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

Phase 1/2

Active, not recruiting

• Conditions: Hereditary Angioedema

• Registration Number: 2024-512317-40-00
• Lead Sponsor: Intellia Therapeutics Inc.

Brief Summary

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

Placebo Crossover and Follow-on Dosing Substudy: To evaluate the safety of a 50 mg dose of NTLA-2002 in subjects who previously received placebo in Phase 2 or a 25 mg dose of NTLA 2002 in Phase 1 or Phase 2

Detailed Description

Not available

Study Timeline

• Study First Posted: 2024-05-13
• Last Update Posted: 2024-11-22

Recruitment & Eligibility

• Status: Ongoing, recruitment ended
• Sex: Not specified
• Target Recruitment: 15

Inclusion Criteria

Subjects ≥ 18 years of age at the time of signing the informed consent.

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

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.

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.

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

Exclusion Criteria

Use of ecallantide from 1 week prior to the start of Screening through the 16-week primary observation period.

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.

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Phase 1: Primary Endpoint: - Safety and tolerability as determined by adverse events (AEs) - Dose-limiting toxicities (DLTs) Phase 2: - Number of HAE attacks per month (by HAE Attack Assessment and Reporting Procedure – see Section 10.3), Weeks 1 to 16 - Placebo Crossover and Follow-on Dosing Substudy: Safety as determined by AEs		Phase 1: Primary Endpoint: - Safety and tolerability as determined by adverse events (AEs) - Dose-limiting toxicities (DLTs) Phase 2: - Number of HAE attacks per month (by HAE Attack Assessment and Reporting Procedure – see Section 10.3), Weeks 1 to 16 - Placebo Crossover and Follow-on Dosing Substudy: Safety as determined by AEs

Secondary Outcome Measures

Name	Time	Method
Phase 1: - Change from baseline in total plasma prekallikrein/kallikrein protein level		Phase 1: - Change from baseline in total plasma prekallikrein/kallikrein protein level
Phase 1: • 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 1: • 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: Safety and tolerability as determined by AEs		Phase 2: Safety and tolerability as determined by AEs
Phase 2: Number of HAE attacks per month (by HAE Attack Assessment and Reporting Procedure – see Section 10.3) (Weeks 5 to 16) and number of HAE attacks requiring acute therapy per month (Weeks 1 to 16, Weeks 5 to 16)		Phase 2: Number of HAE attacks per month (by HAE Attack Assessment and Reporting Procedure – see Section 10.3) (Weeks 5 to 16) and number of HAE attacks requiring acute therapy per month (Weeks 1 to 16, Weeks 5 to 16)
Phase 2: Number of moderate or severe HAE attacks per month (Weeks 5 to 16)		Phase 2: Number of moderate or severe HAE attacks per month (Weeks 5 to 16)
Phase 2: Change from baseline in total plasma prekallikrein/kallikrein protein level		Phase 2: Change from baseline in total plasma prekallikrein/kallikrein protein level
Phase 2: Plasma and urine concentrations for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA		Phase 2: Plasma and urine concentrations for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
Placebo Crossover and Follow-on Dosing Substudy: • Number of HAE attacks per month (Weeks 1 to 16 and Weeks 5 to 16 following crossover or follow-on dose) • Number of HAE attacks requiring acute therapy per month (Weeks 1 to 16 and Weeks 5 to 16 following crossover or follow-on dose) • Number of moderate or severe HAE attacks per month (Weeks 1 to 16 and Weeks 5 to 16 following crossover or follow-on dose) • Plasma and urine concentrations for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA		Placebo Crossover and Follow-on Dosing Substudy: • Number of HAE attacks per month (Weeks 1 to 16 and Weeks 5 to 16 following crossover or follow-on dose) • Number of HAE attacks requiring acute therapy per month (Weeks 1 to 16 and Weeks 5 to 16 following crossover or follow-on dose) • Number of moderate or severe HAE attacks per month (Weeks 1 to 16 and Weeks 5 to 16 following crossover or follow-on dose) • Plasma and urine concentrations for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA

Trial Locations

Locations (4)

Centre Hospitalier Universitaire De Lille; 🇫🇷 Lille Cedex, France

Centre Hospitalier Universitaire Grenoble Alpes; 🇫🇷 Grenoble Cedex 9, France

Charite Universitaetsmedizin Berlin KöR; 🇩🇪 Berlin, Germany

Academic Medical Center At The University Of Amsterdam; 🇳🇱 Amsterdam, Netherlands

Centre Hospitalier Universitaire De Lille

🇫🇷Lille Cedex, France

David Launay

Site contact

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David.LAUNAY@CHRU-LILLE.FR