1. Tratamiento específico para la deficiencia de A1AT: ¿Cómo funciona y qué habrá en el futuro? Robert A. Sandhaus, MD, PhD, FCCP National Jewish Health University of Colorado Alpha-1 Foundation AlphaNet

2. Potential Conflicts Served on advisory boards and/or have presented at events sponsored by: Bayer, Grifols, CSL Behring, AstraZeneca, Baxter, Kamada, Tuteur Receive salary from two not-for-profit organizations that receive industry funding: Alpha-1 Foundation and AlphaNet

3. Alpha-1 Antitrypsin (AAT) 52,000 molecular weight protein coded for by single gene on long arm of chromosome 14 Synthesis predominantly in the liver, but also expressed by other cells Transported to blood where it bathes all tissues Prototype SERPIN Primary target: neutrophil elastase Acute phase reactant Anti-inflammatory 52,000 molecular weight protein coded for by single gene on long arm of chromosome 14 Synthesis predominantly in the liver, but also expressed by other cells Transported to blood where it bathes all tissues Prototype SERPIN Primary target: neutrophil elastase Acute phase reactant Anti-inflammatory

4. Diseases associated with AATD Lung disease – Pulmonary emphysema – Bronchiectasis Liver disease – Fulminant liver failure of the newborn – Cirrhosis in the adult Other – Necrotizing panniculitis – Granulomatosis with polyangiitis – ± Susceptibility to non-tuberculous mycobacteria

5. The Lung in Alpha-1 Silverman & Sandhaus, NEJM 2009;360:2749-57

6. The Liver in Alpha-1 Silverman & Sandhaus, NEJM 2009;360:2749-57

7. Specific therapy Of these only pulmonary emphysema caused by AATD has a specific therapy – Known as Replacement Therapy or Augmentation therapy – Human plasma derived alpha-1 antitrypsin protein – “Alpha 1 Proteinase Inhibitor (Human)” – Goal of therapy: Slow or halt progression of emphysema – No expected benefit to liver or other disease associated with AATD

8. Evidence for Effectiveness Biochemical evidence – Weekly i.v. administration at 60 mg/kg body weight Raises trough blood levels above “magic protective level” Raises lung levels in BAL to normal range Clinical evidence – Multiple case controlled trials

9. Biochemical Efficacy 200 150 100 80 50 0246121416182022 2426 810 Threshold. Biochemical Evidence in Support of Replacement Therapy Weeks Serum  1 -antitrypsin trough level (mg/dl)

10. Clinical Efficacy of Augmentation Therapy Observational studies in US (NHLBI Registry) and Germany (German-Danish study) – Decreased lung function decline – Decreased mortality (US) – German retrospective study Danish-Dutch randomized trial – Underpowered – Suggested decreased loss of CT lung density Canadian retrospective analysis EXACTLE – Randomized CT densitometry trial RAPID – Randomized CT densitometry trial The Alpha-1-Antitrypsin Deficiency Registry Study Group. AJRCCM 1998; 158:49 Seersholm, N, Kok-Kensen A, Dirksen A. AJRCCM 1995; 152:1922 Wencker M, Fuhrmann B, Banik N, et al. Chest 2001; 119:737-744 ERJ Express, February 5, 2009 Thorax in press

11. NIH Mortality Data

12. Canadian Data

13. EXACTLE Knowingly underpowered Prospectively defined CT densitometry endpoint barely missed Post-hoc CT densitometry analyses – Statistically significant reduction in loss of lung tissue – Combined data from Danish/Dutch and EXACTLE highly significant

14. RAPID Question if prospectively defined endpoint met CT densitometry at TLC statistically significant decrease in long tissue loss Extension study promising

15. RAPID -6.48 -5.43 -4.38 -2.19 0 -2 -3 -4 -5 -6 -7 -8 012243648 A1-P1 Placebo -1.45 -2.95 -4.03 -5.16 Month Decline Adjusted Lung Density (g/L, 95% Cl)

16. Does Augmentation Therapy Work? Can depend on whom you ask If you ask me... – Yes

17. The Future Augmentation therapy – Inhaled therapy – Recombinant – Gene therapy Liver directed therapy – Gene silencing – Polymerization prevention – Depolymerization – Gene therapy – Stem cell therapy For lung repair For liver reconstitution

18. Sandhaus, NEJM 2012; 366:567 ✖

19. Summary Alpha-1 antitrypsin deficiency (Alpha-1): – The most common genetic risk factor for COPD – Accounts for about 1% of all COPD, although most remain undiagnosed – Specific plasma-derived therapy and disease management is available that improves survival and lung tissue loss – The diagnosis of Alpha-1 is a laboratory diagnosis, not a clinical diagnosis All patients with COPD/EPOC should be tested for Alpha-1