Real-world experience with riociguat in CTEPH

Real-world experience with riociguat in CTEPH Matthias Held Center of Pulmonary Hypertension and Pulmonary Vascular Disease, Medical Mission Hospital, Würzburg, Germany Tuesday, 29 September ERS International Congress 2015

Disclosures Honoraria for lectures: Actelion, Bayer HealthCare, Berlin Chemie, Boehringer Ingelheim, GSK, Novartis, Pfizer Honoraria for advisory board activities: Actelion, Bayer HealthCare, GSK Participation in clinical trials: Actelion, Bayer HealthCare, GSK, Pfizer, United Therapeutics Research funding: Actelion

Overview Treatment of CTEPH: PEA, medical treatment or BPA? Medical therapy of CTEPH in inoperable patients before approval of riociguat Follow-up of patients after PEA, and detection of persistent/recurrent CTEPH Medical therapy in patients with persistent/recurrent CTEPH Medical therapy of CTEPH in inoperable patients after approval of riociguat BPA, balloon pulmonary angioplasty; PEA, pulmonary endarterectomy.

CTEPH treatment algorithm Diagnosis confirmed by CTEPH expert center Lifelong anticoagulation Operability assessment by a multidisciplinary CTEPH team Acceptable risk:benefit ratio Technically operable Technically non-operable Copyright protected content. Please view original Non-acceptable content in the following reference: Galiè N et al. Eur Heart risk:benefit J 2015:doi:10.1093/eurheart/ehv317 ratio a Targeted medical therapy Pulmonary endarterectomy Persistent symptomatic PH Consider BPA in expert center b Consider lung transplantation Persistent severe symptomatic PH a Technically operable patients with non-acceptable risk/benefit ratio can also be considered for BPA. b In some centers medical therapy and BPA are initiated concurrently. BPA, balloon pulmonary angioplasty. Galiè N et al. Eur Heart J 2015:doi:10.1093/eurheart/ehv317.

Case study CASE STUDY October 2009 68-year-old female; history of PE 2007 Parameter Nov 2009 PAP (mmhg) 101/45 (65) PVR (dyn sec m 5 ) 1222 CI (L/min/m 2 ) 2.1 CTEPH Board decision 2009/2010: Unsuitable for PEA: Poor benefit:risk ratio Medical treatment: Off-label PAH therapy Sequential combination: ERA + PDE5 inhibitor CI, cardiac index; ERA, endothelin receptor antagonist; PDE5, phosphodiesterase type 5; PE, pulmonary embolism; PEA, pulmonary endarterectomy; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance.

PEA Oct 2010; ERA stopped, PDE5 inhibitor continued CASE STUDY Pre-PEA Week 6 post-pea Month 18 post-pea Jul 2010 Jan 2011 May 2012 ERA, endothelin receptor antagonist; PDE5, phosphodiesterase type 5; PEA, pulmonary endarterectomy.

Follow-up after PEA CASE STUDY Improvement in FC ERA stopped post-pea PDE5 inhibitor continued PEA Parameter Sept 2010 Jan 2011 May 2012 Apr 2014 WHO FC IV II I I 6MWD (m) 120 310 300 320 Echo spap (mmhg) 88 n/a n/a n/a April 2014: Riociguat is the only approved medical treatment for inoperable CTEPH, and persistent/recurrent CTEPH post-pea 6MWD, 6-minute walking distance; Echo, echocardiography; ERA, endothelin receptor antagonist; FC, functional class; n/a, not applicable; PDE5, phosphodiesterase type 5; PEA, pulmonary endarterectomy; spap, systolic pulmonary arterial pressure; WHO, World Health Organization. Bayer HealthCare. Adempas EU Summary of Product Characteristics, July 2015.

What would you recommend? 1. No action, follow up in 6 months 2. Stop PDE5 inhibitor 3. Perform RHC VOTE NOW! PDE5, phosphodiesterase type 5; RHC, right heart catheterization.

Importance of RHC in follow-up after PEA PEA CASE STUDY Sept 2010 Jan 2011 May 2012 Apr 2014 WHO FC IV II I I 6MWD (m) 120 310 300 320 Echo spap (mmhg) 88 n/a n/a n/a RHC mpap (mmhg) 67 - - 42 PVR (dyn sec m 5 ) 1467 - - 712 CO (L/min) 3.6 - - 4.88 Follow-up after PEA: Echo can miss the diagnosis of persistent/recurrent CTEPH RHC required 6MWD, 6-minute walking distance; CO, cardiac output; Echo, echocardiography; FC, functional class; n/a, not applicable; mpap, mean pulmonary arterial pressure; PEA, pulmonary endarterectomy; PVR, pulmonary vascular resistance; RHC, right heart catheterization; spap, systolic pulmonary arterial pressure; WHO FC, World Health Organization functional class.

What would you recommend? 1. Stay on PDE5 inhibitor 2. Transition to riociguat 3. Add on riociguat VOTE NOW! PDE5, phosphodiesterase type 5.

Improvements seen following transition from PDE5 inhibitor to riociguat CASE STUDY PEA Riociguat transition Sept 2010 Jan 2011 May 2012 Apr 2014 Jul 2015 WHO FC IV II I I I I Sep 2015 6MWD (m) 120 310 300 320 350 378 Echo spap (mmhg) 88 n/a n/a n/a n/a n/a RHC mpap (mmhg) 67 42 35 PVR (dyn sec m 5 ) 1467 712 339 CO (L/min) 3.6 4.88 5.89 6MWD, 6-minute walking distance; CO, cardiac output; Echo, echocardiography; FC, functional class; mpap, mean pulmonary arterial pressure; n/a, not applicable; PEA, pulmonary endarterectomy; PVR, pulmonary vascular resistance; RHC, right heart catheterization; spap, systolic pulmonary arterial pressure; WHO FC, World Health Organization functional class.

Experience achieving treatment goals: Scenarios for CTEPH in clinical reality Data to be included in manuscript currently in preparation ERA, endothelin receptor antagonist; i.v., intravenous; PDE5i, phosphodiesterase type 5 inhibitor. Held M et al. Manuscript in preparation.

Riociguat is a PH-targeted therapy with proven efficacy in CTEPH Class Drug Randomized pivotal clinical trials in CTEPH Primary endpoint met sgc stimulator Riociguat CHEST-1 and -2 1 3 Prostanoid Epoprostenol Treprostinil Iloprost (AIR 4 ) Selexipag Bosentan BENEFiT 5 ERA PDE5 inhibitor Ambrisentan (AMBER I 6 ) Macitentan recruiting MERIT-1 7 Sildenafil Tadalafil ERA, endothelin receptor antagonist; PDE5, phosphodiesterase type 5; sgc, soluble guanylate cyclase. 1. Ghofrani HA et al. N Engl J Med 2013;369:319 29. 2. Simonneau G et al. Eur Respir J 2015;45:1293 302. 3. Simonneau G et al. Eur Respir J 2014;44(Suppl.58):1802. 4. Olschewski H et al. N Engl J Med 2002;347:322-29. 5. Jaïs X et al. J Am Coll Cardiol 2008;52:2127 34. 6. GlaxoSmithKline. AMBER I. Available at: https://clinicaltrials.gov/ct2/show/nct01884675 (accessed Sept 2015). 7. Actelion. MERIT-1. Available at: https://clinicaltrials.gov/ct2/show/nct02021292 (accessed Aug 2015).

Real-world data: The clinical reality in patients with CTEPH Single-center experience with riociguat beyond clinical studies Medical Mission Hospital, Würzburg Apr 2014 May 2015: N=56 Data overall: Prevalent patients (change of existing therapy) Incident Data patients to be included (initiation in manuscript of new therapy) currently in preparation Held M et al. Manuscript in preparation.

Mean 6MWD (m) Mean NT-proBNP (pg/ml) Improvements in 6MWD and NT-proBNP 3 months after transitioning to riociguat Overall CTEPH population 350 300 294 +40 m (p=0.003) 334 3500 3000 2938 891 pg/ml (p=0.04) 250 200 150 100 2500 2000 Data to be included in manuscript currently in preparation 1500 1000 2047 n=56 50 n=56 n=56 n=56 n=56 500 0 Baseline Follow-up (3 months) 0 Baseline Follow-up (3 months) 6MWD, 6-minute walking distance; NT-proBNP, N-terminal prohormone of brain natriuretic peptide. Held M et al. Manuscript in preparation.

Are symptoms observed in CTEPH necessarily side effects of treatment? (I) Data to be included in manuscript currently in preparation bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. Held M et al. Manuscript in preparation.

Are symptoms observed in CTEPH necessarily side effects of treatment? (II) Data to be included in manuscript currently in preparation *Adverse events occurring in 5% of patients in either group. 1. Ghofrani et al. N Engl J Med 2013;369:319 29; 2. Held M et al. Manuscript in preparation.

How to deal with symptoms and potential side effects (I) CASE STUDY Case 60-year-old patient on riociguat with syncope BP (right arm) 155/85 mmhg Medication Riociguat 2.5 mg tid Ramipril 5/25 mg comp qd/bid Nevibolol 5 mg qd Atorvastatin 10 mg qd L-thyroxin 75 µg qd Omeprazole 40 mg qd Dreisafer (Fe [II] sulfate monohydrate) 100 mg qd ASA 100 mg qd ASA, acetylsalicylic acid; BP, blood pressure; bid; twice daily; qd, once daily; tid, three times daily.

What would you recommend? 1. Watch and wait 2. Stop riociguat 3. Explore and investigate VOTE NOW!

How to deal with symptoms and potential side effects (II) CASE STUDY Flow acceleration in the subclavian artery subclavian stenosis Medication continued Stenting performed Symptoms and potential side effects require a careful diagnostic work-up!

Summary of single-center experience with riociguat beyond clinical studies Medical Mission Hospital, Würzburg High efficacy Mean change in 6MWD: +40 m Mean change in NT-proBNP: 891 pg/ml Good tolerability 64% of patients (n=56) on riociguat 2.5 mg tid Data to be included in manuscript currently in preparation 2% had intermittent treatment interruption Single case of syncope Not riociguat-related Caused by subclavian artery stenosis 6MWD, 6-minute walking distance; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; tid, three times daily. Held M et al. Manuscript in preparation.

Summary: CTEPH and riociguat in the real world Riociguat consistently demonstrates clinically meaningful improvements in patients with inoperable CTEPH or persistent/recurrent CTEPH post-pea In a goal-orientated approach, scheduled follow-up of patients post-pea that includes RHC is important to accurately detect and treat persistent/recurrent CTEPH Careful diagnostic work-up of side effects is essential for correct identification of their cause Patients on historic off-label pretreatment should be carefully assessed PEA, pulmonary endarterectomy; RHC, right heart catheterization.

Thank you