A Trial Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of CTX460 in Adults With Emphysema Associated With Severe Alpha-1 Antitrypsin Deficiency (AATD)

Official Title: A Phase 1/2 Multicenter, Open-label, First-in-Human Trial Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of CTX460, a Lipid Nanoparticle Formulation of SyNTase Editing Components for In Vivo Editing of the Serine Protease Inhibitor A1 (SERPINA1) Gene in Adults With Emphysema Associated With Severe Alpha-1 Antitrypsin Deficiency (AATD)

A Study of CTX460 in Adults with Emphysema Associated with Severe Alpha-1 Antitrypsin Deficiency (AATD).

Study Overview

• Status: Not yet recruiting
• Conditions: Alpha-1 Antitrypsin Deficiency (AATD)
• Intervention / Treatment: Drug: CTX460

Detailed Description

This is a dose finding and expansion study of CTX460 in Adults with Emphysema Associated with Severe Alpha-1 Antitrypsin Deficiency (AATD). Participants will receive CTX460 via intravenous (IV) infusion.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials; Phone Number: 877-214-4634; Email: medicalaffairs@crisprtx.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age: ≥18 and ≤75 years.

2. Able to provide written informed consent.

3. Diagnosis of AATD with PiZZ homozygous genotype.

4. Serum total AAT level <11µM in the absence of augmentation.

5. Emphysema on a CT scan at screening.

6. A postbronchodilator forced expiratory volume in 1 second (FEV1) ≥30% of predicted.

7. Body weight ≥50 kg.

8. All male participants must agree to the use of a highly effective method of contraception and their female partners who are women of childbearing potential (WoCBP) are recommended to use a highly effective method of contraception from consent through 6 months after CTX460 infusion.

9. In Phase 1, female participants must not be WoCBP

10. In Phase 2, All female participants are eligible if they:

    1. Are not pregnant or breastfeeding and
    2. Agree to the use of a highly effective method of contraception, as defined in the protocol, from consent through 6 months after CTX460 infusion or are postmenopausal, as defined in the protocol.

11. Participants agree to abstain from alcohol for 2 weeks before and 2 weeks after CTX460 infusion.

12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, contraceptive guidelines, and other trial procedures.

Exclusion Criteria:

1. Received augmentation therapy within the 6 weeks prior to CTX460 infusion
2. Lung or liver transplant or on waiting list for lung or liver transplant
3. Moderate to severe lung disease other than COPD that may confound results as per investigator discretion
4. Evidence of significant liver fibrosis/cirrhosis
5. Participants with cardiovascular disease
6. Participation in another clinical trial with an investigational drug/product within 30 days of screening or <5 half-lives of the investigational agent
7. Exclude participants with an active infection of HBV and HCV
8. Exclude participants with uncontrolled HIV
9. Systemic steroid use within 30 days prior to CTX460 administration; inhaled steroids are permitted
10. Prior treatment with therapy using viral vectors or intended to permanently change a participant's DNA (except for CTX460).
11. Receipt of LNP vaccines ≤4 weeks prior to screening.
12. Participants with a history of medically significant or severe reactions to any LNP-based product, including severe hypersensitivity reactions or anaphylaxis.
13. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the trial or pose an additional risk in administering trial drug to the participant.
14. Active malignancy within past 3 years with the exception of recent basal cell or squamous cell of the skin.
15. Smokers/vapers (nonsmoking/nonvaping for at least 12 months prior to screening are eligible).
16. Participants with specified laboratory abnormalities at screening, confirmed by repeat testing when clinically appropriate.
17. Participants with alcohol use disorder or alcoholic hepatitis within one year prior to screening.
18. In Phase 1 only, females of childbearing potential or breastfeeding females.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1; Phase 1 begins with dose escalation based on a single infusion of CTX460.	Drug: CTX460; CTX460 is a lipid nanoparticle (LNP) formulation of synthetic nucleotide template polymerase (SyNTase) editor for in vivo gene editing of the serine protease inhibitor A1 (SERPINA1) gene in adults with emphysema associated with severe alpha-1 antitrypsin deficiency (AATD).
Experimental: Phase 2; Recommended Phase 2 dose of CTX460.	Drug: CTX460; CTX460 is a lipid nanoparticle (LNP) formulation of synthetic nucleotide template polymerase (SyNTase) editor for in vivo gene editing of the serine protease inhibitor A1 (SERPINA1) gene in adults with emphysema associated with severe alpha-1 antitrypsin deficiency (AATD).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: To evaluate the safety and tolerability of CTX460 in adults with emphysema associated with severe AATD and to determine the recommended Phase 2 dose(s)	Incidence of DLTs and frequency of AEs	From CTX460 infusion up to 36 months
Phase 2: To assess the efficacy of CTX460 in adults with severe AATD and emphysema	Absolute blood levels of total AAT at Month 6	6 months from CTX460 infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: To assess the preliminary efficacy of CTX460	Absolute blood levels of total AAT at Month 6	6 months from CTX460 infusion
Phase 2: To further characterize the safety of CTX460	Frequency and severity of clinically significant laboratory abnormalities, and clinically significant abnormal vital signs	From CTX460 infusion up to 36 months
Phase 1/2: To assess the efficacy of CTX460	Rate of change in lung density (g/L per year) as measured by centralized, standardized CT lung densitometry	From CTX460 infusion up to 36 months
Phase 1/2: To assess the efficacy of CTX460	Time to first moderate or severe COPD exacerbation	From CTX460 infusion up to 36 months
Phase 1/2: To assess the efficacy of CTX460	Annual rate of moderate or severe COPD exacerbations	From CTX460 infusion up to 36 months
Phase 1/2: To assess the efficacy of CTX460	Change from baseline in St. George's Respiratory Questionnaire score over time	From CTX460 infusion up to 36 months
Phase 1/2: To assess the efficacy of CTX460	Change from baseline in FEV1 over time	From CTX460 infusion up to 36 months
Phase 1/2: To assess the effect of CTX460 on blood PD markers	Blood levels of Z-AAT, M-AAT, and fAAT over time	From CTX460 infusion up to 36 months
Phase 1/2: To characterize the PK of CTX460	Plasma levels of LNPs over time (ionizable lipid and PEG-lipid)	From CTX460 infusion up to 36 months

Collaborators and Investigators

• Sponsor: CRISPR Therapeutics

Study record dates

Study Major Dates

• Study Start (Estimated): October 31, 2026
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): June 30, 2030

Study Registration Dates

• First Submitted: September 21, 2026
• First Submitted That Met QC Criteria: September 25, 2026
• First Posted (Actual): September 30, 2026

Study Record Updates

• Last Update Posted (Actual): September 30, 2026
• Last Update Submitted That Met QC Criteria: September 25, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Liver Diseases; Subcutaneous Emphysema; Emphysema; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: CRSP-460-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No