Fazirsiran for Alpha-1 Antitrypsin Deficiency

Recruiting at 35 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?

The liver produces a protein called alpha-1 antitrypsin (AAT). AAT is normally released into the bloodstream. In some people, the liver makes an abnormal version of the AAT protein, called Z-AAT. Making an abnormal version of the AAT protein can result in liver disease as Z-AAT builds up in liver cells, which leads to liver problems such as liver scarring (fibrosis), continuing liver damage (cirrhosis), and eventually endstage liver disease. Fazirsiran is a medicine that reduces the creation of the Z-AAT protein and thus the build-up of this abnormal protein in the liver. People with this type of liver disease who already have mild liver scarring will take part in the study. They will be treated with fazirsiran or a placebo for about 2 years. This study will check the long-term safety of fazirsiran, whether participants tolerate the treatment and if there are any effects on liver scarring. A liver biopsy, a way of collecting a small tissue sample from the liver, will be taken twice during the study.

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.

What makes the drug Fazirsiran unique for treating Alpha-1 Antitrypsin Deficiency?

Fazirsiran is unique because it specifically targets the underlying genetic cause of Alpha-1 Antitrypsin Deficiency, which is a rare condition with limited treatment options. Unlike other treatments that may only address symptoms, Fazirsiran aims to correct the deficiency at a molecular level. ^{1 2 3 4 5}

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

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) 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]

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]

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]

Citations

1. England pubmed.ncbi.nlm.nih.gov

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

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

AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. [2014]

3. United States 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. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Osteoanabolic and dual action drugs. [2021]

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

Daily nasal spray of hPTH(1-34) for 3 months increases bone mass in osteoporotic subjects: a pilot study. [2018]