A Phase 2 placebo-controlled study to evaluate the mechanistic effect, safety, and tolerability of alvelestat (MPH966) in participants with alpha-1 antitrypsin deficiency

• Register: EUCTR
• Last refreshed on: 10 January 2022
• Main ID: EUCTR2018-001309-95-BE
• Date of registration: 02/07/2019
• Prospective Registration: Yes
• Primary sponsor: Mereo BioPharma 4 Ltd
• Public title: A Phase 2 placebo-controlled study to evaluate the mechanistic effect, safety, and tolerability of alvelestat (MPH966) in participants with alpha-1 antitrypsin deficiency
• Scientific title: 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.
• Date of first enrolment: 06/09/2019
• Target sample size: 182
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001309-95
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, Denmark, Poland, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Clinical Operations Department
• Affiliation: Mereo BioPharma 4 Ltd

• Name: Clinical Operations Department
• Affiliation: Mereo BioPharma 4 Ltd

Key inclusion & exclusion criteria

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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 127
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 55

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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Alpha-1 antitrypsin deficiency
MedDRA version: 23.1 Level: LLT Classification code 10001806 Term: Alpha-1 anti-trypsin deficiency System Organ Class: 100000004850

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Product Name: Alvelestat
Product Code: MPH966
Pharmaceutical Form: Tablet
INN or Proposed INN: Alvelestat tosylate
CAS Number: 1240425-05-1
Current Sponsor code: MPH966
Other descriptive name: ALVELESTAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Blood sample for desmosine/isodesmosine: Base, W4, W8, W12 (EOT) and W16 (Safety FU visit)

Primary 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 Aa-Val360 levels

Main Objective: To evaluate the mechanistic and pharmacodynamic effect of alvelestat (MPH966) administered bid for 12 weeks on blood markers of neutrophil elastase activity

Secondary Objective: • 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

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Blood sample for PD BK and PK: Alvelestat PK; IL-6, IL-8, IL-1ß, RANTES, hsCRP, fibrinogen; desmosine/isodesmosine, neutrophil elastase; Aa-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 Aa-Val360
Sputum collection for biomarkers of desmosine, neutrophil elastase and inflammation RANTES, IL-1ß, 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)

Secondary 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

Secondary ID(s)

101534

MPH966-2-01

2018-001309-95-GB

Source(s) of Monetary Support

Mereo BioPharma Group Limited

Ethics review

Status: Approved
Approval date: 06/09/2019
Contact: