Transthyretin-Related (ATTR) Familial Amyloid PolyneuropathyPhase 1NCT04601051
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)
A Phase 1 study testing NTLA-2001 in people with Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy and Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, run by Intellia Therapeutics at 4 sites in 4 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy, Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, Wild-Type Transthyretin Cardiac Amyloidosis
- What is being tested?
- NTLA-2001
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 72 participants
- Where
- 4 sitesin 4 countries
- Study dates
- 5 Nov 2020to 12 Sep 2025
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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
Trial locations and contacts
4 sites in 4 countries.
4 sites in 4 countries
About this study
Official title: 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)
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)
Read the 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.
- Conditions
- Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy, Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, Wild-Type Transthyretin Cardiac Amyloidosis
- Being tested
- NTLA-2001
- Keywords
- NTLA-2001, Pharmacokinetics, Pharmacodynamics, Neurologic Function, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR, Polyneuropathy, ATTR, Transthyretin, TTR, Amyloidosis, Familial Amyloid Polyneuropathy, FAP, Cardiomyopathy
- Medical subject headings
- Amyloid Neuropathies, Familial, Polyneuropathies, Amyloidosis, Cardiomyopathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NTLA-2001Biological
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
| Study group | Role | What they receive |
|---|---|---|
| Polyneuropathy Part 1: NTLA-2001 | Experimental | Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001. Receives: Biological: NTLA-2001 |
| Polyneuropathy Part 2: NTLA-2001 | Experimental | Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001. Receives: Biological: NTLA-2001 |
| Cardiomyopathy Part 1 (UK only): NTLA-2001 | Experimental | Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001. Receives: Biological: NTLA-2001 |
| Cardiomyopathy Part 2 (UK only): NTLA-2001 | Experimental | Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001. Receives: Biological: NTLA-2001 |
| Polyneuropathy Follow-on Dosing (PN Part 1 Dose Level 1 Subjects only): NTLA-2001 | Experimental | Participants assigned to the follow-on dosing cohort will receive a subsequent dose of NTLA-2001. Receives: Biological: NTLA-2001 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants with Treatment-Emergent Adverse Events
Measured: up to Day 730
Number of Participants with Clinically Significant Clinical Laboratory Test Findings
Measured: up to Day 730
Number of Participants with Clinically Significant Safety Measurements
Measured: up to Day 730
Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA])
Measured: up to Day 730
Percent Change from Baseline in Serum Prealbumin
Measured: 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
Measured: 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
Measured: up to Day 730
Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Measured: up to Day 730
Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Measured: up to Day 730
Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Measured: up to Day 730
Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Measured: up to Day 730
Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Measured: up to Day 730
Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels
Measured: up to Day 730
Secondary outcomes (16)
Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage.
Measured: up to Day 730
Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score
Measured: up to Day 730
Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI)
Measured: up to Day 730
Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS)
Measured: up to Day 730
Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7)
Measured: up to Day 730
Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT)
Measured: up to Day 730
Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN)
Measured: up to Day 730
Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in hs Troponin T
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI)
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in Echocardiogram
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT)
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification
Measured: up to Day 730
Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ)
Measured: up to Day 730
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2020
- Study start5 Nov 2020
- Primary completion12 Sep 2025
- Study completion12 Sep 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Transthyretin-Related (ATTR) Familial Amyloid PolyneuropathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 72 participants (actual)
Sponsor and investigators
- Lead sponsor
- Intellia Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04601051
- Sponsor's protocol ID
- ITL-2001-CL-001
- Other IDs
- 2020-002034-32
- Status last verified
- Jan 2026
- First submitted
- 19 Oct 2020
- Last updated
- 30 Jan 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Gillmore JD, Gane E, Taubel J, Pilebro B, Echaniz-Laguna A, Kao J, Litchy W, Shahda S, Haagensen A, Walsh L, Smith D, Kachadourian J, Ward JH, Lebwohl D, Zhu P, Xu Y, Leung A, Sonderfan A, Gutstein DE, Manvelian G, Adams D. Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy. N Engl J Med. 2025 Oct 9;393(14):1375-1386. doi: 10.1056/NEJMoa2510209. Epub 2025 Sep 25.
PubMed 41002250Fontana M, Solomon SD, Kachadourian J, Walsh L, Rocha R, Lebwohl D, Smith D, Taubel J, Gane EJ, Pilebro B, Adams D, Razvi Y, Olbertz J, Haagensen A, Zhu P, Xu Y, Leung A, Sonderfan A, Gutstein DE, Gillmore JD. CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy. N Engl J Med. 2024 Dec 12;391(23):2231-2241. doi: 10.1056/NEJMoa2412309. Epub 2024 Nov 16.
PubMed 39555828Gillmore 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.
PubMed 34215024Stephenson 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.
PubMed 34175043