Pulmonary arterial hypertension PAH disease and patient population

1
Pulmonary arterial hypertension (PAH) disease
and patient population
2
Definition of PAH

• A rare form of PH, PAH is a clinical syndrome of
  dyspnoea and fatigue, due to a progressive
  increase in resistance of small pulmonary
  vessels, without identifiable cardiac or
  respiratory origin
• Defined as
• A sustained elevation of pulmonary artery
  pressure (PAP) gt25 mmHg at rest or gt30 mmHg with
  exercise, with a mean pulmonary capillary wedge
  pressure and left ventricular end-diastolic
  pressure lt15 mmHg1
• Causes are idiopathic (IPAH), familial or found
  in association with other specific conditions (or
  identified risk factors)

1. Farber HW, Loscalzo J N Engl J Med 2004 351
16551665
3
Clinical classification of pulmonary hypertension
Simonneau G et al. J Am Coll Cardiol 2004 16 43
(12 Suppl S) 5S12S
4
Epidemiology how frequent is PAH?

• PAH is
• A rare disease
• Prevalence is between 1525 cases/million1
• Incidence 24 per million/year13
• Rapidly evolving1
• 75 NYHA FC III at diagnosis
• Median survival of IPAH is 2.8 years
• Incurable4
• Despite appropriate therapy, PAH is a progressive
  disease
• Right heart failure is responsible for symptoms
  (syncope, fluid retention) and has an impact on
  prognosis5
• Pathophysiology is complex

1. Humbert M et al Am J Resp Crit Care Med
2006173 10231030 2. Abenhaim L et al N Engl J
Med 1996 335 609-6163. NICE Health Technology
Appraisal. Appendix A. January 2007 4. Humbert M
et al N Engl J Med 2004 351 14251436 5. Galiè
N et al Eur Heart J 2004 25 22432278
5
NYHA/WHO classification of functional status

• Barst RJ et al. J Am Coll Cardiol 2004 16 43 (12
  Suppl S) 40S47S

6
Pathogenesis of PAH
PULMONARY VASCULAR INJURY
Vasoconstriction proliferation inflammation
thrombosis
Pulmonary vascular disease Clinical syndrome of
PAH
BMPR-2 bone morphogenetic protein receptor type 2
1. Adapted from Gaine S JAMA 2000 284 31603168
7
Pathophysiology of PAH
1) Risk factors and associated conditions
collagen vascular disease, HIV infection, drugs
and toxins
2) Vascular injury endothelial dysfunction
3) Disease progression vascular remodelling
(medial hypertrophy, adventitial and intimal
proliferation)
Susceptibility
Irreversible disease
Reversible disease
Normal artery
1. Adapted from Gaine A. JAMA. 200028431603168.
8
Endothelin 1 plays an integral role in PAH1
Monocytes
Platelets
IL-8
IL-1
oxLDL
ET-1
IL-6
AI
AII
TGF?1
Thr
Endothelial cells
AT1
T
SR
ETB
ACE
NOs
COX-1
ET-1
ET-1
bET-1
NO
PGI2
L-Arg
ECE
AT1
Migration
Smooth muscle cells
ETB
cGMP
ETA
cAMP
Contraction
Proliferation
Relaxation
ETB receptor
ETA receptor
ET-1 clearance Vasodilation/antiproliferative
Vasoconstriction SMC migration proliferation

• Spieker LE et al J Am Coll Cardiol 2001 37
  14931505

9
Increased plasma endothelin levels are a major
prognostic factor in PAH1
Risk of death (n13)
ET
p0.046
CI
p0.044
SvO2
p0.037
RAP
p0.023
0
0.5
1.0
1.5
2.0
-0.5
Hazard ratio

• Galiè N Eur J Clin Investig 1996 26 A48

10
Is the PAH patient population changing?

• Incidence approximately 2-4 cases per million
  population per year1,2
• The PAH patient pool is becoming increasingly
  complex
• Patients are living longer after diagnosis3
• These patients are older than previously thought.
  Older patients have more co-morbidities4,5
• Older patients consume a larger pill burden5
• Drugdrug interactions (DDIs) become increasingly
  prominent5

• Abenhaim L et al. N Engl J Med 1996 335
  609616
• NICE Health Technology Appraisal. Appendix A.
  January 2007
• Mehta S, Shoemaker GJ. Thorax 2005 60 981983
• Thenappan T et al. Eur Respir J 2007 30
  11031110
• Delafuente JC. Crit Rev Oncol Hematol 2003 48
  133143

11
Age and aetiology of PAH patient population
French Registry Network1
674 patients in the French Network on Pulmonary
Hypertension 20032004

• Mean age of patients enrolled 50 15 years
• A significant proportion of the population was
  gt70 years old at the time of diagnosis (9.1)

Distribution of the type of PAH
1. Humbert M et al. Am J Resp Crit Care Med
2006 173 10231030
12
PAH patient population is aging1
A US PAH registry 19822006
70
Mean SD plt0.0001 vs. period lt1996
60
50
52
49
40
41
Mean age at referral (years)

30
20
10
0
19962002
19821996
20022006
N103
N328
N147
A total of 578 of patients were enrolled with
mean age of 48 14 years. 8.5 were above the age
of 70 years at the time of diagnosis

• Thenappan T et al. Eur Respir J 2007 30
  11031110

13
Multiple pathways are involved in the development
of PAH1
PGI2
ERA
Phosphodiesterase type 5
PDE5-i
1. Adapted from Humbert M N Engl J Med 2004
351 14251436
14
Currently available ERAs

• Two available ERAs (of sulphonamide class) for
  the treatment of PAH
• Bosentan and sitaxentan
• Non-selective ERA bosentan has been shown in
  randomised controlled trials to improve
• Exercise capacity
• Haemodynamics
• Symptoms1
• In addition, bosentan may improve survival in
  IPAH when compared with mortality predicted by
  the NIH equation for untreated patients²

• Rubin LJ et al N Engl J Med 2002 346 896903
• McLauglin VV et al Eur Respir J 2005 25
  244249

15
Limitations of current ERAs - LFT abnormalities

• Both bosentan and sitaxentan have reported events
  potentially related to hepatoxicity
• Bosentan and its metabolites can inhibit the
  hepatic bile salt export pump (BSEP) which may
  lead to increased plasma transaminase
• BSEP mediates the rate-limiting step in bile salt
  secretion from blood to bile1
• Incidence of liver function abnormalities (gt 3
  times the upper limit of normal) in clinical
  trials
• Sitaxentan 7.0 vs 5.0 placebo2
• Bosentan 11.2 vs 1.8 placebo3

1. Fattinger K et al Clin Pharmacol Ther 2001
69 223231 2. Thelin Summary of Product
Characteristics 3. Tracleer Summary of Product
Characteristics
16
Inhibition of bile salt export pump may
contribute to hepatotoxicity1
Bile
Hepatocyte
Plasma
Bosentan Metabolites
Bosentan
Bosentan

BSEP
Bile salts
Bile salts
Bile salts
ALTAST
1. Fattinger K et al Clin Pharmacol Ther 2001
69 223231
17
Limitations of current ERAs - DDIs
1. Thelin Summary of Product Characteristics2.
Tracleer Summary of Product Characteristics
Bosentan 125 mg bid causes 63 reduction of
sildenafil AUC Sildenafil 80 mg tid results in
50 increase in AUC of bosentan
18
Summary there is currently an unmet need in PAH
treatment1

• The patient phenotype is becoming more complex
• Patients older at diagnosis with increased
  co-morbidities1,2
• Current issues with available ERAs
• DDIs with many commonly used drugs (e.g.
  warfarin, oral contraceptive pill)
• Risk of hepatic toxicity
• A tailored treatment approach is required
• Clearly defined, ambitious treatment goals
• Potential to uptitrate to achieve goals with
  monotherapy
• Combination therapies may be required3

1. Thenappan T et al. Eur Respir J 2007 30
110311102. Elliot GC et al. Chest 2007631S 3.
Galiè N Eur Heart J 2004 25(24) 22432278
19
Basistext lt. AMG

• Volibris 5 mg Filmtabletten
• Volibris 10 mg Filmtabletten
• Wirkstoff Ambrisentan. Zusammensetzung eine
  Tablette enthält 5 (10) mg Ambrisentan. Sonstige
  Bestandteile jede Tablette enthält
  Lactose-Monohydrat (ca. 95 mg), Sojalecithin
  (E322) (ca. 0,25 mg) und Allurarot AC
  Aluminiumlake (E129) (ca. 0,11 mg).
  Anwendungsgebiete Behandlung von Patienten mit
  pulmonal arterieller Hypertonie (PAH) der
  WHO-Funktionsklassen II und III, zur Verbesserung
  der körperlichen Belastbarkeit. Die Wirksamkeit
  wurde bei idiopathischer PAH (IPAH) und PAH
  assoziiert mit einer Bindegewebserkrankung
  nachgewiesen. Gegenanzeigen Überempfindlichkeit
  gegenüber dem Wirkstoff, Soja oder einem der
  sonstigen Bestandteile Schwangerschaft
  Anwendung bei Frauen im gebärfähigen Alter ohne
  sichere Kontrazeptionsmethode Stillzeit stark
  eingeschränkte Leberfunktion (mit oder ohne
  Zirrhose) Ausgangswerte der Leber-Aminotransferas
  en (Aspartataminotransferasen AST und/oder
  Alaninaminotransferase ALT) gt 3 x ULN lt18
  Jahre. Nebenwirkungen sehr häufig (gt10)
  periphere Ödeme, Kopfschmerzen. Häufig (gt1 und
  lt10) Anämie, Schleimhautschwellungen der oberen
  Atemwege, Sinusitis, Nasopharyngitis, Rhinitis,
  Verstopfung, Bauchschmerzen, Hautrötungen,
  Palpitationen. Gelegentlich (lt1)
  Überempfindlichkeitsreaktionen. Bei einigen
  Patienten Herzschwäche (verbunden mit
  Schwellungen/Flüssigkeitseinlagerungen),
  Verschlechterung der Kurzatmigkeit kurz nach
  Beginn der Behandlung.
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• Stand Januar 2009