Riociguat Phase II clinical trials

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LEBANESE INTERNATIONAL UNIVERSITY SCHOOL OF PHARMACY Fall 2012

ADVANCED PPE NERMINE CHOUMANE PRESENTED TO: Dr. Etwal Bou Raad, Pharm D

Outline

I. Background II. Treatment III. Rationale IV. Discovery V. Clinical Trials VI. Reference

Background What are pulmonary arteries? 1,2 The human body has two major sets of blood vessels that distribute blood from the heart to the body 2 Sets

One pumps blood from the right heart to the lungs

One pumps blood from the left heart to the rest of the body

Background The portion of the circulation that distributes oxygen rich blood from the left side of the heart, throughout the body, is referred to as the Systemic Circulation The blood then returns from the body to the right side of the heart and passes through the lungs to replenish oxygen, this is referred to as the Pulmonary Circulation

Background  •

What is pulmonary hypertension? 1,2 Pulmonary Hypertension (PH) is an increase of blood pressure in the: - pulmonary artery - pulmonary vein - pulmonary capillaries

 NL : PAP <<< SCP

≠ ABNL: PAP >>> SCP

 It is referred to as pulmonary hypertension or pulmonary artery hypertension (PAH)

Background

Constriction/stif fening of the pulmonary arteries

Difficult for the heart to pump blood through the lungs

Enlargement of the right heart + fluid build up in the liver + other tissues

Background 

What are primary and secondary pulmonary hypertension? 1,2,3,4

In the conventional classification, pulmonary hypertension, is divided into two main categories: 1) 2)

Primary PH = not caused by any other disease or condition Secondary PH = caused by another underlying condition

Secondary pulmonary hypertension is much more common than primary pulmonary hypertension

Newer Venice 2003 classification is based on the main underlying cause of pulmonary hypertension

ypertension : Newer Venice 2003 classification is based on the main underlying cause of pulmonary hypertension :

Background  What are the signs and symptoms of pulmonary hypertension? 1,2,3,4 Shortness of breath Non-productive cough Peripheral edema Fainting

Fatigue Angina pectoris Syncope Hemoptysis

N.B : Pulmonary venous hypertension  shortness of breath while lying flat or sleeping

≠ Pulmonary arterial hypertension

Treatment

Treatment  What is the treatment of pulmonary hypertension? 1,3,4,5 1. General measures recommendations

2. Supportive therapy:

- Oral anticoagulant - Diuretics - Digoxin - Oxygen

3. Specific drug therapy: - CCB - Prostanoids - Endothelin receptor antagonists - PDE5 Inhibitors 4. Surgery 5. Future therapy: - Activators of soluble guanylate cyclase

Treatment CCB

Prostanoids

Endothelin Receptor Antagonist

Nifedipine

Epoprostanol

Bosentan

Sildenafil

Amlodipine

Illoprost

Sitaxentan

Tadalafil

Diltiazem

Treprostinil

Ambrisentan

PDE5 inhibitors

Treatment  Prostanoids PGI2 is produced by arachidonic acid  Stimulates CAMP production

 Induces vasodilation

Drug (Brand)

Epoprostanol (Flolan)

FDA Indication

-PAH with NYHA class 3-4

Route of administration

Continuous infusion via central IV line

- PAH with scleroderma Illoprost (Ventavis)

Treprostinil (Remodulin)

NYHA class 2-4

NYHA class 3-4

Continuous infusion via central IV line or continuous SQ infusion

Aerosolized Inhalation

Starting dose & titration schedule 2ng/kg/min increased by 2ng/kg/min q.15min till dose limiting side effect occurs 2.5mcg 6-9 times/d, increased to maxim 5 mcg 69 times/d

1.25ng/kg/min increased by 1.25ng/kg/min weekly for 1rst 4 weeks then 2.5ng/kg/min

Half life

Side effects

- HA 2-7 min - N&V - Infusion site reaction - Pain - Flu like Sx - Hypotension 4 hrs

20-30 min

- HA - N&V - Infusion site reaction - Pain - Flu-like Sx

- HA - Flushing - Hypotension - Flu like Sx - Cough - Trismus

Treatment  Endothelin Receptor Antagonist

Drug (Brand)

Bosentan (Tracleer)

FDA Indication

Route of administrati on

Starting dose & titration schedule

WHO class III-IV

Oral Tablet

-62.5mg bid for 4 weeks then increase to 125 mg bid

Half life

5 hrs

- If <40kg  62.5 mg bid

Ambrisentan (Letairis)

WHO class II-III

Oral Tablet

5 mg/d then increase to 10mg/d

915hrs

Side effects

- HA - Anemia - Chest pain - Syncope - Resp Tract Infection - Perip edema -BBW= Hepatotoxicity + Teratogenicity - Same as Bosentan

Treatment  PDE5 Inhibitors

Drug (Brand)

Sildenafil (Revatio)

Tadalafil (Adcirca)

FDA Indication

Route of administrati on

Starting dose & titration schedule

Half life

WHO class I-IV

Oral Tablet

-20 mg tid (4-6hrs apart)

4 hrs

IV Bolus

- 10 mg tid

Oral Tablet

40 mg/d

WHO class I-IV

Side effects

- HA - Dyspnea - Flushing - Hearing loss - Epistaxis

35 hrs - HA - Flushing - Hypotension -Nasopharyngitis - RTI - Myalgia - Hearing/vision loss

Treatment  Future therapy: 1. (NO)–independent direct activator of sGC “Cinaciguat”

2. (NO)–independent direct stimulator of sGC “Riociguat”

Rationale • The first nitric oxide(NO) independent, sGC stimulator

YC-1, was described in 1978 2,6,7 • sGC stimulator YC-1 increased sGC activity and acted in synergy with NO to stimulate sGC • However, YC-1 was a weak vasodilator and had side effects

Rationale “ We know that with the existing 3 classes — endothelinreceptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins — even if the patient has received extensive combination therapies, disease may still progress. So every new class of drug is definitely welcomed“ Dr. Ghofrani

The search began for novel compounds that were more potent and more specific sGC stimulators

Discovery • The result was the identification of BAY 41-2272 and BAY 41- 8543 2,7,8 Both compounds improved systemic arterial oxygenation in various preclinical studies on different animal models

• To improve the pharmacologic and pharmacokinetic profile, an additional 1000 compounds were screened leading to the discovery of Riociguat

Discovery  Mechanism Of Action 2,6 • NO acts on vascular smooth muscle cells to induce

vasodilation • NO binds to soluble guanylate cyclase (sGC) and mediates the synthesis of the secondary messenger cyclic guanosine monophosphate (cGMP) • The synthesised cGMP acts as a secondary messenger and activates cGMPdependent protein kinase (protein kinase G) to regulate cytosolic calcium ion concentration 1. Changes the actin–myosin contractility  vasodilation 2. Reduces pulmonary smooth muscle cell growth 3. Antagonizes platelet inhibition

Discovery •In patients with PAH, endothelial NO synthase expression is reduced  Reduced vasodilation of smooth muscle cells • Stimulator Riociguat will: 1. directly stimulates sGC activity independent of NO 2. acts in synergy with NO to produce: - Anti-aggregatory - Anti-proliferative - Vasodilatory effects

Discovery • Activator Cinaciguat will: activates dysfunctional sGC  increasing production of cGMP  vasodilating effect

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Cinaciguat • Cinaciguat (BAY 58-2667) is the first member of a new class of organ protective vasodilators called (sGC) activators 8,9,10

• It is currently being investigated for the treatment of acute decompensated heart failure (ADHF) • Investigating Cinaciguat in ADHF: In preclinical and clinical studies to date, Cinaciguat showed efficacy and tolerability, with no evidence of patients becoming less responsive to it

• Cinaciguat is currently in phase II clinical trials

Riociguat • Riociguat (BAY 63-2521) constitutes the first drug of a novel class of sGC stimulators 8,11

• It is currently in clinical development by Bayer • At the moment, Phase III clinical trials investigate the use of Riociguat as a new approach to treat two forms of PH: 1. Chronic thromboembolic pulmonary hypertension (CTEPH) 2. Pulmonary arterial hypertension (PAH)

Clinical Trials

Riociguat Phase I clinical trials 2,7 • One of the first studies was designed to test the safety profile, pharmacokinetics and pharmacodynamics of single oral doses of Riociguat (0.25–5 mg) • In a randomized placebo-controlled trial - 58 healthy male subjects - Riociguat orally (oral solution or immediate-release tablet) - 0.25-5mg - Doses were increased stepwise Riociguat was well tolerated up to 2.5 mg

Riociguat Phase II clinical trials 2,7  A proof-of-concept study, reported by the University of Gießen Lung Center, was the first small study in PAH patients to investigate: 1. Safety 2. Tolerability 3. Pharmacokinetics 4. Effects on hemodynamics, exercise capacity and functional class

Riociguat Phase II clinical trials 75 adult patients in WHO class II/III

42 with CTEPH

33 with PAH

Riociguat Phase II clinical trials • Riociguat was given TID for 12 weeks • Doses were titrated at 2-week intervals from 1mg TID to a maximum of 2.5 mg TID • Riociguat had a favorable safety profile • It significantly improved exercise capacity and hemodynamic parameters such as: - Pulmonary vascular resistance - Cardiac output - Pulmonary arterial pressure

Riociguat Phase II clinical trials 12  Another phase II study of Riociguat is:

Impact of Multiple Doses of BAY63-2521 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Patients With Interstitial Lung Disease (ILD) Associated Pulmonary Hypertension (PH) • First received: June 9, 2008 • Last updated: October 5, 2012 • Last verified: October 2012 • Estimated Primary Completion Date: October 2015  Active Study

Descriptive Information Brief Title

Impact of Multiple Doses of BAY63-2521 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Patients With Interstitial Lung Disease (ILD) Associated Pulmonary Hypertension

Official Title

• A Multi-center • Non-randomized • Non Blinded • Non-controlled Study  to Investigate, in Patients With Interstitial Lung Disease Associated Pulmonary Hypertension, the Impact of Multiple Doses of BAY63-2521 on: 1. Safety 2. Tolerability 3. Pharmacokinetics 4. Pharmacodynamics

Brief Summary

The purpose of this study is to assess multiple ascending doses of a new drug (BAY63-2521) given orally, to evaluate if it is safe and can help to improve the well-being, symptoms (e.g. disturbed breathing) and outcome of pulmonary hypertension associated with lung fibrosis Patients living with pulmonary hypertension associated with interstitial lung disease have a risk of increased number of hospitalizations because of worsening of their condition

Descriptive Information Brief Summary

Until now there is no approved medication for this disease The current treatment of pulmonary hypertension associated with interstitial lung disease consists of oxygen and medical treatment with vasodilators, e.g. so-called Calcium-antagonists Therefore, there is a need for new drugs in the treatment of pulmonary hypertension associated with interstitial lung disease

Recruitment Information Gender

Both= 22

Ages

18 Years and older

Accepts Healthy Volunteers

No

Tracking Information Original Primary Outcome Measures

Safety and tolerability

Current Primary Outcome Measures

Same as original

Original Secondary Outcome Measures

. Pharmacokinetics . 6-Minute Walk Test . Quality of life assessments . Hemodynamic parameters . Laboratory Parameters . Electrocardiogram (ECG) . Blood pressure and heart rate

Current Secondary Same as original Outcome Measures

Condition Intervention

Pulmonary Hypertension Riociguat (BAY63-252 titrated from 1,0 mg TID to 2,5 mg TID

Recruitment Information Eligibility Criteria: 1. Diagnosis of an interstitial lung disease 2. Interstitial lung disease (ILD) must have been stable for at least 3 months Inclusion

i.e. no significant changes in pulmonary function testing and stable medication in terms of ILD (e.g., corticosteroids, immunosuppressants) 3. Mean pulmonary vascular resistance (PVR) > 400 dyne sec cm-5 or mean pulmonary arterial pressure (PAP mean) > 30 mmHg 4. Pulmonary capillary wedge pressure (PCWP) < 15 mmHg

5. Hemodynamic parameters at baseline (PAP, PCWP, cardiac output [CO], systemic mean arterial pressure [SAP] 6. High resolution computer tomography (HRCT) (should not be older than 12 months prior start of the study) 7. Heart rate > 55 beats per minute (BPM) and < 105 BPM at rest 8. Systolic blood pressure (SBP) > 90 mmHg 9. WHO functional class II, III and IV 10. 6 Minute Walking Test (6MWT) > 100m and < 450 m 11. Stable controlled arterial hypertension according to current guidelines 12. Women of childbearing potential included if the pregnancy test is negative and combination of condoms & contraception method is

Recruitment Information Eligibility Criteria: Exclusion

1. Co-medication: Patients pretreated with specific medication for pulmonary arterial hypertension (PAH) like endothelin receptor antagonists, prostaglandins or phosphodiesterase type 5 (PDE 5) blockers are excluded from the trial. Requirement for concomitant use of nitrates are contraindicated. 2. Pre-existing clinically relevant lung disease other than ILD including 3. Bronchial asthma and (COPD) 4. PH of another WHO group 5. Severe congenital abnormalities of the lungs, thorax and diaphragm 6. Clinical or radiological evidence of a pulmovenoocclusive disease (PVOD) 7. Systemic hemodynamics 8. Acute or severe chronic left heart failure (ejection fraction (EF) < 50%) 9. Severe coronary artery disease (CAD; EF < 50%); CAD patients must be asymptomatic and stable 10. Congenital or acquired valvular or myocardial disease 11. FEV1 < 60% predicted 12. Pa CO2 > 45 mmHg 13. Pa O2 < 50 mmHg 14. Moderate or severe hepatic insufficiency 15. Moderate or severe renal insufficiency (creatinine > 2 mg/dl)

Riociguat Phase II clinical trials 13  Another phase II study of Riociguat is:

Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters. (PATENT PLUS) • First received: August 10, 2010 •Last updated: November 28, 2012 •Last verified: November 2012 • Estimated Primary Completion Date: October 2013  Active Study

Descriptive Information Brief Title

Official Title

Brief Summary

Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters.

An Interaction Study to Evaluate Changes in Blood Pressure Following 1, 1.5, 2, and 2.5 mg Riociguat Tid (Dose Titration) Compared to Placebo Treatment on the Background of Stable Sildenafil Pretreatment in Subjects With Symptomatic Pulmonary Arterial Hypertension

PAH is a severe progressive disease with a high mortality. Although several drugs are available for the treatment of PAH none offer a cure, therefore there is still a high medical need for new treatments Soluble guanylate cyclase (sGC) is one of the chemicals involved in the pathways controlling vascular tone, which is impaired in patients with PAH. This causes constriction and thickening of the blood vessels wall in the lungs and increase of blood pressure in the lungs. This can lead to the very debilitating symptoms of PAH such as tiredness, shortness of breath on exertion, collapse and often the inability of the patient to perform their daily life activities.

Descriptive Information Brief Summary

Inhalation of Nitric Oxide, which activates sGC is used to treat PAH, but its effect wears off as soon as inhalation stops. Direct stimulation of sGC using this new compound Riociguat may be a new approach for the treatment of PAH. The PDE5-inhibitor Sildenafil is one of licensed treatments for PAH. The Patent Plus is a double-blind, placebo-controlled safety study, designed to investigate the effect of Riociguat on blood pressure in patients with PAH when given in combination with Sildenafil.

Tracking Information Original Primary Outcome Measures Current Primary Outcome Measures Original Secondary Outcome Measures

Maximum change in supine systolic blood pressure from baseline within 4 h of dosing with riociguat for the individual dose steps or placebo Same as original . Maximum change in standing SBP from baseline within 4 h of dosing with study medication . Maximum change in standing diastolic blood pressure (DBP) from baseline within 4 h of dosing with study medication..

. Maximum change in supine DBP from baseline within 4 h of dosing with study medication. . Maximum change in supine and standing HR from baseline within 4 h of dosing with study medication . Area under effect curve (AUEC) for change from baseline in standing and supine systolic and diastolic BP, and HR within 6 h of dosing with riociguat or placebo Current Secondary Same as original Outcome Measures Condition Pulmonary Hypertension

Intervention

Drug: Riociguat : 1 mg tid - 2,5 mg tid oral for 12 weeks.

Recruitment Information Eligibility Criteria: 1. 18 to 75 years of age at Visit 1 Inclusion 2. Male and female subjects with symptomatic PAH ,a 6-min walking distance (6MWD) of more than 150 m, a pulmonary vascular resistance (PVR) >300 and a mean pulmonary artery pressure (PAPmean) ≥ 25mmHg 3. For Study Part 1: subjects on stable pretreatment with sildenafil at a dose of 20 mg tid

4.Unspecific treatments which may also be used for the treatment of PAH such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants (if indicated) must have been started at least 30 days before Visit 1 and treatment with diuretics needs to be stable for at least 30 days before Visit 1 5. Subjects with supplemental long-term oxygen therapy may be included, if the amount of supplemental oxygen and the delivery method was stable on average for at least 90 days before Visit 1 6. SBP >/=95 mmHg and heart rate (HR)
Recruitment Information Eligibility Criteria: Exclusion

1. Subject's participating in another clinical trial or who have done so within 30 days before Visit 1 2. Previous assignment to treatment during this study 3. Pregnant women 4. Subjects with a medical disorder, condition, or history of such that would impair the subject's ability to participate or complete this study in the opinion of the investigator 5. Subjects with substance abuse (eg alcohol or drug abuse) within the previous 180 days before Visit 1 6. Subjects with underlying medical disorders with an anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass) 7. Subjects with a history of severe allergies or multiple drug allergies 8. Subjects with hypersensitivity to the investigational drug or any of the excipients 9. Subjects unable to perform a valid 6MWD test, eg subjects with a severe peripheral artery occlusive disease

Recruitment Information Gender

Both = 22

Ages

18 Years to 75 Years

Accepts Healthy Volunteers

No

Riociguat Phase II clinical trials 14  Another phase II study of Riociguat is:

A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Diastolic Dysfunction (DILATE) •First received: July 19, 2010 •Last updated: November 7, 2012 •Last verified: November 2012  Completed Study

Descriptive Information Brief Title

A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Diastolic Dysfunction

Official Title

Acute Hemodynamic Effects of Riociguat in Patients with Pulmonary Hypertension Associated With Diastolic Heart Failure: A Randomized, Doubleblind, Placebo-controlled, Single-dose Study in Three Ascending Dose Cohorts

Brief Summary

The aim of this study is to assess whether single oral doses of Riociguat safely improve the cardiovascular function in patients with pulmonary hypertension associated with left ventricular diastolic dysfunction

Recruitment Information Gender

Both= 39

Ages

18 Years to 90 Years

Accepts Healthy Volunteers

No

Tracking Information Original Primary Outcome Measures Current Primary Outcome Measures Original Secondary Outcome Measures

Pulmonary artery mean pressure at rest

Same as original • Adverse event collection • Plasma concentrations to obtain pharmacokinetic profile of Riociguat

Current Secondary Same as original Outcome Measures

Condition

• Pulmonary Hypertension • Left Ventricular Dysfunction

Intervention

Drug: Drug: Drug: Drug:

Riociguat 0.5 mg single oral dose Riociguat 1 mg single oral dose Riociguat 2 mg single oral dose Placebo single oral dose

Recruitment Information Eligibility Criteria • Inclusion Criteria: Male and female patients with symptomatic pulmonary hypertension due to left ventricular diastolic dysfunction

•Exclusion Criteria: Types of pulmonary hypertension other than group 2.2 of Dana Point Classification

Riociguat Phase II clinical trials  In addition to (DILATE) trial:

- The Phase II trials Left ventricular systolic dysfunction associated with Pulmonary Hypertension Riociguat Trial (LEPHT) is ongoing and is assessing the hemodynamic and clinical effect 15 - Phase II trials with Riociguat in patients with PH owing to interstitial lung disease (PH-ILD) and PH owing to chronic obstructive pulmonary disease (PH-COPD) have met their primary endpoints 16

Riociguat Phase II clinical trials  It demonstrates the safety, tolerability, pharmakokinetic and pharmacodynamic effect of a single oral dose of Riociguat in patients with PH due to COPD (Two doses, 1 and 2.5 mg BAY63-2521 given as a single dose, were tested )

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Riociguat Phase III clinical trials  Completed Study: - PATENT-1 - CHEST-1  Active Study: - PATENT-2 - CHEST-2

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Riociguat Phase III clinical trials  Completed Study: - PATENT-1 17 A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Pulmonary Arterial Hypertension (PATENT-1) •First received: December 17, 2008 •Last updated: June 19, 2012 •Last verified: June 2012

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Descriptive Information Brief Title

Official Title

Brief Summary

A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Pulmonary Arterial Hypertension (PAH)

Randomized, Double-blind, Placebo-controlled, Multi-centre, Multi-national Study to Evaluate the Efficacy and Safety of Oral BAY63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg Tid) in Patients With Symptomatic Pulmonary Arterial Hypertension (PAH) The aim of the study is to assess the efficacy and safety of different doses of BAY63-2521 given orally for 12 weeks, in patients with symptomatic Pulmonary Arterial Hypertension (PAH)

Recruitment Information Gender

Both= 445

Ages

18 Years to 80 Years

Accepts Healthy Volunteers

No

Tracking Information Original Primary Outcome Measures Current Primary Outcome Measures Original Secondary Outcome Measures

6 minute Walking Distance

Same as original

• Change from baseline in Pulmonary Vascular Resistance (PVR) • Change from baseline in NT-pro BNP • Change from baseline in WHO functional class • Time To Clinical Worsening • Change from baseline in Borg Dyspnoea Score • Change from baseline in EQ-5D visual analogue scale • Health Economics questionnaires

Current Secondary Same as original Outcome Measures

Condition

Pulmonary Hypertension

Intervention

Drug: Riociguat: 1mg tid - 2.5mg tid orally for 12 weeks Drug: Riociguat : 1.5mg tid orally for 12 weeks Drug: Matching Placebo tid orally for 12 weeks

Recruitment Information Eligibility Criteria • Inclusion Criteria: 1. Male and female patients with symptomatic PAH (Idiopathic, Familial, Associated PAH due to connective tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, or due to anorexigen or amphetamine use) 2. Treatment naive patients and patients pre-treated with an Endothelin Antagonist or a Prostacyclinanalogue (except I.V.). •Exclusion Criteria: All types of pulmonary hypertension except subtypes of Venice Group I specified in the inclusion criteria, severe COPD, uncontrolled arterial hypertension, left heart failure

Riociguat Phase III clinical trials  Conclusion: PATENT-1 1. PATENT-1 has met its primary end point, with Riociguat shown to significantly improve exercise capacity in treatment-naïve and pre-treated patients with symptomatic PAH from baseline after 12 weeks compared with placebo

2. In the study, Riociguat demonstrated a statistically significant improvement in the six-minute walk test (6MWT) and in the secondary endpoints 3. Riociguat was well-tolerated with a good safety profile

Riociguat Phase III clinical trials  Completed Study: - CHEST-1 18 A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Chronic thromboembolic pulmonary hypertension,CTEPH. (CHEST-1)

• First received: December 15, 2008 • Last updated: August 6, 2012 • Last verified: August 2012

Descriptive Information Brief Title

Official Title

Brief Summary

A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH

Randomized, Double-blind, Placebo-controlled, Multi-centre, Multi-national Study to Evaluate the Efficacy and Safety of Oral BAY63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg Tid) in Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

The aim of the study is to assess the efficacy and safety of different doses of BAY63-2521, given orally for 16 weeks, in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Recruitment Information Gender

Both= 261

Ages

18 Years to 80 Years

Accepts Healthy Volunteers

No

Tracking Information Original Primary Outcome Measures Current Primary Outcome Measures Original Secondary Outcome Measures

6 minute Walking Distance

Same as original

• Change from baseline in Pulmonary Vascular Resistance (PVR) • Change from baseline in NT-pro BNP • Change from baseline in WHO functional class • Time To Clinical Worsening • Change from baseline in Borg Dyspnea Score • Change from baseline in EQ-5D visual analogue scale • Safety variables: adverse events, laboratory parameters, ECG, vital signs

Current Secondary Same as original Outcome Measures

Condition

Pulmonary Hypertension

Intervention

Drug: Riociguat: 1mg tid - 2.5mg tid orally for 16 weeks Drug: Matching Placebo tid orally for 16 weeks

Recruitment Information Eligibility Criteria • Inclusion Criteria: Male and female patients with CTEPH either inoperable or with persistent or recurrent PH after surgery.

•Exclusion Criteria: All types of pulmonary hypertension except subtypes 4.1 and 4.2 of the Venice Clinical Classification of Pulmonary Hypertension

Riociguat Phase III clinical trials  Conclusion: CHEST-1

1. CHEST-1 has met its primary end point, with Riociguat shown to be the first ever drug to significantly improve exercise capacity in patients with CTEPH 2. In the study, Riociguat demonstrated a statistically significant improvement in the six-minute walk test (6MWT) and in the secondary endpoints 3. Riociguat was well tolerated with a good safety profile in patients with CTEPH

Riociguat Phase III clinical trials  Active Study: - PATENT-2 19 BAY63-2521:Long-term Extension Study in Patients With Pulmonary Arterial Hypertension (PATENT-2)  PATENT-2 is investigating the sustainability of the efficacy

• First received: March 13, 2009 • Last updated: October 12, 2012 • Last verified: October 2012 • Estimated Primary Completion Date: January 2014

Descriptive Information Brief Title

BAY63-2521:Long-term Extension Study in Patients With Pulmonary Arterial Hypertension

Official Title

Long-term Extension, Multicentre, Multi-national Study to Evaluate the Safety and Tolerability of Oral BAY63-2521 (1mg, 1.5 mg, 2.0 mg, 2.5 mg Tid) in Patients With Symptomatic Pulmonary Arterial Hypertension (PAH)

Brief Summary

Patients who have completed the 12 weeks treatment of the PATENT-1 trial (study number 12934) will be asked to participate in this long term extension study with BAY63-2521.

Recruitment Information Gender

Both= 396

Ages

18 Years to 80 Years

Accepts Healthy Volunteers

No

Tracking Information Original Primary Outcome Measures Current Primary Outcome Measures Original Secondary Outcome Measures

Safety (adverse events collection) and tolerability

Same as original

• Change in 6MWD (6 minute walking distance) from baseline

Current Secondary Same as original Outcome Measures

Condition

Pulmonary Hypertension

Intervention

Drug: Riociguat: 1mg tid - 2.5mg tid orally for 16weeks Drug: Matching Placebo tid orally for 16 weeks

Recruitment Information Eligibility Criteria • Inclusion Criteria: Patients who have completed 12 weeks of treatment in the double blind trial PATENT 1

• Exclusion Criteria: Patients who have an ongoing serious adverse event from PATENT 1 that is assessed as related to BAY63-2521 are not allowed to participate in the extension trial

Riociguat Phase III clinical trials  Active Study: - CHEST-2 20 BAY63-2521 - Long-term Extension Study in Patients With Chronic Thromboembolic Pulmonary Hypertension (CHEST-2)  CHEST-2 is investigating the sustainability of the efficacy results, as well as longer term safety aspects of Riociguat for CTEPH patient • First received: May 27, 2009 • Last updated: November 9, 2012 • Last verified: November 2012 • Estimated Primary Completion Date: September 2014

Descriptive Information Brief Title

BAY63-2521 - Long-term Extension Study in Patients With Chronic Thromboembolic Pulmonary Hypertension

Official Title

Long-term Extension, Multicentre, Multi-international Study to Evaluate the Safety and Tolerability of Oral BAY63-2521 (1mg, 1.5 mg, 2.0 mg, 2.5 mg Tid) in Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Brief Summary

Patients who have completed the 16 weeks treatment of the CHEST-1 trial (study number 11348) will be asked to participate in this long term extension study with BAY63-2521. The aim of the long term study is to collect additional information to evaluate the safety and tolerability of BAY63-2521. Patients will be treated with open label medication on their individual optimal dose between 0,5 mg - 2,5 mg tid

Recruitment Information Gender

Both= 237

Ages

18 Years to 80 Years

Accepts Healthy Volunteers

No

Tracking Information Original Primary Outcome Measures Current Primary Outcome Measures Original Secondary Outcome Measures

Safety (adverse events collection) and tolerability

Same as original

•Change in 6MWD (6 minute walking distance) from baseline

Current Secondary Same as original Outcome Measures

Condition

Pulmonary Hypertension

Intervention

Drug: Riociguat: 1mg tid - 2.5mg tid orally till end of the study

Recruitment Information Eligibility Criteria • Inclusion Criteria: Patients who have completed 16 weeks of treatment in the double blind trial CHEST 1

•Exclusion Criteria: Patients who have an ongoing serious adverse event from CHEST 1 that is assessed as related to BAY63-2521 are not allowed to participate in the extension trial

Conclusion • Although the prognosis for patients with PH has improved in recent years there is still a high need for more efficient therapies • Existing drug treatments are only approved to treat one of the five types of PH, namely PAH, and all current treatments have significant limitations • With its novel mode of action, Riociguat has the potential to overcome a number of limitations, including non-sustainable and limited efficacy, and NO dependence, and holds promise in other forms of PH, such as CTEPH, where no pharmacological treatment is approved

References 1. Wikipedia/Riociguat/Pharmacology 2. Escguidelines: Pulmonary Hypertension: http://www.escardio.org/guidelines

3. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension 4. Uspharmacist/Riociguat 5. Recent trends in pulmonary arterial hypertension, Department of Pulmonary and Critical Care Medicine, University of Massachusetts, Worcester, MA, USA:

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References 6. Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease 7. Pulmonary Vascular Involvement in COPD: http://journal.publications.chestnet.org/article. 8. Allen LA, O’Connor CM. Management of acute decompensated heart failure. CMAJ 2007;176(6):797-80

9. http://www.epresspack.net/bayerriociguat/dynamic/2012

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References 10. Nieminen MS, Bohm M, Cowie MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:384416. (Page 386, left column) 11. Impact of Multiple Doses of BAY63-2521 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Patients With Interstitial Lung Disease (ILD) Associated Pulmonary Hypertension (PH)

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References 12. Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters. (PATENT PLUS) 13. A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Diastolic Dysfunction (DILATE) 14. A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction (LEPHT)

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References 15. Single Dose Study in Patients With Chronic Obstructive Pulmonary Disease (COPD) Associated Pulmonary Hypertension 16. A Study to Evaluate Efficacy and Safety of Oral BAY632521 in Patients With Pulmonary Arterial Hypertension (PAH) (PATENT-1) 17. A Study to Evaluate Efficacy and Safety of Oral BAY632521 in Patients With CTEPH. (CHEST-1)

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References 18. BAY63-2521:Long-term Extension Study in Patients With Pulmonary Arterial Hypertension (PATENT-2) 19. BAY63-2521 - Long-term Extension Study in Patients With Chronic Thromboembolic Pulmonary Hypertension (CHEST-2)