Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy, Wild-Type Transthyretin Cardiac Amyloidosis
Conditions
Keywords
NTLA-2001, Pharmacokinetics, Pharmacodynamics, Neurologic Function, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR, Polyneuropathy, ATTR, Transthyretin, TTR, Amyloidosis, Familial Amyloid Polyneuropathy, FAP, Cardiomyopathy
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.
Interventions
BIOLOGICALNTLA-2001
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
Sponsors
Intellia Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
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: 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/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants with Treatment-Emergent Adverse Events | 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 |
| 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 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 |
| 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 Terminal Half-Life (t½) 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 |
| Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA | up to Day 730 |
| Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels | up to Day 730 |
Secondary
| Measure | Time frame |
|---|---|
| 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 Body Mass Index (mBMI) | up to Day 730 |
| Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS) | up to Day 730 |
| Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7) | 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 |
| Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L | 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 hs Troponin T | up to Day 730 |
| Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI) | 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 |
| Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ) | up to Day 730 |
Countries
France, New Zealand, Sweden, United Kingdom
Outcome results
None listed