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

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Brief Title

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

Official Title

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

Brief Summary

      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 alpha-1
      (Pi*ZZ, Pi*SZ, Pi*Z Null, or Pi*Null phenotype) antitrypsin deficiency (AATD)-related
      emphysema.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Within-individual % change in plasma desmosine/isodesmosine


Condition

Alpha-1 Antitrypsin Deficiency (AATD)

Intervention

Alvelestat (MPH966)

Study Arms / Comparison Groups

 Alvelestat (MPH966)
Description:  Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

66

Start Date

April 8, 2019

Completion Date

August 2021

Primary Completion Date

August 2021

Eligibility Criteria

        Inclusion Criteria:

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

          1. 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

          2. Age ≥18 and ≤80 years

          3. Patients with a diagnosis or confirmation of AATD (Pi*ZZ, Pi*SZ, Pi*Z Null, or Pi*Null
             genotype/phenotype). Historical laboratory reports are acceptable.

          4. FEV1 ≥25% predicted

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

          6. 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.

          7. 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

          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. History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices,
             ascites or hepatic encephalopathy.

          9. 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).

         10. 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).

         11. 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.

         12. Fibrosis-4 (FIB-4) score >3.25

         13. 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

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

         15. 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

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

         17. 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

         18. Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable
             or higher equivalent dose, or use of other immunosuppressant therapies are prohibited

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

         20. 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.

         21. 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

         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

         26. Known hypersensitivity to medications used in the study procedures (e.g. midazolam,
             fentanyl, and lidocaine for bronchoscopy)
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Mark T Dransfield, MD, 205-934-5555, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03679598

Organization ID

IRB-300002338

Secondary IDs

4UH3TR002450-02

Responsible Party

Principal Investigator

Study Sponsor

University of Alabama at Birmingham

Collaborators

 National Institutes of Health (NIH)

Study Sponsor

Mark T Dransfield, MD, Principal Investigator, University of Alabama at Birmingham


Verification Date

June 2020