What is the mechanism of action of this treatment?

The most common treatments for Alpha-1 Antitrypsin Deficiency (AATD) aim to reduce liver scarring and inflammation by targeting the abnormal Z-AAT protein that accumulates in the liver. Fazirsiran, for example, works by reducing the levels of this abnormal protein, thereby decreasing liver injury and fibrosis. This is crucial for AATD patients as it helps to prevent the progression of liver disease, improve liver function, and potentially extend the patient's lifespan. By addressing the root cause of liver damage, these treatments offer a targeted approach to managing the complications associated with AATD.

What side effects are associated with this type of intervention?

Common treatments for Alpha-1 Antitrypsin Deficiency (AATD) include augmentation therapy with alpha-1 antitrypsin (AAT) protein derived from human plasma, which can cause side effects such as headache, dizziness, and injection site reactions. For treatments targeting liver scarring and inflammation, like Fazirsiran, potential side effects may include liver enzyme elevations, fatigue, and gastrointestinal symptoms. These treatments aim to reduce the accumulation of abnormal Z-AAT protein, thereby mitigating liver damage and inflammation.

What prior FDA approvals exist?

Alpha-1 Antitrypsin Deficiency (AATD) has been primarily treated with augmentation therapy using purified alpha-1 antitrypsin (AAT) from human plasma, such as Prolastin, Aralast, and Zemaira, which are FDA-approved. These treatments aim to increase AAT levels in the blood and lungs to prevent emphysema. However, they do not directly address liver disease caused by the accumulation of abnormal Z-AAT protein. Fazirsiran, currently under investigation, represents a novel approach by targeting the underlying genetic defect to reduce liver scarring and inflammation, potentially offering a more comprehensive treatment for AATD-related liver disease.

What other types of research exist?

Promising alternatives to Fazirsiran for Alpha-1 Antitrypsin Deficiency patients include Tenofovir alafenamide, which has shown efficacy in reducing liver inflammation and fibrosis in hepatitis B patients, and Janus kinase inhibitors (JAKINIBS) like Tofacitinib and Baricitinib, which have been effective in treating inflammatory conditions. These treatments could potentially be repurposed for AATD, but clinical trials would be necessary to confirm their efficacy and safety in this specific context.

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siRNA

Fazirsiran for Alpha-1 Antitrypsin Deficiency

Phase 3

Recruiting

Research Sponsored by Takeda

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

An adult participant must have a body mass index (BMI) between 18.0 and 39.0 kilograms per meter square (kg^m2), inclusive.

The participant must have a diagnosis of the Z allele homozygotes (PiZZ) genotype AATD. PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, participants must undergo PiZZ confirmatory testing (genotyping for PiS and PiZ alleles) at screening. PiMZ or PiSZ genotypes are not permitted.

Must not have

The participant has previously been treated with fazirsiran or any other RNAi for AATD-LD.

The participant has a history of liver decompensating events (overt hepatic encephalopathy [West Haven Grade >=2] documented by a physician, clinically significant ascites, spontaneous bacterial peritonitis, GI bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or portal gastropathy).

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline, week 106, week 196 and week 202

Awards & highlights

Pivotal Trial

Summary

This trial is testing fazirsiran, a drug that may reduce liver scarring and improve liver health, in patients with liver fibrosis. The drug works by decreasing harmful proteins and reducing inflammation in the liver.

Who is the study for?

Adults aged 18-75 with Alpha-1 Antitrypsin Deficiency (AATD) causing liver scarring, who are non-smokers for at least a year and have a BMI of 18.0-39.0 kg/m2 can join this trial. They must not have liver cancer, drug abuse history within the last year, certain blood or liver issues, other chronic liver diseases, recent malignancies except some skin cancers or in situ cervical cancer.

What is being tested?

The study is testing if Fazirsiran injections can reduce liver scarring compared to placebo in people with AATD-related fibrosis. It will also assess how the body processes Fazirsiran and its impact on disease progression using biopsies and biomarkers.

What are the potential side effects?

While specific side effects aren't listed here, participants will be closely monitored for any adverse reactions to Fazirsiran as compared to those receiving a placebo.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My BMI is between 18.0 and 39.0.

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I have been diagnosed with the PiZZ genotype for AATD.

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My liver fibrosis is at stage F2, F3, or F4 based on a recent biopsy.

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I do not have liver cancer, confirmed by tests.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been treated with RNAi therapy for AATD-LD before.

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I have had serious liver-related health events.

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I have had a procedure to connect my liver and vein.

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I have a chronic liver disease such as hepatitis, cirrhosis, or liver cancer.

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I will be exposed to harmful dust or metals at work during the study.

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I have a blood clot in the vein to my liver.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline, week 106, week 196 and week 202

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline, week 106, week 196 and week 202

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline, week 106, week 196 and week 202 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy at Week 106 in AATD-LD With METAVIR Stage F2 and F3 Fibrosis

Secondary study objectives

Change From Baseline in Intrahepatic Portal Inflammation

Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining

Change From Baseline in Liver Injury

+14 more

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: FazirsiranExperimental Treatment1 Intervention

Participants will receive fazirsiran 200 milligram per milliliter (mg/ml) subcutaneous (SC) injection on Day 1, at Week 4, and then every 12 weeks (Q12 W) thereafter up to Week 196.

Group II: PlaceboPlacebo Group1 Intervention

Participants will receive placebo on Day 1, at Week 4, and Q12 W thereafter up to Week 196.

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Alpha-1 Antitrypsin Deficiency (AATD) aim to reduce liver scarring and inflammation by targeting the abnormal Z-AAT protein that accumulates in the liver. Fazirsiran, for example, works by reducing the levels of this abnormal protein, thereby decreasing liver injury and fibrosis. This is crucial for AATD patients as it helps to prevent the progression of liver disease, improve liver function, and potentially extend the patient's lifespan. By addressing the root cause of liver damage, these treatments offer a targeted approach to managing the complications associated with AATD.