Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition primarily affecting the lungs and liver. This condition, more common in individuals of Northern European descent, can lead to lung and liver diseases. Learn about the genetics, clinical presentation, and treatment options for AATD including augmentation therapy.
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OBJECTIVES Understand alpha-1 antitrypsin deficiency genetics and clinical presentation Compare alpha-1 antitrypsin deficiency and COPD Evaluate efficacy of augmentation therapy Mock up a managed category for alpha-1 proteinase inhibitors
ABOUT ALPHA-1 ANTITRYPSIN DEFICIENCY (AATD) Rare inherited condition affecting primarily the lungs and liver More common in individuals of northern European background ~100,000 individuals in US 1 in 1500 to 3500 people worldwide of European descent Has also been called genetic chronic obstructive pulmonary disease (COPD) https://www.alpha1.ie/ What is Alpha-1? Alpha-1 Foundation. Alpha-1 Antitrypsin Deficiency. StatPearls
ALPHA-1 ANTITRYPSIN (AAT) Common protease inhibitor (PI) that targets neutrophil elastase in the lungs Produced in hepatocytes Mutations in SERPINA1 (serine protease inhibitor) result in misfolded AAT protein Symptoms caused by deficiency may manifest after being exposed to triggers Lung disease smoking, irritants Liver disease chronic/excessive alcohol intake Alpha-1 Antitrypsin Deficiency. StatPearls Am J Respir Crit Care Med. 2003;168(7):818-900. Chronic Obstr Pulm Dis. 2016;3(3):668-682. Ther Adv Respir Dis. 2014;8(5):150-161. Neutrophil Elastase and Chronic Lung Disease (2021)
GENETICS Normal Normal plasma levels (> 20 mol/L) M type: PI*MM Deficient Plasma levels < 20 mol/L Null No AAT detected in plasma Normal levels of AAT but Dysfunctional not functional PI*F variant Converted to antithrombin Z type most common: PI*ZZ Other types: S type, M-like, S-like - Protective threshold of 11 mol/L Heterozygous less likely to have disease Null genotype less likely to have liver disease but more likely to have severe respiratory disease Alpha-1 Antitrypsin Deficiency. StatPearls Am J Respir Crit Care Med. 2003;168(7):818-900. Chronic Obstr Pulm Dis. 2016;3(3):668-682. Ther Adv Respir Dis. 2014;8(5):150-161.
AATD VS COPD AATD COPD Older age at diagnosis Centrilobular apical emphysema Earlier onset (age < 45) Basilar emphysema Non-respiratory presentations Respiratory symptoms Smoking history Alpha-1 Antitrypsin Deficiency. StatPearls Am J Respir Crit Care Med. 2003;168(7):818-900. Chronic Obstr Pulm Dis. 2016;3(3):668-682. Ther Adv Respir Dis. 2014;8(5):150-161.
WHO TO SCREEN? Anyone with unexplained chronic liver disease Anyone with necrotizing panniculitis Anyone with COPD Family members of anyone with identified genomic abnormality Alpha-1 Antitrypsin Deficiency. StatPearls Am J Respir Crit Care Med. 2003;168(7):818-900. Chronic Obstr Pulm Dis. 2016;3(3):668-682. Ther Adv Respir Dis. 2014;8(5):150-161.
AATD TREATMENT Smoking cessation COPD treatments for respiratory symptoms inhaled bronchodilators as appropriate Appropriate general treatment for liver disease No specific approved treatments for AATD-associated liver disease Transplantation Augmentation therapy with alpha-1 proteinase inhibitors (PI) in appropriate patients Efficacy? Alpha-1 Antitrypsin Deficiency. StatPearls Am J Respir Crit Care Med. 2003;168(7):818-900. Chronic Obstr Pulm Dis. 2016;3(3):668-682. Ther Adv Respir Dis. 2014;8(5):150-161.
AUGMENTATION THERAPY EFFICACY Observational studies Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group (1998) augmentation therapy reduced mortality and reduced the decline of FEV1 in those with a baseline FEV1 between 35-49% Augmentation Therapy for Severe Alpha-1 Antitrypsin Deficiency Improves Survival and Is Decoupled from Spirometric Decline A Multinational Registry Analysis (2023) augmentation therapy reduced mortality and reduced the decline of FEV1 in those with a baseline FEV1 between 50-80% Randomized clinical trials RAPID Trial Study Group Intravenous augmentation treatment and lung density in severe 1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial (2015) augmentation therapy reduced loss of lung density but did not reduce exacerbations, hospitalizations, improve lung function Am J Respir Crit Care Med. 1998;158(1):49-59. Am J Respir Crit Care Med. 2023;208(9):964-974. Lancet. 2015;386(9991):360-368. Am J Respir Crit Care Med. 2023;208(9):948-949.
GUIDELINE RECOMMENDATIONS 2016 Alpha-1 Antitrypsin Foundation Guidelines FEV1 65% or necrotizing panniculitis, FEV1 > 65% can consider risk-benefit discussion Do not use in: current smokers, PI*MZ genotype 2025 Canadian Thoracic Society Guidelines FEV1 < 80%, nonsmoker, severely deficient AATD levels (< 11 mol/L) Package Inserts Chronic augmentation and maintenance therapy in adults with clinically evident emphysema due to severe hereditary AATD Limitations of use The effect of augmentation therapy with any Alpha-1 PI on pulmonary exacerbations and on the progression of emphysema in AATD has not been conclusively demonstrated in randomized, controlled clinical trials Clinical data demonstrating the long-term effects of chronic augmentation or maintenance therapy are not available Not indicated as therapy for lung disease in patients in whom severe AATD has not been established. Chronic Obstr Pulm Dis. 2016;3(3):668-682. Eur Respir Rev. 2023;32(170):230170. Chest. Published online January 27, 2025. doi:10.1016/j.chest.2024.08.037 Prolastin-C Liquid. Package insert. 2022. Aralast NP. Package insert. 2024. Zemaira. Package insert. 2024. Glassia. Package insert. 2025.
ALPHA-1 PROTEINASE INHIBITORS (ALPHA-1 PI) Prolastin-C Aralast NP Zemaira Glassia Dose Contraindications and Warnings 60 mg/kg IV infusion every week Immunoglobulin A (IgA) deficient patients with antibodies against IgA History of anaphylaxis or other severe systemic reaction to Alpha1-PI May carry a risk of transmitting infectious agents such as viruses, the variant Creutzfeldt- Jakob disease (vCJD) and theoretically, the Creutzfeldt-Jakob disease (CJD) agent Diarrhea, fatigue, headache, upper respiratory infection, COPD exacerbations Replacement for Prolastin No reconstitution Specific vial strength may vary (confirm with packing) Side Effects Clinical Pearls Replacement for Aralast Requires reconstitution Requires reconstitution Specific vial strength may vary (confirm with packing) Can be administered at home by patient/caregiver after appropriate training Prolastin-C Liquid. Package insert. 2022. Aralast NP. Package insert. 2024. Zemaira. Package insert. 2024. Glassia. Package insert. 2025.
MANAGED CATEGORY MOCK-UP Respiratory Agents: Proteinase Inhibitors PREFERRED AGENTS NON-PREFERRED AGENTS PA CRITERIA Prolastin-C LiquidPA Aralast NP Zemaira Glassia LENGTH OF AUTHORIZATIONS: 365 Days CLINICAL PA CRITERIA: Must provide documentation of alpha-1 antitrypsin deficiency diagnosis: Genotype: homozygous ZZ or null Serum alpha-1 antitrypsin level < 11 mol/L FEV1 < 80% NON-PREFERRED CRITERIA: Must have had an inadequate clinical response of at least 365 days with at least one preferred drug with attestation of adherence
REFERENCES What is Alpha-1? Alpha-1 Foundation. https://alpha1.org/what-is-alpha1/ Meseeha M, Sankari A, Attia M. Alpha-1 Antitrypsin Deficiency. [Updated 2024 Aug 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK442030/ American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. doi:10.1164/rccm.168.7.818 Sandhaus RA, Turino G, Brantly ML, et al. The Diagnosis and Management of Alpha-1 Antitrypsin Deficiency in the Adult. Chronic Obstr Pulm Dis. 2016;3(3):668-682. Published 2016 Jun 6. doi:10.15326/jcopdf.3.3.2015.0182 Campos MA, Lascano J. 1 Antitrypsin deficiency: current best practice in testing and augmentation therapy. Ther Adv Respir Dis. 2014;8(5):150-161. doi:10.1177/1753465814542243 Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1998;158(1):49-59. doi:10.1164/ajrccm.158.1.9712017 Fraughen DD, Ghosh AJ, Hobbs BD, et al. Augmentation Therapy for Severe Alpha-1 Antitrypsin Deficiency Improves Survival and Is Decoupled from Spirometric Decline-A Multinational Registry Analysis. Am J Respir Crit Care Med. 2023;208(9):964-974. doi:10.1164/rccm.202305-0863OC Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe 1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360-368. doi:10.1016/S0140-6736(15)60860-1
REFERENCES Brantly M. Treatment for Alpha-1 Antitrypsin Deficiency: Does Augmentation Therapy Work?. Am J Respir Crit Care Med. 2023;208(9):948-949. doi:10.1164/rccm.202309-1585ED Miravitlles M, Anzueto A, Barrecheguren M. Nine controversial questions about augmentation therapy for alpha-1 antitrypsin deficiency: a viewpoint. Eur Respir Rev. 2023;32(170):230170. Published 2023 Dec 6. doi:10.1183/16000617.0170-2023 Hernandez P, Boss Y, Bush P, et al. Alpha-1-Antitrypsin Deficiency Targeted Testing and Augmentation Therapy: A Canadian Thoracic Society Meta-Analysis and Clinical Practice Guideline. Chest. Published online January 27, 2025. doi:10.1016/j.chest.2024.08.037 Prolastin-C Liquid. Package insert. Grifols Therapeutics; 2022. Aralast NP. Package insert. Takeda Pharmaceuticals; 2024. Zemaira. Package insert.CSL Behring; 2024. Glassia. Package insert. Takeda Pharmaceuticals; 2025.
