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)

Intellia Therapeutics

Status and phase: Active, not recruiting; Phase 1

Conditions: Wild-Type Transthyretin Cardiac Amyloidosis; Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy; Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy

Treatments: Biological: NTLA-2001

Study type: Interventional

Funder types: Industry

Identifiers

NCT04601051

2020-002034-32 (EudraCT Number)

ITL-2001-CL-001

Details and patient eligibility

About

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)

Full 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.

Enrollment: 72 patients

Sex: All

Ages: 18 to 90 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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/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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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72 participants in 5 patient groups

Polyneuropathy Part 1: NTLA-2001

Experimental group

Description:

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

Treatment:

Biological: NTLA-2001

Polyneuropathy Part 2: NTLA-2001

Experimental group

Description:

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

Treatment:

Biological: NTLA-2001

Cardiomyopathy Part 1 (UK only): NTLA-2001

Experimental group

Description:

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

Treatment:

Biological: NTLA-2001

Cardiomyopathy Part 2 (UK only): NTLA-2001

Experimental group

Description:

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

Treatment:

Biological: NTLA-2001

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

Experimental group

Description:

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

Treatment:

Biological: NTLA-2001