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

Fazirsiran effects on lung proteomic signatures in AATD-associated liver disease clinical trials (ERS 2026) - P2 | "Tx with fazirsiran (≤2 years) did not impact serum proteomic profiles associated with LgD/function in Ph2 trials."

Clinical • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases

Fazirsiran treatment reduces serum biomarkers that predict major adverse liver outcomes in patients with alpha-1 antitrypsin deficiency-associated liver disease (EASL 2026) - No abstract available

Adverse events • Biomarker • Clinical • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

Novel serum proteomic signatures associated with disease burden in alpha-1 antitrypsin deficiency-associated liver disease (EASL 2026) - P2 | " Baseline serum samples from 41 adults with fibrosis and a Pi*ZZ genotype from phase 2 trials (AROAAT- 2001/-2002 [NCT03945292/NCT03946449]) of fazirsiran (an investigational siRNA therapy) were used for biomarker discovery via Olink Explore HT (~5,400 unique proteins)... This study identified novel serum proteins correlated with AATD-LD disease burden, advancing understanding of AATD-LD pathophysiology. Possible use of these markers for diagnosis, prognosis and/or monitoring treatment response in AATD-LD will be investigated in future studies. Study/writing funding: Takeda Development Center Americas, Inc."

Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Pulmonary Disease • Respiratory Diseases • FABP1 • FGFR2 • FSTL1

Fazirsiran treatment reduces serum biomarkers that predict major adverse liver outcomes in patients with alpha-1 antitrypsin deficiency-associated liver disease (EASL 2026) - P2 | "Fazirsiran treatment in pts with AATD-LD reduced levels of circulating biomarkers that predicted MALOs from the UKB-PPP data, supporting evaluation of the therapeutic potential of fazirsiran in a phase 3 clinical trial. Cell-type enrichment and pathway analyses are ongoing to better understand the biological and clinical relevance of these proteins following fazirsiran treatment. Study/writing funding: Takeda Development Center Americas, Inc."

Adverse events • Biomarker • Clinical • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • GDF15 • IGFBP7 • KRT18 • KRT18 • THBS2

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: Aug 2030 ➔ Dec 2031 | Trial primary completion date: Feb 2028 ➔ Jan 2029

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

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