Evaluation of NTLA-2002 Efficacy and Safety in Hereditary Angioedema Patients: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2024-515741-42-00
Protocol: ITL-2002-CL-301
Sponsor: Intellia Therapeutics Inc.

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Diseases & Conditions

Hereditary angioedema

Objectives

The primary objective of this Phase 3, multinational, randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** of NTLA-2002 in participants with **hereditary angioedema** (HAE) due to C1 esterase inhibitor deficiency (Type 1 or 2). This is measured by the number of HAE attacks from Week 5 through Week 28, compared to placebo. The clinical relevance of this objective lies in its potential to reduce the frequency of HAE attacks, thereby improving patient outcomes and quality of life.

Secondary objectives include:

Evaluating the efficacy of NTLA-2002 by the number of HAE attacks requiring on-demand treatment from Week 5 through Week 28, compared to placebo.
Assessing the efficacy of NTLA-2002 by the number of moderate or severe HAE attacks from Week 5 through Week 28, compared to placebo.
Determining the efficacy of NTLA-2002 by the percentage of participants who are attack-free from Week 5 through Week 28, compared to placebo.
Evaluating the impact of NTLA-2002 on participant-reported quality of life related to angioedema (AE-QoL) compared to placebo.

Participants

The clinical trial involves a total of **38 participants** diagnosed with **hereditary angioedema due to C1 esterase inhibitor deficiency (Type 1 or 2)**. 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 a clinical history consistent with hereditary angioedema, requiring at least two investigator-confirmed attacks during an 8-week run-in period. The trial includes individuals who are part of a vulnerable population, with specific lifestyle considerations such as refraining from long-term prophylactic therapies and having access to on-demand medications for angioedema attacks. Participants must meet certain laboratory criteria, including liver function tests and renal function, and adhere to contraception guidelines if applicable. The selection process ensures that participants do not partake in other interventional studies during the trial period.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and safety of NTLA-2002 in participants with **hereditary angioedema** due to C1 esterase inhibitor deficiency (Type 1 or 2). The trial is set to commence recruitment on February 3, 2025, and is estimated to conclude by September 22, 2027. Participants will be randomly assigned to receive either NTLA-2002, an advanced therapy medical product, or a placebo, both administered via **intravenous infusion**. The primary objective is to assess the efficacy of NTLA-2002 by measuring the time-normalized number of investigator-confirmed HAE attacks from Week 5 through Week 28 compared to placebo.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, clinical history, and laboratory parameters. Participants must have a clinical history consistent with HAE and meet laboratory criteria, including C1-INH levels and other relevant biomarkers. The screening phase will be followed by a run-in period of up to 8 weeks, during which participants must experience at least two investigator-confirmed HAE attacks to qualify for randomization. The primary observation period will last 28 weeks, during which the efficacy and safety of the intervention will be closely monitored.

Participants will be involved in the study for approximately 36 weeks, including the run-in and primary observation periods. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the protocol, and any adverse events. The end-of-study visit will occur after the completion of the primary observation period, where final assessments will be conducted to evaluate the overall outcomes of the trial. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that pose a significant risk to the participant's health.

Treatment

The clinical trial involves the administration of **NTLA-2002**, an advanced therapy medical product (ATMP) designed for the treatment of **Hereditary Angioedema (HAE)**. NTLA-2002 is a **dispersion for infusion** containing the active substances **ziclumeran** and **lonvoguran**, both originating from nucleic acids. Ziclumeran is synonymous with Messenger RNA encoding Cas9, while lonvoguran is a single guide RNA targeting the human KLKB1 gene. The pharmaceutical form of NTLA-2002 is a dispersion for infusion, and it is administered via **intravenous infusion**. The maximum daily and total dose is 50 mg, with a treatment period limited to one day. The trial aims to evaluate the efficacy of NTLA-2002 by measuring the number of HAE attacks from Week 5 through Week 28, compared to a placebo.

The comparator treatment in this study is **Sodium Chloride**, which serves as the placebo. Sodium Chloride is a **solution for infusion** and is classified as a chemical product. It is also administered via intravenous infusion, with a maximum daily and total dose of 250 ml, and a treatment period of one day. Sodium Chloride is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy

The efficacy of NTLA-2002 in the treatment of **Hereditary Angioedema (HAE)** will be assessed in a Phase 3, multinational, randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the time-normalized number of Investigator-confirmed HAE attacks from Week 5 through Week 28. Secondary endpoints include the time-normalized number of Investigator-confirmed HAE attacks requiring on-demand treatment, the time-normalized number of moderate or severe Investigator-confirmed HAE attacks, Investigator-confirmed HAE attack-free status, and the change from baseline to Week 28 in the Angioedema Quality of Life (AE-QoL) Questionnaire total score.

Efficacy parameters will be measured and collected at specified timepoints, with the primary observation period extending from Week 5 to Week 28. The assessment of HAE attacks will be conducted by investigators, ensuring that the data collected is reliable and consistent. The AE-QoL Questionnaire will be utilized to evaluate changes in quality of life related to angioedema symptoms, providing a comprehensive view of the treatment's impact on patients' daily lives. The analysis of these endpoints will be conducted in accordance with the trial's statistical analysis plan, ensuring rigorous evaluation of NTLA-2002's efficacy compared to placebo.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants must be ≥ 16 years of age.
Clinical history consistent with HAE (recurrent episodes of subcutaneous or mucosal swelling without accompanying urticaria) and all of the following characteristics consistent with HAE-C1INH (Type 1 or 2): a. Symptom onset before age 40 OR documented normal C1q levels to rule out acquired angioedema. b. Functional C1-INH level < 40% of normal OR between 40% and 50% of normal with C4 level below the lower limit of the reference range. Laboratory testing (C1-INH, C4, and C1q) during SCR-2, 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, local genetic testing for known variants in the SERPING1 gene may be used to confirm eligibility upon consultation with the Sponsor.
Participants must have at least 2 Investigator-confirmed and documented HAE attacks during the 8-week Run-in Period. a. Participants experiencing ≥ 2 attacks meeting the above criteria within the first 28 days of the Run-in Period may be randomized at any time after Day 28 of the Run-in Period provided that all eligibility criteria have been met. b. Participants who do not have at least 2 attacks in the first 28 days of the Run-in Period must remain in the Run-inPeriod for the full duration of 8 weeks (56 days).
Participants must agree to refrain from the use of long-term prophylactic therapies from within 5 half-lives prior to the start of the Run-in Period through the end of the 28-week Primary Observation Period, and the Investigator must confirm that this does not place the participant at undue safety risk. Short-term prophylaxis prior to dental or medical procedures is allowed.
Participants must have access to, and the ability to use, on-demand medication(s) to treat angioedema attacks.
Participants must meet the following laboratory criteria: a. AST, ALT, and total bilirubin (see exception for Gilbert’s Syndrome below) ≤ 1.5 × ULN. b. For participants with a history of Gilbert’s Syndrome, total bilirubin ≤ 3 × ULN. c. eGFR is > 30 mL/min/1.73 m2 as measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. d. Platelet count ≥ 100,000 cells/mm3 and ≤ 400,000 cells/mm3. e. INR ≥ 0.8 and ≤ 1.5. f. Within reference range or Principal Investigator-determined clinically nonsignificant aPTT.
Male participants with partners of childbearing potential must agree to using a condom from the date of randomization through 4 months after the second administration of blinded study intervention.
Male participants must agree not to donate sperm from the date of randomization through 4 months after the second administration of blinded study intervention. The time frame may be extended beyond the 4 months if sperm donation is contraindicated based on country-specific guidelines.
Female participants of childbearing potential must agree to use a protocol-specified highly effective method of contraception from completion of the informed consent/assent process through 7 months after the second administration of blinded study intervention. This is not required of female participants who are either: a. Postmenopausal (defined as no menses for 12 months without an alternative medical cause) prior to SCR-2. In addition, at least 2 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 (ie, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) at least 1 month prior to SCR-2.
Female participants must agree to not undergo oocyte retrieval for in vitro fertilization from the date of randomization through 7 months after the second administration of blinded study intervention.
Participants ≥ 18 years of age, emancipated minors, and legal guardians of participants 16 to < 18 years of age must be capable of providing signed informed consent. Participants 16 to < 18 years of age, whose legal guardian provides informed consent, must be willing and able to read, understand, and sign an assent form.
Participants must agree not to participate in another interventional study for the duration of this study.

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Exclusion Criteria

HAE with normal C1-INH or concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema.
History of cirrhosis.
History of venous thromboembolism.
History of hemophilia or other bleeding diathesis.
Active or chronic hepatitis B or C infection or positive HBsAg or HCV Ab test.
History of positive HIV status.
Known or suspected systemic viral, parasitic, or fungal infection, or received antibiotics for bacterial infection or vaccines within 14 days prior to study intervention (30 days for live vaccines)
History of active malignancy within 3 years prior to SCR-2 or during the Run-in Period, except: a. Basal cell carcinoma of skin. b. Curatively resected squamous cell carcinoma of the skin. c. Cervical carcinoma in situ curatively treated. d. Nonmetastatic prostate adenocarcinoma stably managed on hormonal therapy by a medical oncologist or for which appropriate management is observation alone.
History of alcohol or drug abuse within 3 years prior to SCR-2.
Exposure to ACE inhibitors or any estrogen-containing medications with systemic absorption within 90 days prior to study intervention.
Antithrombotic therapy (eg, warfarin, dabigatran, apixaban) other than low-dose aspirin (< 100 mg) within 14 days of study intervention.
Prior liver, heart, or other solid organ transplant; bone marrow transplant; or anticipated transplant within 1 year of SCR-2. Note: Prior history of or planned corneal transplant is not exclusionary.
Previous treatment with gene therapy for HAE.
Known or suspected intolerance or contraindication to the IMP, auxiliary products, or ingredients of either, including placebo solution.
Unable or unwilling to take the required pretreatment medication regimen.
Female participants of childbearing potential are excluded from the study if they: a. Are breastfeeding or plan to breastfeed from the date of randomization through 3 months after the second administration of blinded study intervention. b. Are pregnant or have a positive pregnancy test at SCR-2 and/or Day -1.
Any condition, laboratory abnormality, or other reason that, in the Investigator’s opinion, could adversely affect the safety of the participant, impair the assessment of study results, or preclude adherence to the study protocol.
Unwilling to comply with study procedures including follow-up as specified by the protocol or unwilling to cooperate fully with the Investigator.