Fazirsiran for Alpha-1 Antitrypsin Deficiency

Recruiting at 11 trial locations

Overseen By Takeda Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Takeda

Must not be taking: Chronic anticoagulants

Disqualifiers: Chronic liver diseases, Major surgery, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: Up to 10 years

37 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on chronic anticoagulants, you may be allowed to continue them after consultation with the medical monitor, provided you do not have cirrhosis or a history of liver decompensating events.

How is the drug Fazirsiran different from other treatments for Alpha-1 Antitrypsin Deficiency?

Fazirsiran is unique because it is a small interfering RNA (siRNA) therapy designed to reduce the production of the abnormal alpha-1 antitrypsin protein in the liver, which is different from traditional treatments that focus on augmenting the levels of the protein in the blood. ^{1 2 3 4 5}

What is the purpose of this trial?

The main aim of this study is to learn if fazirsiran is safe during long-term use in people with liver disease caused by the abnormal Z-alpha-1 antitrypsin (Z-AAT) protein. People who have taken part in previous fazirsiran studies (AROAAT2001 \[NCT03945292\] or AROAAT2002 \[NCT03946449\]) can continue to receive fazirsiran every 3 months as long as they participate in this study, the study is ongoing or until health authorities in their country approve fazirsiran to be publicly available. The study may also provide information on whether fazirsiran has a long-term effect in reducing liver fibrosis or slowing down the progression of liver fibrosis in people with liver disease due to the abnormal Z-AAT protein.

Research Team

Study Director

Principal Investigator

Takeda

Eligibility Criteria

This trial is for people with Alpha-1 Antitrypsin Deficiency causing liver disease, who have already been in previous fazirsiran studies. They must be able to follow the study rules and fill out questionnaires. Smokers or those using e-cigarettes can't join.

Inclusion Criteria

I do not have liver cancer and will be screened for it before joining.

The participant/participant's legally acceptable representative has provided informed consent (ICF) (that is, in writing, documented via a signed and dated ICF) and any required privacy authorization before the initiation of any study procedures.

I am willing and able to follow the study's procedures and requirements.

Exclusion Criteria

Participants with major protocol deviations in previous studies

I have a history of blood clots or I am on long-term blood thinners.

Participants not meeting specific ALT, AST, and Creatinine criteria

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive fazirsiran, 200 mg, injection subcutaneously on Day 1 and once every 12 weeks thereafter

Up to 10 years

1 visit every 12 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may continue to receive fazirsiran until it is commercially available or the study is terminated

Long-term

Treatment Details

Interventions

• Fazirsiran

Trial Overview The trial tests the long-term safety of Fazirsiran injections given every three months over two years, with an additional six-month follow-up. It aims to see if it reduces or slows down liver fibrosis caused by Z-AAT protein.

Participant Groups

Group I: Fazirsiran 200 mg Experimental Treatment 1 Intervention

Participants who are currently taking part in or who have completed their treatment in parent studies AROAAT2001 (NCT03945292) and AROAAT2002 (NCT03946449) may rollover in this study to receive fazirsiran, 200 milligrams (mg), injection, subcutaneously on Day 1 and once every 12 weeks (Q12W) thereafter until fazirsiran receives approval and is commercially available in the participant's country, until a participant withdraws from the study or the sponsor decides to terminate the study.

Who Is Running the Clinical Trial?

Takeda

Lead Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

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]

Intrapleural administration of AAV5 vectors expressing human alpha1-antitrypsin (halpha1AT) in mice resulted in significantly higher serum and lung levels of alpha1AT compared to traditional intramuscular delivery, achieving levels 10-fold higher than AAV2 delivery.

At 40 weeks post-administration, the AAV5-halpha1AT vector maintained serum alpha1AT levels of 900 microg/ml, surpassing the therapeutic threshold of 570 microg/ml, suggesting that this method could be a promising gene therapy approach for treating alpha1-antitrypsin deficiency in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrapleural administration of a serotype 5 adeno-associated virus coding for alpha1-antitrypsin mediates persistent, high lung and serum levels of alpha1-antitrypsin. De, B., Heguy, A., Leopold, PL., et al.[2012]

A new plasma-derived alpha1-Proteinase Inhibitor (Zemaira) was shown to be bioequivalent to the existing treatment (Prolastin) in restoring serum Alpha1-antitrypsin levels in individuals with AAT deficiency, achieving levels above the protective threshold of 11 microM.

The study, involving 44 subjects over a 10-week double-blind phase, found that Zemaira was well tolerated with a lower incidence of treatment-related adverse events (7%) compared to Prolastin (21%), and there were no cases of viral transmission, indicating its safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. Stocks, JM., Brantly, M., Pollock, D., et al.[2019]

References

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

Pharmacokinetics and Biochemical Efficacy of an α1-Proteinase Inhibitor (Aralast NP) in α1-Antitrypsin Deficiency: a Cross-Product Retrospective Comparability Analysis. [2022]

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

Comparative biochemical efficacy analysis of an alpha1-proteinase inhibitor (Glassia®) in patients with alpha-1 antitrypsin deficiency. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

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

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

Intrapleural administration of a serotype 5 adeno-associated virus coding for alpha1-antitrypsin mediates persistent, high lung and serum levels of alpha1-antitrypsin. [2012]

5. England pubmed.ncbi.nlm.nih.gov

Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. [2019]