Trial Review

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04601051




Registration number
NCT04601051
Ethics application status
Date submitted
19/10/2020
Date registered
23/10/2020
Date last updated
8/09/2023

Titles & IDs
Public title
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)
Scientific 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)
Secondary ID [1] 0 0
2020-002034-32
Secondary ID [2] 0 0
ITL-2001-CL-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy 0 0
Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy 0 0
Wild-Type Transthyretin Cardiac Amyloidosis 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Metabolic and Endocrine 0 0 0 0
Other metabolic disorders
Neurological 0 0 0 0
Neurodegenerative diseases
Metabolic and Endocrine 0 0 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - NTLA-2001

Experimental: Polyneuropathy Part 1: NTLA-2001 - Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.

Experimental: Polyneuropathy Part 2: NTLA-2001 - Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.

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.

Experimental: Cardiomyopathy Part 2 (UK only): NTLA-2001 - Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.

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.


Other interventions: NTLA-2001
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants with Treatment-Emergent Adverse Events
Timepoint [1] 0 0
up to Day 730
Primary outcome [2] 0 0
Number of Participants with Clinically Significant Clinical Laboratory Test Findings
Timepoint [2] 0 0
up to Day 730
Primary outcome [3] 0 0
Number of Participants with Clinically Significant Safety Measurements
Timepoint [3] 0 0
up to Day 730
Primary outcome [4] 0 0
Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA])
Timepoint [4] 0 0
up to Day 730
Primary outcome [5] 0 0
Percent Change from Baseline in Serum Prealbumin
Timepoint [5] 0 0
up to Day 730
Primary outcome [6] 0 0
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
Timepoint [6] 0 0
up to Day 730
Primary outcome [7] 0 0
Mean Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Timepoint [7] 0 0
up to Day 730
Primary outcome [8] 0 0
Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Timepoint [8] 0 0
up to Day 730
Primary outcome [9] 0 0
Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Timepoint [9] 0 0
up to Day 730
Primary outcome [10] 0 0
Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Timepoint [10] 0 0
up to Day 730
Primary outcome [11] 0 0
Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Timepoint [11] 0 0
up to Day 730
Primary outcome [12] 0 0
Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Timepoint [12] 0 0
up to Day 730
Primary outcome [13] 0 0
Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels
Timepoint [13] 0 0
up to Day 730
Secondary outcome [1] 0 0
Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage.
Timepoint [1] 0 0
up to Day 730
Secondary outcome [2] 0 0
Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score
Timepoint [2] 0 0
up to Day 730
Secondary outcome [3] 0 0
Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI)
Timepoint [3] 0 0
up to Day 730
Secondary outcome [4] 0 0
Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS)
Timepoint [4] 0 0
up to Day 730
Secondary outcome [5] 0 0
Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7)
Timepoint [5] 0 0
up to Day 730
Secondary outcome [6] 0 0
Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT)
Timepoint [6] 0 0
up to Day 730
Secondary outcome [7] 0 0
Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN)
Timepoint [7] 0 0
up to Day 730
Secondary outcome [8] 0 0
Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L
Timepoint [8] 0 0
up to Day 730
Secondary outcome [9] 0 0
Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
Timepoint [9] 0 0
up to Day 730
Secondary outcome [10] 0 0
Cardiomyopathy only: Change from Baseline in hs Troponin T
Timepoint [10] 0 0
up to Day 730
Secondary outcome [11] 0 0
Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI)
Timepoint [11] 0 0
up to Day 730
Secondary outcome [12] 0 0
Cardiomyopathy only: Change from Baseline in Echocardiogram
Timepoint [12] 0 0
up to Day 730
Secondary outcome [13] 0 0
Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test
Timepoint [13] 0 0
up to Day 730
Secondary outcome [14] 0 0
Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT)
Timepoint [14] 0 0
up to Day 730
Secondary outcome [15] 0 0
Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification
Timepoint [15] 0 0
up to Day 730
Secondary outcome [16] 0 0
Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ)
Timepoint [16] 0 0
up to Day 730

Eligibility
Key inclusion criteria
Polyneuropathy

- 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
Minimum age
18 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
5/11/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/08/2026
Actual
Sample size
Target
Accrual to date
Final
72
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
France
State/province [1] 0 0
Paris
Country [2] 0 0
New Zealand
State/province [2] 0 0
Auckland
Country [3] 0 0
Sweden
State/province [3] 0 0
Umea
Country [4] 0 0
United Kingdom
State/province [4] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Intellia Therapeutics
Address
Country

Ethics approval
Ethics application status

Summary
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)
Trial website
https://clinicaltrials.gov/ct2/show/NCT04601051
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries