Riociguat (1) – Adempas®

• Clinical trials
  • The assessment of the extent of the additional benefit of riociguat in the therapeutic indication CTEPH is based on the CHEST-1 study. This study is a randomised, placebo-controlled, multicentre, double-blind Phase III trial with a two-arm design, in which the efficacy and safety of treating CTEPH with riociguat at a dose of 1.0 to 2.5 mg three times daily were investigated in comparison with placebo over a 16-week treatment period – including an 8-week titration phase.
  • The assessment of the extent of the additional benefit of riociguat in the therapeutic indication of PAH is based on the PATENT-1 study. This study is a randomised, placebo-controlled, multicentre, double-blind Phase III trial with a three-arm design.

a) Adult patients with CTEPH

• The G-BA classifies the extent of the additional benefit of riociguat as ‘minor’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a reduction in non-serious symptoms of the disease (the ‘morbidity’ endpoint) is achieved.
• mortality
  • Deaths were recorded from the first administration of the study medication until the end of treatment with the study medication after 16 weeks plus 2 days as part of the safety analysis.
  • There were 2 deaths (1.2%) in the riociguat arm, compared with 3 (3.4%) in the control arm. The results were not statistically significant.
• Morbidity – Change in the six-minute walk distance (6MWD)
  • The primary endpoint was the absolute change in the six-minute walk distance (6MWD). The 6MWD is a measure of physical fitness and was determined using the six-minute walk test. A clinically relevant change in the six-minute walk distance is of clinical significance to patients.
  • The adjusted treatment difference between the riociguat and placebo arms was approximately 46 m (a deterioration of 5.5 m in the placebo arm versus an improvement of 38.9 m in the riociguat arm) and was statistically significant in favour of riociguat (LS mean difference: 45.69; 95% CI: [24.74; 66.63]; p < 0.0001).
  • There were statistically significantly more responders in the riociguat arm (52.6 per cent) than in the placebo arm (23.9 per cent) (OR: 3.541; 95 per cent CI: [1.994; 6.285]; p < 0.0001). The absolute extent of this improvement in exercise capacity is considered to be minor.
• Morbidity – Change in WHO/NYHA class
  • The WHO/NYHA classification encompasses the symptoms of dyspnoea, fatigue, chest pain and syncope, and thus provides information on morbidity.
  • Analysis of the change in functional classes shows a higher proportion of patients in the riociguat arm with an improvement of at least one WHO functional class than in the placebo arm (32.9% vs. 14.9%). The treatment difference was statistically significant (p = 0.0026) in favour of riociguat.
  • There is no validation of the endpoint as a surrogate for a patient-relevant endpoint. There are differing views within the G-BA regarding the patient relevance of this endpoint. However, this does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Clinical deterioration
  • The composite endpoint ‘clinical deterioration’ comprises, for CTEPH and PAH, death, a heart or lung transplant, hospital admission due to persistent worsening of pulmonary hypertension (PH), the initiation of PH-specific therapy, a persistent reduction in 6MWD or a persistent deterioration in WHO functional class. For the CTEPH therapeutic indication, the event of a pulmonary endarterectomy (PEA) due to persistent worsening of PH is added; for the PAH indication, an atrioseptostomy is added.
  • No validation studies are available for this combined endpoint. The rationale for the selection of the endpoint components cannot be deduced. The clinical relevance of the combined endpoint cannot be clearly determined due to its composition of different endpoint categories with varying degrees of severity.
  • Taken together, the results for the ‘clinical deterioration’ endpoint do not allow a conclusion to be drawn regarding the extent of the additional benefit.
• Morbidity – Change in dyspnoea and perceived fatigue on the Borg scale
  • Borg scale scores were recorded after all 6MWD tests. The Borg CR10 scale or the modified Borg dyspnoea scale was used for this purpose.
  • The adjusted treatment difference was statistically significant in favour of riociguat (LS mean difference: –1.07; 95% CI: [–1.60; –0.52]; p = 0.0035). At the end of the intervention, the score on the Borg dyspnoea scale for patients in the placebo arm was almost identical to the baseline value (a deterioration of 0.17 points), whilst patients in the riociguat arm had improved by 0.83 points.
  • In the riociguat arm, the proportion of responders (50.3%) was significantly higher than in the placebo arm (37.5%) (OR: 1.686; 95% CI: [0.998; 2.849]; p = 0.0491). The change in dyspnoea and perceived fatigue on the Borg scale is considered minor in absolute terms.
• With regard to the endpoints in the morbidity category, there is overall a minor additional benefit
  • With regard to the endpoints in the morbidity category, there is overall a minor additional benefit in terms of the change in 6-MWD and the change in dyspnoea and perceived fatigue on the Borg scale.
• quality of life
  • The patient-relevant endpoint of quality of life was assessed using the generic EQ-5D questionnaire and a disease-specific instrument, the Living with Pulmonary Hypertension (LPH) questionnaire.
  • Quality of life, as measured by the EQ-5D, improved statistically significantly in the riociguat arm compared with the placebo arm (LS mean difference: 0.13; 95% CI: [0.06; 0.21]; p < 0.0001). A post-hoc responder analysis also showed a significant treatment benefit for riociguat: 42.4% responders in the riociguat arm versus 18.4% responders in the control arm (OR: 3.272; 95% CI: [1.758; 6.089]; p < 0.0001).
  • Quality of life, as measured by the LPH questionnaire, showed no statistically significant difference between placebo and riociguat.
• Side effects
  • In the CHEST-1 trial, adverse events (AEs) were recorded only up to 2 days after the end of treatment with the study medication. However, no data analysis was carried out 28 days after the end of treatment.
  • The proportion of patients experiencing at least one AE was 91.9% in the riociguat arm and 86.4% in the placebo arm. Serious AEs occurred in 19.7% of patients in the riociguat arm compared with 15.9% in the placebo arm. In the riociguat arm, 5 out of 173 patients (2.9%) discontinued treatment due to AEs; in the placebo arm, 2 patients (2.3%) did so. No statistically significant difference was observed.
  • Overall, based on the available results, no conclusion regarding additional benefit can be drawn with regard to side effects.

b) Adult patients with PAH

• For adult patients in WHO functional classes II to III with pulmonary arterial hypertension (PAH), riociguat offers a minor additional benefit in improving physical performance.
• The G-BA classifies the extent of the additional benefit of riociguat as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a reduction in non-serious symptoms of the disease (the ‘morbidity’ endpoint) is achieved.
• For the operationalisation of the following endpoints, see the explanations in the therapeutic indication CTEPH.
• mortality
  • Deaths were recorded as part of the safety analysis from the first administration of the study medication until the end of treatment with the study medication after 12 weeks plus 2 days.
  • There were 2 deaths (0.8%) in the riociguat arm, versus 3 (2.4%) in the control arm. The results were not statistically significant.
• Morbidity – Change in 6MWD
  • The adjusted treatment difference between the riociguat and placebo arms was just under 36 m (a deterioration of 5.6 m in the placebo arm versus an improvement of 29.6 m in the riociguat arm) and was statistically significant in favour of riociguat (LS mean difference: 35.78; 95% CI: [20.06; 51.51]; p < 0.0001).
  • There were statistically significantly more responders in the riociguat arm (42.9%) than in the placebo arm (23.0%) (OR: 2.541; 95% CI: [1.550; 4.078]; p < 0.0001). The absolute extent of improvement in exercise capacity is considered to be minor.
• Morbidity – Change in WHO/NYHA class
  • Analysis of the change in functional classes shows a higher proportion of patients in the riociguat arm with an improvement of at least one WHO functional class than in the placebo arm (20.9% vs. 14.4%). The treatment difference was statistically significant (p = 0.0033) in favour of riociguat.
  • There is no validation of the endpoint as a surrogate for a patient-relevant endpoint. There are differing views within the G-BA regarding the patient relevance of this endpoint. However, this does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Clinical deterioration
  • The treatment effect for the endpoint ‘time to clinical deterioration’ was statistically significant in favour of riociguat (p = 0.0046). The incidence of cases of clinical deterioration by the end of the 12-week treatment period was also statistically significant in favour of riociguat (p = 0.0285), with few cases in both treatment arms (8 (6.3%) in the placebo arm and 3 (1.2%) in the riociguat arm).
  • No validation studies are available for this composite endpoint. The rationale for the selection of the endpoint components cannot be deduced. The clinical relevance of the composite endpoint cannot be clearly determined due to its composition of different endpoint categories with varying degrees of severity.
  • Taken together, the results for the ‘clinical deterioration’ endpoint do not allow a conclusion to be drawn regarding the extent of the additional benefit.
• Morbidity – Change in dyspnoea and perceived fatigue on the Borg scale
  • The adjusted treatment difference was statistically significant in favour of riociguat (LS mean difference: -0.53; 95% CI: [-0.89; -0.17]; p = 0.0022). At the end of the intervention, the score on the Borg dyspnoea scale for patients in the placebo arm was almost identical to the baseline value (a worsening of 0.09 points), whereas patients in the riociguat arm had improved by 0.44 points.
  • There were statistically significantly more responders in the riociguat arm (43.7%) than in the placebo arm (27.8%) (OR: 2.018; 95% CI: [1.271; 3.202]; p = 0.0023). The change in dyspnoea and perceived fatigue on the Borg scale is considered minor in absolute terms.
• With regard to the endpoints in the morbidity category, there is overall a minor additional benefit
  • With regard to the endpoints in the morbidity category, there is overall a minor additional benefit in terms of the change in 6MWD and the change in dyspnoea and perceived fatigue on the Borg scale.
• quality of life
  • Quality of life, as measured by the EQ-5D, showed no statistically significant difference between placebo and riociguat.
  • Quality of life, as measured by the LPH questionnaire, improved statistically significantly by week 12 by an average of 5.99 points in the riociguat arm, compared with a deterioration of 0.36 points in the placebo arm (LS mean difference: -6.17; 95% CI: [-9.79; -2.54], p = 0.0019).
  • Post-hoc responder analyses of patients who showed an improvement of at least 7 points in the total score and at least 3 points in the physical domain, or at least 7 points in the total score and at least 3 points in the emotional domain, showed a statistically significant advantage in favour of riociguat (OR: 1.95; 95% CI: [1.194; 3.212]; p = 0.0063] for the physical domain; for the emotional domain, OR: 1.701; 95% CI: [1.015; 2.852]; p = 0.0392).
• Side effects
  • In the PATENT-1 trial, adverse events (AEs) were recorded only up to 2 days after the end of treatment with the study medication. However, no data analysis was carried out 28 days after the end of treatment.
  • The proportion of patients experiencing at least one AE was 89.4% in the riociguat arm and 85.7% in the placebo arm. Serious AEs occurred in 11.4% of patients in the riociguat arm compared with 18.3% in the placebo arm. In the riociguat arm, 8 out of 254 patients (3.1%) discontinued treatment due to AEs; in the placebo arm, 7 out of 126 patients (5.6%) did so. No statistically significant difference was observed.
  • Overall, based on the available results, no conclusion regarding additional benefit can be drawn with regard to side effects.

Courtesy translation only, please refer to the German original.