BMN 349 for Alpha-1 Antitrypsin Deficiency

(PiZZ Trial)

Recruiting at 5 trial locations

Overseen By Trial Specialist

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: BioMarin Pharmaceutical

Must not be taking: AAT augmentation therapy

Disqualifiers: INR > 1.2, ALT/AST > 125, pneumonia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

12 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to assess the safety and tolerability of a single oral dose of BMN 349 in participants with PiZZ or PiMZ/MASH. Primary outcome measures include incidence of any adverse events (including serious adverse events, dose limit toxicities, and adverse events of special interest), incidence of any laboratory test abnormalities, incidence of lung function test abnormalities and 12-lead ECG parameters. Participants will receive a single dose of either BMN 349 or placebo and then monitored for safety and tolerability.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, it does exclude those currently or recently using AAT augmentation therapy.

How does the drug BMN 349 differ from existing treatments for Alpha-1 Antitrypsin Deficiency?

BMN 349 is a novel treatment for Alpha-1 Antitrypsin Deficiency, which currently has limited treatment options, primarily involving augmentation therapy with human alpha-1 proteinase inhibitor. This new drug may offer a different mechanism of action or administration method, potentially providing an alternative to the existing standard treatment. ^{1 2 3 4 5}

Research Team

Medical Director, MD

Principal Investigator

BioMarin Pharmaceutical

Eligibility Criteria

This trial is for adults with Alpha-1 Antitrypsin Deficiency, specifically those with PiZZ or PiMZ/MASH genetic variations. Participants will be given a single dose of either the study drug BMN 349 or a placebo to assess safety.

Inclusion Criteria

My genetic test shows I have PiZZ or PiMZ genotype.

I haven't used tobacco or nicotine products in the last 6 months.

Exclusion Criteria

I was diagnosed with pneumonia in the last 3 months.

International normalized ratio (INR) > 1.2

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels > 125 U/L

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single oral dose of BMN 349 or placebo

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

78 days

Multiple visits (in-person and virtual)

Treatment Details

Interventions

• BMN 349

Trial Overview The study tests the safety and tolerability of BMN 349, an oral medication. Patients are randomly chosen to receive one dose of either BMN 349 or a placebo, followed by monitoring for any side effects and changes in lung function and heart health.

Participant Groups

Group I: Group B (PiMZ) Experimental Treatment 2 Interventions

5:1 (349:Placebo)

Group II: Group A (PiZZ) Experimental Treatment 2 Interventions

5:1 (349:Placebo)

Who Is Running the Clinical Trial?

BioMarin Pharmaceutical

Lead Sponsor

Trials

162

Recruited

115,000+

Alexander Hardy

BioMarin Pharmaceutical

Chief Executive Officer since 2023

MBA from INSEAD

Greg Friberg

BioMarin Pharmaceutical

Chief Medical Officer

MD from New York Medical College

Findings from Research

In a long-term study of seven patients with Alpha-1-Antitrypsin Deficiency, weekly intravenous augmentation therapy significantly slowed the decline in lung function (FEV1) compared to the three years prior to the program, indicating its efficacy in managing COPD symptoms.

The home care program, 'Alpha-1-Mobile', was found to be safe and well-accepted, with minimal hospitalizations due to exacerbations and no adverse events related to the augmentation therapy, highlighting its practicality for ongoing patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. Wilke, A., Semper, H., Gross, C., et al.[2022]

This study analyzed 1684 individuals tested for Alpha-1 antitrypsin deficiency (AATD) in Portugal from 2006 to 2015, revealing a significant prevalence of severe cases, with 24.7% of subjects classified as having severe to very severe AATD.

The findings indicate a low awareness of AATD among healthcare professionals, emphasizing the urgent need for a national registry and guidelines to improve diagnosis and management of this underrecognized condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-1 Antitrypsin Deficiency Detection in a Portuguese Population. Meira, L., Boaventura, R., Seixas, S., et al.[2019]

Two new alleles of the SERPINA1 gene, QOVigo and QOAachen, were identified in patients with Alpha-1 antitrypsin deficiency (AATD) that produce a null phenotype, meaning they do not produce functional AAT protein.

These alleles result from combined mutations with the common Pi*S allele, leading to severe AAT polymerization and almost undetectable AAT secretion, highlighting the importance of considering additional genetic variations for accurate diagnosis and understanding of AATD clinical variability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency. Matamala, N., Gomez-Mariano, G., Perez, JA., et al.[2020]

In a long-term study involving four Japanese patients with alpha1-antitrypsin deficiency, weekly intravenous infusions of 60 mg/kg Alpha-1 MP were found to be generally safe and well-tolerated over a period of 52 weeks, with most reported adverse events being mild.

The treatment did not lead to significant changes in pulmonary function tests or laboratory parameters, indicating that Alpha-1 MP does not adversely affect lung function or overall health in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency. Seyama, K., Suzuki, M., Tasaka, S., et al.[2022]

The study successfully purified a variant form of alpha1-antitrypsin from a subject with a mild deficiency, revealing that its molecular weight and trypsin inhibitory activity are similar to those of normal alpha1-antitrypsin proteins.

A key structural difference was identified: an amino acid substitution from glutamic acid to valine in the variant protein, which aligns with known changes in the Pi S-Christchurch variant, potentially impacting its function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular abnormality of PI S variant of human alpha1-antitrypsin. Yoshida, A., Ewing, C., Wessels, M., et al.[2020]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Alpha-1 Antitrypsin Deficiency Detection in a Portuguese Population. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency. [2020]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Molecular abnormality of PI S variant of human alpha1-antitrypsin. [2020]