.

The clinical trial involves the administration of **NTLA-2001**, an advanced therapy investigational medicinal product (IMP) classified as gene therapy. NTLA-2001 is formulated as a **dispersion for infusion** and is administered via **intravenous use**. The active substances in NTLA-2001 include **ziclumeran** and a **single guide RNA targeting the human TTR gene**. Ziclumeran is a nucleic acid, specifically a messenger RNA encoding Cas9, while the single guide RNA is designed to target the human transthyretin (TTR) gene. The maximum daily and total dose of NTLA-2001 is 1 mg/kg, with a maximum treatment period of one day. The product is not a pediatric formulation and has been designated as an orphan drug under the designation number EU/3/21/2419.

In this study, NTLA-2001 is the primary experimental treatment, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial's main objective is to evaluate the long-term safety of NTLA-2001 in participants who have been previously treated. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial is conducted by Intellia Therapeutics Inc, and the product is authorized for use in this clinical setting.

Efficacy in the clinical trial of NTLA-2001 will be assessed through the evaluation of primary and secondary endpoints. The primary endpoints focus on the incidence of treatment-related serious adverse events (SAEs) and protocol-specified adverse events of special interest (AESIs) in participants with **ATTR-CM** and **ATTRv-PN**. Secondary endpoints include the measurement of pharmacodynamic (PD) biomarkers for ATTR over time, specifically serum transthyretin (TTR) and serum prealbumin levels. These biomarkers will be monitored to assess the therapeutic impact of NTLA-2001 on the disease process.