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

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.

• CTX460 (Drug): 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).

Primary outcomes

• 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) [From CTX460 infusion up to 36 months]: Incidence of DLTs and frequency of AEs
• Phase 2: To assess the efficacy of CTX460 in adults with severe AATD and emphysema [6 months from CTX460 infusion]: Absolute blood levels of total AAT at Month 6

Secondary outcomes

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

Sex: All, ages: 18 Years to 75 Years

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.