Transcript American Heart Association meeting, Fall 2007

Bringing Proteomics to the Clinic:
From Discovery to Validation
November 4, 2007
“Biomarkers of Pulmonary Arterial Hypertension”
Frank J. Accurso, MD
Professor of Pediatrics
University of Colorado
Disclosures: None
Support: NHLBI, NIDDK, NCRR, AHA, Cystic Fibrosis Foundation
Acknowledgements – Dunbar Ivy, MD; Steve Abman, MD
1
Biomarkers of Pulmonary Arterial
Hypertension (PAH): Overview
• PAH in adults and children
• PAH and biomarkers
• Exploratory protein biomarker studies in PAH in
children
Take home messages:
1. Improved biomarkers are needed to quickly
“test” new treatment approaches.
2. Biomarker studies should be incorporated into
clinical trials and investigations in PAH.
2
PAH - definition
• Sustained elevation of mean pulmonary arterial
pressure to > 25 mm Hg at rest or >30 mm Hg
with exercise, with a mean pulmonary capillary
and left atrial pressure < 15 mm Hg at rest.
• “fixed” (structural) and “reactive” components
• Better treatments are needed.
Rubin, Chest supplement, 2004
3
WHO Classification of PH (Venice, 2003)
Former
Primary Pulmonary Hypertension (PPH)
– idiopathic or unknown cause
OR
Secondary Pulmonary Hypertension (SPH)
– all other causes
Current
1.
2.
3.
4.
5.
WHO (Venice, 2003)
Pulmonary arterial hypertension
Pulmonary hypertension with left heart failure
PH with lung diseases and/or hypoxemia
PH due to chronic thrombotic and/or embolic diseases
Miscellaneous
Simonneau G, et al. J Am Coll Cardiol , Supplement, 2004.
4
PAH (WHO Group I)
• Idiopathic (IPAH)
• Familial (FPAH)
• Associated with (APAH)
– Collagen vascular disease
– HIV infection
– Congenital systemic-to-pulmonary shunts
– Drugs/toxins
– Portal hypertension
– Other
• Associated with significant venous or capillary
involvement
– Pulmonary veno-occlusive disease (PVOD)
– Pulmonary capillary hemangiomatosis (PCH)
• Persistent pulmonary hypertension of the newborn
Simonneau G, et al. J Am Coll Cardiol , Supplement, 2004.
5
PAH: Diagnostic Evaluation
• Physical
• Physiologic*
- Lung function
- Exercise testing
• Blood
• Imaging
• EKG
• Sleep study
• ECHO
• Right Heart Catheterization
• History*
* Difficult in young children
? Biochemical biomarkers of disease
6
Idiopathic PAH: Survival
Untreated - survival worse in children
100
Adult median survival: 2.8 years (n=194)
Pediatric median survival: 0.8 years (n=16)
% Survival
80
60
68%
40
48%
20
34%
(n=194)
0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Years of Follow-up
D’Alonzo, et al. Ann Internal Med 1991
7
PAH: Acute vasodilator response
depends on age
Barst et al.
8
PAH: Treatment Approaches
• Pathophysiology
- “fixed” – structural, associated with proliferation
- “reactive” – amenable to vasodilator treatment
- treatments based on known pathways of vasoactivity
• Calcium channel blockers – vasodilators
• Prostacyclin – vasodilator, antiproliferative
• Nitric oxide – vasodilator, antiproliferative
• Endothelin – vasoconstrictor, proliferative – need antagonist
• Vascular reactivity is a favorable prognostic sign
9
Idiopathic PAH in Children:
Event Free Proportion
Survival and Treatment Success with
Chronic Oral CCB in Acute Responders
10
Years after Diagnosis Yung, et al. Circulation 2004
Complex, long-term PAH treatment
strategies have been developed
Yes
Acute Vasodilator Response
No
Epoprostenol
Nitric Oxide
CHF
No
Yes
Epoprostenol
Treprostinil
Incomplete
response
Trial of
Calcium Channel
Blocker
Incomplete response
Trial of :
Bosentan
Ambrisentan
Sildenafil
Iloprost
Treprostinil
Epoprostenol
Biomarkers would be helpful in adding treatments.
Adapted from Rashid A, Ivy D. 2006: Current Paediatrics
11
Biomarkers of Pulmonary Arterial
Hypertension (PAH)
• PAH in Adults and Children
• Biomarkers and PAH
• Exploratory Biomarker Studies in PAH in
Children
12
Outcome Measures
Clinical efficacy measures: A characteristic or variable that
reflects how a patient feels, functions, or survives.
Surrogate endpoint: A laboratory measurement or physical
sign that is used in therapeutic trials as a substitute for a
clinically meaningful endpoint that is a direct measure of how
a patient feels, functions, or survives and is expected to
predict the effect of therapy.
Biomarker: A characteristic that is objectively measured and
evaluated as an indicator of normal biologic process,
pathogenic process, or pharmacologic response to a
therapeutic intervention.
Pulmonary Hypertension Review : Snow and Kawut, 2007 ; Hamblett et al, 2007
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Biomarker Need in PAH
Need
Current biochemical biomarker
Diagnosis
- Early identification
- Staging
No
No
Prognosis
- Rapid progression of disease
- Ongoing structural Injury
- Predict complications
Treatment
- Select treatment
- Response to treatment
- Toxicity with treatment
- Clinical Trials
a. Stratification
b. Proof of concept
c. Efficacy
No
No
No
No
No
No
No
No
No
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Value Added: Proof of Concept
15
The specific goals of the Clinical Proteomics Program are
to:
(1) design panels of candidate proteins for disease areas
(2) develop high throughput analytic methods
(3) assess the predictive value of these proteomic
measurements using biological specimens and clinical
data from existing study populations
(4) establish procedures and standards for quality control
http://www.mc.vanderbilt.edu/root/vumc.php?site=proteomics
16
Approaches to Protein Biomarkers
Single/Few
Protein
Assay(s)
(Hypothesis)
Multiplex Protein
Assay(s)
(Hypothesis/
Discovery)
Candidate
- Single
- Panel
Validation
Value
Added
Proteomics
(Discovery)
17
Candidate Biomarker Pathways in PAH
Candidate
Natriuretic peptide (BNP)
Troponin T
Source
myocytes
myocytes
Uric acid
Endothelin-1
Serotonin
Angiotensin system
ubiquitous
endothelium
platelets
vascular wall
NO related products
Cyclic nucleotides
endothelium
vascular wall,
smooth muscle
Fibrinogen related products
Cytokines, Growth factors
Acute Phase Reactants
fibrin
variety
liver
Aubert, Swiss Med Weekly, 2007
18
Caveat: Different Reagent Sources
Serum Il-6
• Controls
Agree
• Duplicate
Clinical samples
do not agree
• A second analytical
method is needed
for validation.
Brand Y
• Standards
Agree
Brand X
19
Biomarkers of Pulmonary Arterial
Hypertension (PAH): Overview
• PAH in adults and children
• PAH and biomarkers
• Exploratory protein biomarker studies in PAH in
children
Take home messages:
1. Improved biomarkers are needed to quickly
“test” new treatment approaches.
2. Biomarker studies should be incorporated into
clinical trials and investigations in PAH.
20
Characteristics of biomarkers
• Is the outcome measure specific to a process occurring
either early or late in the disease process?
• Is the biomarker in the causal pathway of the drug?
• How is the biomarker expected to change in response to
the drug?
• How long will it take to see an expected change in
response to the drug?
21