Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN)

• ClinicalTrials.gov Identifier: NCT04601051
• Recruitment Status: Recruiting
• First Posted: October 23, 2020
• Last Update Posted: December 4, 2020
• Sponsor: Intellia Therapeutics
• Information provided by (Responsible Party): Intellia Therapeutics

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).

Condition or disease	Intervention/treatment	Phase
Hereditary Transthyretin Amyloidosis	Biological: NTLA-2001	Phase 1

Detailed Description:

This 2-part first in human (FIH) study consists of an open-label, single ascending dose Part 1, which may identify the optimal biologically active dose (OBD) of NTLA-2001, followed by Part 2, if applicable, an open-label, single-dose expansion at the OBD to further characterize activity of NTLA-2001, provide an initial assessment of the effect of NTLA-2001 on clinical measures of neuropathy and neurologic function, and obtain additional safety data at the OBD.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 38 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: November 5, 2020
• Estimated Primary Completion Date: April 2022
• Estimated Study Completion Date: March 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: NTLA-2001; Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001 on Day 1 and will then be followed for up to 24 months.	Biological: NTLA-2001; a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
Experimental: Part 2: Participants will receive the optimal biologically active dose (OBD) of NTLA-2001 identified in Part 1 as a single dose on Day 1 and will then be followed for up to 24 months.	Biological: NTLA-2001; a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration

Outcome Measures

Primary Outcome Measures :

1. 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) ]
2. 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) ]
3. 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) ]
4. 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) ]
5. 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) ]
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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) ]

Secondary Outcome Measures :

1. 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) ]
2. 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) ]
3. 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) ]
4. 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) ]
5. 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) ]
6. 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) ]
7. 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) ]
8. 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) ]
9. 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) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 50 to 90 kilograms (kg) at Screening visit
• Lack of access to approved treatments for transthyretin amyloidosis and/or progression of hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) despite use of approved treatment for ATTRv-PN

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 the specified timeframe:

  1. Patisiran (small interfering ribonucleic acid [siRNA] therapeutic formulated LNP):

     • Part 1: prior history of use;
     • Part 2: last dose administered less than 90 days prior to study drug administration.

  2. Inotersen (antisense oligonucleotide [ASO)]):

     • Part 1: prior history of use;
     • Part 2: last dose administered less than 160 days prior to study drug administration.
  3. Vutrisiran (investigational siRNA therapeutic GalNAc conjugate): prior history of use;
  4. Tafamidis (TTR stabilizer): last dose administered less than 14 days prior to study drug administration;
  5. Diflunisal (TTR stabilizer): last dose administered less than 3 days prior to study drug dosing;
  6. Doxycycline and/or tauroursodeoxycholic acid (TTR matrix solvent): last dose administered less than 14 days of study drug dosing.
  7. Any other investigational agent for the treatment of ATTRv-PN: last dose administered less than 30 days or 5 half-lives, whichever is longer, prior to study drug dosing.

Contacts and Locations

Contacts

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

Locations

New Zealand

Clinical Trial Site; Recruiting

Auckland, New Zealand

United Kingdom

Clinical Trial Site; Recruiting

London, United Kingdom

Sponsors and Collaborators

Intellia Therapeutics

More Information

• Responsible Party: Intellia Therapeutics
• ClinicalTrials.gov Identifier: NCT04601051
• Other Study ID Numbers: ITL-2001-CL-001
• First Posted: October 23, 2020
• Last Update Posted: December 4, 2020
• Last Verified: December 2020

• 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

Keywords provided by Intellia Therapeutics:

NTLA-2001; Pharmacokinetics; Pharmacodynamics; neurologic function; clustered regularly interspaced short palindromic repeats; CRISPR; polyneuropathy; ATTR; transthyretin; TTR; amyloidosis; familial amyloid polyneuropathy; FAP

Additional relevant MeSH terms:

Polyneuropathies; Amyloid Neuropathies, Familial; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Amyloid Neuropathies; Genetic Diseases, Inborn; Amyloidosis, Familial; Metabolism, Inborn Errors