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

NCT03679598 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: IRB-3000023384UH3TR002450-02
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 10

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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.

  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 (TEAE) will be measured.

  baseline, week 16

Secondary Outcomes (1)

• 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

Study Arms (2)

Alvelestat (MPH966)

ACTIVE COMPARATOR

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

Drug: Alvelestat (MPH966)

Placebo

PLACEBO COMPARATOR

4 Placebo tablets twice daily by mouth for 12 weeks

Other: Placebo

Interventions

Alvelestat (MPH966) DRUG

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.

Alvelestat (MPH966)

Placebo OTHER

Placebo is a pill or tablet that does not contain any study drug.

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• National Institutes of Health (NIH): collaborator
• Mereo BioPharma: collaborator
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (10)

The University of Alabama at Birmingham Lung Health Center

Birmingham, Alabama, 35294, United States

Location

UCLA

Los Angeles, California, 90095, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27517, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Temple University

Philadelphia, Pennsylvania, 19140, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425-6300, United States

Location

The University of Texas Health Science Center at Tyler

Tyler, Texas, 75708, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency; Emphysema; Pulmonary Disease, Chronic Obstructive

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lung Diseases, Obstructive; Chronic Disease; Disease Attributes

Results Point of Contact

• Title: Dr. James Wells
• Organization: University of Alabama at Birmingham

LungHealth@uabmc.edu

2059345555

Study Officials

• Mark T Dransfield, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: randomized (1:1), placebo-controlled

Study Record Dates

• First Submitted: September 18, 2018
• First Posted: September 20, 2018
• Study Start: April 8, 2019
• Primary Completion: November 30, 2023
• Study Completion: December 1, 2023
• Last Updated: August 20, 2024
• Results First Posted: July 9, 2024

Record last verified: 2024-07

Locations

US (10)