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

Phase 2

Recruiting

Conditions: HAE
Hereditary Angioedema
10027664

Registration Number: NL-OMON54405

Lead Sponsor: Intellia Therapeutics, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 4

Inclusion Criteria

Prospective approval of protocol deviations to recruitment and enrollment
criteria, also known as protocol waivers or exemptions, are not permitted.
Participants are eligible to be included in the study only if all of the
following criteria apply:
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

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:
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 t

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Phase 1<br /><br>• Safety and tolerability as determined by adverse events (AEs)<br /><br>• Dose-limiting toxicities (DLTs)<br /><br>•<br /><br>Phase 2<br /><br>• Number of HAE attacks per month (by HAE Attack Assessment and Reporting<br /><br>Procedure and Reporting Procedure - see Section 10.3), Weeks 1 to 16</p><br>

Secondary Outcome Measures