Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bayer AG, 51368, Leverkusen, Germany
Pharmacotherapeutic group: Antihypertensives (antihypertensives for pulmonary arterial hypertension)
ATC code: C02KX05
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.
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.
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 Events 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%).
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 to 2 years and 89% after 3 years of riociguat treatment.
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 Events 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.
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 events.
For patients with assessments at baseline and at week 24:
Two patients were hospitalized 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%) subjects in total including the main phase. Hospitalization for right heart failure was reported in 5 (20.8%) subjects. No deaths occurred during the observation period.
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 events in patients treated with riociguat and a lack of efficacy. More patients taking riociguat died (11% vs. 4%) and had serious adverse events (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).
The absolute bioavailability of riociguat is high (94%). Riociguat is rapidly absorbed with maximum concentrations (Cmax) appearing 1-1.5 hours after tablet intake. Intake with food reduced riociguat AUC slightly, Cmax was reduced by 35%.
Bioavailability (AUC and Cmax) is comparable for riociguat administered orally as a crushed tablet suspended in apple sauce or in water compared to a whole tablet (see section 4.2).
Children received riociguat tablet with or without food intake. Population PK modeling has shown that riociguat is readily absorbed in children as in adults, after oral administration.
Plasma protein binding in adults is high at approximately 95%, with serum albumin and alpha 1-acidic glycoprotein being the main binding components. The volume of distribution is moderate with volume of distribution at steady state being approximately 30 L.
No data on riociguat plasma protein binding specific to children is available. Vss estimated via population PK modeling in children (age range 6 to <18 years) following oral administration of riociguat is 26 L on average.
N-demethylation, catalysed by CYP1A1, CYP3A4, CYP3A5 and CYP2J2 is the major biotransformation pathway of riociguat leading to its major circulating active metabolite M-1 (pharmacological activity: 1/10th to 1/3rd of riociguat) which is further metabolised to the pharmacologically inactive N-glucuronide.
CYP1A1 catalyses the formation of riociguat’s main metabolite in liver and lungs and is known to be inducible by polycyclic aromatic hydrocarbons, which, for example, are present in cigarette smoke.
No metabolism data specific to children is available.
Total riociguat (parent compound and metabolites) is excreted via both renal (33-45%) and biliary/faecal routes (48-59%). Approximately 4-19% of the administered dose was excreted as unchanged riociguat via the kidneys. Approximately 9-44% of the administered dose was found as unchanged riociguat in faeces.
Based on in vitro data riociguat and its main metabolite are substrates of the transporter proteins P-gp (P-glycoprotein) and BCRP (breast cancer resistance protein). With a systemic clearance of about 3-6 L/h, riociguat can be classified as a low-clearance drug. Elimination half-life is about 7 hours in healthy subjects and about 12 hours in patients.
No mass balance study and metabolism data specific to children are available. Clearence estimated via population PK modeling in children (age range 06 to < 18 years) following oral administration of riociguat is on average of 2.48 L/h. The geometric mean values for half-lives (t1/2) estimated via population PK modeling was 8.24 h.
Riociguat pharmacokinetics are linear from 0.5 to 2.5 mg. Inter-individual variability (CV) of riociguat exposure (AUC) across all doses is approximately 60%. The PK profile is similar in children as in adults.
Pharmacokinetic data reveal no relevant differences due to gender in the exposure to riociguat.
Elderly patients (65 years or older) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 40% higher in elderly, mainly due to reduced (apparent) total and renal clearance.
In adults pharmacokinetic data reveal no relevant inter-ethnic differences.
In adults pharmacokinetic data reveal no relevant differences due to weight in the exposure to riociguat.
In cirrhotic adult patients (non-smokers) with mild hepatic impairment (classified as Child Pugh A) riociguat mean AUC was increased by 35% compared to healthy controls, which is within normal intra-individual variability. In cirrhotic patients (non-smokers) with moderate hepatic impairment (classified as Child Pugh B), riociguat mean AUC was increased by 51% compared to healthy controls. There are no data in patients with severe hepatic impairment (classified as Child Pugh C). No clinical data is available in children with hepatic impairment.
Patients with ALT >3 x ULN and bilirubin >2 x ULN were not studied (see section 4.4).
Overall, mean dose- and weight-normalised exposure values for riociguat were higher in subjects with renal impairment compared to subjects with normal renal function. Corresponding values for the main metabolite were higher in subjects with renal impairment compared to healthy subjects. In non-smoking individuals with mild (creatinine clearance 80-50 mL/min), moderate (creatinine clearance <50-30 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment, riociguat plasma concentrations (AUC) were increased by 53%, 139% or 54%, respectively.
Data in patients with creatinine clearance <30 mL/min are limited and there are no data for patients on dialysis.
Due to the high plasma protein binding riociguat is not expected to be dialysable.
No clinical data is available in children with renal impairment.
Non-clinical data revealed no specific hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, phototoxicity, genotoxicity and carcinogenicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic activity of riociguat (haemodynamic and smooth muscle relaxing effects).
In growing, juvenile and adolescent rats, effects on bone formation were seen. In juvenile rats, the changes consisted of thickening of trabecular bone and of hyperostosis and remodeling of metaphyseal and diaphyseal bone, whereas in adolescent rats an overall increase of bone mass was observed at doses 10 times the unbound AUC in the pediatric population. The clinical relevance of this finding is not known. No such effects were observed in juvenile rats at doses ≤2 times the unbound AUC in the pediatric population, or in adult rats. No new target organs were identified.
In a fertility study in rats, decreased testes weights occurred at systemic exposure of about 7-fold of human exposure, whereas no effects on male and female fertility were seen. Moderate passage across the placental barrier was observed. Developmental toxicity studies in rats and rabbits have shown reproductive toxicity of riociguat. In rats, an increased rate of cardiac malformation was observed as well as a reduced gestation rate due to early resorption at maternal systemic exposure of about 8-fold of human exposure (2.5 mg 3 times daily). In rabbits, starting at systemic exposure of about 4-fold of human exposure (2.5 mg 3 times daily) abortion and foetal toxicity were seen.
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