Simeprevir (1) – Olysio®

• Clinical trials
  • PILLAR was a randomised, double-blind, controlled trial (Phase IIb). The study included treatment-naïve patients (without cirrhosis = no patients with a Metavir score of F4) with HCC genotype 1.
  • QUEST-1 was a randomised, double-blind, placebo-controlled, two-arm trial (Phase III). The study included treatment-naïve patients (with [12 %] / without [88 %] cirrhosis) with HCV genotype 1.
  • QUEST-2 was a randomised, double-blind, placebo-controlled, two-arm study (Phase III). The study included treatment-naive patients (with [approx. 8%] / without [approx. 92%] cirrhosis) with HCV genotype 1.
  • PROMISE was a randomised, double-blind, placebo-controlled, two-arm Phase III trial involving patients with HCV genotype 1 infection who had relapsed following prior interferon-based therapy.
  • ATTAIN is a double-blind RCT in which adults with chronic hepatitis C virus infection of genotype 1 were treated. The patients were non-responders, i.e. they had been pre-treated at least once with peginterferon alfa-2a or 2b in combination with ribavirin for ≥ 12 weeks (null responders) or ≥ 20 weeks (partial responders).
  • RESTORE (N=107) is an ongoing, open-label, single-arm Phase IIIstudy involving patients with HCV genotype 4 infection who are treatment-naïve or in whom previous therapy with peginterferon alfa and ribavirin has failed (including previous relapsers, partial responders or non-responders).
  • Study C212 (N=106) is an open-label, single-arm Phase III study involving patients with HIV-1 and HCV genotype 1 co-infection who are treatment-naïve (N=53) or in whom previous treatment with peginterferon alfa and ribavirin had failed (relapsers (N=15), partial responders (N=10) and non-responders (N=28)).
  • COSMOS is an open-label, randomised Phase IIa trial that enrolled adult patients with confirmed chronic HCV genotype 1 infection, who were included either as non-responders without advanced liver fibrosis in Cohort 1 (N=80) or as treatment-naïve patients or non-responders, each with advanced liver fibrosis, in Cohort 2 (N=87).

a) Treatment-naïve patients (with and without cirrhosis), genotype 1: simeprevir in combination with peginterferon alfa + ribavirin versus peginterferon alfa + ribavirin

• A review of the results from the PILLAR, QUEST-1 and QUEST-2 studies identifies a considerable additional benefit, particularly due to the statistically significant improvement in SVR.
• The G-BA classifies the extent of the additional benefit of simeprevir as considerable, 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.
• With regard to the certainty of the findings, an indication of additional benefit is therefore established.
• mortality
  • In the QUEST-1 study, two deaths occurred in the simeprevir arm. An additional benefit with regard to mortality is not proven.
• Morbidity – sustained virological response (SVR)
  • All three included studies show statistically significant results for SVR 24 in favour of simeprevir + PEG + RBV, with absolute risk reductions of between 15.6% and 30.5%.
  • The results of the sensitivity analysis for SVR 24 also show a statistically significant advantage for simeprevir.
  • For the SVR 24 endpoint, there is an indication of effect modification by the Q80K polymorphism and proof of effect modification by the IL28B genotype.
  • In patients without the Q80K polymorphism and in patients with an IL28B genotype (CT/TT), there is a statistically significant advantage in favour of simeprevir + PEG + RBV compared with the appropriate comparator therapy.
  • In patients with an IL28B genotype CC and in patients with the Q80K polymorphism, there are no statistically significant results regarding the achievement of SVR.
• Morbidity – depression assessed using the Centre for Epidemiologic Studies Depression Scale (CES-D)
  • The meta-analytic synthesis of the results from QUEST-1 and QUEST-2 shows a statistically significant advantage in favour of simeprevir + PEG + RBV. The 95% CI of Hedges’ g does not lie entirely below the irrelevance threshold of –0.2.
• Morbidity – Fatigue assessed using the Fatigue Severity Scale (FSS)
  • The meta-analysis of all three studies on the endpoint of fatigue shows a statistically significant advantage in favour of simeprevir + PEG + RBV. The 95% CI of Hedges’ g does not lie entirely below the irrelevance threshold of –0.2.
  • For this endpoint, there are indications of effect modification by the characteristics of fibrosis status (Metavir score) and Q80K polymorphism.
  • There are statistically significant results in favour of simeprevir for the patient populations ‘patients with a Metavir score of F0–F2’ and ‘patients without the Q80K polymorphism’. The respective 95% CI for Hedges’ g lies entirely below the irrelevance threshold of –0.2.
• Morbidity – Health status as measured by the European Quality of Life 5-Dimensions Visual Analogue Scale (EQ-5D VAS)
  • The meta-analytic synthesis of the results from QUEST-1 and QUEST-2 shows a statistically significant advantage in favour of simeprevir + PEG + RBV. The 95% CI of Hedges’ g does not lie entirely above the irrelevance threshold of 0.2.
  • For this endpoint, there is proof of effect modification by the Q80K polymorphism. There is a statistically significant result in favour of simeprevir for the patient population ‘patients without the Q80K polymorphism’. The 95% CI of Hedges’ g lies entirely above the irrelevance threshold of 0.2.
• Side effects – severe adverse events (SAEs)
  • For the endpoints SAE (severe adverse events) and discontinuation due to AE (adverse events), there is no statistically significant difference between the treatment arms.
  • For the SUE endpoint, there is an indication of effect modification by the characteristic ‘fibrosis status’ (Metavir score). In patients with a Metavir score of F3 to F4, statistically significantly fewer SAE occur under simeprevir treatment.
• Side effects – pruritus and rash
  • For the endpoints of pruritus and rash, there is neither an advantage nor a disadvantage of simeprevir compared with the appropriate comparator therapy.
• Overall assessment
  • For treatment-naive patients (with and without cirrhosis) with chronic hepatitis C virus infection (genotype 1), an overall review of the results on mortality, morbidity and side effects provides an indication that simeprevir in combination with peginterferon alfa and ribavirin offers a considerable additional benefit compared with the appropriate comparator therapy [peginterferon alfa + ribavirin].
  • The G-BA classifies the extent of the additional benefit of simeprevir as considerable, based on 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. Compared with the appropriate comparator therapy, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a considerable improvement in therapy-relevant benefit, resulting in particular from a statistically significant improvement in sustained virological response (SVR).
  • Taking the results of the PILLAR, QUEST-1 and QUEST-2 studies together, a considerable additional benefit is identified, particularly due to the statistically significant improvement in SVR. The statistically significant result regarding the prevention of serious adverse events in the patient population with a Metavir score of F3–F4, as well as the positive impact on fatigue and health status in the patient population of patients without the Q80K polymorphism, and the positive impact on fatigue in the patient population of patients with a Metavir score of F0–F2, are also taken into account in this decision.

b) Treatment-experienced patients (relapse), genotype 1: simeprevir in combination with peginterferon alfa + ribavirin versus peginterferon alfa + ribavirin

• An overall assessment of the results regarding mortality, morbidity and side effects provides an indication that simeprevir in combination with peginterferon alfa and ribavirin offers a considerable additional benefit compared with the appropriate comparator therapy [peginterferon alfa + ribavirin].
• The G-BA classifies the extent of the additional benefit of simeprevir as considerable, based on 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.
• With regard to the certainty of the findings, the overall assessment provides an indication of additional benefit.
• mortality
  • In the PROMISE study, one death occurred in the simeprevir arm and one in the control arm. There is no statistically significant difference. An additional benefit with regard to mortality is not proven.
• Morbidity – sustained virological response (SVR)
  • The PROMISE study shows a statistically significant result in favour of simeprevir + PEG + RBV for SVR 24, with an absolute risk reduction of 43.5%.
  • The results of the sensitivity analysis for SVR 24 also show a statistically significant advantage for simeprevir.
  • The SVR rate at week 72 (SVR W72) shows a statistically significant result.
• Morbidity – Depression as measured by the Centre for Epidemiologic Studies Depression Scale (CES-D)
  • For the endpoint of depression, the PROMISE trial shows a statistically significant advantage in favour of simeprevir + PEG + RBV. The 95% confidence interval for Hedges’ g does not lie entirely below the non-significance threshold of –0.2.
• Morbidity – Fatigue as measured by the Fatigue Severity Scale (FSS)
  • For the endpoint of fatigue, the PROMISE study shows a statistically significant advantage in favour of simeprevir + PEG + RBV. The 95% CI of Hedges’ g lies entirely below the irrelevance threshold of –0.2.
• Morbidity – Health status as measured by the European Quality of Life-5-Dimensions Visual Analogue Scale (EQ-5D VAS)
  • For the health status endpoint, the PROMISE study shows a statistically significant advantage in favour of simeprevir + PEG + RBV. The 95% CI of Hedges’ g lies entirely above the irrelevance threshold of 0.2.
  • For this endpoint, there is proof of effect modification by both the Q80K polymorphism and genotype 1a/1b. There is a statistically significant result in favour of simeprevir for both the patient populations ‘patients without the Q80K polymorphism’ and ‘patients with genotype 1b’. The 95% CI of Hedges’ g lies entirely above the irrelevance threshold of 0.2 in each case.
• Side effects – severe adverse events (SAEs) and discontinuation due to adverse events (AEs)
  • There are no statistically significant differences between the treatment arms for the endpoints SAE (severe adverse events) and discontinuation due to AEs (adverse events).
• Side effects – eye diseases
  • For the endpoint of eye diseases, there is a statistically significant difference in favour of simeprevir + PEG + RBV.
• Side effects – influenza-like illness and dyspnoea
  • For the endpoints of flu-like illness and dyspnoea, there are statistically significant differences in favour of the comparator treatment, placebo + PEG + RBV. However, the extent of these effects is no longer considered to be more than minor.
• Overall assessment
  • For treatment-experienced patients (relapse) with chronic hepatitis C virus infection (genotype 1), an overall analysis of the results on mortality, morbidity and side effects indicates an indication for a considerable additional benefit of simeprevir, in combination with peginterferon alfa and ribavirin, compared with the appropriate comparator therapy [peginterferon alfa + ribavirin].
  • The G-BA classifies the extent of the additional benefit of simeprevir as considerable, 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. Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a considerable improvement in treatment-related benefit, which is demonstrated in particular by a statistically significant improvement in sustained virological response (SVR), a statistically significant and clinically relevant positive effect on fatigue and health status, and the significant reduction in side effects.

c) Treatment-experienced patients (previous non-responders), genotype 1: simeprevir in combination with peginterferon alfa + ribavirin versus peginterferon alfa + ribavirin + protease inhibitor (boceprevir or telaprevir)

• For treatment-experienced patients (non-responders) with chronic hepatitis C virus infection (genotype 1), an overall analysis of the results regarding mortality, morbidity and side effects indicates an indication for considerable additional benefit with simeprevir in combination with peginterferon alfa and ribavirin compared with the appropriate comparator therapy [telaprevir + peginterferon alfa + ribavirin].
• The G-BA classifies the extent of the additional benefit of simeprevir as considerable, 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 treating the disease.
• With regard to the certainty of the findings, an indication of additional benefit is established.
• mortality
  • In the ATTAIN study, three deaths occurred in the control arm (telaprevir + PEG + RBV). There is no statistically significant difference. An additional benefit with regard to mortality is not proven.
• Morbidity – sustained virological response (SVR)
  • The ATTAIN study shows no statistically significant result for SVR 12. There is no additional benefit with regard to achieving SVR.
• Morbidity – depression as measured by the Centre for Epidemiologic Studies Depression Scale (CES-D)
  • For the endpoint of depression, the ATTAIN study shows no statistically significant difference.
• Morbidity – fatigue as measured by the Fatigue Severity Scale (FSS)
  • For the endpoint of fatigue, the ATTAIN study shows no statistically significant difference between the treatment arms.
• Morbidity – Health status as measured by the European Quality of Life-5-Dimensions Visual Analogue Scale (EQ-5D VAS)
  • For the health status endpoint, the ATTAIN study showed a statistically significant advantage in favour of simeprevir + PEG + RBV. The 95% confidence interval for Hedges’ g does not lie entirely above the irrelevance threshold of 0.2.
• Side effects – severe adverse events (SAEs) and discontinuation due to adverse events (AEs)
  • For the endpoints SAE (severe adverse events) and discontinuation due to AE (adverse events), statistically significant differences were observed between the treatment arms in each case.
• Side effects – disorders of the skin and subcutaneous tissue, disorders of the gastrointestinal tract and serious anaemia
  • Statistically significant differences in favour of simeprevir + PEG + RBV were also observed for the endpoints ‘skin and subcutaneous tissue disorders’, ‘gastrointestinal disorders’ and ‘serious anaemia’.
• Overall assessment
  • For treatment-experienced patients (non-responders) with chronic hepatitis C virus infection (genotype 1), an overall analysis of the results regarding mortality, morbidity and side effects provides an indication of a considerable additional benefit of simeprevir in combination with peginterferon alfa and ribavirin compared with the appropriate comparator therapy [telaprevir + peginterferon alfa + ribavirin].
  • The G-BA classifies the extent of the additional benefit of simeprevir as considerable, 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. Compared with the appropriate comparator therapy, this constitutes, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a considerable improvement in treatment-related benefit, resulting in particular from the significant avoidance of serious side effects.

d) Treatment-naïve patients and treatment-experienced patients (relapse), genotype 4: simeprevir in combination with peginterferon alfa + ribavirin versus peginterferon alfa + ribavirin

• For the patient groups listed, there is a hint of a minor additional benefit compared with the appropriate comparator therapy.
• The G-BA assesses the extent of the additional benefit of simeprevir 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 as a whole.
• The certainty of the findings is classified as an indication, on the one hand, due to the presence of a single-arm study demonstrating an adequate response in terms of SVR and the comparative analysis of the adverse reaction profiles of the simeprevir regimen, and, on the other hand, due to the longer duration of treatment with an interferon-containing regimen used as the appropriate comparator therapy, on the other hand, is classified as a hint of certainty.
• Morbidity – sustained virological response (SVR)
  • The RESTORE study is an ongoing, open-label, single-arm Phase III trial. Among patients for whom SVR12 could be assessed, the overall SVR12 rate was 85% (52/61); the SVR12 rates were 88 per cent (28/32) in treatment-naïve patients, 91 per cent in previous relapsers (19/21), 33 per cent (1/3) in previous partial responders and 80 per cent (4/5) in previous non-responders.
  • Among treatment-naïve patients or those with a previous relapse who met the RGT criteria defined in the protocol and were treated for a total of 24 weeks, the SVR12 rates were 92% (47/51).
  • Given the magnitude of the SVR rates achieved, it is assumed – despite this being a single-arm study – that treatment with a simeprevir regimen is equivalent to dual therapy (ribavirin plus peginterferon) with regard to these endpoints.
• Side effects
  • Taking into account the adverse effects of treatment with peginterferon, which are both sufficiently proven in studies and described in the summary of product characteristics (SmPC), the significant reduction in treatment duration compared with the appropriate comparator therapy for treatment-naïve HCV patients and patients who have relapsed following previous therapy (relapse) is considered relevant in terms of avoiding side effects.

e) Treatment-experienced patients (previous non-responders), genotype 4: Simeprevir in combination with peginterferon alfa + ribavirin versus peginterferon alfa + ribavirin

• For the patients listed, an additional benefit is not proven compared with the appropriate comparator therapy.
• There are insufficient data available to assess the additional benefit. These patients are treated for 48 weeks with a combination of simeprevir, ribavirin and peginterferon alfa. There is no reduction in the duration of treatment with an interferon-containing regimen compared with the appropriate comparator therapy. Therefore, the additional benefit for the patient groups listed is not proven.

f) Treatment-naïve patients (without cirrhosis) and treatment-experienced patients (relapse without cirrhosis) with HIV co-infection, genotype 1, 4: Simeprevir in combination with peginterferon alfa + ribavirin versus peginterferon alfa + ribavirin

• For the patient groups listed, there is a hint of a minor additional benefit compared with the appropriate comparator therapy.
• The G-BA assesses the extent of the additional benefit of simeprevir 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 as a whole.
• The certainty of the findings is classified as an indication due to the presence of a single-arm study for demonstrating an adequate response in terms of SVR and the comparative analysis of the adverse reaction profiles of the simeprevir regimen on the one hand, and the interferon-containing appropriate comparator therapy on the other, is classified as a hint.
• Morbidity – sustained virological response (SVR)
  • In the C212 study, 79% (42/53) of treatment-naïve patients; 87% of previous relapsers (13/15); 70% (7/10) of previous partial responders and 57% (16/28) of previous non-responders achieved an SVR 12.
  • For a total treatment duration of 24 weeks, 89% (54/61) of treatment-naïve patients or previous relapsers without cirrhosis treated with simeprevir qualified by meeting the RGT criteria defined in the protocol (HCV-RNA < 25 IU/ml detectable or undetectable at week 4 and no detectable HCV-RNA at week 12). In these patients, the SVR12 rate was 87 per cent.
  • Given the magnitude of the SVR rates achieved, it is assumed – despite this being a single-arm study – that treatment with a simeprevir regimen is equivalent to dual therapy (ribavirin plus peginterferon) with regard to these endpoints.
• Side effects
  • Taking into account the proof of the adverse effects of treatment with peginterferon, which has been provided in studies and described in the summary of product characteristics (SmPC), the significant reduction in treatment duration compared with the appropriate comparator therapy is considered relevant in terms of avoiding side effects for HIV-co-infected treatment-naïve HCV patients and patients who have relapsed following previous therapy (relapse) without cirrhosis.

g) Treatment-naive patients (with cirrhosis) and treatment-experienced patients (previous non-responders with or without cirrhosis; relapse with cirrhosis) with HIV co-infection, genotypes 1 and 4: simeprevir in combination with peginterferon alfa + ribavirin versus peginterferon alfa + ribavirin

• For the patients listed, an additional benefit is not proven compared with the appropriate comparator therapy.
• There are insufficient data available to assess the additional benefit. These patients are treated for 48 weeks with a combination of simeprevir plus ribavirin plus peginterferon alfa. There is no reduction in the duration of treatment with an interferon-containing regimen compared with the appropriate comparator therapy. Therefore, the additional benefit for the patient groups listed is not proven.

Courtesy translation only, please refer to the German original.