Evaluation of NTLA-3001 Safety and Pharmacokinetics in Adults with Alpha-1 Antitrypsin Deficiency-Associated Pulmonary Emphysema
- Trial ID
- 2023-508138-33-00
- Protocol
- ITL-3001-CL-101
- Sponsor
- Intellia Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of NTLA-3001 following a single treatment in adult participants with Alpha-1 Antitrypsin Deficiency (AATD)-associated lung disease, specifically pulmonary emphysema. This is clinically relevant as it aims to ensure that the investigational gene therapy, NTLA-3001, can be administered safely to patients, which is a critical step before assessing its therapeutic efficacy.
Secondary objectives include:
- Pharmacodynamics (PD): To evaluate the PD effect of NTLA-3001.
- Pharmacokinetics (PK): To evaluate the PK of NTLA-3001.
- Immunogenicity: To evaluate the immune response to NTLA-3001.
- Shedding (Phase 2 only): To evaluate AAV vector shedding following administration of NTLA-3001.
- Exploratory: To evaluate the effect of NTLA-3001 on health-related quality of life (HRQoL).
These secondary objectives are essential for understanding the broader impact of NTLA-3001, including its biological activity, distribution, potential immune reactions, and overall influence on patient well-being.
Participants
The clinical trial involves a total of **26 participants** diagnosed with **pulmonary emphysema** associated with Alpha-1 Antitrypsin Deficiency (AATD). The study population includes both male and female adults aged between **18 to 75 years**. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of AATD-associated lung disease and the ability to provide informed consent. The trial population is required to adhere to certain lifestyle considerations, such as restrictions on alcohol consumption and smoking, as evidenced by a negative cotinine test. Participants must also meet specific laboratory criteria and agree to contraceptive requirements. The study does not include individuals with a prior diagnosis of protein-losing enteropathy, nephropathy, or a history of hypoalbuminemia. The trial aims to evaluate the safety and tolerability of NTLA-3001 following a single treatment in this specific patient group.
Plans and Procedures
The clinical trial is a **Phase 1/2** multicenter, open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-3001 in adult participants with **alpha-1 antitrypsin deficiency** (AATD)-associated lung disease, specifically **pulmonary emphysema**. The trial employs a non-randomized, open-label design, allowing for the collection of comprehensive safety and efficacy data. The study is expected to commence recruitment on November 1, 2024, and conclude by May 1, 2030, with the overall duration spanning approximately six years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, diagnosis, and laboratory parameters. Following the screening, eligible participants will receive a single treatment of NTLA-3001 via **intravenous infusion**. Subsequent follow-up visits will be scheduled to monitor treatment-emergent adverse events (TEAEs) and to assess secondary endpoints such as circulating alpha-1 antitrypsin protein levels, plasma concentration-time profiles, and immunogenicity markers. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected and analyzed.
Participant involvement is anticipated to last for a minimum of 12 weeks post-dosing, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The trial's primary endpoint focuses on the incidence of TEAEs, while secondary endpoints include pharmacokinetic and pharmacodynamic assessments, immunogenicity evaluations, and exploratory quality of life measures. The study aims to provide valuable insights into the therapeutic potential of NTLA-3001 for individuals with AATD-associated lung disease.
Treatment
The clinical trial involves the administration of two experimental medications, both of which are **gene therapy** products developed by Intellia Therapeutics, Inc. The first experimental medication is **SERPINA1(human)-AAV8-1 DP**, a dispersion for infusion. This product is designed to site-specifically introduce a copy of the therapeutic transgene, wild-type **SERPINA1**, into participants. The active substance, **SERPINA1(human)-AAV8-1**, is a structurally diverse substance. The medication is administered via **intravenous infusion**. The dosing schedule and frequency of administration are determined by the study protocol, and participant compliance is monitored throughout the trial.
The second experimental medication is **LNP1265 DP**, also a dispersion for infusion. This product contains **messenger RNA encoding Cas9** and a **single guide RNA** with a sequence complementary to the human ALB locus gene, intron 1, target region. Both active substances are classified as nucleic acids. Similar to the first medication, LNP1265 DP is administered through **intravenous infusion**. The administration schedule is outlined in the study protocol, and adherence to the dosing regimen is closely monitored to ensure participant compliance.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the experimental medications in participants with Alpha-1 Antitrypsin Deficiency (AATD)-associated lung disease. The study is conducted in an open-label format, allowing for direct observation of the effects of the treatments on the participants.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the evaluation of treatment-emergent adverse events (TEAEs) to determine the safety profile of the investigational product, NTLA-3001, in participants with Alpha-1 Antitrypsin Deficiency (AATD)-associated lung disease. Secondary endpoints will include pharmacodynamic (PD) assessments, such as measuring circulating **alpha-1 antitrypsin (AAT)** protein levels, and pharmacokinetic (PK) evaluations, which will involve analyzing plasma concentration-time profiles and PK parameters of the study intervention components.
Additional secondary endpoints will assess immunogenicity by measuring total antibodies (TAb) and neutralizing antibodies (NAb) to AAV, antibodies to AAT protein, anti-drug antibodies to LNP, and anti-Cas9 protein antibodies. Shedding will be evaluated in Phase 2 only, by determining AAV vector genome copy number (VGCN) per cell in blood, urine, saliva, and semen samples. Exploratory endpoints will include patient-reported outcomes using the St George’s Respiratory Questionnaire and the 36-item short form health survey questionnaire (SF-36). These assessments will be conducted at specified timepoints throughout the trial to ensure comprehensive data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participants, 18 to 75 years of age inclusive, at the time of signing informed consent.
- Diagnosis of AATD-associated lung disease meeting specific criteria.
- Per Investigator assessment, the participant has either maximized or refused available standard of care. For participants on AAT augmentation therapy, the Investigator determines that it is clinically acceptable to hold augmentation therapy for at least 4 weeks prior to dosing and refrain from initiating augmentation therapy for at least 12 weeks postdosing. The Investigator will review the protocol with the participant, including temporary withholding of AAT augmentation therapy, and potential consequences.
- No prior diagnosis of protein-losing enteropathy or nephropathy or history of hypoalbuminemia.
- AAV TAb below the laboratory assay cut-off titer.
- Participants must meet specific laboratory criteria.
- aPTT, INR, fibrinogen and D-dimer within the reference range or clinically nonsignificant per Investigator assessment.
- Male participants must agree to the contraceptive requirements and sperm donation restrictions.
- Female participants must not be pregnant or breastfeeding and must agree to the contraceptive requirements and egg (ova, oocyte) restrictions.
- Participants must provide written informed consent before any protocol-specified assessment is performed.
- Participants must agree to the alcohol consumption restrictions.
- Participants must have a negative cotinine test and agree to the smoking and nicotine restrictions.
Exclusion Criteria
- Impaired liver function.
- Any of the following within 12 months prior to Screening: (a) Myocardial infarction; (b) Transient ischemic attack; (c) Cerebrovascular accident; (d) Pulmonary embolism; (e) New York Health Association Class III or IV heart failure.
- History of hepatitis B or C infection or positive hepatitis B surface antigen (HbsAg) or hepatitis C virus antibody (HCV Ab) test. Laboratory results confirmed at Day -1.
- History of positive HIV status or positive HIV status at Screening. Laboratory results confirmed at Day -1.
- Known or suspected systemic parasitic, fungal, or viral infection, including COVID-19, or received antibiotics for bacterial infection; vaccines within 14 days prior to Screening; live vaccines within 30 days prior to Screening. Status confirmed at Day -1.
- Use of corticosteroids above 5 mg/day of prednisone (or equivalent) or other immunosuppressive medications within 4 weeks prior to Screening.
- Have had a serious COPD exacerbation (as determined by the Investigator) or used antibiotics for a COPD exacerbation or respiratory infection within 4 weeks prior to Screening.
- History of anaphylaxis or severe systemic reaction to AAT augmentation therapy, or immune response to AAT augmentation therapy as indicated by clinical history of an adverse immune response to infusion with decreased therapeutic effect in combination with documentation of serum anti-AAT antibodies.
- History of alcohol or drug abuse within 3 years prior to Screening.
- History of active malignancy within 5 years prior to Screening or during the Screening period, except curatively resected basal cell or squamous cell carcinoma of skin.
- Prior liver, heart, or other solid organ transplant; lung volume reduction surgery (LVRS); bone marrow transplant; or anticipated transplant or LVRS within 1 year of Screening. Note: Prior history of or planned corneal transplant is not exclusionary.
- Prior receipt of any gene therapy.
- Receiving an investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the drug prior to Screening. Note: Observational, non-interventional registry trials (studies with no procedural assessments) are acceptable.
- Uncontrolled hypertension (systolic BP > 160 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.
- Participants who have known hypersensitivity to any LNP component (or its excipients) or formulation buffer used to suspend the viral vector, or contraindication to high-dose steroids.
- Unable or unwilling to take the required pretreatment medication regimen or postinfusion corticosteroid regimen.
- Participant is not considered suitable for study inclusion in the opinion of the Investigator for other reasons.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Ireland | Not Recruiting | 01 Nov 2024 | 4 |
Sites & Investigators
Research sites
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 |
|---|---|---|---|---|---|---|
SERPINA1(human)-AAV8-1 DP | Test | DISPERSION FOR INFUSION | INTRAVENOUS INFUSION | — | — | PRD11465081 |
LNP1265 DP | Test | DISPERSION FOR INFUSION | INTRAVENIOUS INFUSION | — | — | PRD11465082 |