NTLA-2002 in Adults With Hereditary Angioedema (HAE)

Study Overview
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Brief Summary
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This study will be conducted to evaluate the safety, tolerability, activity, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults with Hereditary Angioedema (HAE).

Official Title
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Phase 1/2 Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2002 in Adults With Hereditary Angioedema (HAE)

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Biological: Biological NTLA-2002
* Other: Normal Saline IV Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Diagnosis of HAE Types I or II Ability to provide evidence of HAE attacks to meet the screening requirement Subjects must have access to, and the ability to use, ≥ 1 acute medication(s) to treat angioedema attacks. Adequate chemistry and hematology measures at screening Subjects must agree not to participate in another interventional study for the duration of this trial. Subjects must be capable of providing signed informed consent Exclusion Criteria: Concurrent diagnosis of any other type of recurrent angioedema Subjects who have known negative reaction or hypersensitivity to any lipid nanoparticles (LNP) component. Any condition that, in the Investigator's opinion, could adversely affect the safety of the subject. Unwilling to comply with study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Study Arm<br>Participants assigned to 1 of 3 dose-escalation cohorts will receive a single dose of NTLA-2002 on Day 1 and will then be followed for 104 weeks. Primary observation period is 16 weeks. | Biological: Biological NTLA-2002<br>* CRISPR/Cas9 gene editing system delivered by LNP for IV administration<br>|
| Experimental: Phase 2 Experimental Study Arm<br>Participants randomized to NTLA-2002 (2 dose levels), will receive a single dose of NTLA-2002 on Day 1 and will then be followed for 104 weeks. Primary observation period is 16 weeks. | Biological: Biological NTLA-2002<br>* CRISPR/Cas9 gene editing system delivered by LNP for IV administration<br>|
| Placebo Comparator: Phase 2 Placebo Comparator Study Arm<br>Participants randomized to placebo will receive IV normal saline on Day 1 and will then be followed for up to 104 weeks. Primary observation period is 16 weeks. | Other: Normal Saline IV Administration<br>* The administration of IV normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of NTLA-2002 as determined by adverse events (AEs) and dose limiting toxicities (DLTs) | (Phase 1 only) | From NTLA-2002 infusion up to week 104 post-infusion | 
| Number of HAE attacks per month (Weeks 1-16) | (Phase 2 only) | From study drug infusion up to week 16 post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in total plasma kallikrein protein level | (Phase 1 & 2) | From NTLA-2002 infusion up to week 104 post-infusion | 
| Plasma and urine concentrations for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA | (Phase 1 & 2) | From NTLA-2002 infusion up to week 104 post-infusion | 
| Safety and tolerability of NTLA-2002 as determined by AEs | (Phase 2 only) | From study drug infusion up to week 104 post-infusion | 
| Number of HAE attacks per month (Weeks 5-16) | (Phase 2 only) | From week 6 post-infusion up to week 16 post-infusion | 
| Number of HAE attacks per month requiring acute therapy (Weeks 1-16, Weeks 5-16) | (Phase 2 only) | From study drug infusion up to week 16 post-infusion |