Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency

Inclusion Criteria

Participants are eligible to be included in the study only if ALL of the following criteria apply:

• Capable of giving signed informed consent as described in Appendix 3, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol
• Age ≥18 and ≤80 years
• Patients with a confirmed diagnosis of AATD: Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level 1.5 × upper limit of normal or total bilirubin > upper limit of normal (unless Gilbert's disease with normal conjugated bilirubin)
• Any of the following laboratory abnormalities are present at baseline:
• Platelet count 20g/ day in female subjects and >30g/ day in male subjects.
• Fibrosis-4 (FIB-4) score >3.25
• Any of the following cardiovascular conditions within 6 months prior to the screening visit:
• Myocardial infarction or unstable angina
• Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid revascularization procedure
• Uncontrolled hypertension
• Stroke or transient ischemic attack
• Congestive heart failure (New York Heart Association III/IV) with left ventricular ejection fraction 450 ms or history of significant cardiac dysrhythmia, including long QT syndrome
• History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma of the skin
• Other documented comorbidities or laboratory abnormalities that in the opinion of the Investigator could affect the outcome of the study assessments, participant safety, or ability of the participant to comply with the requirements of the protocol

Excluded Prior/Concomitant Therapy

• Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable or higher equivalent dose, or use of other immunosuppressant therapies are prohibited
• Immunomodulating monoclonal antibodies within 6 months prior to screening are prohibited
• Daily use of non-steroidal anti-inflammatory drugs (NSAIDs) is prohibited. Daily use of acetaminophen up to 2 g per day and aspirin up to 325 mg per day is permitted.
• Initiation of drugs known for hepatotoxic potential within the 28 days prior to screening including but not limited to: statins, NSAIDS, amoxicillin/clavulanate, PDE inhibitors (theophylline, roflumilast), and anti-epileptics. Subjects on established treatment for more than 28 days prior to screening will not be excluded. Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic index (eg, warfarin, phenytoin) is prohibited

Excluded Prior/Concurrent Clinical Study Experience

• Participation in any clinical investigation using medical devices or non-biologic treatments within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initial dosing (or longer if required by local regulations) is prohibited
• Participation in any clinical investigation using biologic treatment within 6 months of screening is prohibited
• Previous participation in a gene therapy study for AATD at any time is prohibited

Other Exclusions

• History of hypersensitivity to alvelestat (MPH966) or any of its excipients or the class of neutrophil elastase inhibitors
• Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine for bronchoscopy)