Fazirsiran for Alpha-1 Antitrypsin Deficiency

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if fazirsiran is safe for long-term use in individuals with liver disease caused by a faulty protein called Z-alpha-1 antitrypsin. The researchers seek to assess whether fazirsiran can reduce or slow liver damage over time. The trial is recruiting individuals who have participated in earlier fazirsiran studies and have liver fibrosis (scarring of the liver). Participants should be nonsmokers and must not have liver cancer or other chronic liver diseases. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

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.

Is there any evidence suggesting that fazirsiran is likely to be safe for humans?

Research has shown that fazirsiran is generally well-tolerated by patients. In one study, about 58% of participants experienced less liver scarring, suggesting that the treatment might help reduce liver damage over time.

Another study found that fazirsiran lowered levels of the harmful Z-AAT protein in both the blood and liver. This is positive because high levels of this protein can damage the liver.

Studies on the long-term use of fazirsiran have aimed to ensure its safety over time. So far, results are promising, with no major safety issues reported.

In summary, fazirsiran appears safe for use based on these studies. However, ongoing research will continue to provide more detailed information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Alpha-1 Antitrypsin Deficiency, which often involve augmentation therapy using plasma-derived alpha-1 antitrypsin, Fazirsiran offers a novel approach. Fazirsiran works by targeting the underlying genetic cause of the condition through RNA interference (RNAi), reducing the production of faulty protein in the liver. This innovative mechanism holds promise for more directly addressing the root problem rather than just managing symptoms, which is why researchers are particularly excited about its potential. Additionally, Fazirsiran is administered subcutaneously every 12 weeks, which could offer a more convenient option compared to regular infusions required by current therapies.

What evidence suggests that fazirsiran might be an effective treatment for liver disease caused by the abnormal Z-AAT protein?

Research has shown that fazirsiran, which participants in this trial will receive, may help treat liver disease caused by the abnormal Z-alpha-1 antitrypsin (Z-AAT) protein. One study found that 58% of patients who took 200 mg of fazirsiran experienced a reduction in liver scarring. Additionally, there was an average decrease of 83% in the buildup of the harmful Z-AAT protein. Early results indicated significant drops in blood levels of Z-AAT, which is linked to liver damage. These findings suggest that fazirsiran could reduce liver scarring and potentially improve liver health over time. ^{2 3 4 6 7}

Who Is on the Research Team?

Study Director

Principal Investigator

Takeda

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

Citations

1. takeda.com takeda.com/newsroom/newsreleases/2022/results-from-phase-2-study-of-fazirsiran-in-patients-with-alpha-1-antitrypsin-deficiency-published-in-new-england-journal-of-medicine/

Results from Phase 2 Study of Fazirsiran in Patients with ... Fibrosis regression observed in 58% (7 of 12) of patients receiving 200 mg fazirsiran; Median reduction of 83% of Z-AAT accumulation in the ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05677971

NCT05677971 | Study to Check the Safety of Fazirsiran ... The main aim of this study is to learn if fazirsiran reduces liver scarring (fibrosis) compared to placebo. Other aims are to learn if fazirsiran slows down ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38964420/

Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency ... Results: At week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83%, and -94% with fazirsiran 25, 100, and 200 mg, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03946449

Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With ... Normal results are usually between 2 and 7 kilopascals (kPa), with results higher than the normal range if liver disease is present. The highest possible result ...

5. ir.arrowheadpharma.com ir.arrowheadpharma.com/static-files/071c3533-3265-46f3-be7d-951b13aac69e

long-term safety and efficacy of fazirsiran in patients with ... In the fazirsiran 200 mg open-label extension, there was a trend towards improved laboratory measures of liver health, stable pulmonary function ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05677971

NCT05677971 | Study to Check the Safety of Fazirsiran ... The main aim of this study is to learn if fazirsiran reduces liver scarring (fibrosis) compared to placebo. Other aims are to learn if fazirsiran slows down ...

7. clinicaltrials.eu clinicaltrials.eu/trial/study-on-long-term-safety-of-fazirsiran-for-patients-with-alpha-1-antitrypsin-deficiency-related-liver-disease/

Study on Long-Term Safety of Fazirsiran for Patients with ... This clinical trial investigates the long-term safety of Fazirsiran, a subcutaneous injection therapy, for patients suffering from Alpha-1 ...