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    Summary
    EudraCT Number:2018-001309-95
    Sponsor's Protocol Code Number:MPH966-2-01
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-07-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-001309-95
    A.3Full title of the trial
    A Phase 2, proof-of-concept, multicentre, double-blind, randomised, dose-ascending, sequential group, placebo-controlled study to evaluate the mechanistic effect, safety, and tolerability of 12 weeks twice daily oral administration of alvelestat (MPH966) in participants with alpha-1 antitrypsin deficiency.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 placebo-controlled study to evaluate the mechanistic effect, safety, and tolerability of alvelestat (MPH966) in participants with alpha-1 antitrypsin deficiency
    A.4.1Sponsor's protocol code numberMPH966-2-01
    A.5.4Other Identifiers
    Name:INDNumber:101534
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMereo BioPharma 4 Ltd
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMereo BioPharma Group Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMereo BioPharma 4 Ltd
    B.5.2Functional name of contact pointClinical Operations Department
    B.5.3 Address:
    B.5.3.1Street Address1 Cavendish Place
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW1G 0QF
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number4403330237300
    B.5.5Fax number4403330237301
    B.5.6E-mailenquiries@mereobiopharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAlvelestat
    D.3.2Product code MPH966
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAlvelestat tosylate
    D.3.9.1CAS number 1240425-05-1
    D.3.9.2Current sponsor codeMPH966
    D.3.9.3Other descriptive nameALVELESTAT
    D.3.9.4EV Substance CodeSUB130609
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alpha-1 antitrypsin deficiency
    Alpha-1 antitrypsin deficiency
    E.1.1.1Medical condition in easily understood language
    Alpha-1 antitrypsin deficiency is a genetic disorder that may result in lung disease or liver disease.
    Alpha-1 antitrypsin deficiency is a genetic disorder that may result in lung disease or liver disease.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10001806
    E.1.2Term Alpha-1 anti-trypsin deficiency
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the mechanistic and pharmacodynamic effect of alvelestat (MPH966) administered bid for 12 weeks on blood markers of neutrophil elastase activity
    E.2.2Secondary objectives of the trial
    • To evaluate the effect of alvelestat (MPH966) on neutrophil elastase activity
    • To characterize the pharmacokinetic (PK) profile of alvelestat
    • To evaluate the safety and tolerability of alvelestat (MPH966) administered bid for 12 weeks and effect of within subject dose-escalation on safety and tolerability of within-subject dose escalation in the 240 mg bid dose
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Sputum will either be induced or spontaneously produced by participants.
    • Sputum will be collected from all participants that spontaneously produce sputum according to the MPH966-2-01 Study Procedures Manual.
    • Participants who do not spontaneously produce sputum will be invited to participate in the induced sputum subset study. The aim to meet the study objectives is to include approximately 30% to 50% of non-sputum producers in the subset study. Sputum induction will not be undertaken if the baseline FEV1 for the procedure is less than 1 L. Further details of sputum induction will be included in the MPH966-2-01 Study Procedures Manual.
    E.3Principal inclusion criteria
    1. Age 18 to 75 years at screening
    2.Participants with a diagnosis or confirmation of AATD (PiZZ or, null or other rare phenotype/genotype) with an associated serum AAT levelslevel of <11 µM or <57.2 mg/dL
    3.Post-bronchodilator FEV1≥20% predicted at screening
    4.Computerised tomography (CT) scan evidence of emphysema
    5.Non-smokers (for at least 12 months prior to baseline)
    6.Absence of advanced liver fibrosis or cirrhosis:
    a.Fibrosis-4 (FIB-4) score <1.45 or
    b.FIB-4 score >1.45 and ≤3.25 with transient elastography measurement <12.5 kPa within 3 months of baseline
    7.Male or female
    Male participants: A male participant 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
    Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least 1 of the following conditions applies:
    a.Not a woman of childbearing potential as defined in Appendix 5 OR
    b.A woman of childbearing potential who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 4 days after the last dose of study treatment
    8.Capable of giving signed informed consent as described in Appendix 3, which includes a commitment to comply with the requirements and restrictions listed in the informed consent form (ICF) and within this protocol
    E.4Principal exclusion criteria
    1. Participants with PiMZ, PiFF or PiSZ AATD phenotypes/genotypes
    2. Primary clinical diagnosis of bronchiectasis or evidence of significant bronchiectasis on CT scan (per Investigator judgement and with CT scan performed during the 3 years prior to dosing)
    3. Acute exacerbation of underlying lung disease requiring oral corticosteroids, antibiotics, and/or change in regular treatments within 4 weeks of baseline
    4. Acute or chronic hepatitis, including hepatitis B and or C virus infection (positive hepatitis B surface antigen, and /or hepatitis C antibody) at screening
    5. Known history or present diagnosis of cirrhosis (on imaging or biopsy), oesophageal varices, ascites or hepatic encephalopathy
    6. History of other chronic liver diseases such as autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson’s disease, haemochromatosis
    7. History of non-alcoholic fatty liver disease (NAFLD).
    8. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening, defined as an average of >20 g / day in female subjects and >30 g/ day in male subjects
    (For reference, 14g of alcohol are contained in the following: 12fl oz (355ml) regular beer containing ~5% alcohol; 8-9fl oz (235 to 265ml) malt liquor containing ~7% alcohol; 5fl oz (150ml) of table wine containing ~12% alcohol or 1.5fl oz (45ml) of distilled spirits (e.g. gin, rum, vodka, whiskey) containing ~40% alcohol)
    9. History of alcohol and/or drug abuse within the 15 years prior to screening
    10. HIV infection OR known other immunodeficiency OR an absolute neutrophil count ≤1.0 × 109/L at screening
    11. Any of the following lab abnormalities suggestive of liver disease: abnormal liver-related biochemistry at screening (alanine aminotransferase, aspartate aminotransferase) >1.5 × upper limit of normal OR gamma-glutamyl transferase >2 × upper limit of normal OR total bilirubin > upper limit of normal (unless Gilbert’s disease with normal conjugated bilirubin), platelet count <150 x 109/L, serum albumin ≤ 3.5g/dL or INR ≥1.2 (in the absence of drugs known to elevate INR, for example anticoagulant therapy) or CPK ≥1.5 x ULN
    12. FIB-4 score >3.25 at screening
    13. Any of the following cardiovascular conditions within 6 months prior to the screening visit:
    a. Myocardial infarction or unstable angina
    b. Stroke or transient ischaemic attack
    c. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid revascularisation procedure
    d. Uncontrolled hypertension within the 3 months prior to screening in the Investigators judgement
    e. Congestive heart failure (New York Heart Association III/IV)
    14. Any clinically significant 12-lead electrocardiogram abnormalities at screening or baseline OR corrected QT interval by Fridericia’s correction method >450 ms OR history of significant cardia dysrhythmia, including long QT syndrome
    15. Significant renal disease or infection (as determined by the Investigator) including stage 4 chronic kidney disease or estimated glomerular filtration rate <45 mL/min
    16. History of cancer within the 5 years prior to screening, except for well-treated cutaneous basal cell carcinoma, squamous cell carcinoma of the skin and cervical cancer
    17. Other clinically relevant haematology parameters that could impact the safety of the participant in the Investigator’s judgement
    18. Other documented comorbidities that in the opinion of the Investigator could affect the outcome of the study assessments or ability of the participant to comply with the requirements of the protocol
    19. Lung or lung volume reduction surgery (LVRS) or liver transplant has been performed or the participant is listed and active on a transplant waiting list
    Prior/Concomitant Therapy
    20. Immunosuppressive therapies including regular systemic corticosteroids (>5 mg daily or equivalent for greater than 14 consecutive days) within the month prior to baseline
    21. Immunomodulating monoclonal antibodies within the 6 months prior to baseline
    22. Previous AAT augmentation therapy within the 6 months prior to baseline
    23. A clinical requirement to initiate new treatment with drugs associated with NAFLD or hepatoxicity (See Appendix 8) during the study period (Baseline through Week 12 Visit) or within the 4 weeks prior to baseline. Stable therapy initiated more than 4 weeks prior to Baseline is acceptable.
    E.5 End points
    E.5.1Primary end point(s)
    Within individual change from baseline up to end of treatment (weeks 4, 8 and week 12) and in comparison to placebo in:
    • Blood Neutrophil Elastase activity
    • Plasma desmosine/isodesmosine levels
    • Blood Aα-Val360 levels
    E.5.1.1Timepoint(s) of evaluation of this end point
    Blood sample for desmosine/isodesmosine: Base, W4, W8, W12 (EOT) and W16 (Safety FU visit)
    Blood sample for desmosine/isodesmosine: Base, W4, W8, W12 (EOT) and W16 (Safety FU visit)
    E.5.2Secondary end point(s)
    •Within individual change from baseline up to end of treatment (weeks 4, 8 and week 12) and in comparison to placebo in:
    • Frequency of neutrophil elastase levels below the limit of detection from baseline to end of treatment (weeks 4, 8 and 12)
    • Pharmacokinetic concentration and derived parameters up to week 12
    Numbers and % of participants who
    experience at least 1 treatment-emergent
    adverse event
    • Adverse events of special interest (liver function abnormalities, corrected QT interval/cardiac, infections, and neutropenia)
    • Relationship of pharmacokinetics (PK) and safety
    • Adverse event profile in 240 mg bid dose group in within-subject dose-escalation and no within-subject dose-escalation subgroups
    E.5.2.1Timepoint(s) of evaluation of this end point
    Blood sample for PD BK and PK: Alvelestat PK; IL-6, IL-8, IL-1β, RANTES, hsCRP, fibrinogen; desmosine/isodesmosine, neutrophil elastase; Aα-Val360; PGP; neutrophil elastase, EL-NE, EL-CG, EP-3, C6M, C1M, PRO-C6, PRO-C3, C3M, C4Ma3: Base, W4, W8, W12 (EOT) + W16 (Safety FU visit) for desmosine/isodesmosine, neutrophil elastase and Aα-Val360
    Sputum collection for biomarkers of desmosine, neutrophil elastase and inflammation RANTES, IL-1β, IL-6, IL-8, LTB4, PGP: Base, W4, W8, W12 (EOT). For induced sputum collection: Screening, baseline, W12 (EOT)
    Lung function tests (FEV1, FVC, FEV1/FVC, maximal mid-expiratory flow): Base, W4, W8, W12 (EOT)
    12-Lead ECG: Baseline, W4, W8, W12 (EOT)
    Clinical laboratory tests: Scr, Base, W2, W4, W8, W12, Safety FU visit
    SGRQ-C: Base, W4, W8, W12 (EOT)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Mechanistic effect
    Mechanistic effect
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    Denmark
    Poland
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of all data being entered into the study database and the database being locked and ready for analysis.

    Mereo BioPharma 4 Ltd (sponsor) considers that the trial is ended when the clinical database is locked and all data is ready for analysis, which should occur within 1 month after the last patient last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days15
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 127
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 117
    F.4.2.2In the whole clinical trial 182
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-08-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-05-20
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