BMN 349 for Alpha-1 Antitrypsin Deficiency
(PiZZ Trial)
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: BioMarin Pharmaceutical
Must not be taking: AAT augmentation therapy
Disqualifiers: INR > 1.2, ALT/AST > 125, pneumonia, others
No Placebo Group
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.
12345Eligibility 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 am between 18 and 64 years old.
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
+1 more
Trial 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)
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Group B (PiMZ)Experimental Treatment2 Interventions
5:1 (349:Placebo)
Group II: Group A (PiZZ)Experimental Treatment2 Interventions
5:1 (349:Placebo)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California, San DiegoSan Diego, CA
The Medical University of South CarolinaCharleston, SC
Saint Louis UniversitySaint Louis, MO
Medpace Clinical Pharmacology UnitCincinnati, OH
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Who Is Running the Clinical Trial?
BioMarin PharmaceuticalLead Sponsor
References
[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. [2022]Augmentation with human alpha-1 proteinase inhibitor is the only specific treatment for Alpha-1-Antitrypsin Deficiency (AATD), a rare genetic disease with symptoms of progressive COPD.
Alpha-1 Antitrypsin Deficiency Detection in a Portuguese Population. [2019]Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease characterised by low serum levels of this molecule. Its epidemiology remains unknown in many countries, mainly due to its underdiagnosed state and lack of patients' registries. We aim to evaluate and characterise a sample of Portuguese individuals tested for AATD, between 2006 and 2015, based on a retrospective analysis from the database of a laboratory offering AATD genetic diagnosis service. 1684 individuals were considered, covering almost every region in Portugal. Genetic diagnosis resulted from requests of clinicians from different areas of expertise, mainly pulmonology (35.5%). Most subjects could be distributed into more common genotypes: MZ (25.4%, n = 427), MS (15.5%, n = 261), SZ (11.2%, n = 188), ZZ (9.4%, n = 158) and SS (5.6%, n = 95). 9.5% of the subjects were found to carry at least one rare deleterious allele, including the recently described PGaia, Q0Oliveira do Douro, Q0Vila Real and a novel SGaia variant. This study comprises 417 subjects (24.7%) with severe to very severe AATD and 761 carriers (45.2%), 22.7% of those identified by familial screening. The present study represents the most complete survey of AATD in Portugal so far and discloses a high rate of severe and very severe deficiency cases, attributed not only to ZZ and SZ genotypes but also to a large number of rare combinations with other null and deficiency alleles. It also uncovers a low awareness to AATD among the medical community, highlighting the need to create a Portuguese national registry and AATD guidelines and increase the awareness about this condition.
New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency. [2020]Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing the SERPINA1 gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in cis in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual cis-acting variants in the SERPINA1 gene. The possible existence of other unrevealed variants combined in the PI*S alleles should be considered to improve the genetic diagnosis of the patients.
Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">Safety and pharmacokinetics (PK) of alpha1-proteinase inhibitor, modified process (Alpha-1 MP), was evaluated in a clinical trial of Japanese patients with alpha1-antitrypsin deficiency (AATD). The present study aimed to evaluate the long-term safety of weekly intravenous infusions of 60 mg/kg Alpha-1 MP in Japanese patients with AATD.
Molecular abnormality of PI S variant of human alpha1-antitrypsin. [2020]Alpha1-antitrypsin variant protein was purified to homogeneity from a PI S-S subject with a mild deficiency of plasma trypsin inhibiting capacity. Molecular weight, specific trypsin inhibitory activity, and composition of amino acids and carbohydrates were similar to the proteins purified from Pi M-M individuals with normal alpha1-antitrypsin activity. The structural difference between the normal and the variant alpha1-antitrypsin was elucidated by peptide mapping of their tryptic digests. An amino acid substitution of glutamic acid in the normal protein to valine in the variant protein was found. The result is consistent with the previously reported amino acid substitution in Pi S-Christchurch.