Riociguat: Mode of action Riociguat increases the sensitivity of native soluble guanylate cyclase (sGC) to NO NO Riociguat sGC* cGMP Riociguat directly stimulates the native sGC independently of NO Both actions lead to vasodilatation (and anti-proliferation) Constricted Pressure Flow rate Relaxed Pressure Flow rate Effect of riociguat is not limited by low NO levels (unlike PDE-5-I) * native (intact) PDE-5-I = phosphodiesterase-5-inhibitor NO = mitroc oxide Anti-remodeling effects of riociguat in a rat model of PH Rats 20–70 µm percentage of total vessel count Vessel muscularization 100 * * † 80 60 40 20 0 MCT Riociguat * * N P – – M † † N P M * N P M + – N P M + – MCT 21 days + + MCT 35 days *p < 0.05 versus control animals without PH; †p < 0.05 versus untreated animals with PH at day 35. N, non-muscularized; P, partially muscularized; M, fully muscularized. Schermuly et al., ERJ 2008 2 Haemodynamic effects of BAY 632521: decrease in vascular resistance BAY 63-2521 Pulmonary vascular resistance 1 mg study group (n = 5) Systemic vascular resistance 2.5 mg study group (n = 10) -5 -10 -15 -20 -25 -30 -35 -45 *p < 0.05 0 Point estimate of decrease from baseline (%) Point estimate of decrease from baseline (%) 0 -40 iNO 1 mg study group 2.5 mg study group (n = 5) (n = 10) ‡ § * ‡ -5 ‡p -10 §p < 0.001 < 0.0001 -15 -20 BAY 63-2521 -25 iNO -30 -35 -40 § -45 -50 § § § Grimminger et al., ERJ 2009 3 Haemodynamic effects of BAY 63-2521: increase in cardiac index Point estimate of increase from baseline (%) 45 § § 50 § iNO § §p 40 35 30 BAY 63-2521 25 iNO 20 15 10 5 0 1 mg study group 2.5 mg study group (n = 5) (n = 10) Cardiac index Grimminger et al., ERJ 2009 BAY 63-2521 < 0.0001 Riociguat phase 2 study • Multicenter, open-label, individual dosetitration study • Primary objective: to investigate the safety, tolerability and feasibility of individual titration of riociguat according to peripheral systolic blood pressure • Secondary objectives: to assess the pharmacodynamics and pharmacokinetics of riociguat 5 Dose titration scheme • If trough SBP > 100 mmHg, increase dose (+0.5 mg t.i.d.) • If trough SBP 90–100 mmHg, maintain dose • If trough SBP < 90 mmHg without symptoms of hypotension, reduce dose (–0.5 mg t.i.d.) • If trough SBP < 90 mmHg with symptoms of hypotension, restart after 24 hours with reduced dose (–0.5 mg t.i.d.) 2.5 mg t.i.d. 2.0 mg t.i.d. 1.5 mg t.i.d. 1 mg t.i.d. Day 1 Week 2 Week 4 Week 6 6 Week 8 Week 12 Baseline demographics Demographic variable Total patients PAH CTEPH Age (years) Race White Sex Men Women Body mass index (kg/m2) n (%) or mean 75 (100%) 33 (44%) 42 (56%) 60.3 (range: 19–76) 75 (100%) 34 (45%) 41 (55%) 26.1 (SD: 4.4) 7 Baseline hemodynamic and functional parameters Parameter mPAP (mmHg) n (%) or mean ± SD 45.3 ± 10.8 CO (L/min) RAP (mmHg) PCWP (mmHg) 4.1 ± 1.1 6.6 ± 4.3 8.0 ± 4.2 PVR/SVR NYHA class: I II III IV 6-minute walking distance (m) 45.7 ± 15.7 0 (0%) 15 (21%) 56 (78%) 1 (1%) 354.4 ± 111.0 8 Six-minute walking distance: all patients CTEPH n = 41 PAH n = 31 All n = 72 Change in 6-minute walking distance (m) 100 80 60 40 20 0 Baseline 2 4 6 8 10 Duration of treatment (weeks) Titration phase Baseline values PAH: 316.7 127.4; CTEPH: 382.9 88.1; All: 354.4 111.0 9 12 n = 20 n = 30 n = 50 PAH CTEPH All 0 –2 –4 –6 *** –8 *** –10 –12 –14 * *p < 0.05; ***p < 0.001 Mean decrease from baseline in pulmonary vascular resistance (dyn.s/cm5) Mean decrease from baseline in pulmonary arterial pressure (mmHg) Pulmonary arterial pressure and pulmonary vascular resistance 10 n = 19 n = 29 n = 48 PAH CTEPH All 0 –50 –100 –150 –200 –250 *** –300 –350 *** –400 –450 –500 *** Functional class 100% Proportion of patients (%) 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Baseline 12 weeks PAH n = 72 NYHA class IV Baseline 12 weeks CTEPH n = 41 NYHA class III NYHA class II Baseline Total n = 31 NYHA class I CTEPH, chronic thromboembolic pulmonary hypertension; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension 11 12 weeks Riociguat phase III clinical program: PATENT -1 and -2 PATENT: Pulmonary Arterial Hypertension sGC-Stimulator Trial Secondary Outcome Measures Primary Outcome Measure • Change from baseline in 6 Minute Walk • Change from baseline in Pulmonary Test after 16 weeks* *Secondary outcome in extension, ** primary outcome in extension; p.o.: per os - oral; TID: three times daily; NT-pro BNP: N-terminal pro brain natriuretic peptide; EQ-5D: quality-of-life measures; MLHF-Q: Minnesota Living with Heart Failure Questionnaire • Vascular Resistance (PVR), change from baseline in WHO functional class, change from baseline in NT-pro BNP, change from baseline in Borg dyspnea, change from baseline in EQ-5D and MLHF-Q, time to clinical worsening Safety** Riociguat phase III clinical program: CHEST -1 and -2 CHEST: Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial Primary Outcome Measure • Change from baseline in 6 Minute Walk Test after 16 weeks* *Secondary outcome in extension, ** primary outcome in extension; p.o.: per os - oral; TID: three times daily; NT-pro BNP: N-terminal pro brain natriuretic peptide; EQ-5D: quality-of-life measures; MLHF-Q: Minnesota Living with Heart Failure Questionnaire Secondary Outcome Measures • Change from baseline in Pulmonary • Vascular Resistance (PVR), change from baseline in WHO functional class, change from baseline in NT-pro BNP, change from baseline in Borg dyspnea, change from baseline in EQ-5D and MLHF-Q, time to clinical worsening Safety**