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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)

Primary Purpose

Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy, Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, Wild-Type Transthyretin Cardiac Amyloidosis

Status

Active

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

NTLA-2001

About this trial

This is an interventional treatment trial for Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy focused on measuring NTLA-2001, Pharmacokinetics, Pharmacodynamics, Neurologic Function, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR, Polyneuropathy, ATTR, Transthyretin, TTR, Amyloidosis, Familial Amyloid Polyneuropathy, FAP, Cardiomyopathy

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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/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

Sites / Locations

Clinical Trial Site
Clinical Trial Site
Clinical Trial Site
Clinical Trial Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Polyneuropathy Part 1: NTLA-2001

Polyneuropathy Part 2: NTLA-2001

Cardiomyopathy Part 1 (UK only): NTLA-2001

Cardiomyopathy Part 2 (UK only): NTLA-2001

Polyneuropathy Follow-on Dosing (PN Part 1 Dose Level 1 Subjects only): NTLA-2001

Arm Description

Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.

Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.

Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001.

Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.

Participants assigned to the follow-on dosing cohort will receive a subsequent dose of NTLA-2001.

Outcomes

Primary Outcome Measures

Number of Participants with Treatment-Emergent Adverse Events

Number of Participants with Clinically Significant Clinical Laboratory Test Findings

Number of Participants with Clinically Significant Safety Measurements

Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA])

Percent Change from Baseline in Serum Prealbumin

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

Mean Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels

Secondary Outcome Measures

Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage.

Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score

Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI)

Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS)

Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7)

Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT)

Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN)

Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L

Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)

Cardiomyopathy only: Change from Baseline in hs Troponin T

Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI)

Cardiomyopathy only: Change from Baseline in Echocardiogram

Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test

Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT)

Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification

Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ)

Full Information

NCT ID

NCT04601051

First Posted

October 19, 2020

Last Updated

September 6, 2023

Sponsor

Intellia Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT04601051

Brief 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)

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)

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 5, 2020 (Actual)

Primary Completion Date

August 2025 (Anticipated)

Study Completion Date

August 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Intellia Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy, Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, Wild-Type Transthyretin Cardiac Amyloidosis

Keywords

NTLA-2001, Pharmacokinetics, Pharmacodynamics, Neurologic Function, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR, Polyneuropathy, ATTR, Transthyretin, TTR, Amyloidosis, Familial Amyloid Polyneuropathy, FAP, Cardiomyopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

72 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Polyneuropathy Part 1: NTLA-2001

Arm Type

Experimental

Arm Description

Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.

Arm Title

Polyneuropathy Part 2: NTLA-2001

Arm Type

Experimental

Arm Description

Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.

Arm Title

Cardiomyopathy Part 1 (UK only): NTLA-2001

Arm Type

Experimental

Arm Description

Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001.

Arm Title

Cardiomyopathy Part 2 (UK only): NTLA-2001

Arm Type

Experimental

Arm Description

Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.

Arm Title

Polyneuropathy Follow-on Dosing (PN Part 1 Dose Level 1 Subjects only): NTLA-2001

Arm Type

Experimental

Arm Description

Participants assigned to the follow-on dosing cohort will receive a subsequent dose of NTLA-2001.

Intervention Type

Biological

Intervention Name(s)

NTLA-2001

Intervention Description

A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration

Primary Outcome Measure Information:

Title

Number of Participants with Treatment-Emergent Adverse Events

Time Frame

up to Day 730

Title

Number of Participants with Clinically Significant Clinical Laboratory Test Findings

Time Frame

up to Day 730

Title

Number of Participants with Clinically Significant Safety Measurements

Time Frame

up to Day 730

Title

Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA])

Time Frame

up to Day 730

Title

Percent Change from Baseline in Serum Prealbumin

Time Frame

up to Day 730

Title

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

Title

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

Title

Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Time Frame

up to Day 730

Title

Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Time Frame

up to Day 730

Title

Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Time Frame

up to Day 730

Title

Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Time Frame

up to Day 730

Title

Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Time Frame

up to Day 730

Title

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

Secondary Outcome Measure Information:

Title

Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage.

Time Frame

up to Day 730

Title

Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score

Time Frame

up to Day 730

Title

Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI)

Time Frame

up to Day 730

Title

Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS)

Time Frame

up to Day 730

Title

Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7)

Time Frame

up to Day 730

Title

Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT)

Time Frame

up to Day 730

Title

Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN)

Time Frame

up to Day 730

Title

Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in hs Troponin T

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI)

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in Echocardiogram

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT)

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification

Time Frame

up to Day 730

Title

Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ)

Time Frame

up to Day 730

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility 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: 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

Facility Information:

Facility Name

Clinical Trial Site

City

Paris

Country

France

Facility Name

Clinical Trial Site

City

Auckland

Country

New Zealand

Facility Name

Clinical Trial Site

City

Umea

Country

Sweden

Facility Name

Clinical Trial Site

City

London

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

34215024

Citation

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.

Results Reference

derived

PubMed Identifier

34175043

Citation

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.

Results Reference

derived

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