Study to Check the Safety of Fazirsiran and Learn if Fazirsiran Can Help People With Liver Disease and Scarring (Fibrosis) Due to an Abnormal Version of Alpha-1 Antitrypsin Protein

Official title

A Randomized, Double-blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Fazirsiran in the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease With METAVIR Stage F2 to F4 Fibrosis

Overview

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 the disease worsening in the liver, to get information on how fazirsiran affects the body (called pharmacodynamics), to learn if fazirsiran reduces other liver injury (inflammation) and the abnormal Z-AAT protein in the liver, to get information on how the body processes fazirsiran (called pharmacokinetics), to test how well fazirsiran works compared with a placebo in improving measures of liver scarring including imaging and liver biomarkers (substances in the blood that the body normally makes and help show if liver function is improving, staying the same, or getting worse) as well as to check for side effects in participants treated with fazirsiran compared with those who received placebo. Participants will either receive fazirsiran or placebo. Liver biopsies, a way of collecting a small tissue sample from the liver, will be taken twice during this study.

Interventions

• Drug Fazirsiran Injection
  Participants will receive fazirsiran 200 mg/ml SC injection on Day 1, at Week 4, and Q12 W thereafter up to Week 196.
• Other Placebo
  Participants will receive placebo (sterile normal saline \[0.9% NaCl\]) SC injection on Day 1, at Week 4, and Q12 W thereafter up to Week 196.

Primary outcome measures

• 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 [Time frame: Baseline, Week 106]

Secondary outcome measures (12)

• Percent Change from Baseline in Intrahepatic Z-AAT Protein in Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (AATD-LD) with METAVIR Stage F2 to F3 Fibrosis at Week 106 [Time frame: Baseline, Week 106]
• Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy [Time frame: Baseline, Week 106 and Week 202]
• Number of Participants With Liver Related Clinical Events up to Week 202 [Time frame: Baseline up to Week 202]
• Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein [Time frame: Baseline, Week 106, Week 202]
• Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining [Time frame: Baseline, Week 106, Week 202]
• Change From Baseline in Intrahepatic Portal Inflammation [Time frame: Baseline, Week 106, Week 202]
• Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)/Magnetic Resonance Elastography (MRE)-derived Liver Stiffness [Time frame: Baseline, Week 106, Week 196 and Week 202]
• Change From Baseline in Model of End-Stage Liver Disease (MELD) Score [Time frame: Baseline, Week 106, and Week 202]
• Change From Baseline in Liver Injury [Time frame: Baseline, Week 106 and Week 202]
• Percent Change from Baseline in Intrahepatic Z-AAT Protein in AATD-LD With METAVIR Stage F2 to F4 Fibrosis [Time frame: Baseline, Week 106 and Week 202]
• Observed Plasma Concentrations of Fazirsiran [Time frame: Pre-dose up to Week 220]
• Number of Participants with Treatment-emergent adverse event (TEAE) and Serious TEAEs [Time frame: From start of study drug administration up to end of the study (EOS) (Week 230)]

Eligibility criteria

Inclusion criteria

• 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.
• The participant, of any sex, is aged 18 to 75 years, inclusive.
• The participant's liver biopsy core sample collected should meet the requirements of the protocol.
• The participant has evidence of METAVIR stage F2, F3, or F4 liver fibrosis, evaluated by a centrally read baseline liver biopsy during the screening period; or confirmed as meeting all the entry criteria by central reading of a previous biopsy conducted within 6 months before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual.
• The participant has a pulmonary status meeting the protocol's requirements.
• It must be confirmed that the participant does not have HCC. Participants will be screened for HCC with alpha-fetoprotein (AFP) and abdominal ultrasound. If the participant has any of the following, they will be required to have contrast-enhanced CT or MRI imaging to exclude HCC before randomization.
• An adult participant must have a body mass index (BMI) greater than or equal to (>=) 18.0 kilograms per meter square (kg\^m2).
• The participant is a nonsmoker for at least 6 months before screening.

Exclusion criteria

• The participant has a history of liver decompensating events (overt hepatic encephalopathy \[West Haven Grade >=2\] documented by a physician or healthcare professional, clinically significant ascites, spontaneous bacterial peritonitis, GI bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or bleeding portal hypertensive gastropathy).
• The participant has a history of the presence of medium or large varices or varices with red wale signs based on a previous esophagogastroduodenoscopy (EGD) within 6 months before the estimated enrollment date. For certain participants, an EGD will be required at screening if there is no EGD available within 6 months before the estimated enrollment date. Presence of small varices with no red wale signs on EGD and no history of bleeding will be acceptable for study eligibility.
• The participant has evidence of chronic liver disease attributable to other diseases, including viral hepatitis B or C, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis.
• The participant has alanine transaminase (ALT) or aspartate transaminase (AST) levels >250 units per liter (U/L).
• The participant has a platelet count <60,000 per cubic millimeter (mm\^3) (<60 × 10\^9 per liter \[10\^9/L\]).
• The participant has albumin <=2.8 gram per deciliter (g/dL) (28 grams per liter \[g/L\]).
• The participant has international normalized ratio (INR) >=1.7.
• The participant is expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study such as may occur with occupational exposure to mineral dusts or metals.
• The participant has a history of drug abuse (such as cocaine, phencyclidine) within 1 year before the screening visit or has a positive urine drug screen at screening.
• The participant has previously been treated with fazirsiran or any other RNAi for AATD-LD.
• The participant has portal vein thrombosis.
• The participant has a prior transjugular portosystemic shunt procedure.
• The participant has a history of malignancy within the last 5 years, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and a greater than 1-year disease-free interval may be entered after approval by the medical monitor.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 37 centers

• University of Alabama at Birmingham — Birmingham
• St. Joseph's Hospital and Medical Center — Phoenix
• Mayo Clinic — Phoenix
• University of Arizona Thomas D. Boyer Liver Institute — Tucson
• Gastroenterology & Liver Institute — Escondido
• University of California San Diego, Altman Clinical and Translational Institute — La Jolla
• UCLA Pulmonary and Critical Care — Los Angeles
• Stanford University — Palo Alto
• … and 29 more centers

France · 6 centers

• Hôpital Beaujon — Clichy
• Hôpital de La Croix Rousse — Lyon
• Centre Francois Magendie — Pessac
• Hopital PONTCHAILLOU CHU de Rennes — Rennes
• Hospital Purpan — Toulouse
• Hôpital Paul Brousse — Val-de-Marne

United Kingdom · 6 centers

Center list to be confirmed — check the primary protocol.

Germany · 5 centers

• Universitätsklinikum der RWTH Aachen — Aachen
• Charité - Campus Virchow-Klinikum-Ostring 1 — Berlin
• Hannover Medical School — Hanover
• Universitätsklinikum Schleswig-Holstein - Campus Kiel — Kiel
• Universitätsklinikum Tübingen — Tübingen

Austria · 4 centers

• LKH-Universitätsklinikum Graz — Graz
• Medizinische Universität Innsbruck — Innsbruck
• Klinikum Klagenfurt Am Wörthersee — Klagenfurt
• Medizinische Universität Wien (Medical University of Vienna) — Vienna

Italy · 4 centers

• Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico — Milan
• Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone — Palermo
• Fondazione IRCCS Policlinico San Matteo di Pavia — Pavia
• IRCCS Istituto Clinico Humanitas — Rozzano

Spain · 4 centers

• Hospital Universitario Vall d'Hebron - PPDS — Barcelona
• Hospital Universitario Virgen de la Victoria — Málaga
• Hospital Universitario Marques de Valdecilla — Santander
• Hospital Universitario Virgen del Rocio - PPDS — Seville

Brazil · 3 centers

• Hospital de Base do Distrito Federal — Brasília
• Hospital Sirio-Libanes — São Paulo
• Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina Campus de Bot — São Paulo

Canada · 3 centers

• GI Research Institute — Vancouver
• Queen Elizabeth II Health Sciences Center — Halifax
• Inspiration Research Limited — Toronto

Portugal · 3 centers

• CCA Hospital Braga — Braga
• Hospital Nélio Mendonça — Funchal
• Centro Hospitalar do Porto — Porto

Australia · 2 centers

• Royal Adelaide Hospital — Adelaide
• St Vincents Hospital Melbourne - PPDS — Fitzroy

Belgium · 2 centers

• UZ Antwerpen — Antwerp
• UZ Leuven — Leuven

Netherlands · 2 centers

• Amsterdam UMC - VUmc - De Boelelaan — Amsterdam
• Leiden University Medical Center — Leiden

Poland · 2 centers

• ID Clinic Arkadiusz Pisula — Śląskie
• WIP Warsaw IBD Point Profesor Kierkus — Warsaw

Sweden · 2 centers

Center list to be confirmed — check the primary protocol.

Czechia · 1 center

• Institut klinicke a experimentalni mediciny — Prague

Denmark · 1 center

• Hvidovre Hospital — Hvidovre

Ireland · 1 center

• Beaumont Hospital — Dublin

Switzerland · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT05677971 · TAK-999-3001 · 2022-501943-34-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗