Alvelestat (MPH996) for the Treatment of ALpha-1 ANTitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of chronic obstructive
pulmonary disease (COPD) and early-onset emphysema. AATD is characterized by low AAT levels;
leading to excessive neutrophil elastase (NE) mediated lung destruction. Current treatment
requires the periodic infusion of pooled AAT derived from human plasma, but this therapeutic
approach does not definitively slow the rate of emphysema progression and is very expensive.
Alvelestat (MPH996, formerly AZD9668) is a potent, selective, and reversible, oral inhibitor
of human NE. Suppression of NE is expected to reduce lung damage and may slow disease
progression. This study is to establish proof of clinical concept by investigating the
mechanistic effect and safety of alvelestat (MPH996) in patients with AATD.

Inclusion Criteria:

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

Type of Participant and Disease Characteristics

1. Capable of giving signed informed consent , which includes compliance with the
requirements and restrictions listed in the informed consent form and in this protocol

2. Age ≥25 and ≤80 years

3. Patients with a diagnosis or confirmation of AATD (Pi*ZZ, Pi*SZ, or Pi*NullNull
genotype/phenotype)

4. FEV1 ≥30% predicted

5. Computed tomography (CT) scan evidence of emphysema by visual reading by local
investigator

6. Male or female sex a. Male participants must agree to use a highly effective
contraception as detailed in Appendix 5 during the treatment period and for at least 4
days after the last dose of study treatment and refrain from donating sperm during
this period b. Female participants are eligible to participate if not pregnant; not
breastfeeding; and at least one of the following conditions is met: i. Not a woman of
childbearing potential OR ii. A woman of childbearing potential who agrees to follow
the specified contraceptive guidance during the treatment phase and for at least 4
days after the last dose of study medication.

Exclusion Criteria:

- Participants are excluded from the study if ANY of the following criteria apply:

Excluded Medical Conditions:

1. Subjects with other AATD phenotypes/genotypes including Pi*MZ

2. Any clinically diagnosed lung disease other than COPD such as diffuse interstitial
lung diseases, cystic fibrosis, or clinically significant bronchiectasis as determined
by the Investigator

3. Acute exacerbation of underlying lung disease requiring oral steroids and/or
antibiotics within 4 weeks of baseline

4. Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies,
including hepatitis B and C antibody)

5. HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 ×
109/L

6. Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase,
gamma-glutamyl transferase) >1.5 × upper limit of normal or total bilirubin > upper
limit of normal (unless Gilbert's disease with normal conjugated bilirubin)

7. Any of the following laboratory abnormalities are present at baseline:

1. Platelet count <150×109/L

2. Serum albumin ≤ 3.5 g/dL

3. INR ≥1.2

4. CPK ≥ ULN.

8. Significant liver fibrosis as evidenced by Fibrosis-4 (FIB-4) score >3.25

9. Cirrhosis

10. Hyperlipidemia requiring statins, where treatment would be initiated during the study
treatment period (subjects on established treatment >28 days will not be excluded)

11. Any of the following cardiovascular conditions within 6 months prior to the screening
visit:

1. Myocardial infarction or unstable angina

2. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary
intervention, or carotid revascularization procedure

3. Uncontrolled hypertension

4. Stroke or transient ischemic attack

12. Congestive heart failure (New York Heart Association III/IV) with left ventricular
ejection fraction < 40%

13. Any clinically significant 12-lead electrocardiogram abnormalities at screening or
baseline, including corrected QT interval by Fridericia's correction method >450 ms or
history of significant cardiac dysrhythmia, including long QT syndrome

14. History of cancer within the last 5 years, except for well-treated basal cell
carcinoma and squamous cell carcinoma of the skin

15. 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:

16. Theophylline, roflumilast, daily use of macrolide antibiotics, daily use of prednisone
(>10mg daily) or other systemic glucocorticoids, and use of other immunosuppressant
therapies are prohibited

17. Immunomodulating monoclonal antibodies within 6 months prior to screening are
prohibited

18. AAT augmentation therapy will be discontinued during the run-in period and will not be
permitted until after completion of the week 12 study visit

19. Daily use of acetaminophen ≥2g/day or daily use of non-steroidal anti-inflammatory
drugs (NSAIDs) is prohibited

20. Initiation of treatment with drugs known for hepatotoxic potential (including but not
restricted to statins, anti-epileptics, antibiotics such as amoxicillin,
amoxicillin/clavulanate, and NSAIDs) within 1 month prior to screening is prohibited

21. Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic
index (eg, warfarin) is prohibited

Excluded Prior/Concurrent Clinical Study Experience:

22. 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

23. Participation in any clinical investigation using biologic treatment within 6 months
of screening is prohibited

24. Previous participation in a gene therapy study for AATD at any time is prohibited

Other Exclusions:

25. 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)