Phase 1 study for people with Alpha-1 Antitrypsin Deficiency

Reproduced exactly, unedited. Written for researchers rather than for patients.

Inclusion Criteria:

1. Male or female participants >18 years and <75 years of age at the time of signing informed consent
2. Total serum AAT levels < 11µM (57 mg/dL)
3. Pi*ZZ genotype confirmed by DNA sequencing within the SERPINA1 gene with no known co-occurring SERPINA1 null variants
4. Spirometry: Forced expiratory volume in 1 second (FEV1) ≥ 40% of predicted
5. Non-smoker, including vaping, for at least 6 months prior to screening
6. Body mass index between 18-33.0 kg/m²
7. Body weight ≥ 45 kg and ≤110 kg
8. Willing and able to give written informed consent prior to the initiation of any study procedure by the participant
9. Negative beta human chorionic gonadotropin (β-hCG) at enrolment for women of childbearing potential (WOCBP) only.
10. Participants who are either a WOCBP or male participant who is heterosexually active with a WOCBP must consent to use a highly effective method of contraception from screening visit until at least 4 weeks after the last dose of investigational medicinal product (IMP).
11. Willing and able to comply with the study design schedule, all study procedures, and other requirements

Exclusion Criteria:

1. Female participants who are nursing or lactating

2. Participant has received AAT augmentation therapy within 30 days prior to Screening Visit or plans to receive AAT augmentation therapy at any time during study participation.

3. Known or suspected allergy or intolerance to AIR-001 or its components

4. Acute respiratory tract infection or clinically-diagnosed chronic obstructive pulmonary disease (COPD) exacerbation that required antibiotic treatment and/or systemic corticosteroids within the 8 weeks prior to dosing.

5. Positive screening test for COVID-19 and/or Influenza.

6. Lung disease that requires use of continuous oral corticosteroids, continuous supplemental oxygen, day-time ventilatory support, or any participant who is on a lung transplant waiting list.

7. Liver Fibrosis score > 10 kPa defined by screening liver elastography, historical liver biopsy showing ≥ F3 fibrosis (METAVIR or comparable scoring system), or established diagnosis of hepatic cirrhosis.

8. Any of the following screening laboratory abnormalities:

   1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma-glutamyl transferase (GGT) > 3 x upper limit of normal (ULN)
   2. Total bilirubin > ULN (note: for participants with documented Gilbert's syndrome and direct bilirubin ≤ ULN , exclusion criterion is total bilirubin is > 2.5 mg/dL)
   3. INR > ULN (for participants taking stable doses of anticoagulants, the exclusion criterion is INR > 3.0)
   4. Platelet count ≤ 150 k/μL
   5. Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m² by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation
   6. Urine Albumin-to-Creatinine Ratio > 300 mg/g
   7. Urine Protein-to-Creatinine Ratio > 500 mg/g

9. Prolonged QT interval on electrocardiogram (ECG), defined as QTcF ≥ 450ms (men) or ≥ 470ms (women)

10. ECG findings at screening that render measurements of QT interval imprecise.

11. History of congestive heart failure, serious cardiac arrythmias requiring anti-arrhythmic medications or unexplained black-outs or fainting episodes with a suspected cardiac origin

12. Positive screening test or known chronic infection with Hepatitis B, Hepatitis C, or HIV.

13. Known history of coagulopathy or bleeding diathesis

14. History or intolerance to subcutaneous (SC) injection including relevant dermatological conditions affecting standard injection sites

15. History or presence of any medical condition, behavioral or psychiatric disorder, or planned surgical procedure or surgical history that may interfere with participation in the study or interpretation of study results, and/or put the participant at significant risk (in the opinion of the investigator) if he/she participates in the study.

16. History of any lung-volume reduction procedure in the 6 months prior to screening.

17. Laboratory value(s) outside the laboratory reference range that is (are) considered to be clinically significant and may affect the safety, efficacy, PK, or PD assessments or interpretation by the Investigator, at screening

18. History of alcohol or drug abuse within the past three months

19. Current or previous participation in any other clinical study where the participant has received a dose of an IMP within 3 months or 5 half-lives of the IMP, whichever is longest, prior to Screening Visit

20. Any previous gene replacement or DNA-editing therapy

21. Any previous use of an RNA-based therapeutic (except for AIR-001 or RNA-based vaccines) within the 6 months prior to the Screening Visit or at any time if stopped due to drug-related adverse event.

22. Use of any new prescription, vaccine, herbal remedy, over-the-counter medication, or supplement, or changes in chronic therapies within the 28 days prior to dosing unless approved by study Medical Monitor.