Adempas

Pharmacotherapeutic group: Antihypertensives (antihypertensives for pulmonary arterial hypertension) ATC code: C02KX05 Mechanism of action Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO).​‍​​​​​‍​‍‍‍‍​‍‍ When NO binds to sGC, the enzyme catalyses synthesis of the signalling molecule cyclic guanosine monophosphate (cGMP). Intra-cellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis, and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitises sGC to endogenous NO by stabilising the NO-sGC binding. Riociguat also directly stimulates sGC independently of NO. Riociguat restores the NO-sGC-cGMP pathway and leads to increased generation of cGMP. Pharmacodynamic effects Riociguat restores the NO-sGC-cGMP pathway resulting in a significant improvement of pulmonary vascular haemodynamics and an increase in exercise ability. There is a direct relationship between riociguat plasma concentration and haemodynamic parameters such as systemic and pulmonary vascular resistance, systolic blood pressure and cardiac output. Clinical efficacy and safety Efficacy in adult patients with CTEPH A randomised, double-blind, multi-national, placebo controlled, phase III study (CHEST-1) was conducted in 261 adult patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) (72%) or persistent or recurrent CTEPH after pulmonary endarterectomy (PEA; 28%). During the first 8 weeks riociguat was titrated every 2-weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg 3 times daily) which was then maintained for a further 8 weeks. The primary endpoint of the study was the placebo adjusted change from baseline in 6-minute walk distance (6MWD) at the last visit (week 16). At the last visit, the increase in 6MWD in patients treated with riociguat was 46 m (95% confidence interval (CI): 25 m to 67 m; p<0.0001), compared to placebo. Results were consistent in the main sub-groups evaluated (ITT analysis, see table 2). Table 2: Effects of riociguat on 6MWD in CHEST-1 at last visit Entire patient population Riociguat (n=173) Placebo (n=88) Baseline (m) [SD] 342 [82] 356 [75] Mean change from baseline (m) [SD] 39 [79] -6 [84] Placebo-adjusted difference (m) 95% CI, [p-value] 46 25 to 67 [<0.0001] FC III patient population Riociguat (n=107) Placebo (n=60) Baseline (m) [SD] 326 [81] 345 [73] Mean change from baseline (m) [SD] 38 [75] -17 [95] Placebo-adjusted difference (m) 95% CI 56 29 to 83 FC II patient population Riociguat (n=55) Placebo (n=25) Baseline (m) [SD] 387 [59] 386 [64] Mean change from baseline (m) [SD] 45 [82] 20 [51] Placebo-adjusted difference (m) 95% CI 25 -10 to 61 Inoperable patient population Riociguat (n=121) Placebo (n=68) Baseline (m) [SD] 335 [83] 351 [75] Mean change from baseline (m) [SD] 44 [84] -8 [88] Placebo-adjusted difference (m) 95% CI 54 29 to 79 Patient population with CTEPH post-PEA Riociguat (n=52) Placebo (n=20) Baseline (m) [SD] 360 [78] 374 [72] Mean change from baseline (m) [SD] 27 [68] 1.8 [73] Placebo- adjusted difference (m) 95% CI 27 -10 to 63 Improvement in exercise capacity was accompanied by improvement in multiple clinically relevant secondary endpoints. These findings were in accordance with improvements in additional haemodynamic parameters. Table 3: Effects of riociguat in CHEST-1 on PVR, NT-proBNP and WHO functional class at last visit PVR Riociguat (n=151) Placebo (n=82) Baseline (dyn·s·cm -5 ) [SD] 790.7 [431.6] 779.3 [400.9] Mean change from baseline (dyn·s·cm -5 ) [SD] -225.7 [247.5] 23.1 [273.5] Placebo-adjusted difference (dyn·s·cm -5 ) 95% CI, [p-value] -246.4 –303.3 to –189.5 [<0.0001] NT-proBNP Riociguat (n=150) Placebo (n=73) Baseline (ng/L) [SD] 1508.3 [2337.8] 1705.8 [2567.2] Mean change from baseline (ng/L) [SD] -290.7 [1716.9] 76.4 [1446.6] Placebo-adjusted difference (ng/L) 95% CI, [p-value] -444.0 -843.0 to -45.0 [<0.0001] Change in WHO Functional Class Riociguat (n=173) Placebo (n=87) Improved 57 (32.9%) 13 (14.9%) Stable 107 (61.8%) 68 (78.2%) Deteriorated 9 (5.2%) 6 (6.9%) p-value 0.0026 PVR= pulmonary vascular resistance Adverse reactions leading to discontinuation occurred at a similar frequency in both treatment groups (riociguat individual dose titration (IDT) 1.0-2.5 mg, 2.9%; placebo, 2.3%). Long-term treatment of CTEPH An open-label extension study (CHEST-2) included 237 adult patients who had completed CHEST-1. At the end of the study, mean (SD) treatment duration in the total group was 1285 (709) days and median duration was 1174 days (ranging from15 to 3512 days). In total, 221 patients (93.2%) had a treatment duration of approximately 1 year (at least 48 weeks), 205 patients (86.5%) of approximately 2 years (at least 96 weeks) and 142 patients (59.9%) of approximately 3 years (at least 144 weeks). Treatment exposure was 834 person years in total. The safety profile in CHEST-2 was similar to that observed in pivotal trials. After treatment with riociguat, the mean 6MWD improved in the overall population by 53 m at 12 months (n=208), 48 m at 24 months (n=182), and 49 m at 36 months (n=117) compared to baseline. Improvements in 6MWD persisted until the end of the study. Table 4 shows the proportion of patients* with changes in WHO functional class during riociguat treatment compared to baseline. Table 4: CHEST-2: Changes in WHO Functional Class Changes in WHO Functional Class (n (%) of patients) Treatment duration in CHEST-2 Improved Stable Worsened 1 year (n=217) 100 (46%) 109 (50%) 6 (3%) 2 years (n=193) 76 (39%) 111 (58%) 5 (3%) 3 years (n=128) 48 (38%) 65 (51%) 14 (11%) *Patients participated in the study until the drug was approved and commercially available in their countries. The probability of survival was 97% after 1 year, 93% after 2 years and 89% after 3 years of riociguat treatment. Efficacy in adult patients with PAH A randomised, double-blind, multi-national, placebo controlled, phase III study (PATENT-1) was conducted in 443 adult patients with PAH (riociguat individual dose titration up to 2.5 mg 3 times daily: n=254, placebo: n=126, riociguat “capped” dose titration (CT) up to 1.5 mg (exploratory dose arm, no statistical testing performed; n=63)). Patients were either treatment-naïve (50%) or pre-treated with ERA (43%) or a prostacyclin analogue (inhaled (iloprost), oral (beraprost) or subcutaneous (treprostinil); 7%) and had been diagnosed with idiopathic or heritable PAH (63.4%), PAH associated with connective tissue disease (25.1%) and congenital heart disease (7.9%). During the first 8 weeks riociguat was titrated every 2-weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg 3 times daily), which was then maintained for a further 4 weeks. The primary endpoint of the study was placebo-adjusted change from baseline in 6MWD at the last visit (week 12). At the last visit the increase in 6MWD with riociguat individual dose titration (IDT) was 36 m (95% CI: 20 m to 52 m; p<0.0001) compared to placebo. Treatment-naïve patients (n=189) improved by 38 m, and pre-treated patients (n=191) by 36 m (ITT analysis, see table 5). Further exploratory subgroup analysis revealed a treatment effect of 26 m, (95% CI: 5 m to 46 m) in patients pre-treated with ERAs (n=167) and a treatment effect of 101 m (95% CI: 27 m to 176 m) in patients pre-treated with prostacyclin analogues (n=27). Table 5: Effects of riociguat on 6MWD in PATENT-1 at last visit Entire patient population Riociguat IDT (n=254) Placebo (n=126) Riociguat CT (n=63) Baseline (m) [SD] 361 [68] 368 [75] 363 [67] Mean change from baseline (m) [SD] 30 [66] -6 [86] 31 [79] Placebo-adjusted difference (m) 95% CI, [p-value] 36 20 to 52 [<0.0001] FC III patients Riociguat IDT (n=140) Placebo (n=58) Riociguat CT (n=39) Baseline (m) [SD] 338 [70] 347 [78] 351 [68] Mean change from baseline (m) [SD] 31 [64] -27 [98] 29 [94] Placebo-adjusted difference (m) 95% CI 58 35 to 81 FC II patients Riociguat IDT (n=108) Placebo (n=60) Riociguat CT (n=19) Baseline (m) [SD] 392 [51] 393 [61] 378 [64] Mean change from baseline (m) [SD] 29 [69] 19 [63] 43 [50] Placebo-adjusted difference (m) 95% CI 10 -11 to 31 Treatment-naïve patient population Riociguat IDT (n=123) Placebo (n=66) Riociguat CT (n=32) Baseline (m) [SD] 370 [66] 360 [80] 347 [72] Mean change from baseline (m) [SD] 32 [74] -6 [88] 49 [47] Placebo-adjusted difference (m) 95% CI 38 14 to 62 Pre-treated patient population Riociguat IDT (n=131) Placebo (n=60) Riociguat CT (n=31) Baseline (m) [SD] 353 [69] 376 [68] 380 [57] Mean change from baseline (m) [SD] 27 [58] -5 [83] 12 [100] Placebo- adjusted difference (m) 95% CI 36 15 to 56 Improvement in exercise capacity was accompanied by consistent improvement in multiple clinically relevant secondary endpoints. These findings were in accordance with improvements in additional haemodynamic parameters (see table 6). Table 6: Effects of riociguat in PATENT-1 on PVR and NT-proBNP at last visit PVR Riociguat IDT (n=232) Placebo (n=107) Riociguat CT (n=58) Baseline (dyn·s·cm -5 ) [SD] 791 [452.6] 834.1 [476.7] 847.8 [548.2] Mean change from PVR baseline (dyn·s·cm -5 ) [SD] -223 [260.1] -8.9 [316.6] -167.8 [320.2] Placebo-adjusted difference (dyn·s·cm -5 ) 95% CI, [p-value] -225.7 -281.4 to -170.1[<0.0001] NT-proBNP Riociguat IDT (n = 228) Placebo (n = 106) Riociguat CT (n=54) Baseline (ng/L) [SD] 1,026.7 [1,799.2] 1,228.1 [1,774.9] 1,189.7 [1,404.7] Mean change from baseline (ng/L) [SD] -197.9 [1721.3] 232.4 [1011.1] -471.5 [913.0] Placebo-adjusted difference (ng/L) 95% CI, [p-value] -431.8 -781.5 to -82.1 [<0.0001] Change in WHO Functional Class Riociguat IDT (n = 254) Placebo (n = 125) Riociguat CT (n=63) Improved 53 (20.9%) 18 (14.4%) 15 (23.8%) Stable 192 (75.6%) 89 (71.2%) 43 (68.3%) Deteriorated 9 (3.6%) 18 (14.4%) 5 (7.9%) p-value 0.0033 Riociguat-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0046; Stratified log-rank test) (see table 7). Table 7: Effects of riociguat in PATENT-1 on events of clinical worsening Clinical Worsening Events Riociguat IDT (n=254) Placebo (n=126) Riociguat CT (n=63) Patients with any clinical worsening 3 (1.2%) 8 (6.3%) 2 (3.2%) Death 2 (0.8%) 3 (2.4%) 1 (1.6%) Hospitalisations due to PH 1 (0.4%) 4 (3.2%) 0 Decrease in 6MWD due to PH 1 (0.4%) 2 (1.6%) 1 (1.6%) Persistent worsening of Functional Class due to PH 0 1 (0.8%) 0 Start of new PH treatment 1 (0.4%) 5 (4.0%) 1 (1.6%) Patients treated with riociguat showed significant improvement in Borg CR 10 dyspnoea score (mean change from baseline (SD): riociguat -0.4 (2), placebo 0.1 (2); p = 0.0022). Adverse reactions leading to discontinuation occurred less frequently in both riociguat treatment groups than in the placebo group (riociguat IDT 1.0-2.5 mg, 3.1%; riociguat CT 1.6%; placebo, 7.1%). Long-term treatment of PAH An open label extension study (PATENT-2) included 396 adult patients who had completed PATENT-1. In PATENT-2, mean (SD) treatment duration in the total group (not including exposure in PATENT-1) was 1375 (772) days and median duration was 1331 days (ranging from 1 to 3565 days). In total, treatment exposure was approximately 1 year (at least 48 weeks) for 90%, 2 years (at least 96 weeks) for 85%, and 3 years (at least 144 weeks) for 70% of patients. Treatment exposure was 1491 person years in total. The safety profile in PATENT-2 was similar to that observed in pivotal trials. After treatment with riociguat, the mean 6MWD improved in the overall population by 50 m at 12 months (n=347), 46 m at 24 months (n=311) and 46 m at 36 months (n=238) compared to baseline. Improvements in 6MWD persisted until the end of the study. Table 8 shows the proportion of patients* with changes in WHO functional class during riociguat treatment compared to baseline. Table 8: PATENT-2: Changes in WHO Functional Class Changes in WHO Functional Class (n(%) of patients) Treatment duration in PATENT-2 Improved Stable Worsened 1 year (n=358) 116 (32%) 222 (62%) 20 (6%) 2 years (n=321) 106 (33%) 189 (59%) 26 (8%) 3 years (n=257) 88 (34%) 147 (57%) 22 (9%) *Patients participated in the study until the study drug was approved and commercially available in their countries. The probability of survival was 97% after 1 year, 93% after 2 years and 88% after 3 years of riociguat treatment. Efficacy in paediatric patients with PAH PATENT-CHILD The safety and tolerability of riociguat 3 times daily for 24 weeks was evaluated in an open-label uncontrolled study in 24 paediatric patients with PAH aged 6 to less than 18 years (median 9.5 years). Only patients who were receiving stable doses of ERA (n=15, 62.5%) or ERA + prostacyclin analogue (PCA) (n=9, 37.5%) were enrolled, and they continued their PAH treatment during the study. The main exploratory efficacy endpoint of the study was exercise capacity (6MWD). The aetiologies of PAH were idiopathic (n=18, 75.0%), persistent congenital PAH despite shunt closure (n=4, 16.7%), heritable (n=1, 4.2%), and pulmonary hypertension associated with developmental abnormalities (n=1, 4.2%). Two distinct age groups were included (≥ 6 to < 12 years [n=6] and ≥ 12 to < 18 years [n=18]). At baseline, the majority of patients were WHO functional class II (n=18, 75%) one patient (4.2%) was WHO functional class I and five patients (20.8%) were WHO functional class III. The mean 6MWD at baseline was 442.12 m. The 24-week treatment period was completed by 21 patients while 3 patients withdrew from the study due to adverse reactions. For patients with assessments at baseline and at week 24: • mean change in 6MWD from baseline +23.01 m (SD 68.8) (n=19) • WHO functional class remained stable compared to baseline (n=21). • median change in NT-proBNP was -12.05 pg/mL (n=14) Two patients were hospitalised for right heart failure Long-term data were generated from 21 patients who completed the first 24 weeks of treatment in PATENT-CHILD. All patients continued to receive riociguat in combination with either ERA or ERA + PCAs. The mean overall duration of exposure to riociguat treatment was 109.79 ± 80.38 weeks (up to 311.9 weeks), with 37.5% (n=9) of patients treated for at least 104 weeks and 8.3% (n=2) for at least 208 weeks. During the long-term extension (LTE) phase improvements or stabilization in 6MWD were maintained for patients on treatment with observed mean changes from baseline (before start of treatment [PATENT-CHILD]) of +5.86 m at month 6, -3.43 m at month 12; +28.98 m at month 18 and -11.80 m at month 24. A majority of patients remained stable regarding WHO functional class II between baseline and month 24. Clinical worsening was observed in 8 (33.3%) patients in total including the main phase. Hospitalisation for right heart failure was reported in 5 (20.8%) patients. No deaths occurred during the observation period. Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) A randomised, double blind, placebo-controlled phase II study (RISE-IIP) to evaluate the efficacy and safety of riociguat in adult patients with symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) was terminated early due to an increased risk of mortality and serious adverse reactions in patients treated with riociguat and a lack of efficacy. More patients taking riociguat died (11% vs. 4%) and had serious adverse reactions (37% vs. 23%) during the main phase. In the long-term extension, more patients who switched from the placebo group to riociguat (21%) died than those who continued in the riociguat group (3%). Riociguat is therefore contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (see section 4.3).