Alpha-1 Antitrypsin Deficiency (AATD), Emphysema or COPD, 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
Conditions
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 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
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.
Interventions
DRUGAlvelestat (MPH966)
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.
OTHERPlacebo
Placebo is a pill or tablet that does not contain any study drug.
Sponsors
National Institutes of Health (NIH)
Mereo BioPharma
National Center for Advancing Translational Sciences (NCATS)
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
double blind
Intervention model description
randomized (1:1), placebo-controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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 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. 4. FEV1 ≥25% predicted 5. 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. 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 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 Pi\*MZ, Pi\*FM, Pi\*MS, Pi\*SS, or other AATD phenotypes/genotypes not known to be independently associated with emphysema. 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Within-individual % Change in Plasma Desmosine/Isodesmosine | baseline, week 12 | To evaluate the effect of alvelestat (MPH966) administered twice daily (bid) for 12 weeks on blood markers of within-individual % change in plasma desmosine/isodesmosine will be measured. |
| Numbers and % of Subjects Who Experience at Least 1 Treatment-emergent Adverse Event | baseline, week 16 | 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 (TEAE) will be measured. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | baseline, week 12 | To evaluate the effect of Alvelestat (MPH966) on other blood pharmacodynamic markers of neutrophil activation and elastase activity including plasma desmosine/isodesmosine (change compared to placebo; within-individual change is the primary outcome), plasma Aa-Val-360, serum NE activity, plasma proteinase 3, plasma cathepsin B, plasma CRP, plasma IL-6, plasma IL-8, plasma IL-1b, plasma RANTES, plasma LTB4, plasma MMP9, plasma MMP12, plasma MPO, and plasma PGP. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alvelestat (MPH966) Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks
Alvelestat (MPH966): 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. | 30 |
| Placebo 4 Placebo tablets twice daily by mouth for 12 weeks
Placebo: Placebo is a pill or tablet that does not contain any study drug. | 31 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Alvelestat (MPH966) |
|---|---|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 12.9 | 54.6 years STANDARD_DEVIATION 11.9 | 52.4 years STANDARD_DEVIATION 14 |
| Alpha-1 antitrypsin Genotype Pi*NN | 5 Participants | 3 Participants | 2 Participants |
| Alpha-1 antitrypsin Genotype Pi*SZ | 10 Participants | 4 Participants | 6 Participants |
| Alpha-1 antitrypsin Genotype Pi*ZZ | 46 Participants | 24 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 30 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 61 Participants | 31 Participants | 30 Participants |
| Sex: Female, Male Female | 44 Participants | 22 Participants | 22 Participants |
| Sex: Female, Male Male | 17 Participants | 9 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 31 |
| other Total, other adverse events | 25 / 32 | 23 / 31 |
| serious Total, serious adverse events | 0 / 32 | 0 / 31 |
Outcome results
Primary
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 (TEAE) will be measured.
Time frame: baseline, week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alvelestat (MPH966) | Numbers and % of Subjects Who Experience at Least 1 Treatment-emergent Adverse Event | 25 Participants |
| Placebo | Numbers and % of Subjects Who Experience at Least 1 Treatment-emergent Adverse Event | 23 Participants |
Primary
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 within-individual % change in plasma desmosine/isodesmosine will be measured.
Time frame: baseline, week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alvelestat (MPH966) | Within-individual % Change in Plasma Desmosine/Isodesmosine | 10.0619 % change | Standard Deviation 27.8489 |
| Placebo | Within-individual % Change in Plasma Desmosine/Isodesmosine | 8.5627 % change | Standard Deviation 29.2973 |
Secondary
Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo
To evaluate the effect of Alvelestat (MPH966) on other blood pharmacodynamic markers of neutrophil activation and elastase activity including plasma desmosine/isodesmosine (change compared to placebo; within-individual change is the primary outcome), plasma Aa-Val-360, serum NE activity, plasma proteinase 3, plasma cathepsin B, plasma CRP, plasma IL-6, plasma IL-8, plasma IL-1b, plasma RANTES, plasma LTB4, plasma MMP9, plasma MMP12, plasma MPO, and plasma PGP.
Time frame: baseline, week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma MPO | -4516.01 ng/ mL | Standard Deviation 24994.15 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma desmosine/isodesmosine | 0.0307 ng/ mL | Standard Deviation 0.1012 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma Aa-Val-360 | -1.6279 ng/ mL | Standard Deviation 4.1028 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Serum NE | -16.7926 ng/ mL | Standard Deviation 41.1503 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma proteinase 3 | 1.9412 ng/ mL | Standard Deviation 59.2846 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma cathepsin B | 7.2882 ng/ mL | Standard Deviation 24.9583 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma CRP | -0.0247 ng/ mL | Standard Deviation 1.1066 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma IL-6 | 0.3417 ng/ mL | Standard Deviation 2.1615 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma IL-8 | -0.2955 ng/ mL | Standard Deviation 2.9877 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma IL-1b | 0.0962 ng/ mL | Standard Deviation 0.3819 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma RANTES | 0.0903 ng/ mL | Standard Deviation 3.9356 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma LTB4 | -369.093 ng/ mL | Standard Deviation 11118.482 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma MMP9 | -2.8218 ng/ mL | Standard Deviation 18.624 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma MMP12 | -1.0733 ng/ mL | Standard Deviation 8.0076 |
| Alvelestat (MPH966) | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma PGP | -0.6619 ng/ mL | Standard Deviation 3.8013 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma MPO | 3156.253 ng/ mL | Standard Deviation 13798.49 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma IL-8 | 0.2386 ng/ mL | Standard Deviation 0.8844 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma desmosine/isodesmosine | 0.0047 ng/ mL | Standard Deviation 0.0817 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma MMP9 | 2.6188 ng/ mL | Standard Deviation 8.7639 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma Aa-Val-360 | -0.9937 ng/ mL | Standard Deviation 4.3209 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma IL-1b | 0.1137 ng/ mL | Standard Deviation 0.5218 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Serum NE | 3.9660 ng/ mL | Standard Deviation 19.4462 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma PGP | -0.0139 ng/ mL | Standard Deviation 0.5418 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma proteinase 3 | -10.6390 ng/ mL | Standard Deviation 38.6356 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma RANTES | 0.0652 ng/ mL | Standard Deviation 6.4001 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma cathepsin B | -1.1086 ng/ mL | Standard Deviation 14.6929 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma MMP12 | -0.0940 ng/ mL | Standard Deviation 1.6722 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma CRP | -0.1975 ng/ mL | Standard Deviation 1.688 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma LTB4 | 170.2617 ng/ mL | Standard Deviation 1380.099 |
| Placebo | Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo | Plasma IL-6 | -0.3730 ng/ mL | Standard Deviation 2.7773 |