Fazirsiran for Alpha-1 Antitrypsin Deficiency

Recruiting at 44 trial locations

Overseen By Viviana Figueroa Diaz

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Takeda

Disqualifiers: Liver fibrosis, Chronic liver diseases, Malignancy, others

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: 9

Duration: 100 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test fazirsiran, a treatment for individuals with liver disease caused by alpha-1 antitrypsin deficiency (AATD), a condition where the liver produces a faulty protein that can lead to liver damage. The study will explore whether fazirsiran can safely reduce liver scarring by lowering the production of this faulty protein. Participants will receive either fazirsiran or a placebo to compare results over two years. Individuals with mild liver scarring from this condition who do not smoke might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that if you are taking statins, ACE inhibitors, angiotensin II receptor blockers, or beta-1 selective adrenergic receptor inhibitors, you must have been on a stable dose for at least 8 weeks before joining and should continue the same dose during the study. If you are on respiratory medications, the doses must have been unchanged for at least 14 days before screening.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that fazirsiran is generally well-tolerated. In studies, fazirsiran lowered levels of the abnormal protein Z-AAT in both the blood and liver, suggesting it could help prevent liver damage in people with Alpha-1 Antitrypsin Deficiency.

Some patients experienced improvements in liver inflammation. However, every treatment can have side effects. So far, fazirsiran has not raised major safety concerns in the studies conducted. Participants have continued with the treatment without serious side effects.

Since this trial is in a later phase, earlier studies have already assessed its safety in humans. While this does not eliminate risk, it suggests a certain level of safety has been established. Participants should always discuss potential risks with their healthcare providers before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Alpha-1 Antitrypsin Deficiency that typically involve augmentation therapy with intravenous infusions of alpha-1 antitrypsin protein, fazirsiran offers a novel approach by using RNA interference to target the underlying genetic cause of the disease. This means fazirsiran can potentially reduce the production of the faulty protein that causes lung and liver damage. Researchers are excited about fazirsiran because it is administered subcutaneously and less frequently—every 12 weeks—compared to the weekly or bi-weekly infusions required by current therapies. This new mechanism and easier administration could significantly improve patient convenience and quality of life.

What evidence suggests that fazirsiran might be an effective treatment for alpha-1 antitrypsin deficiency?

Research has shown that fazirsiran, which participants in this trial may receive, may help treat liver problems caused by the build-up of an abnormal protein called AAT. In one study, 58% of patients who took 200 mg of fazirsiran experienced less liver scarring. The treatment also reduced the harmful protein in the liver by 83%. Another study found that fazirsiran lowered the levels of this abnormal protein in the blood by up to 94%. These findings suggest that fazirsiran could help reduce liver damage in people with this condition. Participants in this trial may also receive a placebo for comparison. ^{2 3 6 7 8}

Who Is on the Research Team?

Study Director

Principal Investigator

Takeda

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with Alpha-1 Antitrypsin Deficiency (AATD) and mild liver scarring. Participants must have a specific genetic form of AATD (PiZZ), no liver cancer, and be able to follow the study plan. They need a negative COVID-19 test and must consent to two liver biopsies.

Inclusion Criteria

I have been diagnosed with the PiZZ genotype for AATD.

I understand and can follow the study's requirements.

My lung function meets the study's requirements.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive fazirsiran or placebo subcutaneously on Day 1, at Week 4, and then every 12 weeks for up to Week 100

100 weeks

9 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Fazirsiran
• Placebo

Trial Overview The trial tests Fazirsiran, which aims to reduce abnormal alpha-1 antitrypsin protein in the liver that causes scarring. Over about 2 years, participants will receive either Fazirsiran or a placebo injection to assess long-term safety and treatment tolerance.

How Is the Trial Designed?

Group I: Fazirsiran 200 mg Experimental Treatment 1 Intervention

Participants will receive fazirsiran 200 milligrams (mg), injection, subcutaneously on Day 1, at Week 4 and then every 12 weeks (Q12W) for up to Week 100.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive fazirsiran matching placebo injection, subcutaneously on Day 1, at Week 4 and Q12W for up to Week 100.

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

A nasal spray formulation of parathyroid hormone (hPTH(1-34)) was shown to effectively increase lumbar bone mineral density (L-BMD) in a dose-dependent manner, with the 1,000 microg dose resulting in a 2.4% increase after 3 months in 90 osteoporotic subjects aged 52-84.

The nasal spray was found to be safe and well tolerated, with only transient hypercalcemia observed in a few subjects, indicating it could be a more patient-friendly alternative to daily subcutaneous injections for osteoporosis treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily nasal spray of hPTH(1-34) for 3 months increases bone mass in osteoporotic subjects: a pilot study. Matsumoto, T., Shiraki, M., Hagino, H., et al.[2018]

Teriparatide (TPTD) significantly improves bone mineral density (BMD) in postmenopausal women with osteoporosis at the lumbar spine, total hip, and femoral neck compared to placebo, although the effect on the femoral neck is less clear.

The combination of TPTD with certain antiresorptive agents, like hormone replacement therapy and denosumab, shows an additive effect on BMD, while combining TPTD with alendronate does not enhance BMD at the total hip and femoral neck, indicating that the effectiveness of these combinations can vary based on the specific antiresorptive agent used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single and combined use of human parathyroid hormone (PTH) (1-34) on areal bone mineral density (aBMD) in postmenopausal women with osteoporosis: evidence based on 9 RCTs. Song, J., Jin, Z., Chang, F., et al.[2018]

ZT-031, a 31-amino acid analog of parathyroid hormone, has shown efficacy in preventing bone loss and increasing bone mineral density in both animal models and postmenopausal women with osteoporosis, indicating its potential as a treatment for bone-related disorders.

The treatment was found to be safe and well tolerated, with infrequent episodes of hypercalcemia, particularly at higher doses, suggesting a favorable safety profile compared to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZT-031, a cyclized analog of parathyroid hormone(1-31) for the potential treatment of osteoporosis. Nemeth, EF.[2008]

The calcilytic AXT914 was well tolerated in healthy volunteers and postmenopausal women, effectively inducing the desired release of parathyroid hormone (PTH) after oral administration.

Despite the successful PTH release, AXT914 did not lead to the expected increases in bone formation biomarkers and caused significant increases in serum calcium levels, leading to the trial's termination due to safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. John, MR., Harfst, E., Loeffler, J., et al.[2014]

Teriparatide (TPTD) and abaloparatide (ABL) are effective osteoanabolic drugs for treating osteoporosis, both reducing the risk of vertebral and non-vertebral fractures, and should be followed by antiresorptive agents to maintain bone density gains after a maximum of 24 months of treatment.

Romosozumab, a monoclonal antibody, also shows promise in osteoporosis treatment by stimulating bone formation and reducing bone resorption, significantly lowering the incidence of new vertebral and non-vertebral fractures when administered monthly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osteoanabolic and dual action drugs. Tabacco, G., Bilezikian, JP.[2021]

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. 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 ...

5. 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 ... The purpose of this study is to evaluate the long-term safety and effectiveness of Fazirsiran in people with Alpha-1 Antitrypsin Deficiency- ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03946449

Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With ... The purpose of this study is to evaluate the the safety and efficacy of the investigational product, fazirsiran (TAK-999, ARO-AAT), administered subcutaneously ...

7. gastrojournal.org gastrojournal.org/article/S0016-5085(24)05181-3/fulltext

Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency ... Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively.

8. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT06165341

UCSF Alpha-1 Antitrypsin Deficiency Trial This study will check the long-term safety of fazirsiran, whether participants tolerate the treatment and if there are any effects on liver scarring.