tratamiento específico para la deficiencia de a1at: ¿cómo funciona y qué habrá en el futuro?...
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Tratamiento específico para la deficiencia de A1AT: ¿Cómo funciona y qué habrá en el
futuro?
Robert A. Sandhaus, MD, PhD, FCCPNational Jewish HealthUniversity of Colorado
Alpha-1 FoundationAlphaNet
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
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
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
The Lung in Alpha-1
Silverman & Sandhaus, NEJM 2009;360:2749-57
The Liver in Alpha-1
Silverman & Sandhaus, NEJM 2009;360:2749-57
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– “Alpha1 Proteinase Inhibitor (Human)”– Goal of therapy: Slow or halt progression of
emphysema– No expected benefit to liver or other disease
associated with AATD
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
Biochemical Efficacy
200
150
10080
50
0 2 4 6 12 14 16 18 20 22 24 268 10
Threshold
.
Biochemical Evidence in Supportof Replacement Therapy
Weeks
Ser
um
a1-
anti
try
psi
n t
rou
gh
lev
el (
mg
/dl)
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 trialThe Alpha-1-Antitrypsin Deficiency Registry Study Group. AJRCCM 1998; 158:49
Seersholm, N, Kok-Kensen A, Dirksen A. AJRCCM 1995; 152:1922Wencker M, Fuhrmann B, Banik N, et al. Chest 2001; 119:737-744ERJ Express, February 5, 2009 Thorax in press
NIH Mortality Data
Canadian Data
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
RAPID
• Question if prospectively defined endpoint met
• CT densitometry at TLC statistically significant decrease in long tissue loss
• Extension study promising
RAPID
-6.48
-5.43
-4.38
-2.19
0
-1
-2
-3
-4
-5
-6
-7
-80 12 24 36 48
A1-P1Placebo
-1.45
-2.95
-4.03
-5.16
Month
Dec
line
Adj
uste
d Lu
ng D
ensi
ty(g
/L, 9
5% C
l)
Does Augmentation Therapy Work?
• Can depend on whom you ask• If you ask me. . .
– Yes
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
Sandhaus, NEJM 2012; 366:567
✖
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