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

Study Overview
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Brief Summary
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This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of alvelestat (MPH966) in subjects with confirmed AATD defined as Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired AAT including F or I mutations.

Detailed Description
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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 (termed augmentation) does not definitively slow the rate of emphysema progressionlung function decline and is very expensive. In addition, it is not clear that the currently recommended dose for augmentation fully controls lung inflammation and destruction. Alvelestat (MPH966, 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 (MPH966) in patients with AATD.

Official Title
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A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency a Genetically Linked Orphan Disease

Conditions
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Alpha-1 Antitrypsin Deficiency (AATD), Pi*ZZ, Pi*SZ, Pi*Null, Another Rare Phenotype/Genotype Known to be Associated With Either Low or Functionally Impaired AAT Including F or I Mutations, Emphysema or COPD

Intervention / Treatment
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* Drug: Alvelestat (MPH966)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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 <11 μM or <57.2 mg/dL) or functionally impaired AAT including F or I mutations. FEV1 ≥25% predicted Patients will be eligible if they are either a) are not currently receiving augmentation treatment and have not received augmentation in the 12 weeks prior to screening or b) have received weekly infusions of augmentation at 60 mg/kg for at least 12 weeks prior to screening and intend to continue augmentation through the study period. 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 as defined in Appendix 5 OR ii. A woman of childbearing potential who agrees to follow the contraceptive guidance in Appendix 5. 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 Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes/genotypes not known to be independently associated with emphysema. 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 Acute exacerbation of underlying lung disease requiring oral steroids and/or antibiotics within 4 weeks of baseline Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, including hepatitis B and C antibody) HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 × 109/L 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) Any of the following laboratory abnormalities are present at baseline: Platelet count <150×109/L Serum albumin ≤ 3.5 g/dL INR ≥1.2 CPK ≥ ULN. History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices, ascites or hepatic encephalopathy. Evidence of other forms of chronic liver disease based on diagnostic testing as per the guidelines (i.e. autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, Hemochromatosis or iron overload). Patients with nonalcoholic fatty liver disease (NAFLD) as diagnosed by any imaging modality (or use of drugs associated with NAFLD for more than 2 weeks in the year prior to screening). Subjects with a history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening, defined as average of >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 < 40% 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized (1:1), placebo-controlled
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Alvelestat (MPH966)<br>Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks | Drug: Alvelestat (MPH966)<br>* Alvelestat was developed as treatment for lung diseases like Chronic Obstructive Pulmonary Disease. Alevelestat works by blocking certain proteins in the body that are responsible for inflammation and damage to the lungs that can lead to COPD symptoms.<br>|
| Placebo Comparator: Placebo<br>4 Placebo tablets twice daily by mouth for 12 weeks | Other: Placebo<br>* Placebo is a pill or tablet that does not contain any study drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Within-individual % change in plasma desmosine/isodesmosine | To evaluate the effect of alvelestat (MPH966) administered twice daily (bid) for 12 weeks on blood markers of neutrophil elastase activity, within-individual % change in plasma desmosine/isodesmosine will be measured. | baseline, week 12 | 
| Numbers and % of subjects who experience at least 1 treatment-emergent adverse event | To evaluate the safety and tolerability of alvelestat (MPH966) administered twice daily (bid) for 12 weeks treatment numbers and % of subjects who experience at least 1 treatment-emergent adverse event will be measured. | baseline, week 16 |