Fazirsiran for Alpha-1 Antitrypsin Deficiency
Recruiting in Palo Alto (17 mi)
+30 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Takeda
Disqualifiers: Liver fibrosis, Chronic liver diseases, Malignancy, others
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
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.
12345Eligibility Criteria
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.
+7 more
Trial Timeline
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Fazirsiran 200 mgExperimental Treatment1 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: PlaceboPlacebo Group1 Intervention
Participants will receive fazirsiran matching placebo injection, subcutaneously on Day 1, at Week 4 and Q12W for up to Week 100.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
St Joseph's Hospital and Medical CenterPhoenix, AZ
Indiana University School of Medicine-IndianapolisIndianapolis, IN
University of Michigan Hospital - 1500 E Medical Center DrAnn Arbor, MI
University Of Iowa Hospitals And ClinicsIowa City, IA
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
TakedaLead Sponsor
References
ZT-031, a cyclized analog of parathyroid hormone(1-31) for the potential treatment of osteoporosis. [2008]ZT-031 is a cyclic 31-amino acid analog of parathyroid hormone (PTH) that is in development by Zelos Therapeutics Inc for the treatment of osteoporosis and other bone-related disorders. ZT-031 activates the PTH type 1 receptor - the molecular target of the currently marketed osteogenic peptides PTH and PTH(1-34). Daily subcutaneous injections of ZT-031 prevented bone loss and replaced bone that had already been lost in an ovariectomized rat model of osteoporosis. Daily subcutaneous injections of ZT-031 in gonad-intact monkeys increased bone mineral density (BMD) at cortical and cancellous bone sites and increased serum levels of bone formation markers. The daily subcutaneous administration of ZT-031 to postmenopausal women with osteoporosis elicited a dose-dependent increase in BMD of the lumbar spine, proximal femur and total hip area. Plasma levels of bone formation markers were significantly increased above baseline after 1 month of dosing, and prior to increases in bone resorption markers. ZT-031 was demonstrated to be safe and well tolerated; episodes of hypercalcemia were infrequent and observed with a frequency greater than with placebo only at the highest doses tested for the drug. Although available data are limited, the results obtained following treatment with ZT-031 have generally been at least as favorable as those obtained with other osteogenic PTH peptides. A novel dosing paradigm has been planned for the drug.
AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. [2014]Antagonism of the calcium-sensing receptor in the parathyroid gland leads to parathyroid hormone (PTH) release. Calcilytics are a new class of molecules designed to exploit this mechanism. In order to mimic the known bone-anabolic pharmacokinetic (PK) profile of s.c. administered PTH, such molecules must trigger sharp, transient and robust release of PTH. The results of two early clinical studies with the orally-active calcilytic AXT914, a quinazolin-2ne derivative are reported. These were GCP-compliant, single and multiple dose studies of PK/PD and tolerability in healthy volunteers and postmenopausal women. The first study, examined single ascending doses (4 to 120 mg) and limited multiple doses (60 or 120 mgq.d. for 12 days) of AXT914. The second study was a randomized, double-blind, active- and placebo-controlled, 4-week repeat-dose parallel group study of healthy postmenopausal women (45 and 60 mg AXT914, placebo, 20 μg Forteo/teriparatide/PTH(1-34) fragment). AXT914 was well tolerated at all doses and reproducibly induced the desired PTH-release profiles. Yet, 4 weeks of 45 or 60 mg AXT914 did not result in the expected changes in circulating bone biomarkers seen with teriparatide. However total serum calcium levels increased above baseline in the 45 and 60 mg AXT914 treatment groups (8.0% and 10.7%, respectively), compared to that in the teriparatide and placebo groups (1.3% and 1.0%, respectively). Thus the trial was terminated after a planned interim analysis due to lack of effect on bone formation biomarkers and dose-limiting effects on serum calcium. In conclusion, AXT914 was well tolerated but the observed transient and reproducible PTH-release after repeat oral administration of AXT914 which showed an exposure profile close to that of s c. PTH, did not translate into a bone anabolic response and was associated with a persistent dose-related increase in serum calcium concentrations.
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]Human parathyroid hormone (PTH) (1-34) or teriparatide (TPTD) is an anabolic agent for osteoporosis. This recombinant protein stimulates positive bone formation balance and bone remodeling. However, when concomitantly used with antiresorptive (AR) agents, previous studies reported conflicting results in their potential additive and synergistic effects on bone metabolism and bone mineral density (BMD). This study aimed to integrate previous evidence to assess the effect of TPTD monotherapy and the additive effect of TPTD on AR agents in postmenopausal women with osteoporosis.
Osteoanabolic and dual action drugs. [2021]Teriparatide (TPTD) and abaloparatide (ABL) are the only osteoanabolic drugs available, at this time, for treatment of osteoporosis. TPTD is a 34-amino acid fragment that is identical in its primary sequence to the 34 amino acids of full-length human parathyroid hormone [hPTH(1-84)]. ABL is identical to parathyroid hormone-related peptide (PTHrP) through the first 22 residues with significantly different amino acids inserted thereafter, between residues 22 and 34. The osteoanabolic actions of PTH are due directly to its effects on cells of the osteoblast lineage and indirectly by stimulating IGF-I synthesis and suppressing sclerostin and associated enhancement of Wnt signalling. Both TPTD and ABL are ligands that bind to and activate the PTH receptor type 1 (PTHR1) receptor but they appear to do so differently: ABL favours the transient, more anabolic configuration of the receptor. Both TPTD and ABL reduce the risk of vertebral fractures and non-vertebral fractures. Both drugs are administered for a maximum of 24 months, and should be followed by an antiresorptive agent to maintain gains in bone mineral density (BMD). Romosozumab, a monoclonal antibody that binds to and inhibits sclerostin, appears to have dual actions by stimulating bone formation and reducing bone resorption. In the pivotal clinical trial, romosozumab, administered as a 210 mg monthly subcutaneous dose, significantly reduced new vertebral fractures and in a subsequent study reduced both vertebral and non-vertebral fractures.
Daily nasal spray of hPTH(1-34) for 3 months increases bone mass in osteoporotic subjects: a pilot study. [2018]Although intermittent parathyroid hormone (PTH) injection can lead to strong anabolic effects on bone, daily subcutaneous injection is a disadvantage for patient acceptance. We have developed a nasal spray formula of parathyroid peptide [hPTH(1-34)] with peak serum hPTH(1-34) concentrations by nasal spray of 1,000 microg similar to those by subcutaneous injections of 20 microg hPTH(1-34).