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