Aralast NP (alpha 1-antitrypsin) / Omni Bio Pharma, Takeda - LARVOL DELTA

A Study in Adults to Learn About Inherited Alpha-1 Antitrypsin Deficiency (AATD) and AATD Related Liver Problems (clinicaltrials.gov) - P=N/A | N=500 | Recruiting | Sponsor: Takeda | N=1000 ➔ 500

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

LIVER DISEASE PROGRESSION IN PATIENTS WITH METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS WITH AND WITHOUT ALPHA-1 ANTITRYPSIN DEFICIENCY: RESULTS: FROM A RETROSPECTIVE COHORT STUDY IN THE USA (AASLD 2025) - "In this matched cohort study, pts with MASH and AATD were more likely to have LD progression than pts with MASH alone, underscoring the incremental clinical burden associated with AATD. Testing for AATD in pts with MASH may guide treatment decisions and inform monitoring of LD progression. Writing support provided by R Tooze, Oxford PharmaGenesis."

Retrospective data • Alpha-1 Antitrypsin Deficiency • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Pulmonary Disease • Respiratory Diseases

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 DISEASE PROGRESSION IN INDIVIDUALS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED GENOTYPES: INSIGHTS FROM A LARGE GENETIC DATABASE LINKED TO ELECTRONIC MEDICAL RECORDS IN THE USA (AASLD 2025) - "This study leveraged genetic data with linked EMRs and provides evidence that patients carrying the Pi*ZZ genotype have the highest risk of liver disease progression, followed by Pi*SZ and other genotypes. Additionally, a higher APRI score at index was a strong predictor of liver disease progression, underscoring its value in identifying patients at higher risk for liver-related outcomes. Writing support provided by S Chambers, Oxford PharmaGenesis."

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

PERFORMANCE OF VIBRATION-CONTROLLED TRANSIENT ELASTOGRAPHY RELATIVE TO BIOPSY FOR LIVER FIBROSIS STAGING IN PATIENTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE AND A PI*ZZ GENOTYPE (AASLD 2025) - "In this study on the performance of VCTE versus liver biopsy for fibrosis staging in adults with AATD-LD and a Pi*ZZ genotype, VCTE performed similarly to biopsy in staging F2/F3 fibrosis. The optimal cut-off values of VCTE-based staging for UoF data were slightly lower than predefined thresholds based on clinical practice. Findings should be interpreted with caution and validated in larger studies."

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

A CLINICAL DECISION SUPPORT TOOL FOR THE IDENTIFICATION OF PATIENTS AT RISK OF DEVELOPING ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE: INTERIM RESULTS: (AASLD 2025) - "The ensemble model provided the best performance of the models evaluated, achieving a 233×- and > 9,300×-fold improvement in AATD-LD diagnosis versus incidence in pts with LD or the general population, respectively, in the SSM/SLU database. Prospective validation is in progress to support use of this AI/ML-CDST for the diagnosis of AATD-LD. Writing support provided by E L Wescott, Oxford PharmaGenesis."

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

LIVER TRANSCRIPTOMIC SIGNATURES IN PATIENTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY-ASSOCIATED LIVER DISEASE WITH A PI*ZZ GENOTYPE ARE SIMILAR TO THOSE IN OTHER FIBROTIC LIVER DISEASES (AASLD 2025) - "This is the first known liver transcriptomics study including the Pi*ZZ genotype. In pts with AATD-LD and fibrosis with a Pi*ZZ genotype, transcriptomic profiles were similar to those identified in MASH and PSC. Findings from this study advance the understanding of AATD-LD pathophysiology and highlight potential non-invasive biomarkers with utility in the diagnosis and management of AATD-LD."

Clinical • Alpha-1 Antitrypsin Deficiency • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Pulmonary Disease • Respiratory Diseases • IL1B • 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

Connecting the Clues: Lung and Liver Considerations in Diagnosing Alpha-1 Antitrypsin Deficiency (AASLD 2025) - "Consequences of a delayed AATD diagnosis. Emerging treatment approaches for AATD-associated liver disease Have greater competence related to identifying patients at risk of AATD-associated liver disease Demonstrate greater confidence in their ability to addressing barriers related to the delayed diagnosis of AATD-associated liver disease"

Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • 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

Bioanalytical Method Validations of Three Alpha1-Antitrypsin Measurement Methods Required for Clinical Sample Analysis. (PubMed, Pharmaceuticals (Basel)) - "Furthermore, the short-time stability of the analyte was also demonstrated. All three AAT measurement methods met the acceptance criteria defined by the guidelines on bioanalytical assay validation, qualifying these methods for clinical sample analysis."

Journal • Alpha-1 Antitrypsin Deficiency • ELANE

Anti-inflammatory Therapy to Improve Outcomes After TPIAT (clinicaltrials.gov) - P4 | N=43 | Completed | Sponsor: University of Minnesota | Active, not recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Pancreatitis • Transplantation

Application of an Artificial Intelligence Model to Detect Alpha-1 Antitrypsin Deficiency: Model Performance (ATS 2025) - "A previously developed machine learning model for identifying patients with AATD was successfully calibrated and validated using patient data from the Cleveland Clinic EMR. As measured by ROC and PR on unseen validation data, the model achieved high levels of performance, demonstrating differentiation between AATD and similar conditions or randomly selected controls."

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

Application of an Artificial Intelligence Model to Detect Alpha-1 Antitrypsin Deficiency: Characterizing the Study Population (ATS 2025) - "Within the Cleveland Clinic EMR, this analysis identified phenotypic and treatment pattern differences among cohorts of patients confirmed to have AATD. Lower frequencies of comorbidities, as well as lower rates of patients who received augmentation therapy for AATD, were observed in patients with mild deficiency of AAT compared with patients with confirmed genetic diagnoses and those with severe deficiency of AAT."

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

Clinical Study Support by Long-Term Stability Studies of Alpha1-Proteinase Inhibitor and Urea in Relevant Biological Matrices. (PubMed, Pharmaceuticals (Basel)) - "Interestingly, the analyte concentration did not significantly influence the results in either of the sample matrices. The data confirmed the appropriate stability of the three analytes in the matrices of citrated plasma and BAL-mimicking samples for at least up to 15 months."

Journal • ELANE

Liver disease progression in patients with alpha-1 antitrypsin deficiency and a Pi*ZZ genotype: a retrospective natural history study (EASL 2025) - "Among pts with AATD and a Pi*ZZ genotype, almost one in four experienced liver disease progression by 3.5 years based on matched fibrosis staging methods. Pts with more advanced fibrosis may have a higher proportion of liver disease progression. Study/writing funding: Takeda Development Center Americas, Inc."

Retrospective data • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Pulmonary Disease • Respiratory Diseases

Estimating the diagnosis rate of alpha-1 antitrypsin deficiency: insights from population-based cohorts in the USA (EASL 2025) - "In this study, < 2.0% of individuals with AATD genotypes had an AATD Dx code in their EMR. Those with a Dx had a higher prevalence of liver/lung disease and other comorbidities than those without a Dx in their EMR. Among those with a Pi*ZZ genotype, AATD Dx rate ranged from ~50–70%, which may be attributed to greater symptom manifestations associated with this genotype."

Clinical • Alpha-1 Antitrypsin Deficiency • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Obesity • Pulmonary Disease • Respiratory Diseases

Takeda: The alpha-1 antitrypsin deficiency liver care journey: From early signs to effective strategies (EASL 2025) - "Sponsored by Takeda. Recall the tools and strategies available to ensure a timely diagnosis of alpha-1 antitrypsin deficiency (AATD)-associated liver diseaseIdentify early signs of AATD-associated liver disease, including recognizing potential indicators in asymptomatic patients Outline a collaborative care plan for people with AATD-associated liver disease, incorporating pulmonology and hepatology perspectives Describe current and future AATD-associated liver disease management strategies"

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

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

Patient experience of alpha-1 antitrypsin deficiency-associated liver disease: a qualitative study. (PubMed, Qual Life Res) - "Several concepts were frequently reported as moderately/highly bothersome/disturbing. Further investigation of the experience of patients with AATD-LD in a large, diverse population across all fibrosis stages and genotypes is warranted. Clinical outcome assessments that capture salient concepts are needed."

Journal • Alpha-1 Antitrypsin Deficiency • Back Pain • CNS Disorders • Fatigue • Fibrosis • Gastroesophageal Reflux Disease • Genetic Disorders • Hepatology • Immunology • Infectious Disease • Musculoskeletal Pain • Pain • Pulmonary Disease • Respiratory Diseases • Sleep Disorder

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