Evaluation of NTLA-2002, a CRISPR-Cas9 Gene Editing Therapy, for Safety and Efficacy in Adults with Hereditary Angioedema (HAE)
- Trial ID
- 2024-512317-40-00
- Sponsor
- Intellia Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 1/2 study is to evaluate the **safety** of NTLA-2002 in adults with **Hereditary Angioedema** (HAE) and to identify appropriate dose(s) for use in Phase 2. Additionally, the study aims to assess the effect of NTLA-2002 on HAE attacks. In the placebo crossover and follow-on dosing substudy, the safety of a 50 mg dose of NTLA-2002 will be evaluated in subjects who previously received placebo in Phase 2 or a 25 mg dose of NTLA-2002 in Phase 1 or Phase 2. These objectives are clinically relevant as they aim to establish a safe and effective treatment regimen for managing HAE, a condition characterized by recurrent episodes of severe swelling.
Secondary objectives include:
- Phase 1: To evaluate the **pharmacodynamics** (PD) and **pharmacokinetics** (PK) of NTLA-2002.
- Phase 2: To evaluate the safety of the selected dose(s) of NTLA-2002, alternate measures of the effect of NTLA-2002 on HAE attacks, and the PD and PK of NTLA-2002.
- Substudy: To evaluate the effect of NTLA-2002 on HAE attacks in subjects who previously received placebo in Phase 2 or a 25 mg dose of NTLA-2002 in Phase 1 or Phase 2, and to evaluate the PK of NTLA-2002.
Participants
The clinical trial involves a total of **22 participants** diagnosed with **Hereditary Angioedema** (HAE), a rare genetic disorder. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent. Participants were selected based on their documented diagnosis of HAE Type I or II, confirmed by laboratory assessments. The trial includes individuals who have experienced a minimum of three HAE attacks in the three months preceding the screening. Participants must have access to acute medications for treating angioedema attacks and agree to specific lifestyle considerations, such as limiting alcohol consumption to one drink per day during certain study phases. The trial population is not restricted by gender, and both male and female subjects of childbearing potential are required to adhere to specified contraceptive measures. The study also includes a vulnerable population, ensuring that all participants meet the necessary laboratory criteria for safe participation.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults with **Hereditary Angioedema** (HAE). This is a Phase 1/2 study, structured as a randomized, double-blind, placebo-controlled trial. The trial will involve the administration of NTLA-2002, a **dispersion for infusion**, and a placebo, which is normal saline (0.9% Sodium Chloride Injection). The trial is expected to run from its start date on July 4, 2023, with an estimated end date of June 15, 2026. Recruitment began on October 1, 2021, and is anticipated to conclude by February 6, 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of HAE, and laboratory assessments. Following successful screening, participants will be randomized to receive either NTLA-2002 or placebo. The trial includes multiple follow-up visits to monitor safety and efficacy, with assessments of HAE attack frequency and severity, as well as laboratory evaluations. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected.
The expected length of participant involvement is approximately 16 weeks for the primary observation period, with additional follow-up as required. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities or adverse events that compromise participant safety. Participants are required to adhere to protocol-specified guidelines, including the use of contraception and abstaining from other interventional studies during the trial period. The study aims to identify appropriate dosing for Phase 2 and assess the impact of NTLA-2002 on HAE attack frequency, contributing valuable data to the understanding and management of this condition.
Treatment
The clinical trial involves the administration of **NTLA-2002**, an experimental medication formulated as a **dispersion for infusion**. This investigational product is designed for **intravenous use**. NTLA-2002 comprises two active substances: **ziclumeran** and **lonvoguran**. Ziclumeran is a nucleic acid, specifically a messenger RNA encoding the Cas9 protein, also known as mRNA000042. Lonvoguran is a single guide RNA targeting the human **kallikrein B1 gene (KLKB1)**, referred to as hu-G012267. The lipid nanoparticles containing these active ingredients facilitate the in vivo delivery of the gene-editing components. The dosing schedule and frequency of administration are determined based on the phase of the trial, with the primary objective being the evaluation of safety and dose identification for subsequent phases.
In addition to the experimental treatment, the study employs a placebo control using **normal saline (0.9% Sodium Chloride Injection, USP or local pharmacopeia equivalent)**. This placebo is administered in a manner consistent with the experimental treatment to maintain blinding and ensure the integrity of the trial results. The placebo is not associated with any active substances and serves as a comparator to assess the efficacy and safety of NTLA-2002. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol and accurate assessment of the investigational product's effects.
Efficacy
The efficacy of NTLA-2002 in the treatment of **Hereditary Angioedema (HAE)** will be assessed through a series of primary and secondary endpoints. In Phase 1, the primary endpoint focuses on safety and tolerability, determined by adverse events and dose-limiting toxicities. In Phase 2, the primary endpoint is the number of HAE attacks per month, measured from Weeks 1 to 16 using the HAE Attack Assessment and Reporting Procedure. The Placebo Crossover and Follow-on Dosing Substudy will also evaluate safety through adverse events.
Secondary endpoints in Phase 1 include changes from baseline in total plasma prekallikrein/kallikrein protein levels and plasma and urine concentrations of DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA. In Phase 2, secondary endpoints include the number of HAE attacks per month, the number of attacks requiring acute therapy, and the number of moderate or severe attacks, all measured at various intervals. Additionally, changes from baseline in total plasma prekallikrein/kallikrein protein levels and plasma and urine concentrations of the specified substances will be assessed. The Placebo Crossover and Follow-on Dosing Substudy will similarly evaluate the number of HAE attacks and concentrations of the specified substances.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects ≥ 18 years of age at the time of signing the informed consent.
- 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.
- 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.
- 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.
- Subjects must have access to, and the ability to use, ≥ 1 acute medication(s) to treat angioedema attacks.
- 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
- Follow-On Dosing Substudy: 3. Must meet the following laboratory criteria: a. AST, ALT, and total bilirubin (see exception for Gilbert’s Syndrome below) ≤ ULN range. b. For subjects with a history of Gilbert’s Syndrome, total bilirubin ≤ 2 × ULN. c. Serum creatinine ≤ ULN, or, for subjects in whom serum creatinine is above the ULN, they can be included if the eGFR is > 60 mL/min/1.73 m2 as measured by the Modification of Diet in Renal Disease equation. d. Platelet count ≥ 100,000 cells/mm3.. e. Within reference range or PI-determined clinically nonsignificant aPTT, INR, and fibrinogen.
- Follow-On Dosing Substudy: 4. Male subjects with partners of childbearing potential must agree to using a condom as of the date of substudy informed consent and for 4 months after study drug administration.
- Follow-On Dosing Substudy: 5. Male subjects must agree not to donate sperm for 4 months after study drug administration. The timeframe may be extended beyond the 4 months if sperm donation is contraindicated based on country-specific guidelines
- Follow-On Dosing Substudy: 6. Female subjects of childbearing potential must agree to use a protocol-specified highly effective method of contraception (see Section 10.5) from completion of the substudy informed consent process through 7 months after study drug administration
- Follow-On Dosing Substudy: 7. Must agree not to participate in another interventional study for the duration of this substudy
- Male subjects with partners of childbearing potential must agree to using a condom as of the date of informed consent and for 4 months after study drug administration.
- Male subjects must agree not to donate sperm for 4 months after study drug administration. The time frame may be extended beyond the 4 months if sperm donation is contraindicated based on country-specific guidelines.
- Female subjects of childbearing potential must agree to use a protocol-specified highly effective method of contraception (see Section 10.5) from completion of the informed consent process through 12 months after the last study drug administration. This is not required of female subjects who are either:a. 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 b. Surgically sterile (i.e., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) at least 1 month prior to Screening.
- Follow-On Dosing Substudy: 1. Previously received a 25 mg dose of NTLA-2002 in Phase 1 or Phase 2, and completed the Week 16 assessments.
- Follow-On Dosing Substudy: 2. Must have access to, and ability to use, ≥ 1 acute medication(s) to treat angioedema attacks.
- 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.
- France only: Adults subjects under guardianship are not considered able to provide informed consent
- Follow-On Dosing Substudy: 8. Must be willing to limit alcohol consumption to 1 alcoholic drink per day from Dosing through 28‑days post-dose.
- Follow-On Dosing Substudy: 9. Must be capable of providing signed informed consent.
Exclusion Criteria
- Use of ecallantide from 1 week prior to the start of Screening through the 16-week primary observation period.
- History of cirrhosis.
- 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.
- History of Hepatitis B or C infection or positive Hepatitis B surface antigen (HbsAg) or Hepatitis C virus antibody (HCVAb) test at Screening.
- History of positive human immunodeficiency virus (HIV) status.
- 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.
- Subject has a history of alcohol or drug abuse within 3 years prior to Screening.
- 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.
- Unwilling to comply with study procedures including follow-up as specified by the protocol or unwilling to cooperate fully with the Investigator
- 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.
- Concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema
- 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.
- Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption within 90 days prior to study drug administration.
- Unable or unwilling to take the required pre-treatment medication regimen
- 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.
- Antithrombotic therapy other than aspirin (e.g., warfarin, dabigatran, apixaban) within 14 days prior to study drug administration.
- History of thrombophilia, or positive genetic test for Factor V Leiden and/or prothrombin 20210
- Follow-On Dosing:1. Known hypersensitivity to any LNP component (or its excipients) or who have previously received LNP and experienced any treatment-related clinically significant laboratory abnormalities or AE listed below: a. ALT or AST > 3 × ULN if baseline was normal or > 3 × baseline if baseline was above normal. b. INR or aPTT > 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. IRR to an LNP-containing product (or excipients) requiring discontinuation of infusion; NOTE: slowing of the infusion rate to mitigate an IRR is not considered exclusionary. e. Any LNP treatment-related AE which in the opinion of the Investigator should be exclusionary. 2. Exposure to ACE inhibitors or any estrogen-containing medications with systemic absorption within 90 days prior to study drug administration. 3. Unable or unwilling to take the required pre-treatment medication regimen. 4. Female subjects of childbearing potential are excluded from the substudy 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 Day -1 and/or Day 1. 5. Antithrombotic therapy other than aspirin (e.g., warfarin, dabigatran, apixaban) within 14 days prior to study drug administration. 6. History of thrombophilia, or positive genetic test for Factor V Leiden and/or prothrombin 20210. 7. History of cirrhosis. 8. Known or suspected systemic viral, parasitic, or fungal infection including COVID-19 or received antibiotics for bacterial infection within 14 days prior to Dosing. 9. History of Hepatitis B or C infection. 10. History of positive HIV status. 11. Prior liver, heart, or other solid organ transplant or bone marrow transplant or anticipated transplant within 1 year of Dosing. Note: prior history of or planned corneal transplant is not exclusionary. 12. Subject has a history of alcohol or drug abuse within 3 years prior to Dosing. 13. 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 substudy results, or preclude compliance with the substudy. 14. Unwilling to comply with study procedures including follow-up as specified by the protocol or unwilling to cooperate fully with the Investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Oct 2021 | 2 |
 Germany | Not Recruiting | 01 Oct 2021 | 3 |
 The Netherlands | Not Recruiting | 01 Oct 2021 | — |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
NTLA-2002 | Test | DISPERSION FOR INFUSION | INTRAVENOUS USE | — | — | PRD9172215 |
Normal saline (0.9% Sodium Chloride Injection, USP [or local pharmacopeia equivalent]) will be used for placebo | Placebo | N/A | — | — | — | N/A |