Evaluation of NTLA-2001 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Hereditary Transthyretin Amyloidosis with Polyneuropathy

Trial ID: 2024-511170-69-00
Protocol: ITL-2001-CL-001
Sponsor: Intellia Therapeutics Inc.

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Diseases & Conditions

Hereditary neuropathic amyloidosis

Objectives

The primary objective of this study is to evaluate the **safety**, **tolerability**, **pharmacokinetics** (PK), and **pharmacodynamics** (PD) of NTLA-2001 in patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN). This is crucial for determining the therapeutic potential and risk profile of NTLA-2001, a CRISPR/Cas9-based genome editing therapeutic, in this patient population. Additionally, the study aims to assess the safety, tolerability, PK, and PD of a 55 mg dose of NTLA-2001 in subjects who have previously received a 0.1 mg/kg dose, providing insights into the effects of different dosing regimens.

Secondary objectives include:

Evaluating the effect of NTLA-2001 on clinical measures of neurologic function in subjects with ATTRv-PN during both Part 1 and Part 2 of the study.
Assessing the impact of a 55 mg dose of NTLA-2001 on neurologic function in subjects who previously received a 0.1 mg/kg dose, as part of a follow-on dosing sub-study.

These secondary objectives are intended to further elucidate the clinical efficacy of NTLA-2001 in improving neurologic outcomes in this patient group.

Participants

The clinical trial involves a total of **57 participants** diagnosed with **Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)**. The study population includes both male and female subjects, aged between 18 to 80 years. Participants were selected based on specific inclusion criteria, including a documented TTR mutation and a clinical diagnosis of sensorimotor peripheral neuropathy. The general health status of participants requires them to have a body weight of at least 45 kg and meet certain laboratory criteria, such as normal liver function tests and an estimated glomerular filtration rate above 45 mL/min/1.73m². Lifestyle considerations include a limitation on alcohol consumption to one drink per day during the screening period and for 28 days post-treatment. The trial does not involve a vulnerable population, and participants must lack access to approved treatments for ATTRv-PN or show progression of symptoms despite existing treatments. The selection process ensures a representative sample of the target population, focusing on those who meet the outlined health and lifestyle criteria.

Plans and Procedures

The clinical trial is a **Phase 1** study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001 in patients with **Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)**. The trial is structured in two parts: an open-label, single ascending dose (Part 1) and an open-label, single dose expansion (Part 2). The study is not categorized as low intervention and involves a gene therapy medicinal product of biological/biotechnological origin. The trial is expected to run from November 2020 to April 2026, with participant involvement potentially lasting up to the maximum treatment period of one day, given the single-dose nature of the study.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis, and laboratory values. The screening will ensure that subjects have a documented TTR mutation and meet other clinical criteria. Following the screening, eligible participants will receive the investigational product, NTLA-2001, administered as a **dispersion for infusion**. The primary endpoints include safety assessments, immunogenicity assessments, and pharmacokinetic and pharmacodynamic assessments, while secondary endpoints focus on polyneuropathy assessments.

Follow-up visits will be scheduled to monitor the participants' response to the treatment and to collect data on the primary and secondary endpoints. The end-of-study visit will conclude the trial for each participant, ensuring all necessary data is collected and any adverse events are addressed. Participants may be withdrawn from the study early if they experience significant adverse effects or if they do not comply with the study protocol. The trial aims to provide valuable insights into the potential therapeutic benefits and safety profile of NTLA-2001 for patients with ATTRv-PN.

Treatment

The clinical trial involves the administration of **NTLA-2001**, an experimental medication designed for the treatment of **Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)**. NTLA-2001 is a **CRISPR/Cas9-based genome editing therapeutic** that is administered as a **dispersion for infusion**. The pharmaceutical form is a solution intended for infusion, and the medication is delivered intravenously. The maximum daily and total dose is 55 mg, administered as a single dose. The treatment period is limited to one day. NTLA-2001 is a product of biological/biotechnological origin, classified as an Advanced Therapy Investigational Medicinal Product (ATIMP) and a gene therapy medicinal product. The active substances in NTLA-2001 include **ziclumeran**, a messenger RNA encoding the Cas9 protein, and a single guide RNA targeting the human TTR gene. These components are delivered in a multi-component lipid system.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies as deemed necessary by the clinical investigators. However, no specific non-experimental treatments, such as placebo or comparator treatments, are explicitly mentioned in the trial documentation. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial is structured in two parts: an open-label, single ascending dose phase, and an open-label, single dose expansion phase, with the primary objective of evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001 in the target patient population.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include safety assessments, immunogenicity assessments, pharmacokinetic assessments, and pharmacodynamic assessments. These parameters will be measured to evaluate the therapeutic effects of NTLA-2001 in patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN). Secondary endpoints focus on **polyneuropathy** assessments, which will provide additional insights into the treatment's impact on the disease's progression.

The trial is structured in two parts: an open-label, single ascending dose (Part 1) and an open-label, single dose expansion (Part 2). The efficacy parameters will be collected and analyzed at various timepoints throughout the study to ensure comprehensive evaluation. The study aims to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001, a CRISPR/Cas9-based genome editing therapeutic. This therapeutic consists of an mRNA sequence encoding for Cas9 protein and a single guide RNA targeting the human TTR gene, delivered in a multi-component lipid system.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects must meet the following inclusion criteria: 1. Male and/or female subjects 18 to 80 years of age inclusive, at the time of signing the informed consent. 2. Diagnosis of PN due to TTR amyloidosis (ATTR) based on all of the following: a. Documented TTR mutation (i.e., whole TTR gene sequencing information). b. Clinical diagnosis of sensorimotor peripheral neuropathy. c. Neuropathy Impairment Score (NIS) ≥ 5 and ≤ 130 during Screening. d. Polyneuropathy Disability (PND) score ≤ 3b. 3. Must have a body weight of at least 45 kg at Screening visit. 4. Subjects must meet the following laboratory criteria during Screening: a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (see exception for Gilbert’s Syndrome below), and international normalized ratio (INR) ≤ upper limit of normal (ULN) range at Screening. b. For subjects with a history of Gilbert’s Syndrome, total bilirubin ≤ 2 × ULN at Screening. c. Estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73m2 as measured by the Modification of Diet in Renal Disease equation at Screening. d. Platelet count ≥ 100,000 cells/mm3 at Screening. e. Within laboratory reference range or deemed clinically non significant by the investigator: activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, and D dimer levels at Screening. f. N terminal prohormone of brain natriuretic peptide (NT proBNP) < 2,000 pg/mL during Screening. g. Low density lipoprotein (LDL) cholesterol < 200 mg/dL at Screening, with or without pharmacotherapy. h. Vitamin A ≥ lower limit of normal (LLN) at Screening. i. Thyroid-stimulating hormone (TSH) values within the normal range at Screening. 5. Subjects must be willing to limit alcohol consumption to 1 alcoholic drink per day during Screening and through 28 days after treatment with NTLA 2001. 6. Lack of access to approved treatments for transthyretin amyloidosis (Criterion A) and/or progression of ATTRv PN despite use of approved treatment for ATTRv PN (Criterion B). Criterion A: Lack of access to approved treatments for ATTRv PN defined as one or more of the following: • ATTRv PN-directed therapy not approved in subject’s geographic region. • Subject unable to receive treatment approved for ATTRv PN (e.g., intolerance or other medical reasons, financial reasons, and/or other reasons). Criterion B: Progression of ATTRv PN symptoms per the investigator assessment despite approved treatment for ATTRv PN for at least 6 months and meeting any two of the following criteria: • Increase in Polyneuropathy Disability (PND) score ≥ 1 point. • Increase in Neuropathy Impairment Score (NIS) ≥ 5 points. • Decrease in Modified Body-Mass Index (mBMI) ≥ 25 kg/m2 × g/L. • One of the following: • Decrease in 6 minute walk test ≥ 30 meters. • Decrease in 10 meter walk test ≥ 0.1 meter/second. • Increase in Timed Get Up and Go test ≥ 15% Note: In Part 1, subjects with a history of treatment with TTR lowering therapy (i.e., patisiran, inotersen) will be excluded. In Part 2, up to 6 subjects with progression of ATTRv PN symptoms despite treatment with TTR lowering therapy will be able to be dosed with NTLA 2001. 7. A female subject must be: • Postmenopausal or Surgically sterile. Please see protocol for further inclusion criteria.

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Exclusion Criteria

Subjects must not meet any of the following exclusion criteria: 1. Amyloidosis attributable to non TTR protein, e.g., amyloid light-chain (AL) amyloidosis. 2. Known leptomeningeal transthyretin amyloidosis. 3. Subjects who have known hypersensitivity to any lipid nanoparticles (LNP) component or who have previously received LNP and experienced any treatment related laboratory abnormalities or AE listed below: • ALT or AST > 3 × ULN if baseline was normal or > 3 × baseline if baseline was above normal after receiving an LNP containing product. • INR, aPTT or D dimer > 1.5 × ULN if baseline was normal or > 1.5 × Baseline if baseline was above normal after receiving an LNP containing product. • Any LNP treatment-related AE classified as CTCAE Grade 3 or higher. • Infusion-related reaction (IRR) to an LNP containing product requiring treatment or discontinuation of infusion; NOTE: slowing of the infusion rate to mitigate an infusion-related reaction is not considered exclusionary. • Any LNP treatment-related AE which in the opinion of the investigator should be exclusionary. 4. Use of any of the following TTR directed therapy for ATTR within the specified timeframe: • Patisiran (small interfering ribonucleic acid [siRNA] therapeutic formulated LNP): o Part 1: prior history of use. o Part 2: last dose administered less than 60 days prior to study drug administration. • Inotersen (antisense oligonucleotide [ASO]): o Part 1: prior history of use. o Part 2: last dose administered less than 160 days prior to study drug administration. • Vutrisiran (investigational siRNA therapeutic GalNAc conjugate): prior history of use. • Tafamidis (TTR stabilizer): subject must be on stable dose for a minimum of 14 days. • Diflunisal (TTR stabilizer): last dose administered less than 3 days prior to study drug dosing. • Doxycycline and/or tauroursodeoxycholic acid (TTR matrix solvent): last dose administered less than 14 days of study drug dosing. • Any other investigational agent for the treatment of ATTRv PN: last dose administered less than 30 days or 5 half-lives, whichever is longer, prior to study drug dosing. 5. Other known causes of sensorimotor or autonomic neuropathy (e.g., diabetic neuropathy, autoimmune disease-associated neuropathy, etc.). 6. Type 1 diabetes mellitus or diagnosis of Type 2 diabetes mellitus for ≥ 5 years. 7. Current or prior New York Heart Association (NYHA) class III or IV symptoms due to heart failure or worsening of heart failure symptoms within 90 days prior to or during Screening. 8. Within 6 months of planned NTLA 2001 infusion, any history of myocardial infarction, unstable angina, severe aortic stenosis, symptomatic mitral regurgitation, Mobitz II atrioventricular block, third degree heart block, symptomatic ventricular arrhythmia, symptomatic bradycardia, or newly recognized ventricular tachycardia, cerebral ischemia, symptomatic peripheral vascular disease, pulmonary emboli, deep vein thrombosis, abnormal carotid ultrasound, abnormal coronary perfusion study, or aneurysm under imaging surveillance. For history of the above more than 6 months prior to the planned NTLA 2001 infusion, subject will require formal evaluation by her/his managing medical specialist to document that medical management has been optimized and that the patient’s current health status would be deemed safe to proceed with the equivalent of intermediate risk, non-cardiac surgery. In addition, cardiovascular hospitalization or invasive procedure within 90 days prior to or during Screening will also be exclusionary. 9. Anticipated invasive cardiovascular procedure (e.g., coronary stent, pacemaker placement, etc.) within 28 days after study drug administration. 10. Unable or unwilling to take Vitamin A supplementation. Please refer to protocol for further exclusion criteria.