A Study to Evaluate NTLA-2002 in adults with Hereditary Angioedema (HAE)

Phase 1

Conditions: Hereditary Angioedema
MedDRA version: 23.1Level: PTClassification code 10019860Term: Hereditary angioedemaSystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Registration Number: EUCTR2021-001693-33-DE

Lead Sponsor: Intellia Therapeutics, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 37

Inclusion Criteria

1. Subjects = 18 years of age at the time of signing the informed consent.
2. Documented diagnosis of HAE (Type I or II) confirmed by laboratory assessment of functional C1-INH level and C1-INH concentration:
a. For HAE Type I: Both functional C1-INH level AND C1-INH concentration should be <50% of normal limits (or per local standard)
b. For HAE Type II: Functional C1-INH level should be <50% of normal limits (or per local standard). C1-INH concentration may be normal or
above normal.
C1-INH testing during screening, at either the central or an accredited local laboratory, or previously documented results from an accredited
local laboratory may be used to confirm eligibility. If frequent use of C1- INH for the prevention or treatment of HAE attacks would confound
interpretation of C1-INH testing, genetic testing for known variants in the SERPING1 gene in a local laboratory may be used to confirm
eligibility upon consultation with the Sponsor.
3. Investigator-confirmed attacks (per Appendix 3 in Section 10.3):
a. Phase 1 only: Subjects must have an Investigator-confirmed and documented historical HAE attack number of at least 3 during the
previous 3 months (90 days) from the start of screening.
b. Phase 2 only: Subjects must have an Investigator-confirmed and documented historical HAE attack number of at least 3 during the
previous 3 months (90 days) to enter the Screening/Run-In period and an Investigator-confirmed and documented HAE attacks number of at
least 2 during the up to 8-week (up to 56-day) Screening/Run-In period (or at least 3 to be eligible for early enrollment and randomization).
c. Netherlands only: For both Phase 1 and Phase 2, subjects must have had inadequate control of HAE attacks, as determined by the
Investigator, while receiving at least one prior prophylactic regimen, or have required discontinuation from, or otherwise be ineligible for,
available prophylactic agents.
4. Phase 2 only: Subjects must agree to refrain from the use of prophylactic therapies from within 5 half-lives prior to the start of the
Screening/Run-In period through the end of the 16-week primary observation period, and the Investigator must confirm that this is
medically appropriate and does not place the subject at undue safety risk. See Section 10.2 for a list of prophylaxis agents, half-lives, and
recommended wash-out period.
5. Subjects must have access to, and the ability to use, = 1 acute medication(s) to treat angioedema attacks.
6. Subjects must meet the following laboratory criteria during Screening:
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (see exception for Gilbert's Syndrome below) = upper
limit of normal (ULN) range at Screening.
b. For subjects with a history of Gilbert's Syndrome, total bilirubin = 2 × ULN on screening evaluation.
c. Serum creatinine is = ULN, or, for subjects in whom serum creatinine is above the ULN, they can be included if the estimated glomerular
filtration rate (eGFR) is > 60 mL/min/1.73 m2 as measured by the Modification of Diet in Renal Disease equation at Screening.
d. Platelet count = 100,000 cells/mm3 at Screening.
e. Within reference range or Principal Investigator (PI)-determined clinically non-significant activated partial thromboplastin time (aPTT),
international normalized ratio (INR), fibrinogen and d-dimer levels at Screening.
7. Male subjects with partners of childbearing potential must agree to using a condom as of the date of informed consent an

Exclusion Criteria

1. Use of ecallantide from 1 week prior to the start of Screening through the 16-week primary observation period.
2. Use of C1 esterase inhibitor (C1-INH) for HAE within 5 half-lives of the agent before initiation of the Phase 2 Screening/Run-In period, i.e., 24-
hour washout is required before starting the Screening/Run-In period after the use of rabbit purified C1-INH (ruconest), and 4-day washout is
required before starting the Screening/Run-In period after the use of human plasma purified C1-INH (berinert). Note: during the
Screening/Run-In period, C1-INH may be used to treat an acute HAE attack.
3. Concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema.
4. Subjects who have known hypersensitivity to any lipid nanoparticles (LNP) component (or its excipients) or who have previously received
LNP and experienced any treatment-related clinically significant laboratory abnormalities or AEs listed below:
a. ALT or AST > 3 × ULN if baseline was normal or > 3 × baseline if baseline was above normal.
b. INR, aPTT or d-dimer > 1.5 × ULN if baseline was normal or > 1.5 × baseline if baseline was above normal.
c. Any LNP treatment-related AEs classified as CTCAE Grade 3 or higher.
d. Infusion-related reaction (IRR) to an LNP-containing product (or excipients) requiring treatment or discontinuation of infusion; NOTE:
slowing of the infusion rate to mitigate an IRR is not considered exclusionary.
e. Any LNP treatment-related AEs which in the opinion of the Investigator should be exclusionary.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption within 90
days prior to study drug administration.
6. Unable or unwilling to take the required pre-treatment medication regimen.
7. Female subjects of childbearing potential are excluded from the study if they:
a. are breastfeeding or plan to breastfeed during treatment and for an additional 12 months after the last study drug administration.
b. have a positive pregnancy test at screening and/or Day 1.
8. Antithrombotic therapy other than aspirin (e.g., warfarin, dabigatran, apixaban) within 14 days prior to study drug administration.
9. History of thrombophilia, or positive genetic test for Factor V Leiden and/or prothrombin 20210.
10. History of cirrhosis.
11. Known or suspected systemic viral, parasitic, or fungal infection including coronavirus disease (COVID-19) or received antibiotics for
bacterial infection within 14 days prior to Screening.
12. History of Hepatitis B or C infection or positive Hepatitis B surface antigen (HbsAg) or Hepatitis C virus antibody (HCVAb) test at Screening.
13. History of positive human immunodeficiency virus (HIV) status.
14. Prior liver, heart, or other solid organ transplant or bone marrow transplant or anticipated transplant within 1 year of Screening. Note: prior history of or planned corneal transplant is not exclusionary.
15. Subject has a history of alcohol or drug abuse within 3 years prior to Screening.
16. Any condition, laboratory abnormality, psycho-social stressor, pattern of behavior, or other reason that, in the Investigator's opinion,
could adversely affect the safety of the subject, impair the assessment of study results, or preclude compliance with the study.
17. Unwilling to comply with study procedures including follow-up as specified by the protocol or unwilling to cooperate fully with the
Investigator.