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-FR

Lead Sponsor: Intellia Therapeutics, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 55

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).
3. Investigator-confirmed attacks:
a. Subjects in Phase 1 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. Phase 1 subjects may not have
received HAE prophylaxis during the 3 months (90 days) historical attack
period.
b. Subjects in Phase 2 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 run-in period, and must have an
Investigator-confirmed and documented historical HAE attack number of
at least 2 during the 8-week (56-day) run-in-period to be eligible for
enrollment and randomization.
4. Subjects must have access to, and the ability to use, = 1 acute medication(s) to
treat angioedema attacks.
5. Subjects must meet the following laboratory criteria during Screening:
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total
bilirubin (see exception for Gilbert’s Syndrome below), and international
normalized ratio (INR) = 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 > 45 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 partial thromboplastin time (aPTT),
prothrombin time (PT), fibrinogen and d-dimer levels at Screening.
6. Male subjects with partners of child-bearing potential must agree to using a
condom prior to Screening and for 90 days after study drug administration.
7. Male subjects must agree not to donate sperm for 90 days after study drug
administration. The time frame may be extended beyond the 90 days, if sperm
donation is contraindicated based on country-specific guidelines.
8. A female subject must be:
? Postmenopausal (defined as no menses for 12 months without an
alternative medical cause) prior to Screening. In addition, at least 2 high
follicle stimulating hormone (FSH) measurements in the postmenopausal
range may be used to confirm a postmenopausal state in women with less
than 12 months of amenorrhea and not using hormonal contraception or
hormonal replacement therapy; OR
? Surgically sterile (i.e., hysterectomy, bilateral salpingectomy, and
bilateral oophorectomy) at least 1 month prior to Screening.
9. Subjects must agree not to participate in another interventional study for the
duration of this trial.
10. Subjects must be capable of providing signed informed consent.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 45
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion Criteria

1. Use of long-term prophylaxis for HAE within 5 half-lives prior to the start of
Screening or during the Phase 1 historic attack period; see Section 10.2 for list
of prophylaxis agents, half-lives, and recommended washout period.
2. Use of ecallantide, attenuated androgens, or anti-fibrinolytics for HAE within
2 days prior to entering the start of Screening visit, or during the Phase 1
historic attack period, or during the Phase 2 run-in period.
3. Use of C1 esterase inhibitor (C1-INH) for HAE within 5 half-lives of the
agent before initiation of the Phase 2 run-in period; i.e., 24-hour washout is
required before starting the run-in period after the use of rabbit purified
C1-INH (ruconest), and 4-day washout is required before starting the run-in
period after the use of human-plasma-purified C1-INH (berinert). Note:
during the run-in period, C1-INH may be used to treat an acute HAE attack.
4. Concurrent diagnosis of any other type of recurrent angioedema, including
acquired or idiopathic angioedema.
5. Subjects who have known hypersensitivity to any lipid nanoparticles (LNP)
component or who have previously received LNP and experienced any
treatment-related clinically significant laboratory abnormalities or adverse
event 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 adverse event classified as CTCAE
Grade 3 or higher.
d. Infusion-related reaction (IRR) to an LNP containing product
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 adverse event which in the opinion of the
Investigator should be exclusionary.
6. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any
estrogen-containing medications with systemic absorption within 90 days
prior to study drug administration.
7. Unable or unwilling to take the required pre-treatment medication regimen.
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 unwil