Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN) and Patients With Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)

Phase 1

Active, not recruiting

• Conditions: Wild-Type Transthyretin Cardiac Amyloidosis; Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy; Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy
• Interventions: Biological: NTLA-2001

• Registration Number: NCT04601051
• Lead Sponsor: Intellia Therapeutics

Brief Summary

This study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NTLA-2001 in participants with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and participants with hereditary transthyretin amyloidosis with cardiomyopathy (ATTRv-CM) or wild type cardiomyopathy (ATTRwt-CM)

Detailed Description

For ATTRv-PN participants, Part 1 consists of an open-label, single-ascending dose study, which identifies the dose for evaluation in the cohort expansion of Part 2. Part 2 will follow as an open-label, dose expansion study to further characterize the activity of NTLA-2001, provide an initial assessment of the effect of NTLA-2001 on clinical measures of neuropathy and neurological function, and obtain additional safety data.

For ATTR-CM participants, Part 1 consists of an open-label, single-ascending dose study, which identifies the dose for evaluation in the cohort expansion of Part 2. Part 2 will follow as an open-label, dose expansion study to further characterize the activity of NTLA-2001, provide an initial assessment of the effect of NTLA-2001 on cardiac measures, and obtain additional safety data.

All participants who are dosed with NTLA-2001 will be offered to participate in a long-term safety monitoring follow-up study via a separate protocol.

Study Timeline

• Study First Submitted: 2020-10-19
• Study First Submitted QC: 2020-10-19
• Study First Posted: 2020-10-23
• Study Start: 2020-11-05
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-06
• Last Update Posted: 2023-09-08
• Primary Completion: 2025-08
• Study Completion: 2026-08

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 72

Inclusion Criteria

• Male and/or female participants 18 to 80 years of age inclusive, at the time of signing the informed consent
• Diagnosis of polyneuropathy (PN) due to transthyretin (TTR) amyloidosis (ATTR)
• Must have a body weight of at least 45 kilograms (kg) at Screening visit
• Lack of access to approved treatments for ATTR and/or progression of hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) despite use of approved treatment for ATTRv-PN

Polyneuropathy

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Exclusion Criteria

• Amyloidosis attributable to non-TTR protein, e.g., amyloid light-chain (AL) amyloidosis

• Known leptomeningeal transthyretin amyloidosis

• Use of any of the following TTR-directed therapy for ATTR within certain timeframe:

  1. Patisiran
  2. Inotersen
  3. Vutrisiran
  4. Tafamidis
  5. Diflunisal
  6. Doxycycline and/or tauroursodeoxycholic acid
  7. Any other investigational agent for the treatment of ATTRv-PN:

• Other protocol defined Inclusion/Exclusion criteria may apply

Cardiomyopathy Inclusion Criteria (UK only):

• Male and/or female participants 18 to 90 years of age inclusive, at the time of signing the informed consent
• Diagnosis of transthyretin (ATTR) amyloidosis with cardiomyopathy, classified as hereditary ATTR amyloidosis with cardiomyopathy (ATTRv-CM) or wild type cardiomyopathy (ATTRwt-CM).
• Must have a body weight of at least 45 kilograms (kg) at Screening visit
• New York Heart Association (NYHA) Class I-III heart failure
• At least 1 prior hospitalization for heart failure and/or clinical evidence of heart failure.
• Able to complete ≥150 meters on the 6-minute walk test (6-MWT) during the Screening period.

Cardiomyopathy Exclusion Criteria (UK only):

• Amyloidosis attributable to non-TTR protein, e.g., amyloid light-chain (AL) amyloidosis

• Known leptomeningeal transthyretin amyloidosis

• Use of any of the following TTR-directed therapy for ATTR within certain timeframes:

  1. Patisiran
  2. Inotersen
  3. Vutrisiran
  4. Tafamidis
  5. Diflunisal
  6. Doxycycline and/or tauroursodeoxycholic acid
  7. Investigational TTR stabilizer (e.g., AG-10)

• Participants with heart failure that in the opinion of the investigator is caused by ischemic heart disease, hypertension, or uncorrected valvular disease and not primarily due to transthyretin amyloid cardiomyopathy.

• Participants with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker is indicated but will not be placed. Pacemaker or defibrillator placement, initiation of or change in anti-arrhythmic medication within 28 days prior to study drug administration.

• Other protocol defined Inclusion/Exclusion criteria may apply

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Polyneuropathy Part 2: NTLA-2001	NTLA-2001	Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
Polyneuropathy Follow-on Dosing (PN Part 1 Dose Level 1 Subjects only): NTLA-2001	NTLA-2001	Participants assigned to the follow-on dosing cohort will receive a subsequent dose of NTLA-2001.
Polyneuropathy Part 1: NTLA-2001	NTLA-2001	Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.
Cardiomyopathy Part 1 (UK only): NTLA-2001	NTLA-2001	Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001.
Cardiomyopathy Part 2 (UK only): NTLA-2001	NTLA-2001	Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.

Primary Outcome Measures

Name	Time	Method
Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels	up to Day 730
Mean Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA	up to Day 730
Number of Participants with Treatment-Emergent Adverse Events	up to Day 730
Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA])	up to Day 730
Percent Change from Baseline in Serum Prealbumin	up to Day 730
Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA	up to Day 730
Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA	up to Day 730
Number of Participants with Clinically Significant Clinical Laboratory Test Findings	up to Day 730
Number of Participants with Clinically Significant Safety Measurements	up to Day 730
Mean Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA	up to Day 730
Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA	up to Day 730
Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA	up to Day 730
Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA	up to Day 730

Secondary Outcome Measures

Name	Time	Method
Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage.	up to Day 730
Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score	up to Day 730
Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7)	up to Day 730
Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)	up to Day 730
Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI)	up to Day 730
Cardiomyopathy only: Change from Baseline in hs Troponin T	up to Day 730
Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI)	up to Day 730
Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L	up to Day 730
Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ)	up to Day 730
Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS)	up to Day 730
Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT)	up to Day 730
Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN)	up to Day 730
Cardiomyopathy only: Change from Baseline in Echocardiogram	up to Day 730
Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test	up to Day 730
Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT)	up to Day 730
Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification	up to Day 730

Trial Locations

Locations (1)

Clinical Trial Site; 🇬🇧 London, United Kingdom