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

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

Correlation of non-invasive tests with histological features and intrahepatic Z-alpha-1 antitrypsin burden in patients with alpha-1 antitrypsin deficiency-associated liver disease (EASL-ILC 2024) - P2 | " Baseline serum and histology samples from phase 2 AROAAT-2001 (NCT03945292) and AROAAT-2002 (NCT03946449) trials of fazirsiran or placebo in pts with AATD-LD were used... The study identified correlations of NITs (ALT, APRI, AST, FIB-4, LSM, Pro-C3, serum Z-AAT) and total intrahepatic Z-AAT to histological features (METAVIR fibrosis stage, portal inflammation and PAS-D globule burden). ALT, AST, Pro-C3, LSM and serum Z-AAT demonstrated adequate–good discriminatory performance in the identification of pts with ≥F2 and ≥F3 fibrosis. Clinical utilities of these NITs in the identification of pts with AATD-LD and in monitoring treatment responses will require validation in larger studies."

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

Study to Learn About the Safety of Fazirsiran and if it Can Help People With Alpha-1 Antitrypsin Liver Disease With Mild Liver Scarring (Fibrosis) (clinicaltrials.gov) - P3 | N=50 | Recruiting | Sponsor: Takeda | Not yet recruiting ➔ Recruiting

Enrollment open • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • 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 | Enrolling by invitation | Sponsor: Takeda | Recruiting ➔ Enrolling by invitation

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

SEQUOIA: Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) (clinicaltrials.gov) - P2 | N=40 | Completed | Sponsor: Arrowhead Pharmaceuticals | Active, not recruiting ➔ Completed

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

Study to Learn About the Safety of Fazirsiran and if it Can Help People With Alpha-1 Antitrypsin Liver Disease With Mild Liver Scarring (Fibrosis) (clinicaltrials.gov) - P3 | N=50 | Not yet recruiting | Sponsor: Takeda

New P3 trial • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases

A Study About Fazirsiran in People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=41 | Recruiting | Sponsor: Takeda | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

DESIGN OF THE FIRST PHASE 3 STUDY (REDWOOD) EVALUATING FAZIRSIRAN IN ADULTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE (AASLD 2023) - P2, P3 | "AATD-LD is a rare disease with no approved treatment options. Redwood is the largest, prospective, placebo-controlled, registrational study to evaluate the first RNAi therapeutic, fazirsiran, as a potential treatment for patients with AATD-LD-Pi*ZZ."

Clinical • P3 data • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Failure • Pulmonary Disease • Rare Diseases • Respiratory Diseases • SERPINA1

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 | Recruiting | Sponsor: Takeda | Not yet recruiting ➔ Recruiting

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

RNAi Therapeutics for Diseases Involving Protein Aggregation: Fazirsiran for Alpha-1 Antitrypsin Deficiency-associated Liver Disease. (PubMed, Expert Opin Investig Drugs) - "The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address."

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

Fazirsiran: “Fazirsiran reduced serum Z-AAT in a dose-dependent manner and was well tolerated“; Alpha-1 antitrypsin deficiency (Arrowhead) - EASL 2023

P2 data • Alpha-1 Antitrypsin Deficiency

Fazirsiran reduces liver Z-alpha-1 antitrypsin synthesis, decreases globule burden and improves histological measures of liver disease in adults with alpha-1 antitrypsin deficiency: a randomized placebo-controlled phase 2 study (EASL-ILC 2023) - P2 | "Fazirsiran reduced serum and liver concentrations of Z-AAT and hepatic PAS+D globule burden in all treated PTPs compared with PBO, leading to improved liver portal inflammation. These results support further development of fazirsiran in larger phase 3 studies. Funded by Arrowhead."

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

Arrowhead Presents Updated Data from Phase 2 SEQUOIA Study of Investigational RNAi Therapy Fazirsiran in Patients with Alpha-1 Antitrypsin Deficiency Liver Disease (Businesswire) - P3 | N=160 | SEQUOIA (NCT05677971) | Sponsor: Takeda | "Arrowhead Pharmaceuticals...today presented updated results from the Phase 2 SEQUOIA clinical study of investigational fazirsiran (TAK-999/ARO-AAT) for the treatment of liver disease associated with alpha-1 antitrypsin deficiency (AATD-LD)....Takeda...and Arrowhead are further investigating fazirsiran in the ongoing pivotal Phase 3 REDWOOD clinical study which is actively recruiting a total of 160 patients....At week 48, patients receiving 25, 100, or 200 mg fazirsiran (n=16) achieved serum Z-AAT reductions of 74%, 89%, and 94%, respectively, versus an increase of 9% observed in patients receiving placebo (n=9)...Fazirsiran has been well tolerated to date. No treatment-emergent adverse events related to study drug causing discontinuation, dose interruptions or premature study withdrawals...Treatment emergent adverse events reported to date generally well balanced between fazirsiran and placebo groups."

Enrollment status • P2 data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

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 | Not yet recruiting | Sponsor: Takeda

New P3 trial • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • AFP

Arrowhead Pharmaceuticals to Participate in Upcoming June 2023 Conferences (Businesswire) - "Arrowhead Pharmaceuticals...today announced that it is scheduled to participate in the following upcoming events...European Association for the Study of the Liver (EASL) Congress 2023 – June 24, 2023...Fazirsiran reduces liver Z-alpha-1 antitrypsin synthesis, decreases globule burden and improves histological measures of liver disease in adults with alpha-1 antitrypsin deficiency: a randomized placebo-controlled phase 2 study..."

P2 data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

Takeda Pharmaceutical Company Limited (NYSE:TAK) Q4 2022 Earnings Call Transcript (Yahoo Finance) - "We also had a number of positive study readouts to further advance our pipeline this year....a Phase II readout for fazirsiran and proof-of-concept data for our Orexin franchise....We initiated a Phase III pivotal trial for fazirsiran."

P2 data • Trial status • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

A Study About Fazirsiran in People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=41 | Not yet recruiting | Sponsor: Takeda

New P1 trial • Hepatology

Cleaning up alpha-1 antitrypsin deficiency related liver disease. (PubMed, Curr Opin Gastroenterol) - "Although the fazirsiran data offer a glimpse of hope to AATD patients, a consensus on appropriate study endpoint, a careful patient selection as well as monitoring of long-term safety will be essential for an approval."

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