- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04601051
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 Two-Part (Open-label, Single Ascending Dose (Part 1) and Open-label, Single Dose Expansion (Part 2)) 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)
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Contact
- Name: Trial Manager at Intellia
- Phone Number: 833-888-0387
- Email: clinicalscience@intelliatx.com
Study Locations
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Paris, France
- Clinical Trial Site
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Auckland, New Zealand
- Clinical Trial Site
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Umea, Sweden
- Clinical Trial Site
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London, United Kingdom
- Clinical Trial Site
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Polyneuropathy 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 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:
- Patisiran
- Inotersen
- Vutrisiran
- Tafamidis
- Diflunisal
- Doxycycline and/or tauroursodeoxycholic acid
- 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:
- Patisiran
- Inotersen
- Vutrisiran
- Tafamidis
- Diflunisal
- Doxycycline and/or tauroursodeoxycholic acid
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Polyneuropathy Part 1: NTLA-2001
Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.
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A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
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Experimental: Polyneuropathy Part 2: NTLA-2001
Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
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A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
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Experimental: Cardiomyopathy Part 1 (UK only): NTLA-2001
Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001.
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A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
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Experimental: Cardiomyopathy Part 2 (UK only): NTLA-2001
Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
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A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
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Experimental: Polyneuropathy Follow-on Dosing (PN Part 1 Dose Level 1 Subjects only): NTLA-2001
Participants assigned to the follow-on dosing cohort will receive a subsequent dose of NTLA-2001.
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A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Number of Participants with Treatment-Emergent Adverse Events
Time Frame: up to Day 730
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up to Day 730
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Number of Participants with Clinically Significant Clinical Laboratory Test Findings
Time Frame: up to Day 730
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up to Day 730
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Number of Participants with Clinically Significant Safety Measurements
Time Frame: up to Day 730
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up to Day 730
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Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA])
Time Frame: up to Day 730
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up to Day 730
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Percent Change from Baseline in Serum Prealbumin
Time Frame: up to Day 730
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up to Day 730
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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
Time Frame: up to Day 730
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up to Day 730
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Mean Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Time Frame: up to Day 730
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up to Day 730
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Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Time Frame: up to Day 730
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up to Day 730
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Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Time Frame: up to Day 730
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up to Day 730
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Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Time Frame: up to Day 730
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up to Day 730
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Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Time Frame: up to Day 730
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up to Day 730
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Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Time Frame: up to Day 730
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up to Day 730
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Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels
Time Frame: up to Day 730
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up to Day 730
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage.
Time Frame: up to Day 730
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up to Day 730
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Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score
Time Frame: up to Day 730
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up to Day 730
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Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI)
Time Frame: up to Day 730
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up to Day 730
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Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS)
Time Frame: up to Day 730
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up to Day 730
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Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7)
Time Frame: up to Day 730
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up to Day 730
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Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT)
Time Frame: up to Day 730
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up to Day 730
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Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN)
Time Frame: up to Day 730
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up to Day 730
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Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in hs Troponin T
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI)
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in Echocardiogram
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT)
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification
Time Frame: up to Day 730
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up to Day 730
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Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ)
Time Frame: up to Day 730
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up to Day 730
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Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML, Seitzer J, O'Connell D, Walsh KR, Wood K, Phillips J, Xu Y, Amaral A, Boyd AP, Cehelsky JE, McKee MD, Schiermeier A, Harari O, Murphy A, Kyratsous CA, Zambrowicz B, Soltys R, Gutstein DE, Leonard J, Sepp-Lorenzino L, Lebwohl D. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. 2021 Aug 5;385(6):493-502. doi: 10.1056/NEJMoa2107454. Epub 2021 Jun 26.
- Stephenson AA, Flanigan KM. Gene editing and modulation for Duchenne muscular dystrophy. Prog Mol Biol Transl Sci. 2021;182:225-255. doi: 10.1016/bs.pmbts.2021.01.029. Epub 2021 Mar 3.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Heart Diseases
- Cardiovascular Diseases
- Metabolic Diseases
- Nervous System Diseases
- Genetic Diseases, Inborn
- Neuromuscular Diseases
- Neurodegenerative Diseases
- Peripheral Nervous System Diseases
- Proteostasis Deficiencies
- Metabolism, Inborn Errors
- Heredodegenerative Disorders, Nervous System
- Amyloidosis, Familial
- Amyloidosis
- Cardiomyopathies
- Polyneuropathies
- Amyloid Neuropathies
- Amyloid Neuropathies, Familial
Other Study ID Numbers
- ITL-2001-CL-001
- 2020-002034-32 (EudraCT Number)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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