Current Treatment of Pulmonary Arterial Hypertension David Badesch MD University of Colorado School of Medicine Denver CO Disclosure of Commercial Inte

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Current Treatment of Pulmonary Arterial Hypertension David Badesch MD University of Colorado School of Medicine Denver CO Disclosure of Commercial Inte Powered By Docstoc
					     Current Treatment of
Pulmonary Arterial Hypertension



                         David Badesch, MD
       University of Colorado School of Medicine Denver, CO
Disclosure of Commercial Interest
 Dr. Badesch has received grant/research support from
 Glaxo Wellcome, United Therapeutics, Actelion,
 Myogen, Encysive, CoTherix, Pfizer, and ICOS.

 Additionally, he has served as a consultant to Astra-
 Merck / Astra Zeneca, Glaxo Wellcome /
 GlaxoSmithKline, Actelion, Berlex, Myogen,
 Intermune, Encysive, Exhale Therapeutics / CoTherix,
 Pfizer, Forrest Labs, Scios, and MondoBiotech.
                 Classification of PH:
                                  WHO - 1998

• Pulmonary Arterial Hypertension
• Pulmonary Venous Hypertension
• PH associated with disorders of the respiratory system
  and/or hypoxemia
• PH due to Chronic Thrombotic and/or Embolic disease


  Rich S, editor. Primary Pulmonary Hypertension - Executive Summary from the World Symposium-
  Primary Pulmonary Hypertension 1998. World Health Organization. Reprints available via the Internet
  (http://www.who.int/ncd/cvd/pph.html)
                        Classification of PH:
              Pulmonary Arterial Hypertension
• Primary Pulmonary Hypertension
   – Sporadic                                                – Familial


• Pulmonary Hypertension associated with:
   – Collagen Vascular Disease                              – Drugs/Toxins
   – Portal Hypertension                                    – HIV Infection
   – Congenital Systemic to                                 – Persistent Pulmonary
       Pulmonary Shunts                                          Hypertension of the Newborn


 Rich S, editor. Primary Pulmonary Hypertension - Executive Summary from the World Symposium-Primary Pulmonary
  Hypertension 1998. World Health Organization. Reprints available via the Internet (http://www.who.int/ncd/cvd/pph.html)
              Classification of PH:
    Primary Pulmonary Hypertension (PPH)

•   Unknown etiology

•   Primarily a disease of young adults

•   Predominantly female population
    (~2:1 female to male ratio)

•   Familial or spontaneous
            Classification of PH:
 Pulmonary Hypertension Associated with
  the Scleroderma Spectrum of Disease
               (PH/SSD)

• Occurs in an older population than PPH

• Predominantly female population

• Poorer prognosis than PPH

• Hemodynamic findings are very similar to those in PPH
           Natural History of PH
• Gradual onset of symptoms
   – Dyspnea on exertion
   – Limitation of exercise capacity

• Progressive deterioration
   – Increased right ventricular afterload
   – Right ventricular failure and progressive decline in cardiac index
   – Symptoms at rest
         NYHA Classification
Class I
• Asymptomatic

Class II
• Fatigue and shortness of breath on exertion

Class III
• Symptoms with daily activity

Class IV
• Symptomatic at rest
      Predictors of Mortality in PH
PPH Survival According to NYHA Functional Class
                      (NIH Registry -1980’s data)




    NYHA Class                               Median Survival
    I and II                                 58.6 months
    III                                      31.5 months
    IV                                       6 months


  D’Alonzo GE et al. Annals of Internal Medicine 105: 343-49, 1991.
        Predictors of Mortality in PH

 • Higher pulmonary artery pressure
 • Depressed cardiac output
 • Elevated right atrial pressure
 • Absence of response to vasodilators
 • Poor NYHA (Class IV) functional status at diagnosis
 • Poor 6 minute walk results




Rubin Chest 104: 236-250, 1993.
Diagnosis of PH: Procedures
•   Electrocardiogram
•   Echocardiogram
•   Ventilation perfusion scan (V/Q scan)
•   Serologic studies
•   Pulmonary function tests (PFT)
•   Arterial blood gases (ABG) (occasionally)
•   Right-heart catheterization
        Diagnosis of PH:
  Findings on the Electrocardiogram


• RVH, RAE, RAD, RBBB
               Diagnosis of PH:
        Findings on Chest Radiography

• Cardiac enlargement

• Prominent proximal PA

• “Pruning” of distal PA
           Diagnosis of PH:
   Findings on the Echocardiogram

• T R (tricuspid regurgitation)

• RVE (right ventricular enlargement)

• RAE (right atrial enlargement)

• RVH (right ventricular hypertrophy)

• Flattening of IVS (interventricular septum)

• Dilated IVC
             Diagnosis of PH:
ECHO May Suggest an Underlying Etiology

• LV diastolic dysfunction
• MS or MR
• LV systolic dysfunction
• Intracardiac shunt lesion (ASD, VSD,
  PDA,etc)
Ventilation Perfusion Lung Scan
             PPH




  Perf                  Vent
           Chronic PE




  Perf                  Vent
             Diagnosis of PH:
      Other Tests That May Be Helpful
         (Use Determined by Patient’s History)



•   Sleep study
•   High resolution chest CT scan
•   Exercise oximetry
•   Hepatitis serology
•   HIV test
              PH is Not
        a Pathologic Diagnosis
• While the plexiform
  lesion is often found in
  PPH, it may occur in
  secondary forms of PH
  as well.


• Patients with severe PH
  are at substantially
  increased operative risk
  with OLBx or VATS bx.
  Right Heart Catheterization
• Confirm dx of PH (PAPm > 25 mm Hg)
• R/O left heart dz (PCWP < 15 mm Hg)
• R/O left to right intracardiac shunt with oximetry run
  (ASD, VSD)
• Assess severity of PH
   – PAPm
   – CO
   – RAP
   – PVR
• Determine pulmonary vasoreactivity, and predict
  responsiveness to calcium blockers
        Algorithm for Assessment of
      Vasoreactivity in Patients with PH
                         Right Heart Catheterization
                      With Acute Vasoreactivity Testing
                       (iNO, prostacyclin, adenosine)




        Non-responder                            Responder




Consider:                                Hemodynamically-monitered Trial of
• Bosentan (Tracleer®)                    Calcium Channel Blocker Therapy
• Continuous IV epoprostenol (Flolan®)
• Continuous SQ UT-15 (Remodulin®)
             “Conventional Therapy”

• Calcium channel blockers
• Anticoagulation
• Diuretics
• Digoxin
• Lung Transplantation

Rich et al. NEJM 327:76-81; 1992
Fuster et al. Circulation 70:580-7;1984.
                    PAH: Advanced Therapy
                                                    cAMP                            Epoprostenol
                              SMC
                                                                                    Treprostinil
A) PGI2        EC                                              Prostanoids          Berapost
                                    PGI2-S
                           Arach. a. → PGI2         PGI2                            Iloprost

         Sildenafil           Terbogrel             TxA2

                                                                             Vasodilation
                             SMC                    cGMP                     Antiproliferative
                                             PDE5
B) NO                                                                        Vasoconstriction
               EC                                    NO                      Proliferation
                L-arginine → L-citrulline

                                                              NO
                    L-arginine
                                                     GI
                              SMC
C) ET-1                                             ETA ETB           Bosentan
               EC
                          Pre-pro-ET → pro-ET         ET-1           Sitaxsentan
                                                                     Ambrisentan
Adapted from Omar Manai
           Epoprostenol in PPH Study
    Median Change from Baseline in
 6-Minute Walk Exercise Test at Week 12
                               50

                               40                                           *P<0.002
      Median Change (meters)



                                          31.0
                               30

                               20

                               10

                                0

                               -10

                               -20

                               -30
                                                                   - 29.0
                               -40

                               -50
                                     Treatment:   Epoprostenol       Conventional
                                                  Baseline = 315     Baseline = 270
Barst RJ et al. NEJM 334: 296-301, 1996.
       Cardiopulmonary Hemodynamic
            Measurements (PPH)
         Epoprostenol vs. Conventional Therapy

                           Epoprostenol                   Conventional
                                        Change from               Change from
Variable         Baseline               Baseline      Baseline    Baseline


PAPm               61 ± 2               -4.8 ± 1.3*    59 ± 2     1.9 ± 1.6
PVR                16 ± 1               -3.4 ± 0.7*    16 ± 1     1.5 ± 1.2
RAPm               13 ± 1               -2.2 ± 1.1*    12 ± 1     0.1 ± 0.9
CI                2.0 ± 0.1              0.3 ± 0.1*   2.1 ± 0.2   -0.2 ± 0.2

Mean change ± standard error
*Significantly different from conventional therapy

Barst RJ et al. NEJM 334: 296-301, 1996.
Survival Among Patients with PPH
                     Epoprostenol vs. Conventional Therapy

                100

                     80
      Survival (%)




                     60

                     40

                     20       Epoprostenol (n = 41)
                              Conventional therapy (n = 40)

                     0
                          0   2        4       6         8    10   12
                                              Week

Barst et al. NEJM 1996;334:296-301.
                               Survival in PPH
                    100


                      80
                                            *
         %                                                             Observed
       Survival
                      60                                *
                                                                  *
                      40
                                                                       Expected

                      20
                           0       6      12       18   24   30   36

                                            Months
*p<0.001.
McLaughlin VV et al. Circulation. 2002;106:1477-1482.
  PAH Associated with Scleroderma:
                                     Median Change from Baseline in
                                           6-Minute Walk Test
                                     90                                                  *P<0.003
                                     80
            Median Change (meters)



                                     70                                         63.5 *
                                     60
                                                              48.5 *
                                     50
                                     40
                                     30
                                     20    13.3
                                     10
                                      0
                                     -10
                                                  - 7.0
                                     -20                               - 14.0
                                     -30
                                     -40                                                 - 36.0
                                     -50
                                           Week 1              Week 6            Week 12
                  Treatment:                      Epoprostenol                  Conventional
                                                  Baseline = 271.5m             Baseline = 240.0m
Badesch, et al. Ann Intern Med, 2000;132:425-434
    PAH Associated with Scleroderma
       Cardiopulmonary Hemodynamic Measurements


                          Epoprostenol                             Conventional
                                         Change from                      Change from
  Variable          Baseline               Baseline        Baseline         Baseline


  PAPm              50.9 ± 1.41           -5.03 ± 1.09*    49.1 ± 1.37       0.94 ± 1.10
  PVR               14.2 ± 0.95            -4.58 ± 0.76*   11.2 ± 0.73       0.92 ± 0.56
  RAPm              13.1 ± 0.67            -1.26 ± 0.82*   11.1 ± 0.74       1.20 ± 0.69

  CI                 1.9 ± 0.08             0.50 ± 0.08*    2.2 ± 0.09       -0.10 ± 0.08


†Mean   change ± standard error
*Significantly different from conventional therapy



Badesch, et al. Ann Intern Med, 2000;132:425-434
                       Treprostinil in PAH
          Exercise Capacity: Six Minute Walk

                                      Change from Baseline

                                   UT-15     Placebo   Effect*   p-value

Exercise (meters)

    Week 12                          +10       0        +16      0.0064
    Week 6                           +13       +4       +11      0.032
    Week 1                           +11       +8        +5       0.27
 *Non-parametric Analysis of Covariance
  (Hodges-Lehmann estimate)
 Last Rank Carried Forward for AE
 Lowest Rank for Death/Deterioration

Simonneau G et al. AJRCCM 165:800-4; 2002.
                          Treprostinil in PAH
    Change in Exercise Versus Dose(Week 12)
                          Mean ± SE Change from Baseline (meters)

                         40                                           +36.1 ± 31
                                                                        (N=58)
                         35
                         30
                         25                                 +20 ± 8
                                                             (N=49)
                         20
                Meters




                                                                                   p-value 0.03
                         15
                         10   +3.3 ± 10   +1.4 ± 9
                               (N=45)        (N=55)
                         5
                         0
                                1st       2nd         3rd      4th
                            Quartile < Quartile 5 Quartile Quartile
                                5.0     to <8.1 8.1 to 13.8 >13.8
                          (2.5 ± 0.2) (5.6 ± 0.1) (9.4 ± 0.2) (16.2 ± 0.4)
                                                      mg/kg/min
Simonneau G et al. AJRCCM 165:800-4; 2002.
      Chronic Inhaled Iloprost in PAH




      Effect of Inhaled Iloprost and Placebo on the Mean ({+/-}SE) Change from Base Line in the
             Distance Walked in Six Minutes, According to an Intention-to-Treat Analysis

Olschewski, H. et al. N Engl J Med 2002;347:322-329
                    PAH: Advanced Therapy
                                                    cAMP                            Epoprostenol
                              SMC
                                                                                    Treprostinil
A) PGI2        EC                                              Prostanoids          Berapost
                                    PGI2-S
                           Arach. a. → PGI2         PGI2                            Iloprost

         Sildenafil           Terbogrel             TxA2

                                                                             Vasodilation
                             SMC                    cGMP                     Antiproliferative
                                             PDE5
B) NO                                                                        Vasoconstriction
               EC                                    NO                      Proliferation
                L-arginine → L-citrulline

                                                              NO
                    L-arginine
                                                     GI
                              SMC
C) ET-1                                             ETA ETB           Bosentan
               EC
                          Pre-pro-ET → pro-ET         ET-1           Sitaxsentan
                                                                     Ambrisentan
Adapted from Omar Manai
                                Endothelin
                  Ser
            Leu         Ser
                              Cys Ser Cys   NH2
          Met

         Asp
            Lys
                  Glu Cys Val Tyr Phe Cys His Leu Asp Ile Ile Trp   CO2



First identified in 1988; at the time,
the most potent endogenous
vasoconstrictor known
Also has effects on inflammation,
proliferation, and fibrosis.
Present within the plexiform lesions
of IPAH/PPH. (Giaid A et al. New Engl J
Med. 1993; 328:1732)
                             PAH:
                       6-Minute Walk Test
                  Change From Baseline Over Time
                100      Placebo (n = 11)        P = 0.02
                         Bosentan (n = 21)

                50
       Meters




                 0
                                                 Primary
                                                 Endpoint
                -50
                               4             8    12
                                      Weeks
Channick et al. Lancet 358:1119-23.
             Pilot Study of Bosentan in PH:
                       Change in Hemodynamics
                       From Baseline to Week 12
                                                  Mean Pulmonary                       Pulmonary Vascular
                  Cardiac Index                   Arterial Pressure                        Resistance
            0.8                          10                                          400
                      P < 0.0001




                                                                      Dyn.sec.cm-5
                                                                                               P = 0.0001
            0.4                                                                      200
 L/min/m2




                                      mm Hg
                                              5
             0                                                                         0
                                                          P = 0.013
                                              0
       -0.4                                                                          -200

       -0.8                               -5                                         -400
                   Week 12                            Week 12                               Week 12

                                                  Placebo (n = 10)
                                                  Bosentan (n = 20)
Channick et al. Lancet 358:1119-23.
                   BREATHE-1: Walk Test ITT
      Change From Baseline to Week 16
                   80         Placebo (n = 69)    Bosentan (n = 144)

                   60
 Δ Walk Distance




                   40
    (meters)




                   20                                      P = 0.0002   Mean ± SEM

                    0

               -20

               -40
                   Baseline    Week 4       Week 8                 Week 16

                        62.5 mg/bid          125 or 250 mg/bid
Rubin et al. NEJM 346:896-903l 2002.
                                      BREATHE-1
                             Time to Clinical Worsening
                                  Up to 28 Weeks
                       100
      Event-Free (%)



                                                                                89 %

                       75                                             P = 0.0015
                                                                                 63 %

                       50

                       25

                        0
                             0    4      8        12    16       20   24     28
                                                 Time (weeks)
                       Bosentan        n = 144         n = 103             n = 20
                       Placebo         n = 69          n = 51              n = 17
Rubin et al. NEJM 346:896-903l 2002.
                                   BREATHE-1
                   Summary of Adverse Events
                     During Study Treatment
                                                 Placebo    Bosentan
                                                 (n = 69)   (n = 144)
                                                    %          %

      Nasopharyngitis                               7.2       11.8
      Headache                                     18.8       20.8
      Flushing                                      4.3        9.0
      Hypotension                                   4.3        6.9
      Syncope                                       5.8        9.0
      Hepatic Funct. Abnormal                       2.9        9.7

       Incidence of events: bosentan > placebo
Rubin et al. NEJM 346:896-903l 2002.
          Bosentan as Initial Therapy*
            Observed and Predicted Survival
                 Kaplan-Meier survival estimates with 99.9% CI

                                          100
               % of event-free patients



                                           90
                                                                                                   Observed
                                           80
                                           70
                                           60
                                           50                                                      Predicted (NIH)
                                           40
                                           30
                                           20
                                           10
                                                Event Rate / year (exponential): 5.5%
                                            0
                                                0     6      12       18      24      30      36   months

                                            169      167    163       153     113     23      16   Patients at risk


                                                                  *As first-line treatment for PPH. Some patients may
                                                                  have been switched to alternative therapies.
McLaughlin V. Eur Respir J 25:244-9; 2005
                          Sitaxsentan in PAH
                            Open-Label Pilot Study: Design

   • Open label study of sitaxsentan in patients with
     primary and secondary pulmonary hypertension
   • 20 patients
         – 8 PPH
         – 10 CHD
         – 2 CTD
   • NYHA Class II-IV
   • 12 weeks of therapy + 52wk extension (211x)
   • 4-6 mg/kg BID




Barst et al. Chest 121:1860-8;2002.
           Sitaxsentan in PAH
        Open-Label Pilot Study: Results
• Significant (p=0.006) improvement in mean 6-minute
  walk distance
• Significant improvements in mPAP, PVR and NYHA
  functional class
• 2 patients experienced LFTs>3X and <5X ULN
  during the study
   – One patient death occurred at 300mg-500 mg bid during
     extension trial
      • Drug was not stopped until patient developed symptomatic
        hepatitis
      • Now recognized that 300mg bid represented a significant (40-50
        fold) overdose


                                                    Barst et al. Chest 121:1860-8;2002.
                          Sitaxsentan in PAH
                              Stride 1: Study Design
       – STRIDE-1 (n = 178):
             • 12 week, multicenter, randomized, double-blind,
               placebo controlled study
       – STRIDE-1X (n = 156):
             • Double-blind extension study with two sitaxsentan
               doses
                    – Placebo (60) → 100mg or 300mg (52)
                    – 100mg (55) → 100mg (52)
                    – 300mg (63) → 300mg (52)
       – STRIDE-1/1X combined
             •   N = 170
             •   Mean ± SD exposure: 26 ± 14 weeks
             •   Median exposure: 24 weeks
             •   Range: 1 day – 58 weeks
Barst et al. AJRCCM 169:441-7; 2004.
                             Sitaxsentan in PAH
       Stride 1: STRIDE-1/1X: Demographics† (n = 170)
                                                                Sitaxsentan   Sitaxsentan
                                                                  100 mg        300 mg
                                                                 N=79 (%)      N=91 (%)
        Sex — Female                                              67 (85)       67 (74)
        Age – years mean ± SD                                     46 ± 14      46 ± 12
        Ethnicity
           Caucasian                                              56 (71)       64 (70)
           Other                                                  23 (29)       27 (30)
        PAH
         Idiopathic                                               38 (48)       50 (55)
         Related to:
           Connective tissue disease                              20 (25)       21 (23)
           Congenital systemic-to-pulmonary shunts
                                                                  21 (27)       20 (22)
        NYHA functional class
              I                                                    1 (1)         1 (1)
            II                                                    27 (34)       32 (35)
          III                                                     51 (65)       58 (64)
          IV                                                       0 (0)         0 (0)
                                       †at   start sitaxsentan treatment
Barst et al. AJRCCM 169:441-7; 2004.
                            Sitaxsentan in PAH
                         Stride 1: Patient Disposition
                                          STRIDE-1                                        STRIDE-1/1X
                                           N = 178                                          N=170



Patients                Placebo             100 mg             300 mg              100 mg         300 mg
Randomized               N = 60             N = 55             N = 63              N = 79         N = 91

Patients
                             5                  0                  7                   5             20
Discontinued                                                                         (6%)          (22%)
                           (8%)               (0%)               (11%)
Prematurely†




† Premature Discontinuations in 1/1X due to AE (10), ↑ LFTs (8), deterioration / death (4),
withdrawal (3)


  Barst et al. AJRCCM 169:441-7; 2004.
                               Sitaxsentan in PAH
       Stride 1: Results - Change in Six Minute Walk Distance

                              30
                                                           *    *
                              20



                              10
                     Meters




                              0



                          -10


                                       Week 6             Week 12
                          -20
                                                Placebo
                                                100 mg          *p<0.01; Mean +/- SE
                                                300 mg

Barst et al. AJRCCM 169:441-7; 2004.
                              Sitaxsentan in PAH
                        Stride 1: Results - Change in Hemodynamics

       1          PAPm                    0.5    Cardiac Index                      100               PVR
                                                                **                                            Placebo
                                                                                                              100 mg
       0                                  0.4                                                                 300 mg
                                                         *




                                                                       dyn • sec • cm-5
   -1                                     0.3                                             0

                                    L/min/m2
mmHg




                                          0.2
   -2
                                          0.1                                    -100
   -3
                                          0.0
   -4
                                         -0.1                                     -200
   -5
                                        -0.2
                                                                                                               *
                                                                                                        *
   -6                                    -0.3                                     -300
                          *
       *p<0.001 vs placebo;                      *p<0.02 vs placebo;                          *p<0.001 vs placebo
       Mean +/- SE                              **p<0.001 vs placebo
 Barst et al. AJRCCM 169:441-7; 2004.
                                     Sitaxsentan in PAH
                      Stride 1: Results - Change in % Predicted PVO2

                                          5

                                          4
                                                           *
                                          3

                                          2
                            % Predicted



                                          1

                                          0

                                          -1

                                          -2

                                                 Week 12

                                               Placebo
                                               100 mg          *p<0.01; Mean +/- SE
                                               300 mg


Barst et al. AJRCCM 169:441-7; 2004.
                     Sitaxsentan in PAH:
                   Effects on 6MWD in Pts w/ CTD

                                                50        p = 0.027
                     6MW (m), ∆ from baseline
                                                        n=9        n=33



                                                                              p ≤ 0.033
                                                 0




                                                -50
                                                      placebo   sitaxsentan


McLaughlin, 2004
                                                      At Week 12
                         Sitaxsentan in PAH:
                                       Stride 1: Safety

                                              Placebo 100mg 300 mg
                                               N=59    N=56  N=63
                                                (%)     (%)   (%)
                                                 58        53     62
      Adverse Events
                                                (98)      (95)   (98)
                                                 28        35     43
      Treatment Related AEs
                                                (47)      (63)   (68)
                                                 9         3      10
      Serious Adverse Events
                                                (15)      (5)    (16)
      Treatment Related SAEs                     3         1      9
Barst et al. AJRCCM 169:441-7; 2004.
                      Sitaxsentan in PAH:
         Stride 1: Most Frequent Adverse Events

                                       Placebo     Sitaxsentan   Sitaxsentan
                                                     100 mg        300 mg
  Adverse Event                        N=59 (%)       N=56 (%)      N=63 (%)

  Headache                               20 (34)       25 (45)        29 (46)
  Peripheral edema                       10 (17)        9 (16)        16 (25)
  Nausea                                 11 (19)       13 (23)        11 (17)
  Increased INR                           3 (5)         8 (14)        15 (24)
  Nasal congestion                        6 (10)        9 (16)        13 (21)
  Dizziness                               6 (10)        8 (14)         6 (10)

Barst et al. AJRCCM 169:441-7; 2004.
                                  Sitaxsentan in PAH:
Stride 1/1x (Longer-Term Exposure): LFT Results
                        40
                                                              Chronic Exposure
                        35                                    (median 24 weeks;
                        30                                    Mean ± SD: 26 ± 14 weeks;
  % Patients With LFT
  Elevations > 3x ULN




                                                              Range 1 day-58 weeks)
                        25
                                                                               (19/91)
                        20              STRIDE-1
                                       (12 weeks)
                        15
                                                     (6/63)
                        10
                                                                     (4/79)
                         5    (2/59)
                                           (0/56)
                         0
                              o


                                         g


                                                    g




                                                                   g


                                                                               g
                            eb




                                                                 0m
                                   0m


                                                0m




                                                                              0m
                          ac


                                  10


                                              30




                                                               10


                                                                         30
                        Pl




 Barst et al. AJRCCM 169:441-7; 2004.
                 Ambrisentan in PAH:
                           Study Schematic
                                                  Optional
                     Blinded Treatment          Open-Label
   Screening               Period             Extension Period
                       Fixed Doses           Dose Adjustment

                           10 mg
                             5 mg
                           2.5 mg                                Long-Term
                             1 mg                                Study




Week    -4   0   2     4    6   8    10   12 14 16 18 20 22 24
       Randomization            Endpoint Evaluation
          Ambrisentan in PAH:
                   Study Endpoints
Primary Efficacy Endpoint
• Exercise capacity using the 6-minute walk distance after 12
   weeks of treatment compared to baseline
Secondary Endpoints
• Borg dyspnea index
• WHO functional class
• Time to clinical worsening of PAH
• Subject global assessment
• Hemodynamics
• Safety and tolerability
• Single-dose and steady-state PK
• Plasma ET-1 concentrations
Ambrisentan in PAH:
   Baseline Demographics
                                     Total
Characteristics                     (n=64)
Female, n (%)                        54 (84)
Age, yr                              51 ±16
Time since diagnosis, yr            3.2 ±3.8
Ethnicity
  White                             45 (70)
Etiology of PAH, n (%)
  PPH                               39   (61)
  Scleroderma spectrum of disease   19   (30)
  Anorexigen use                     4   (6)
  HIV infection                      2   (3)
WHO functional class, n (%)
  II                                23 (36)
  III                               41 (64)
Ambrisentan in PAH:
    Baseline Demographics
                                  Total
Characteristics                   (n=64)
6-minute walk distance, meters
  All patients                   343   ±79
  PPH                            353   ±79
  Secondary PAH                  327   ±79
  WHO class II                   390   ±60
  WHO class III                  316   ±77
Dyspnea score, Borg index        4.0 ±2.3
Hemodynamic parameters            (n=34)
 Mean PAP, mmHg                   49 ±13
 PCWP, mmHg                      8.5 ±3.2
 Mean RAP, mmHg                  7.3 ±4.5
 Cardiac index, liters/min/m 2   2.4 ±0.5
 PVR, dynes⋅sec⋅cm -5            841 ±407
                                   Ambrisentan in PAH:
                                          6-Minute Walk Distance
                                     Change from Baseline at Week 12
                          60
Change in 6MWD (meters)




                          50

                          40

                          30

                          20

                          10

                           0
                                 1 mg       2.5 mg      5 mg      10 mg     All Doses
                                 n=16        n=19       n=16       n=13       n=64
                               p=0.0029    p=0.0004   p=0.0112   p=0.0082   p=0.0001
                                 Ambrisentan in PAH:
                               Change in 6-Minute Walk Distance
                                 Primary vs. Secondary PAH
                          80
                                   PPH (n=39)
                          70
Change in 6MWD (meters)




                                   SPAH (n=25)
                          60
                          50
                          40
                          30

                          20
                          10

                          0
                               Week 4     Week 8   Week 12   Week 16   Week 20   Week 24
                                        Baseline 6MWD: PPH=353 m; SPAH=327 m
                                        Ambrisentan in PAH:
                                    Change in 6-Minute Walk Distance
                                       WHO Class II vs. Class III
                          80
                                   Class II (n=23)
                          70
Change in 6MWD (meters)




                                   Class III (n=41)
                          60
                          50
                          40
                          30
                          20

                          10
                          0
                               Week 4    Week 8       Week 12   Week 16   Week 20   Week 24
                                   Baseline 6MWD: Class II=390 m; Class III=316 m
                      Ambrisentan in PAH:
                           WHO Functional Class
                             Change from Baseline
                      Class I      Class II    Class III    Class IV
      100

          80
Percent




          60

          40

          20

      0
     Week       0      2         4      8     12     16     20      24
               n=64   n=62      n=62   n=58   n=58   n=55   n=54   n=54
                               Ambrisentan in PAH:
                                             Hemodynamics
                                    Week 0 (n=34) and Week 12 (n=29)
                  Mean Pulmonary Artery Pressure                              Cardiac Index
                 54                                              3.0
                                 Δ= -5.2                                       Δ= +0.33
                 50                                              2.8




                                                      L/min/m2
   mmHg




                 46                                              2.6
                 42                                              2.4
                 38                                              2.2
                                 p<0.001                                        p<0.001
                 34                                              2.0
                        Week 0         Week 12                           Week 0          Week 12
                      Pulmonary Vascular Resistance                    Mean Right Atrial Pressure
            1500                                                 8.5
                                 Δ= -226                                        Δ= -0.45
dynes⋅sec⋅cm-5




            1200                                      mmHg       8.0
             900                                                 7.5
             600                                                 7.0
             300                                                 6.5
                                 p<0.001                                          p=ns
               0                                                 6.0
                         Week 0            Week 12                       Week 0           Week 12
             Ambrisentan in PAH:
                          Adverse Events
                     12-Week Blinded Treatment Period

Peripheral Edema
Upper Respiratory
   Tract Infection
Nasal Congestion

        Headache

          Nausea

         Flushing

        LFTs >3X

        LFTs >8X
                     0      5       10      15      20      25   30
                            Percent of Subjects with AE (%)
         Ambrisentan in PAH:
                  Liver Function Tests

• 4 subjects developed transient elevations of serum
  aminotransferases (ALT and/or AST) >3X ULN during
  the 24-week study
   – 1 subject (5 mg) >8X ULN
      • Resolved within 6 weeks of stopping drug
   – 1 subject (5 mg) >3X ULN
      • Dose reduction
      • Eventual drug discontinuation during the long-term study (week
        28)
   – 2 subjects (2.5 mg) slightly above 3X ULN
      • Not confirmed by retest
      • Did not require dose adjustment
                    PAH: Advanced Therapy
                                                    cAMP                            Epoprostenol
                              SMC
                                                                                    Treprostinil
A) PGI2        EC                                              Prostanoids          Berapost
                                    PGI2-S
                           Arach. a. → PGI2         PGI2                            Iloprost

         Sildenafil           Terbogrel             TxA2

                                                                             Vasodilation
                             SMC                    cGMP                     Antiproliferative
                                             PDE5
B) NO                                                                        Vasoconstriction
               EC                                    NO                      Proliferation
                L-arginine → L-citrulline

                                                              NO
                    L-arginine
                                                     GI
                              SMC
C) ET-1                                             ETA ETB           Bosentan
               EC
                          Pre-pro-ET → pro-ET         ET-1           Sitaxsentan
                                                                     Ambrisentan
Adapted from Omar Manai
SUPER-1
Objective


    Evaluate the efficacy and safety of
    oral sildenafil citrate in pulmonary
    arterial hypertension.
SUPER-1
Study Design
    Screening   Randomization       4 Weeks            8 Weeks          12 Weeks


                Placebo t.i.d.


                20mg t.i.d.



                40mg t.i.d.



                80mg t.i.d.



   6 min walk      6 min walk        6 min walk         6 min walk         6 min walk
     BORG            BORG              BORG               BORG               BORG
                                 Clinical Worsening Clinical Worsening Clinical Worsening
                 Hemodynamics                                            Hemodynamics
SUPER-1
Patient Population

  PAH patients ≥ 18 years old, with PAH:
  – Idiopathic
  – Connective tissue disease
  – Surgically corrected congenital left to right shunts

  Baseline 6-Minute Walk Test distance of ≥100m
  and ≤450m

  Patients in functional class I-IV
SUPER-1
Endpoints
 Primary endpoint: 6-Minute Walk Test

 Additional endpoints:
  – Mean PAP, Cardiac Output, Pulmonary Vascular
    Resistance
  – Functional class
  – Time to clinical worsening
  – BORG Dyspnea score

 Analyses stratified for baseline walk distance and
 etiology

 Safety
SUPER-1
Baseline Characteristics
Gender M:F                            25:75
Mean Age (range)                      49 years (18-81)
Etiology PPH (%)
  PPH                                 63
  CTD – Connective Tissue Disease     30
  SR – Surgical Repair                 7

Functional Class (%)
 I                                    0.4
 II                                   39
 III                                  58
 IV                                    3
Mean 6-Minute Walk Distance (range)   344 m (106-505)
Mean mPAP (range)                     53 mmHg (25-116)
SUPER-1
Improvements in 6-Minute Walk Distance

                                                                                          *p<0.0001
                               70
                                                                                                      *
                               60                                                            *
                                                                                         *
    Change from baseline (m)




                               50
                               40
                               30




                                                                                        50 m
                                                                                        46 m
                                                                                        45 m
                               20
                               10
                                 0
                               -10     Week 4                     Week 8               Week 12
                               -20
                               -30

                                     placebo    sildenafil 20mg    sildenafil 40mg   sildenafil 80mg
SUPER-1
Reductions in Mean PAP
  Change from baseline (mmHg) Week 12




                                        4
                                             placebo
                                        2
                                                       sildenafil 20mg   sildenafil 40mg   sildenafil 80mg
                                        0
                                                       -2.7 mmHg         -3.0 mmHg
                                        -2

                                        -4                                                 -5.1 mmHg

                                        -6                P=0.04
                                                                             P=0.01

                                        -8                                                    p<0.001
SUPER-1
Increases in Cardiac Output
 Change from baseline at week 12 (l/min)




                                           1.2                                                  sildenafil 80mg

                                             1                                sildenafil 40mg
                                                            sildenafil 20mg
                                           0.8
                                           0.6
                                           0.4
                                                  placebo
                                           0.2
                                             0               0.5 l/min         0.5 l/min         0.8 l/min
                                                                  p=0.04           p=0.03            P<0.001
                                           -0.2
                                           -0.4
                                           -0.6
SUPER-1
Reductions in PVR

                                   200    placebo
 Change from baseline at week 12




                                   100
                                                    sildenafil 20mg   sildenafil 40mg   sildenafil 80mg
                                     0
           (dyne.s/cm5)




                                                          -171             -192
                                   -100                 dyne.s/cm5
                                                                          dyne.s/cm5



                                   -200                                                      -310
                                                                                            dyne.s/cm5
                                                         p=0.01            p=0.006
                                   -300

                                   -400                                                     P<0.0001
SUPER-1
AEs > 3% and sildenafil > placebo
     Adverse event     Percentage of Patients Reporting Event
                     Sildenafil N = 207         Placebo N = 70
     Headache               46                        39
     Flushing               12                        4
     Dyspepsia              12                        7
     Back Pain              12                        11
     Diarrhoea              11                        6
     Limb pain              10                        6
     Myalgia                 9                        4
     Cough                   7                        6
     Epistaxis               7                        1
     Pyrexia                 6                        3
     Influenza               5                        3
     Gastritis               3                        0
     Vertigo                 3                        1
     Erythema                3                        0
                                                                                                                   ACCP
                                            Therapy for PAH                                                        and
                                                                                                                   3rd World Sym
                                         Functional class II/III/IV (1)                                            DRAFT


                                                   General Care
                 Oral anticoagulants [B for IPAH, E/C for other PAH] + diuretics + oxygen [E/A] + digoxin



               Acute Vasoreactivity Testing [A for IPAH, E/C for other PAH] (2)
    Positive                                                                             Negative


  Oral CCB [B for IPAH,                        Functional Class III                              Functional Class IV
   E/B for other PAH]                                          (5)                                           (4)

                                                                                              Chronic IV Epoprostenol[A]
                                 Endothelin Receptor Antagonists
 Sustained Response (3)                           (Bosentan) [A]                                        Bosentan [B]
                                                          or                                           Treprostinil [B]

      Yes            No              Chronic IV Epoprostenol [A]                                   Chronic IV Iloprost [C]
                                                          or
                                         Prostanoid Analogues                             No improvement
 Continue CCB                                                                             or deterioration
                                  SQ Treprostinil [B], Inh Iloprost [B], Berprost [I])
                                                                                                    Atrioseptostomy +
                                                                                                   Lung Transplantation
Grade of Recommendation Noted                  PDE-5 Inhibitors
in [ ]                                            (Sildenafil) [C]
              PAH is Not
   Simply a Vasoconstrictive Process

  • The plexiform lesion is
    seen in PPH/IPAH, as
    well as some other forms
    of PAH.



While advances have occurred in treating PAH, continued
progress will likely require new strategies more directly
addressing the proliferative component of the disease.