Hereditary Angioedema MedDRA version: 23.1 Level: PT Classification code 10019860 Term: Hereditary angioedema System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Code: NTLA-2002
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: not yet assigned
Current Sponsor code: mRNA000042
Other descriptive name: Messenger RNA encoding Cas9
Concentrat
Sponsors
Intellia Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 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
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1: Primary Objective - To evaluate the safety of NTLA-2002 and identify dose(s) for use in Phase 2 Phase 2: Primary Objective - To evaluate the effect of NTLA-2002 on HAE attacks;Secondary Objective: Phase 1: Secondary Objectives - To evaluate the pharmacodynamics of NTLA-2002; - To evaluate the effect of NTLA-2002 on HAE attacks - To evaluate the PK of NTLA-2002 Phase 2: Secondary Objectives - To evaluate the safety of NTLA-2002 ; - To evaluate alternate measures of the effect of NTLA-2002 on HAE attacks - To evaluate the PD of NTLA-2002 - To evaluate the PK of NTLA-2002;Timepoint(s) of evaluation of this end point: Phase 1: Primary Endpoint: from Day 1 (post dose) through week 104 (2 years) Phase 2: Primary Endpoint: from Baseline through week 104 (2 years);Primary end point(s): Phase 1: Primary Endpoint: - Safety and tolerability as determined by adverse events (AEs) - Dose-limiting toxicities (DLTs) (Phase 1 only) - Dose selection criteria include safety, pharmacokinetic (PK), pharmacodynamic (PD) (as determined by measurement of plasma kallikrein protein level) and estimated activity (as determined by change in HAE attack rate) Phase 2: - Estimated efficacy as determined by measurement of change from baseline in HAE attack rate per week | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1: Secondary Endpoints: - Estimated efficacy as determined by change from baseline in HAE attack rate per week (by HAE Attack Assessment and Reporting Procedure – see Section 10.3), change from baseline in number of HAE attacks requiring acute therapy (Weeks 1-16, Weeks 5-16) - Change from baseline in total plasma kallikrein protein level - Plasma and urine concentrations for DMG-PEG2k, LP000001, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) messenger ribonucleic acid (mRNA), and single guide RNA (sgRNA) Phase 2 - secondary endopoints - Safety and tolerability as determined by AEs - Change from baseline in HAE attack rate per week (by HAE Attack Assessment and Reporting Procedure – see Section 10.3) (Weeks 5-16), change from baseline in number of HAE attacks requiring acute therapy (Weeks 1-16, Weeks 5-16) - Change from baseline in total plasma kallikrein protein level - Plasma and urine concentrations for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA;Timepoint(s) of evaluation of this end point: Phase 1: Secondary Endpoints: (Weeks 1-16, Weeks 5-16) change from baseline Phase 2: Secondary Endpoints - (Weeks 1-16, Weeks 5-16) change from baseline | — |
Countries
Australia, France, Germany, Netherlands, New Zealand, Spain, United Kingdom, United States
Contacts
Public ContactClinical Program Management
Intellia Therapeutics Inc
Outcome results
None listed