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)

• ClinicalTrials.gov Identifier: NCT04601051
• Recruitment Status: Recruiting
• First Posted: October 23, 2020
• Last Update Posted: December 2, 2022
• Sponsor: Intellia Therapeutics
• Information provided by (Responsible Party): Intellia Therapeutics

Tracking Information

• First Submitted Date: October 19, 2020
• First Posted Date: October 23, 2020
• Last Update Posted Date: December 2, 2022
• Actual Study Start Date: November 5, 2020
• Estimated Primary Completion Date: March 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 21, 2021)

• Number of Participants with Treatment-Emergent Adverse Events [ Time Frame: up to Day 730 ]
• Number of Participants with Clinically Significant Clinical Laboratory Test Findings [ Time Frame: up to Day 730 ]
• Number of Participants with Clinically Significant Safety Measurements [ Time Frame: up to Day 730 ]
• Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA]) [ Time Frame: up to Day 730 ]
• Percent Change from Baseline in Serum Prealbumin [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: up to Day 730 ]
• Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
• Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
• Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
• Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
• Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
• 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 ]

Original Primary Outcome Measures (submitted: October 19, 2020)

• Parts 1 and 2: Number of Participants with Treatment-emergent Adverse Events [ Time Frame: up to Day 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Number of Participants with Clinically Significant Clinical Laboratory Test Findings [ Time Frame: up to Day 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Number of Participants with Clinically Significant Safety Measurements [ Time Frame: up to Day 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Percent Change from Baseline in Serum TTR (ELISA) [ Time Frame: Baseline (Predose); Days 7, 14, 28, 56, 112, 168, 252, 365, 545, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Percent Change from Baseline in Serum Prealbumin [ Time Frame: Baseline (Predose); Days 14 and 28 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: 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 168 ]
  Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
• Parts 1 and 2: 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 168 ]
  Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
• Parts 1 and 2: Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
  Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
• Parts 1 and 2: Mean Time to the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
  Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
• Parts 1 and 2: Mean Terminal Half-life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
  Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
• Parts 1 and 2: Mean Apparent Oral Clearance (CL/F) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
  Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
• Parts 1 and 2: Mean Apparent Volume of Distribution (Vd/F) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
  Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
• Part 1 and 2: Change from Baseline in Anti-drug Antibody and Anti-Cas9 Protein Antibody Levels [ Time Frame: Baseline; Days 14, 28, 168, 365, 545, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]

Current Secondary Outcome Measures (submitted: December 21, 2021)

• Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage. [ Time Frame: up to Day 730 ]
• Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score [ Time Frame: up to Day 730 ]
• Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI) [ Time Frame: up to Day 730 ]
• Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS) [ Time Frame: up to Day 730 ]
• Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7) [ Time Frame: up to Day 730 ]
• Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT) [ Time Frame: up to Day 730 ]
• Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) [ Time Frame: up to Day 730 ]
• Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in hs Troponin T [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI) [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in Echocardiogram [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT) [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification [ Time Frame: up to Day 730 ]
• Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ) [ Time Frame: up to Day 730 ]

Original Secondary Outcome Measures (submitted: October 19, 2020)

• Parts 1 and 2: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage [ Time Frame: Baseline (Predose); Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Change from Baseline in Polyneuropathy Disability (PND) Score [ Time Frame: Baseline (Predose); Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Change from Baseline in Modified Body Mass Index (mBMI) [ Time Frame: Baseline (Predose); Days 28, 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Change from Baseline in Serum Neurofilament Light Chain (NfL) Levels [ Time Frame: Baseline (Predose); Days 28, 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Change from Screening in Neuropathy Impairment Score (NIS) [ Time Frame: Screening; Days 28, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Part 2: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7) [ Time Frame: Baseline (Predose); Days 365 and 730 (up to 24 months) ]
• Parts 1 and 2: Change from Screening in 10-Meter Walk Test (10-MWT) [ Time Frame: Screening; Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) [ Time Frame: Baseline (Predose); Days 28, 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
• Parts 1 and 2: Change from Baseline in EuroQOL (EQ)-5D-5L [ Time Frame: Baseline (Predose); Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

Biological: NTLA-2001

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

Study Arms

• Experimental: Polyneuropathy Part 1: NTLA-2001
  Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.
  Intervention: Biological: NTLA-2001
• Experimental: Polyneuropathy Part 2: NTLA-2001
  Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
  Intervention: Biological: 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.
  Intervention: Biological: 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.
  Intervention: Biological: NTLA-2001

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 29, 2022): 72
• Original Estimated Enrollment (submitted: October 19, 2020): 38
• Estimated Study Completion Date: March 2026
• Estimated Primary Completion Date: March 2025 (Final data collection date for primary outcome measure)

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:

  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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Trial Manager at Intellia; 833-888-0387; clinicalscience@intelliatx.com

• Listed Location Countries: France, New Zealand, Sweden, United Kingdom

Administrative Information

• NCT Number: NCT04601051
• Other Study ID Numbers: ITL-2001-CL-001; 2020-002034-32 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Intellia Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Intellia Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Intellia Therapeutics
• Verification Date: November 2022