fazirsiran (TAK-999) / Arrowhead, Takeda - LARVOL DELTA

Alpha-1 antitrypsin deficiency: genetics, clinical manifestations, AI prognostics, and advanced imaging in liver disease. (PubMed, Ann Med Surg (Lond)) - "Novel therapies are reshaping AATD management, including small interfering RNA therapies (fazirsiran, belcesiran), gene-editing techniques (CRISPR-Cas9), regenerative approaches, autophagy-enhancing drugs, proteostasis regulators, aerosolized AAT, and artificial intelligence (AI) for real-time disease tracking via wearable devices. The integration of AI, advanced imaging, and emerging therapies represents a paradigm shift in AATD diagnosis and treatment. This review highlights the need for a multidisciplinary approach, early intervention, and personalized medicine to improve outcomes in both pulmonary and hepatic complications."

Journal • Review • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Fibrosis • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • SERPINA1

SERUM MICRORNA SEQUENCING IDENTIFIED FAZIRSIRAN TREATMENT-RESPONSIVE MICRORNAS IN PATIENTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE AND A PI*ZZ GENOTYPE (AASLD 2025) - P2 | "Changes in miRNA expression suggest that there is reduced HSC activity in pts with AATD-LD treated with fazirsiran and support the potential clinical benefit of fazirsiran among pts with AATD-LD and a Pi*ZZ genotype. The utility of these miRNAs as potential non-invasive biomarkers for AATD-LD require validation in larger studies. Writing support provided by M Reynolds, Oxford PharmaGenesis."

Clinical • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • COL3A1 • MIR122 • MIR16 • MIR195 • MIR200 • TGFB1

LIVER STIFFNESS RESPONSE AND HETEROGENEITY ASSESSED VIA MAGNETIC RESONANCE ELASTOGRAPHY IN ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE: RESULTS: FROM PHASE 2 STUDIES OF FAZIRSIRAN (AASLD 2025) - P2 | "MRE imaging in AATD-LD using histogram-based spatial LSM distribution and heterogeneity metrics offer additional granularity relative to biopsy. After fazirsiran treatment, heterogeneity metrics indicated a trend towards improved liver stiffness uniformity across fibrotic regions. Further MRE image analyses using radiomics from larger cohorts of pts with AATD-LD may yield robust features for monitoring and predicting treatment response."

Heterogeneity • P2 data • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Pulmonary Disease • Respiratory Diseases

FAZIRSIRAN IS EFFECTIVE IN EARLY AND ADVANCED FIBROSIS IN PATIENTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE (AASLD 2025) - P2 | "Hepatocellular ASGR1 and SERPINA1 expression is constant in patients with advanced fibrosis stages although loss of parenchymal cells (hepatocytes) may lead to reduced overall ASGR1 expression. Analysis of fazirsiran phase 2 studies indicates that fazirsiran is effective in both advanced and early fibrosis. Collectively, these findings support further development of fazirsiran in patients with AATD-LD and advanced fibrosis, given that accumulation of the disease-causing Z-AAT protein remains high."

Clinical • Metastases • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Pulmonary Disease • Respiratory Diseases • ASGR • MUC4 • SERPINA1

ARTIFICIAL INTELLIGENCE-BASED QFIBROSIS® ANALYSIS CORRELATES WITH CHANGES IN HISTOLOGICAL FEATURES IN ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE FOLLOWING TREATMENT WITH FAZIRSIRAN (AASLD 2025) - P2 | "METAVIR fibrosis assessed by digital pathology (qF analyses) positively correlated with PAS+D globule burden, portal inflammation, interface hepatitis and hepatocyte cell death in liver biopsy samples from patients with AATD-LD. This study suggests a spatial and pathobiological relationship between change in disease-driving Z-AAT globule burden and changes in portal inflammation and liver fibrosis after fazirsiran treatment. AI-based digital pathology approaches may support therapeutic development in AATD-LD but require validation in larger cohorts with longer observation periods."

Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases

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 (clinicaltrials.gov) - P3 | N=160 | Recruiting | Sponsor: Takeda | Trial completion date: Mar 2029 ➔ Aug 2030 | Trial primary completion date: Mar 2027 ➔ Feb 2028

Trial completion date • Trial primary completion date • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • AFP

TAK-999-1001: A Study About Fazirsiran in People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=34 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed

Trial completion • Hepatology

Fazirsiran for the treatment of alpha-1 antitrypsin deficiency-associated liver disease findings from the SEQUOIA phase 2 trial. (PubMed, Ann Med Surg (Lond)) - "Results demonstrated significant dose-dependent reductions in serum Z-AAT levels (-61% to -94%) and liver Z-AAT concentrations, improved liver histopathology, and a favorable safety profile. These findings support Fazirsiran's potential as a therapeutic option for AATD-associated liver disease."

Journal • P2 data • Alpha-1 Antitrypsin Deficiency • Bronchiectasis • Cholestasis • Chronic Obstructive Pulmonary Disease • Fibrosis • Gastroenterology • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • SERPINA1

Longitudinal assessment of liver stiffness for up to 96 weeks by magnetic resonance elastography and correlation with fibrosis markers in alpha-1 antitrypsin deficiency-associated liver disease: results from phase 2 studies of fazirsiran (EASL 2025) - P2 | "LSM via MRE demonstrated promising utility in monitoring fazirsiran treatment response in a small cohort of pts with AATD-LD. The utility of LSM via MRE and FibroScan will be further evaluated in ongoing phase 3 trials. Study/writing funding: Takeda Development Center Americas, Inc."

P2 data • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases

Artificial intelligence-driven qFibrosis® in alpha-1-antitrypsin deficiency-associated liver disease: correlation with METAVIR stage and other disease specific features (EASL 2025) - P2 | "This study aimed to compare second harmonic generation/two-photon excitation (SHG/TPE) and AI-driven qFibrosis analyses to pathologist-reported METAVIR fibrosis stage, non-invasive tests (NITs) of fibrosis and intrahepatic Z-alpha-1 antitrypsin (Z-AAT) burden using data from phase 2 clinical trials of fazirsiran... qFibrosis stage (METAVIR) and continuous value correlated with pathologist-reported METAVIR fibrosis stage, LSM via FibroScan/MRE and APRI, and identified a spatial correlation with distribution of Z-AAT burden. This suggests value in qFibrosis, an AI-driven, fully quantitative measure of fibrosis and its zonal distribution in AATD-LD. Novel digital pathology approaches may support therapeutic development in AATD-LD but require validation in larger cohorts."

Alpha-1 Antitrypsin Deficiency • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases

Fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease: long-term efficacy and safety results from a phase 2 extension study (EASL 2025) - P2 | "Fazirsiran showed sustained activity and long-term (≤ 3 years) safety in pts with AATD- LD during the extension phase. Fazirsiran was associated with reductions in liver/serum Z-AAT, improvements in measures of AATD-LD and a long-term safety profile that supports further clinical development in pts with AATD-LD. Study/writing"

Clinical • P2 data • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Infectious Disease • Liver Cirrhosis • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases

Patient-level analysis of intrahepatic z-alpha-1 antitrypsin burden in patients with alpha-1 antitrypsin deficiency-associated liver disease following fazirsiran treatment (EASL 2025) - P2, P3 | "A robust and sustained reduction of intrahepatic Z-AAT burden in patients with AATD-LD following fazirsiran treatment was demonstrated using two independent analytical approaches (PAS-D and LC–MS). Current findings will be validated in an ongoing phase 3 trial (NCT05677971) in which the effect of fazirsiran on the reversal of liver fibrosis in patients with AATD-LD will be evaluated. Study/writing"

Clinical • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases

Alpha-1 antitrypsin deficiency-associated liver disease: From understudied disorder to the poster child of genetic medicine. (PubMed, Hepatol Commun) - "Among the liver candidates, small interfering RNA fazirsiran efficiently suppresses AAT production and is currently in phase 3 clinical trial, while several other genetic approaches, such as RNA editing, are at earlier stages. In summary, AATD represents a systemic disorder increasingly seen in the hepatologic routine and requiring thorough interdisciplinary care, since the currently ongoing clinical trials often address only one of the organs it affects."

Journal • Review • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Fibrosis • Gastroenterology • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Pediatrics • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases

TAK-999-1001: A Study About Fazirsiran in People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=34 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Apr 2025 ➔ Sep 2025 | Trial primary completion date: Apr 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Hepatology

TAK-999-1001: A Study About Fazirsiran in People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=34 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

An Extension Study to Learn About the Long-Term Safety of Fazirsiran and if Fazirsiran Can Help People With Alpha-1 Antitrypsin Liver Disease (clinicaltrials.gov) - P3 | N=37 | Active, not recruiting | Sponsor: Takeda | Trial completion date: May 2026 ➔ May 2033 | Trial primary completion date: May 2026 ➔ May 2033

Trial completion date • Trial primary completion date • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • AFP

Takeda Delivers Strong Third-Quarter FY2024 Results; Raises Full Year Outlook, Forecasting Revenue and Core Operating Profit Margin Growth (Businesswire) - "Among the multiple late-stage programs presented, the company expects...Phase 3 data readouts in the calendar year 2025 with filings anticipated in FY2025-FY2026 for the following programs and indications: oveporexton (TAK-861) for the treatment of narcolepsy type 1; zasocitinib for the treatment of psoriasis...Moreover, five additional indication filings for late-stage programs are on pace for FY2027-FY2029. zasocitinib for the treatment of psoriatic arthritis; mezagitamab for treatments of immune thrombocytopenia (ITP), a rare immune-mediated bleeding disorder, and immunoglobulin A nephropathy (IgAN), a chronic progressive autoimmune mediated kidney disease; fazirsiran for the treatment of alpha-1 antitrypsin deficiency-associated liver disease, and elritercept for the treatment of anemia associated with myelodysplastic syndrome."

Filing • P3 data • Alpha-1 Antitrypsin Deficiency • Anemia • IgA Nephropathy • Immune Thrombocytopenic Purpura • Narcolepsy • Psoriasis • Psoriatic Arthritis

Fazirsiran Unveiled: Methodological Considerations for Optimizing Treatment in Alpha-1 Antitrypsin Deficiency. (PubMed, Gastroenterology) - No abstract available

Journal • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

An Extension Study to Learn About the Long-Term Safety of Fazirsiran and if Fazirsiran Can Help People With Alpha-1 Antitrypsin Liver Disease (clinicaltrials.gov) - P3 | N=37 | Active, not recruiting | Sponsor: Takeda | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • AFP

AROAAT2002: Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD) (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Arrowhead Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Aug 2024 ➔ Dec 2023

Trial completion • Trial completion date • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

LONG-TERM SAFETY AND EFFICACY OF FAZIRSIRAN IN PATIENTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE ENROLLED IN THE PHASE 2 PLACEBO-CONTROLLED SEQUOIA TRIAL (AASLD 2024) - "Fazirsiran showed sustained activity and long-term safety in patients with AATD-LD during the OLE phase. Fazirsiran was associated with stable pulmonary function, reduced serum Z-AAT, improved laboratory measures and a safety profile that supports its further clinical development in patients with AATD-LD. Writing assistance provided by R Tooze, PhD, of Oxford PharmaGenesis."

Clinical • P2 data • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases

CONCORDANCE OF HISTOLOGICAL AND LIQUID CHROMATOGRAPHY MASS-SPECTROMETRY-BASED INTRAHEPATIC Z-ALPHA-1 ANTITRYPSIN (Z-AAT) BURDEN ASSESSMENTS IN PATIENTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE (AASLD 2024) - P2 | "We leveraged data from two clinical trials of fazirsiran, an investigational small interfering RNA therapy for AATD-LD, to assess the correlations between PAS-D, intrahepatic Z-AAT and serum Z-AAT... PAS- D and LC-MS, two valuable approaches for the measurement of intrahepatic Z-AAT in patients with AATD-LD, demonstrated good concordance cross-sectionally and longitudinally, despite differences in pre-analytical procedures, analytical characteristics and inherent biases. These biopsy- and serum-based Z-AAT biomarkers are valuable tools to support clinical development of emerging therapies in AATD-LD. Writing assistance provided by EL Wescott, PhD, of Oxford PharmaGenesis."

Clinical • Discordant • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

DIGITAL IMAGE QUANTIFICATION OF COLLAGEN PROPORTIONATE AREA CORRELATES WITH METAVIR FIBROSIS STAGE AND LIVER STIFFNESS MEASUREMENT VIA FIBROSCAN® IN ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE (AASLD 2024) - P2 | "We aimed to establish a digital quantification method for collagen proportionate area (CPA) in AATD-LD and compare it with meta-analysis of histological data in viral hepatitis (METAVIR) fibrosis stage and FibroScan® scores using data from phase 2 clinical trials of fazirsiran... CPA significantly correlated with METAVIR fibrosis stage and liver stiffness measurement, suggesting value in continuous scores for quantifying liver fibrosis and potential for its utility as a measure of fibrosis in AATD-LD biopsy to complement pathologist-led histology evaluation. Novel digital pathology approaches may support therapeutic development in AATD-LD but require further validation. Writing assistance provided by R Tooze, PhD, of Oxford PharmaGenesis."

Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases

Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA). (PubMed, Gastroenterology) - P2 | "Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose dependent manner and reduced hepatic globule burden (NCT03945292)."

Journal • P2 data • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases

Proteomic analysis identified fazirsiran treatment-responsive protein biomarkers in patients with alpha-1 antitrypsin deficiency-associated liver disease (EASL-ILC 2024) - P2 | "This study leveraged a novel platform for proteomic discovery in patients with AATD-LD, identified candidate biomarkers reflecting disease severity, and demonstrated potential benefit of fazirsiran treatment in reducing cellular stress, inflammation and damage. Biomarkers identified in these analyses may have clinical utility but require validation in larger studies."

Biomarker • Clinical • Omic analysis • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases