Treatment guidelines

Update 2014

Confidential for internal use only

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2 Confidential for internal use only

Training Objective
By the end of this section you should understand

The important guidelines for PH/PAH diagnostics, treatment and follow-up

Recommendations for

Diagnostics

Treatment and follow-up

3 Confidential for internal use only

Overview

Guidelines for Management of PH/PAH

Diagnostics

Monitoring and Treatment Options

Summary

4 Confidential for internal use only

Overview

Guidelines for Management of PH/PAH

Diagnostics

Monitoring and Treatment Options

Summary

5 Confidential for internal use only

 European and US Guidelines for Diagnosis and
Treatment of PH

Update planned for 2015*

*http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/publication-schedule.aspx

6 Confidential for internal use only

Treatment Algorithm of PAH (Nice 2013)

7 Confidential for internal use only

New PH Classification was presented at 5th World
Symposium in Nice

Pulmonary Hypertension

WHO GROUP 1 WHO GROUP 2 WHO GROUP 3 WHO GROUP 4 WHO GROUP 5
PAH Left-heart related Lung/hypoxia related CTEPH Other

Idiopathic
Idiopathic (IPAH)
(IPAH) LV
LV systolic
systolic COPD
COPD Chronic
Chronic PH
PH
Heritable PAH
Heritable PAH dysfunction
dysfunction Interstitial
Interstitial lung
lung thromboembolic
thromboembolic with
with unclear
unclear
Drug- LV
LV diastolic disease
disease (ILD) pulmonary
pulmonary multifactorial
multifactorial
Drug- and
and toxin-
toxin- diastolic (ILD)
induced dysfunction Other hypertension
hypertension mechanisms
mechanisms
induced dysfunction Other pulmonary
pulmonary
Associated Valvular
Valvular disease diseases
diseases with
Associated with
with disease with
other
other conditions
conditions Congenital/acquire
Congenital/acquire mixed restrictive
mixed restrictive
(APAH)
(APAH) dd left
left heart
heart inflow/
inflow/ and
and obstructive
obstructive
WHO outflow tract pattern
pattern
WHO Group
Group 1 1 outflow tract
Pulmonary obstruction
obstruction and and Sleep-disordered
Sleep-disordered
Pulmonary veno-
veno-
occlusive congenital
congenital breathing
breathing
occlusive disease
disease
and/or cardiomyopathies
cardiomyopathies Alveolar
and/or pulmonary
pulmonary Alveolar
capillary
capillary hypoventilation
hypoventilation
hemangiomatosis
hemangiomatosis disorders
disorders
WHO Chronic
Chronic exposure
WHO Group
Group II exposure
Persistent to
to high
high altitude
altitude
Persistent
pulmonary
pulmonary Developmental
Developmental lunglung
hypertension
hypertension of of the
the diseases
diseases
newborn (PPHN)
newborn (PPHN)

*Simonneau et al. 2013: JACC, Vol.62, No.25 Suppl: D34- 41

8 Confidential for internal use only

8
 Clinical definitions of PHa
> mPAP 25 mmHg at rest
= pulmonary hypertension1

>> mPAP 25 mmHg >> mPAP 25 mmHg

+ PWCP 15 mmHg at rest + PWCP
= pre-capillary pulmonary hypertension1 >15 mmHg at rest

>>> mPAP 25 mmHg >>> mPAP 25 mmHg

= Post-capillary
+ PWCP 15 mmHg + PWCP 15 mmHg pulmonary
at rest at rest hypertension1
+ 1 segmental + PVR > 3 Wood units
perfusion defect = PAH
= CTEPH2,3

mPAP and PWCP measured by right heart catheterization.

a

COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; mPAP, mean pulmonary arterial pressure;
PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary pressure gradient (mean PAP mean PWP).
1. Hoeper et al. JACC Vol. 62, No. 25, Suppl D, 2013 December 24, 2013:D4250 2. Lang IM. Eur Respir Rev 2009;18:248. 3. Pepke-Zaba J. Eur Respir Rev
9
2010;19:558.
2009 PH Guidelines Prognostic parameters*

*Gali et al.; European Heart Journal (2009); 30: 2493 2537;.

10 Confidential for internal use only

Overview

Guidelines for Management of PH/PAH

Diagnostics

Monitoring and Treatment Options

Summary

11 Confidential for internal use only

Frequency of Symptoms

Rich et al. Ann Int Med 1987

12 Confidential for internal use only

 Diagnostic Approach to Pulmonary
Hypertension, Nice 2013

BGA = blood gas analysis; CHD = congenital heart

disease; CTD =connective tissue disease; CTEPH
=chronic thromboembolic pulmonary hypertension;
DLCO =diffusion
capacity of the lung for carbon monoxide; ECG
=electrocardiogram; HR-CT =high-resolution computed
tomography; PA =pulmonary angiography; PAH
=pulmonary arterial
hypertension; PAPm =mean pulmonary artery
pressure; PAWP =pulmonary arterial wedge pressure;
PCH =pulmonary capillary hemangiomatosis; PEA
=pulmonary endarterectomy;
PFT =pulmonary function testing; PH =pulmonary
hypertension; PVOD =pulmonary veno-occlusive
disease; PVR =pulmonary vascular resistance; RHC
=right
heart catheter; RV =right ventricle; V/Q
=ventilation/perfusion; x-ray =chest radiograph.
* M.H. Hoeper et al. (2013): JACC, Vol. 62, No.25: Suppl.D: D42-50
13
Diagnostic Methods
Clinical history, physical examination
ECG, pulmonary function testing
Chest x-ray
Echocardiography
Clinical chemistry (DD, immunology, genetics)
CT of the chest (if necessary pulmonary angiography, MRI)
Ventilation-perfusion scintigraphy
RH catheterization, vasodilator testing
Exercise testing
(e.g. 6-minute walking test, cardio-pulm. exercise testing)

Olschewski et al. Pneumologie 2006

14 Confidential for internal use only

 Echocardiography is the initial
diagnostic tool for PH
Indirect assessment of PAP
Exclusion of intracardiac shunt or
left heart disease as cause of PH
Indications of PH may include:
Right ventricular dilatation
Hypertrophy and hypokinesis
Right atrial enlargement
Right ventricular pressure
overload
Tricuspid regurgitation
Reproduced with permission from Pericardial effusion
Raisinghani et al. 2006

PAP, pulmonary arterial pressure.

Jenkins D et al. Eur Respir Rev 2012;21:3239.
Wilkens H15
et al. Int J Cardiol 2011;154S:S5460.
Imaging and Hemodynamic Evaluation in PH
Postero-anterior and lateral
chest X-ray
Decreased peripheral
lung vascular markings
Hilar pulmonary
artery prominence
RV and RA enlargement

Electrocardiogram
RA enlargement
RV hypertrophy and strain
Right axis deviation of the
QRS complex

McLaughlin et al. J Am Coll Cardiol 2009;53:1573 619

16 Confidential for internal use only

Imaging and Hemodynamic Evaluation

Transthoracic echocardiography
(A) Parasternal short axis view
(B) Apical 4 chamber view

Evidence of:
Pericardial effusion
RA and RV enlargement
Abnormal contour, flattening, or reverse curvature
of the interventricular septum
Underfilled left heart chambers
No sign of left ventricular systolic or diastolic
dysfunction

McLaughlin et al. J Am Coll Cardiol 2009;53:1573 619

17 Confidential for internal use only

Diagnostic Methods and Contribution
ECGs only provide supportive evidence
RV hypertrophy on ECG is present in 87% and right axis deviation in 79% of patients
with idiopathic PAH (normal ECG in about one-third of patients)
Supraventricular arrhythmias tends to be present in advanced stages
In 90% of patients with idiopathic PAH, chest radiograph is abnormal
Chest radiography reasonably excludes moderate-to-severe lung diseases (group 3)
and pulmonary venous hypertension due to left-sided heart disease (group 2)
Pulmonary function and arterial blood gas data support chest radiograph findings
Hence, group 2 and group 3 PH can be excluded
Transthoracic echocardiography
Conducted routinely to confirm PH
Used to assess right heart haemodynamics, including pulmonary arterial pressure
Does not provide information on PH group
May provide evidence of left-sided heart disease

Gali et al. Eur Heart J 2009;30:24932537

18 Confidential for internal use only

Right Heart Catheterisation
The 2009 ESC/ERS and US guidelines recommend
right heart catheterisation when an echocardiographic
diagnosis of PH is likely
Symptoms
Presence/absence of associated conditions or risks factors
for PAH group 1
Cardiac magnetic resonance imaging evaluates right heart haemodynamics and is
particularly useful for follow-up purposes
Abdominal ultrasound reliably excludes liver cirrhosis and/or portal hypertension
Blood tests and immunology should be conducted after confirmation of the PH diagnosis
by right heart catheterisation to establish cause

Gali et al. Eur Heart J 2009;30:24932537

McLaughlin et al. J Am Coll Cardiol 2009;53:1573 619

19 Confidential for internal use only

6-MWT
6 MWT is an established, validated primary endpoint in PAH studies
(endorsed by authorities, also for our pivotal studies)
6-MWT is the standard non-interventional exercise test and
Marker for disease severity and
Predictor of survival in PAH and CTEPH
6-MWT is highly relevant for early detection of changes in patient status in clinical
practice, and allows for comparison with efficacy data from other studies

Vachiry et al, Eur Respir Rev. 2012: 21:123,40-47.

Barst et al., JACC. 2004: 43:12.
Saouti et al., Respir Med. 2009: 7: 1013-1019.
Reesink et al., Cardiopulmonary Support and Physiology 2007: 510-16
McLaughlin et al., JACC 2009, Vol. 54, No. 1, Suppl S
Condliffe et al., Eur Respir J 2009; 33: 332337

20 Confidential for internal use only

WHO Functional Class (WHO FC)
Class I
Patients with pulmonary hypertension but without resulting limitation in physical activity.
Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near
syncope
Class II
Patients with pulmonary hypertension resulting in slight limitation in physical activity.
They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or
fatigue, chest pain, or near syncope
Class III
Patients with pulmonary hypertension resulting in marked limitation in physical activity.
They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or
fatigue, chest pain, or near syncope
Class IV
Patients with pulmonary hypertension with inability to carry out any physical activity
without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or
fatigue may even be present at rest. Discomfort is increased by any physical activity
Gali et al. Eur Heart J 2009;30:24932537

21 Confidential for internal use only

Overview

Guidelines for Management of PH/PAH

Diagnostics

Monitoring and Treatment Options

Summary

22 Confidential for internal use only

Monitoring and Treatment

IfIf aa patient
patient has
has advanced
advanced PAH,PAH, the
the 2009
2009 ESC/ERS
ESC/ERS andand US
US guidelines advise 33 monthly
guidelines advise monthly follow-
follow-
up
up
LessLess ill
ill patients
patients on
on oral
oral therapy
therapy should
should generally
generally be
be seen
seen every
every 36
36 months
months
Obtain
Obtain an
an assessment
assessment of of functional
functional class
class and
and exercise
exercise capacity
capacity with
with each
each office
office visit
visit
Specialist
Specialist nurse
nurse clinicians
clinicians are
are an
an integral
integral part
part of
of chronic
chronic outpatient
outpatient management
management

At baseline 3-4 months after In case of

Every 3-6
prior to initiation or changes in clinical
months
therapy therapy worsening
Clinical assessment WHO-FC ECG
6MWT
Cardioplulmonary Exercise testing

BNP/NT-pro BNP
Echocardiography

RHC

Gali et al. Eur Heart J 2009;30:24932537
McLaughlin et al. J Am Coll Cardiol 2009;53:1573 619

23 Confidential for internal use only

 Proposed New PAH Evidence-based Treatment
Algorithm 2013
Supervised exercise training (I-A) General measures and supportive therapy Oral anticoagulants
Psycholosocial support (II-C) IPAH heritable PAH and PAH
Avoid excessive physical activity (II-C) due to anorexigens (IIa-C)
Expert referral (IC) APAH (IIb-C)
Avoid pregnancy (I-C)
Influenza and pnemococcal Diuretics (I-C)
Immunisation (I-C) Oxygen (I-C)
Acute vasoreactivity test (IC for IPAH) (IIb-C for APAH) Digoxin (IIb-C)
VASOREACTIVE
Initial PAH Therapy with Approved Drugs
Recommendation Evidence* WHO Class II WHO Class III WHO Class IV
Ambrisentan Ambrisentan , Bosentan Epoprostenol i.v.
WHO Class I-III
Bosentan Epoprostenol i.v.
CCB (I-C)
Macitentan Iloprost inhaled
I A or B Riociguat Macitentan
Sildenafil Riociguat
Tadalafil Sildenafil,Tadalafil
Treprostinil s.c., inhaled**
Sustained response
Iloprost i.v. Ambrisentan , Bosentan
(WHO I-III)
Treprostinil i.v. Iloprost inhaled and i.v.***
Macitentan
IIa C Riociguat
Sildenafil, Tadalafil
Treprostinil s.c., i.v. inhaled**

YES Beraprost#
NO B
Sequential Combination Therapy IA INADEQUATE CLINICAL RESPONSE
IIb
Initial combination therapy Initial combination therapy
C ERAs
INADEQUATE CLINICAL RESPONSE on MAXIMAL THERAPY
Continue CCB
Prostanoids Referral for lung transplantation I-C
PDE5i or sGCS
or BAS IIa- C
*Level of evidence is based on the WHO functional class of the majority of the patients of the studies;
** approved by FDA;EMA *** approved in New Zealand # approved in Japan and S. Korea
Source: adapted from Gali N. et al. (2013), JACC, 2013,Vol.62, No.25: Suppl.D: D60 -72
24 Confidential for internal use only
Evidence-based Treatment Algorithm for PAH
Group 1 Patients (US)

Anticoagulants Diuretics Oxygen

Acute Vasoreactivity Testing
Digoxin

Positive Negative
Oral CCB Lower risk Higher risk

Epoprostenol or
Sustained No ERAs or PDE5 inhibitors (oral), treprostinil (IV), iloprost
epoprostenol or treprostinil (IV), (inhaled), ERAs or PDE5
Response
iloprost (inhaled), treprostinil (SC) inhibitors (oral),
treprostinil (SC)
Yes
Reassess consider
combination therapy

Continue CCB Atrial septostomy

Lung transplant
Investigational protocols
McLaughlin et al. J Am Coll Cardiol 2009;53:1573 619

25 Confidential for internal use only

 5TH World Symposium on PH
Nice, 27 Feb1 Mar, 2013

Task forces at 5th World Symposium

TF 1 Pathology and Pathobiology

TF 2 Genetics and Genomics
TF 3 Definition and Classification
TF 4 Pathophysiology
TF 5 Epidemiology and Registries
TF 6 Diagnosis and Prognosis
TF 7 Therapy Standard of Care
TF 8 Therapy Goal
TF 9 New Trials Design and New Therapies
TF 10 CTEPH
TF 11 PH due to Left Heart Disease and Chronic Lung
TF 12 Pediatric PH
Presented at 5th World congress on PH Nice, 2013
All Nice presentations published in 2013, JACC , Vol 62; No. 25: Suppl. D
26 Confidential for internal use only
 TF 8 Variables used in clinical practice to determine response to therapy and
prognosis in patients with PAH

Functional class
I or II

Haemodynamics
Normalisation of RV function (RAP <8 mm Hg and CI > 2.5 to 3.0 l/min/m 2 )

Echocardiography/ CMR
Normal/Near normal RV size and function

BNP(= B-type natriuretic peptide level)

Normal

6 Minute walk distance

> 380 to 440m; may not be aggressive enough in young individuals

CPET (= cardiopulmonary exercise testing)

CI= cardiac index; CMR= cardiac magnetic resonance; EqCO2 =
Peak VO2 > 15 ml/min/kg and EqCO2< 45 l/min ventilatory equivalent for carbon dioxide; PAH = pulmonary arterial
hypertension; RAP =right atrial pressure; RV =right ventricular;
VO2 = peak oxygen consumption
McLaughlin, V.V. et al. (2013): JACC, Vol.62, No. 25;
27 Suppl.D: D73 D81 Confidential for internal use only
Treat-to-Target Strategies in Pulmonary Arterial
Hypertension: Importance of Using Multiple Goals

Sitbon, O. & Gali, N. (2010): Eur. Respir. Rev.; 19; 118: 272 - 278

28 Confidential for internal use only

 CTEPH Treatment Algorithm
CTEPH Diagnosis
Continue Lifelong Anticoagulation*

Operability Assessment by CTEPH Team

Operable Non-operable

Recommend 2nd Opinion by

Experienced Centre

Pulmonary
Endarterectomy
Targeted Medical Therapy

Persistent Symptomatic Referral for Lung

(PTPA?)
Pulmonary Hypertension Transplantation

Kim, N.H. et al. (2013): JACC Vol 62; No.25, Suppl.D:D 92-99

29 Confidential for internal use only

 Role of Medical therapy in CTEPH
There are compelling reasons for considering PAH targeted therapies in
CTEPH
Medical therapy in CTEPH should not be considered as a replacement for
PEA
In operable CTEPH medical treatment is associated with delays with PEA and
adds no benefit
Recommendations from Nice World Symposium:
Determination of operability is critical in CTEPH and should only be conducted by an
experienced CTEPH team
For inoperable CTEPH and residual disease after PEA, medical therapy is
recommended
Riociguat is the first drug therapy to show positive primary endpoints in an RCT for
those indications
Operable CTEPH cases should be referred for PEA without delay
The role of bridging with medical therapy has not been sufficiently studied and should
be reserved for controlled investigation.

PEA, pulmonary endarterectomy. Kim N.H. et al. (2013): JACC, Vol.62, No. 25 Suppl.D: D92-99
Confidential for internal use only
 TF 10: CTEPH
Level of Evidence* for Medical Therapy

Bosentan
Bosentan and
and Riociguat
Riociguat improve
improve haemodynamics
haemodynamics (level
(level B,
B, 22 RCT)
RCT)
Non-operable Riociguat
Riociguat improves
improves exercise
exercise capacity
capacity (level
(level B,
B, 11 RCT)
RCT)
No
No drug
drug is
is currently
currently approved
approved for
for CTEPH
CTEPH

Patients
Patients with
with PVR>300
PVR>300 66 months
months after
after PEA
PEA (level
(level B)
B)
Postoperative
persistent PH

Routine Medical
Medical treatment
treatment is
is delaying
delaying surgery
surgery (level
(level C)
C)
pre-treatment Efficacy
Efficacy is
is unproven
unproven (level
(level C)
C)
before PEA Medical
Medical treatment
treatment might
might interfere
interfere with
with surgery
surgery by
by making
making material
material more
more
friable
friable (level
(level C)
C)

PEA, pulmonary endarterectomy.

Gali N et al. Eur Heart J 2009;30:2493537.

31 Confidential for internal use only

Other therapies for PAH have not proven efficacy in
CTEPH
Randomized pivotal clinical trials in specific PH groups
Class Drug
PAH CTEPH ILD LVD COPD

Epoprostenol
Barst 19961 FIRSTa,2
Prostacyclin
Treprostinil
(PC) Simonneau 20023

Iloprost
AIRd,4

Endothelin
Bosentan ENABLE-I and -IIb
receptor BREATHE-15 BENEFiT6 BUILD7,8
REACH-1c9,10
antagonist
(ERA)
Ambrisentan
ARIES-1 and -211 ARTEMIS12

Phospho- Sildenafil
SUPER-113
diesterase type 5
inhibitor (PDE5i)
Tadalafil
PHIRST14
= Met primary endpoint = Failed to meet primary endpoint
COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; LVD, left ventricular dysfunction.
aPatients with severe congestive heart failure; bPatients with congestive heart failure;
cPatients with chronic heart failure; dIncluded 54 patients with CTEPH.
1. Barst RJ et al. N Engl J Med 1996;334:296301. 2. Califf RM et al. Am Heart J 1997;134:4454. 3. Simonneau G et al. Am J Respir Crit Care Med
2002;165:8004. 4. Olschewski H et al. N Engl J Med 2002;347:3229. 5. Rubin LJ et al. N Engl J Med 2002 346:896903. 6. Jas X et al. J Am Coll Cardiol
2008;52:212734. 7. King TE Jr et al. Am J Respir Crit Care Med 2008;177:7581. 8. King TE Jr et al.
Am J Respir Crit Care Med 2011;184:929. 9. Rich S & McLaughlin VV. Circulation 2003;108;218490. 10. Kalra PR et al. Int J Cardiol 2002;85:1957. 11. Gali
N et al. Circulation 2008;117:30109.
12. http://clinicaltrials.gov/ct2/show/NCT00768300. 13. Gali N et al. N Engl J Med 2005 353:214857. 14. Gali N et al. Circulation 2009;119:2894903.

32 Confidential for internal use only

Overview

Guidelines for Management of PH/PAH

Diagnostics

Monitoring and Treatment Options

Summary

33 Confidential for internal use only

Summary PH Guidelines

Three major guidelines for PH diagnostics, treatment and follow up

ERS/ESC guideline by Gali et al. 2009

US guideline by McLaughlin et al.2009
US CHEST guideline by Taichman et al.2014 published ahead online

Proceedings from 5th PH World Symposium published 2013 that provide an update
of the current guidelines and newly a CTEPH treatment algorithm
Updated ERS/ESC guidelines expected in 2015, containing recommendations on
Macitentan
Riociguat
Combination therapy

Combination therapies are common practice, although evidence is limited

34 Confidential for internal use only

35
A Phase IIIb pilot study concept with riociguat
(Bay 63-2521) in patients with pulmonary
arterial hypertension (PAH) who demonstrate
an insufficient response to treatment with
approved dosages of PDE5 inhibitors

RESPITE : Riociguat clinical Effects

Studied in PAH patients
Insufficiently Treated with PDE-5
inhibitors
Andreas Mattern
Global Medical Affairs PH

Pa
ge
Study Rationale
PDE-5 inhibitors (PDE5i) have become first line, first-choice therapy for
patients with PAH in many countries around the world
Oral monotherapy (incl. PDE5i) is the recommended treatment approach for
patients with PAH who are classified as WHO functional class II or III
However, many PAH patients fail to reach or maintain treatment goals with
PDE-5i therapy, even when an endothelin receptor antagonist (ERA) is added;
the precise scientific reason for insufficient response to PDE5i therapy
remains unknown
It is hypothesized that Riociguat may have an advantage over PDE5i in these
patients due to increase of cGMP production via stimulation of sGC
independent from endogenous NO levels a opposed to PDE5 inhibitors
Characterization of NO biomarkers in PAH patients could help elucidate the
concept of NO deficiency in PAH patients
Co-administration of PDE-5i and riociguat should be avoided in patients with
PAH
REPLACE concept
There currently is no clinical data to inform clinicians if switching patients
from
PDE-5i to riociguat is safe and if there is clinical benefit
Page 37
Study aims

To generate clinical evidence showing that

PAH patients who are not at treatment goal with PDE5i
therapy can be safely switched to riociguat, and

Riociguat can achieve clinically relevant improvements

in these patients

Responder criteria will be used to design a larger double-

blind replace vs. maintain study

Page 38
 Our mid-term perspective: The
Replace Study
Patients with confirmed PAH (approx. n = 216 (?), to be confirmed) on tadalafil or sildenafil (+/-
ERA)
for 3 months since last change of therapy, no time constraints for time since initial PAH therapy
Stable in the judgment of the investigator, but with insufficient response to therapy
(WHO FC III; 6MWD = 165 440m; CI < 2.5 L/min/m2)
* Stratification based on PDE5i +/- ERA at baseline
1:1
Randomization
double blind
study
MAINTAIN ARM REPLACE ARM

PAH patients: PAH patients:

Maintain PDE5i Replace PDE5i
with riociguat
(+/- ERA) (+/- ERA)

Primary Endpoint: Net Benefit - percentage of patients with event-free

clinical improvement versus clinical worsening at 12-24 weeks
(with monthly clinical assessments)
ITT Assessment of Outcomes 2 years after primary endpoint
3-monthly clinical assessments
Bayers approach:
Exploratory pilot study to assesses the
clinical effects and event rates in PAH
patients with an inadequate response to
PDE-5i therapy
 RESPITE study outline (I)

Title RESPITE: Riociguat clinical Effects Studied in PAH patients Insufficiently

Treated with PDE-5 inhibitors
Rationale Given the unique dual mode of action of riociguat it is reasonable to hypothesize
that patients who do not demonstrate a sustained clinical response to PDE-5i
therapy (potentially due to NO deficiency) may respond to direct stimulation of
sGC with riociguat.
Objective To investigate whether it is safe, feasible and beneficial to replace PDE5i with
Riociguat in PAH patients demonstrating insufficient response to PDE-5 inhibition
Design Open-label, multicenter, uncontrolled, Phase IIIb pilot study
Subject No.: 50-70 patients - Feasible number for a pilot study
Duration: 6 months treatment phase
Outcome Changes from baseline in 6-MWD, cardiac index, NT-proBNP, WHO FC, QoL,
measure SvO2, REVEAL Risk Score, NO and cardiac biomarkers (cGMP, ADMA, GDF-15,
s ST2)
Proportion of patients with: clinical worsening (CW), CI 2.5 L/min/m 2, NT-
proBNP <1500 ng/L, need of new PAH treatments
Responder outcomes:
Proportion of patients w/o CW who achieve at least WHO FC II AND an
improvement in
6-MWD of 30 m
41 Proportion of patients without (CW) who achieve at least WHO FC II AND a
Page 41
 RESPITE study outline (II)

Centers Approx. 15 sites in USA, Canada, Germany, France, Belgium, UK

& Additional high-volume centers in US and further EU countries (CZ, I PL) under
countries consideration
Current CDP endorsement on 12 Apr 2013
status Internal study conduct confirmed
Draft study protocol available
Study committees: Advisory Committee, Adjudication Committee
Timeline FPFV: Nov/Dec 2013
s Investigator meeting: 17 Jan 2014
LPFV: Nov 2014
LPLV: Jun 2015
Results (stat tabs): Oct 2015
Publication/presentation: 1Q 2016

42
Page 42
Study Objectives: Pilot Study

To investigate whether it is safe, feasible and beneficial to

replace PDE5i with Riociguat in PAH patients demonstrating
insufficient response to PDE-5 inhibition

Page 43
Study Design: Pilot Study
Open-label, multicenter, uncontrolled, phase IIIb study of
riociguat in patients with PAH who demonstrate an
insufficient response to treatment with approved dosages of
PDE-5 inhibitors
PAH patients on stable approved doses of tadalafil or
sildenafil for at least 3 months since last change of therapy
Patients can be on stable ERA background therapy (stable dose
3 months)
Study population: 50 PAH patients who demonstrate
insufficient response (not at goal) to PDE5i will be switched to
riociguat:
WHO FC III AND
6MWD = 165 440m AND
CI < 2.5 L/min/m2
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Study Design: Open-label,
multicenter, single-arm
uncontrolled, phase IIIb study

Screening 24 week treatment

period period

Study entry
Screening

Replace PDE-5i with riociguat

(n=50-70 patients)

RHC RHC at week 24

3 days
wash-
out phase
Titration Maintenance

0 8 12 24 weeks

Escalation of PAH background /add-on therapy should be avoided.

However, if escalation of PAH background /add-on therapy is deemed
necessary by the investigator, the patient should remain in the study for
follow-up of vital status .
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Extended drug supply phase : Bayer to provide riociguat free of charge for 18
months
Outcome variables (I)
Standard efficacy outcomes
Change from baseline in 6-MWD
Change in cardiac index
Change in NT-proBNP
Change in WHO FC
Proportion of patients with clinical worsening
Change in QoL (EQ-5D, LPH)
Responder outcomes
Proportion of patients with cardiac index 2.5 L/min/m2
Proportion of patients with NT-proBNP < 1500 ng/L
Proportion of patients without clinical worsening who achieve at least WHO
FC II and an improvement in 6-MWD of 30 m
Proportion of patients without clinical worsening who achieve at least WHO
FC II and a cardiac index 2.5 L/min/m2

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Outcome variables (II)
Additional outcomes
Change in SvO2
Proportion of patients requiring the addition of new PAH targeted
treatments
Change in REVEAL Risk Score
Novel biomarker evaluation: cGMP, ADMA, GDF-15, ST2

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Main inclusion criteria
Patients (n=50-70) with confirmed PAH (Group I / Dana Point Clinical
Classification of Pulmonary Hypertension): IPAH, heritable PAH, PAH-CHD
(only due to atrial septal defect if corrected for greater that 1 year), drug-
induced PAH (anorexigen or methamphetamine)
18-70 years
Patients on a stable, approved dose of either tadalafil or sildenafil for at least
12 weeks and with insufficient response to therapy / not at goal (in the
opinion of the investigator)
Definition of not at goal:
WHO FC III
6MWD = 165 440 m
Cardiac index < 2.5 L/min/m2
RHC at baseline not older than 4 weeks showing: mPAP > 30 mmHg, a PCWP
15 mmHg and a PVR > 480 dynseccm-5 (strict criteria to ensure true
PAH)

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Main exclusion criteria
Other forms of PH
Age > 70 years
BMI > 35 kg/m2
History of atrial fibrillation within the last 3 months before Visit 1
No signs of LV systolic or diastolic dysfunction by echo cardiogram
Moderate to severe bronchial asthma or COPD (Forced Expiratory
Volume < 60% predicted)
Severe restrictive lung disease (Total Lung Capacity < 70%
predicted)
SaO2 < 88%, PaO2 < 55 mmHg, PaCO2 > 45 mmHg despite
supplemental oxygen therapy
Other comorbidities impairing exercise capacity

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Statistical Considerations
This is an exploratory pilot study.
Over a recruitment period of approximately one year we
believe a sample size of 50-70 patients is feasible.
Responder criteria will be used to design a larger double-
blind study

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Study Planning: Operational Aspects
Countries: USA, Canada, Germany, France, Belgium, UK
Focus on most successful PATENT and CHEST sites
Approx. 15 centers
5 sites in US
10 sites in EU
Additional high-volume centers in US, Czech Republic, Italy
and Poland to shorten recruitment period under consideration
Decision depending on budget
Internal study conduct confirmed
Study committees: Advisory Committee, Adjudication
Committee, DMC

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Timelines

Planned key milestones

Milestone OFA assumptions

Protocol Approved 31 July 2013

FPFV 29 Nov 2013
LPFV 31 Oct 2014
LPLV 30 Jun 2015
CDB 28 Jul 2015