Ledipasvir / Sofosbuvir (1) – Harvoni®

• Clinical trials
  • The ION-1 trial was a randomised, open-label Phase III trial designed to evaluate a 12- or 24-week course of treatment with ledipasvir/sofosbuvir, with or without ribavirin, in treatment-naïve patients with chronic hepatitis C genotype 1, including patients with cirrhosis (LDV/SOF 12 weeks: N=217 [n=180 patients without cirrhosis]; LDV/SOF 24 weeks: N=217; LDV/SOF + RBV 12 weeks: N=218; LDV/SOF + RBV 24 weeks: N=218).
  • The ION-3 study was a randomised, open-label Phase III study designed to evaluate an 8-week course of treatment with ledipasvir/sofosbuvir with or without ribavirin, as well as a 12-week course of treatment with ledipasvir/sofosbuvir in 647 treatment-naïve, non-cirrhotic patients with genotype 1 CHC (LDV/SOF 8 weeks: N=215; LDV/SOF 12 weeks: N=216; LDV/SOF + RBV 8 weeks: N=216).
  • The LONESTAR study was a randomised, open-label Phase II trial designed to evaluate an 8- or 12--week course of treatment with ledipasvir/sofosbuvir with or without ribavirin in treatment-naïve, non-cirrhotic patients (Cohort 1), as well as a 12-week course of treatment with ledipasvir/sofosbuvir with or without ribavirin in treatment-experienced patients (with or without cirrhosis) (Cohort 2) with chronic hepatitis C genotype 1 (LDV/SOF 8 weeks: N=20 [naïve]; LDV/SOF 12 weeks: N=19 [naïve]; LDV/SOF + RBV 8 weeks: N=21 [naïve]; LDV/SOF 12 weeks: N=19 [experienced]; LDV/SOF + RBV 12 weeks: N=21 [experienced]).
  • ION-2 is a randomised, open-label Phase III trial to evaluate 12- or 24-week treatment with ledipasvir/sofosbuvir with or without ribavirin (LDV/SOF 12 weeks: N=109; LDV/SOF 24 weeks: N=109; LDV/SOF + RBV 12 weeks: N=111; LDV/SOF + RBV 24 weeks: N=111) in patients with genotype 1 HCV infection, with or without cirrhosis, following failure of a previous interferon-containing therapy, including treatment regimens containing an HCV protease inhibitor.
  • The ELECTRON study is a randomised, open-label Phase IIa study investigating various treatment regimens with sofosbuvir as monotherapy or in combination with other active ingredients (INN) for the treatment of chronic hepatitis C genotypes 1, 2 and 3.
  • The GS-US-337-0113 study is a randomised, open-label Phase IIIb study conducted in Japan.
  • The SIRIUS study is a randomised, double-blind, placebo-controlled Phase II study.
  • The SYNERGY study is an open-label, non-randomised study in which ledipasvir/sofosbuvir was investigated over a 12-week treatment period for the treatment of chronic HCV genotype 4 infection in 21 treatment-naïve and treatment-experienced patients.
  • The GS-US-337-1119 study is an open-label, non-randomised Phase II study in which ledipasvir/sofosbuvir was investigated over a 12-week treatment period for the treatment of chronic HCV genotype 4 infection in treatment-naïve (N=22) and treatment-experienced (N=22) patients.
  • The ERADICATE study is an open-label, single-arm, multicentre study.
  • The ION-4 study is an open-label, single-arm, multicentre study.
  • SOLAR-1 is an open-label study evaluating 12-week and 24-week treatment with ledipasvir/sofosbuvir + ribavirin in patients with genotype 1 or 4 CHC who have advanced liver disease and/or have undergone a liver transplant.

a) Treatment-naïve patients (without cirrhosis), genotype 1

• An historical control (non-adjusted indirect comparison) is available for this patient group. With regard to the SVR endpoint in terms of ‘non-response’, a dramatic effect is observed for ledipasvir/sofosbuvir compared with the appropriate comparator therapy.
• Non-adjusted indirect comparisons are fundamentally subject to methodological uncertainty in their results, even when so-called dramatic effects are observed; consequently, a hint of additional benefit is inferred.
• mortality
  • In the ION-1, ION-3 and LONESTAR (Cohort 1) studies, there were no deaths in the group of ‘treatment-naïve patients without cirrhosis and with genotype 1 HCV infection’. In the studies on appropriate comparator therapy, three deaths (0.2%) occurred.
  • The results of the historical control of mortality between ledipasvir/sofosbuvir and the appropriate comparator therapy cannot be conclusively assessed quantitatively due to the very different observation periods. However, based on the available data, no additional benefit of ledipasvir/sofosbuvir over the appropriate comparator therapy can be identified.
• Morbidity – Sustained virological response (SVR)
  • The proportion of patients who achieved an SVR following 12 weeks’ treatment with ledipasvir/sofosbuvir is significantly higher than after 24 to 48 weeks’ treatment (RGT regimen) with a triple therapy comprising a protease inhibitor (boceprevir or telaprevir), peginterferon and ribavirin. The proportion of patients achieving an SVR is almost 100% with treatment using ledipasvir/sofosbuvir. The relative risk of non-response to antiviral therapy following 12 weeks of treatment with ledipasvir/sofosbuvir was 0.1 compared with the appropriate comparator therapy. This effect is generally regarded as dramatic and is observed equally for both treatment regimens (triple therapy with TVR or BOC).
  • The absolute risk reduction of ledipasvir/sofosbuvir (12 weeks of treatment) compared with the appropriate comparator therapy in terms of achieving an SVR (‘responder’) is 22.6 per cent.
• Side effects
  • In the studies on ledipasvir/sofosbuvir, a lower percentage of adverse events and fewer serious adverse events occurred compared with the appropriate comparator therapy. For the endpoint ‘discontinuation due to an adverse event’, there is a statistically significant result in favour of ledipasvir/sofosbuvir.
  • It is noted that Harvoni® offers the possibility of interferon-free therapy. According to the Harvoni® summary of product characteristics (SmPC), treatment of treatment-naïve patients without cirrhosis and with genotype 1 HCV infection is administered over 8 or 12 weeks.
  • Taking into account the proof of the adverse effects of treatment with peginterferon – which is both sufficient in studies and described in the summary of product characteristics (SmPC) – the option of an interferon-free-free therapy lasting 8 or 12 weeks is considered relevant in terms of avoiding side effects, compared with the appropriate comparator therapy containing interferon.
• quality of life
  • No usable data on health-related quality of life are available in comparison with the appropriate comparator therapy.
• Overall assessment
  • For the patient group listed, an overall assessment of the results on mortality, morbidity, health-related quality of life and side effects provides a hint that ledipasvir/sofosbuvir offers considerable additional benefit compared with the appropriate comparator therapy (triple therapy).
  • The G-BA classifies the extent of the additional benefit of ledipasvir/sofosbuvir 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, resulting in particular from a statistically significant improvement in sustained virological response (a dramatic effect on the relative risk of being a non-responder, as well as the magnitude of the absolute risk reduction in a non-adjusted indirect comparison).

b) Treatment-naive patients (with compensated cirrhosis), genotype 1

• A historical control (non-adjusted indirect comparison) is available for this patient group. With regard to the SVR endpoint in terms of ‘non-response’, a dramatic effect is observed for ledipasvir/sofosbuvir compared with the appropriate comparator therapy (dual therapy with peginterferon alfa and ribavirin).
• Non-adjusted indirect comparisons are fundamentally subject to methodological uncertainty in their results, even when so-called dramatic effects are observed; consequently, a hint of additional benefit is derived.
• mortality
  • In the ION-1 study, there were no deaths in the group of ‘treatment-naïve patients with cirrhosis and genotype 1 HCV infection’. In the studies on appropriate comparator therapy, one death (0.1 per cent) occurred in the overall population of the study arms (‘treatment-naive patients with/without cirrhosis’). No separate analysis is available for the relevant patient population of ‘treatment-naive patients with cirrhosis’.
  • The results of the historical control for mortality between ledipasvir/sofosbuvir and the appropriate comparator therapy cannot be conclusively assessed quantitatively due to the very different observation periods and the lack of data on the relevant patient population of ‘treatment-naïve patients with cirrhosis’. On the basis of the available documentation, therefore, no additional benefit of ledipasvir/sofosbuvir over the appropriate comparator therapy can be identified.
• Morbidity – Sustained virological response (SVR)
  • The proportion of patients who achieved an SVR following 24 weeks’ treatment with ledipasvir/sofosbuvir is significantly higher than after 48 weeks’ treatment with the dual therapy of peginterferon and ribavirin. The proportion of patients achieving an SVR is almost 100% when treated with ledipasvir/sofosbuvir. The relative risk of patients on ledipasvir/sofosbuvir therapy failing to respond to treatment (‘non-response’) compared with the appropriate comparator therapy is 0.05. This effect is generally regarded as dramatic.
  • The absolute risk reduction of ledipasvir/sofosbuvir (24 weeks of treatment) compared with the appropriate comparator therapy in terms of achieving an SVR (‘responder’) is 62.4 per cent.
• Side effects
  • In the dossier, the pharmaceutical manufacturer presented results from the ION-1 study regarding side effects in the overall population of the study arms (“treatment-naïve patients with or without cirrhosis”). An analysis of the relevant patient population of “treatment-naïve patients with cirrhosis” is not available.
  • It is recognised that Harvoni® offers the possibility of interferon-free treatment. According to the Harvoni® summary of product characteristics (SmPC), treatment of treatment-naïve patients with cirrhosis and an HCV genotype 1 infection is administered over 24 weeks (or 12 weeks where appropriate).
  • Taking into account the proof of the adverse effects of treatment with peginterferon, which is both sufficient in studies and described in the summary of product characteristics (SmPC), the option of an interferon--free therapy lasting 24 or 12 weeks, as opposed to the appropriate comparator therapy containing interferon, is considered relevant in terms of avoiding side effects.
• quality of life
  • No usable data on health-related quality of life are available in comparison with the appropriate comparator therapy.
• Overall assessment
  • For the patient group listed, an overall assessment of the results on mortality, morbidity, health-related quality of life and side effects provides a hint that ledipasvir/sofosbuvir offers considerable additional benefit compared with the appropriate comparator therapy (dual therapy with peginterferon alfa and ribavirin).
  • The G-BA classifies the extent of the additional benefit of ledipasvir/sofosbuvir 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, resulting in particular from a statistically significant improvement in sustained virological response (a dramatic effect on the relative risk of being a non-responder, as well as the magnitude of the absolute risk reduction in a non-adjusted indirect comparison).

c) Treatment-experienced patients (without cirrhosis, with compensated cirrhosis), genotype 1

• An historical control (non-adjusted indirect comparison) is available for this patient group. With regard to the SVR endpoint in terms of ‘non-response’, a dramatic effect is observed for ledipasvir/sofosbuvir compared with the appropriate comparator therapy.
• Even when so-called dramatic effects are observed, non-adjusted indirect comparisons are fundamentally subject to methodological uncertainty regarding the results; consequently, a hint of additional benefit is derived.
• mortality
  • In the ION-2, ELECTRON (Part 6), LONESTAR (Cohort 2), GS-US-337-0113 and GS-US-337-0121, there were no deaths in the group of ‘treatment-experienced patients with genotype 1 HCV infection’. In the studies on appropriate comparator therapy, four deaths (0.6%) occurred.
  • The results of the historical control of mortality between ledipasvir/sofosbuvir and the appropriate comparator therapy cannot be conclusively assessed quantitatively due to the very different observation periods. However, based on the available documentation, no additional benefit of ledipasvir/sofosbuvir over the appropriate comparator therapy can be identified.
• Morbidity – Sustained virological response (SVR)
  • The proportion of patients who achieved an SVR following 24 weeks’ treatment with LDV/SOF is significantly higher than after 24 to 48 weeks’ treatment (RGT regimen) with triple therapy comprising a protease inhibitor (boceprevir or telaprevir), peginterferon and ribavirin. The proportion of patients achieving an SVR is almost 100% when treated with ledipasvir/sofosbuvir. The relative risk of non-response to treatment among patients treated with ledipasvir/sofosbuvir, compared with the appropriate comparator therapy, is 0.04. This effect is generally regarded as dramatic and is equally evident for both treatment regimens (triple therapy with TVR or BOC).
  • The absolute risk reduction of ledipasvir/sofosbuvir (24 weeks of treatment) compared with the appropriate comparator therapy in terms of achieving an SVR (‘responder’) is 42.3 per cent.
• Side effects
  • In the studies on ledipasvir/sofosbuvir, there were lower percentages of adverse events (AEs), serious adverse events (SAEs) and discontinuations due to adverse events compared with the appropriate comparator therapy.
  • For the endpoint of discontinuation due to an adverse event (24-week treatment duration), there is statistical significance in favour of ledipasvir/sofosbuvir at a 5% significance level.
  • It should be noted that Harvoni® offers the possibility of interferon-free treatment. According to the Harvoni® summary of product characteristics (SmPC), treatment is administered over 24 weeks (or 12 weeks where appropriate) to treatment-experienced patients with or without cirrhosis who are infected with HCV genotype 1.
  • Taking into account the adverse effects of treatment with peginterferon, which are both provided with sufficient proof in studies and described in the summary of product characteristics (SmPC), the option of an interferon-free-free therapy lasting 24 or 12 weeks, compared with the appropriate interferon-containing comparator therapy, is considered relevant in terms of avoiding side effects.
• quality of life
  • No usable data on health-related quality of life are available in comparison with the appropriate comparator therapy.
• Overall assessment
  • For the patient group listed, an overall assessment of the results on mortality, morbidity, health-related quality of life and side effects provides a hint that ledipasvir/sofosbuvir offers a considerable additional benefit compared with the appropriate comparator therapy (triple therapy).
  • The G-BA classifies the extent of the additional benefit of ledipasvir/sofosbuvir 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, resulting in particular from a statistically significant improvement in sustained virological response (a dramatic effect on the relative risk of being a non-responder, as well as the magnitude of the absolute risk reduction in a non-adjusted indirect comparison).

d) Treatment-naive patients (with compensated cirrhosis) and treatment-experienced patients, genotype 3

• For the patient group listed, an additional benefit over the appropriate comparator therapy is not proven.
• There are insufficient data available for these patients to assess the additional benefit.

e) Treatment-naïve patients and treatment-experienced patients, genotype 4

• For the patient group 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 ledipasvir/sofosbuvir, based on the criteria in Section 5(7) of the AM-NutzenV and taking into account the severity of the disease and the therapeutic goal in the treatment of the disease as a whole, as minor.
• mortality
  • In the SYNERGY and GS-US-337-1119 studies, no deaths occurred among HCV patients (genotype 4).
• Morbidity – Sustained virological response (SVR)
  • In the SYNERGY study, 21 patients with genotype 4 HCV infection received ledipasvir/sofosbuvir over a 12-week treatment period. Of these patients, 95% (20/21) achieved SVR 12.
  • In the GS-US-337-1119 study, 44 patients with genotype 4 HCV infection received ledipasvir/sofosbuvir for a treatment duration of 12 weeks. Of these patients, 93.2% (41/44) achieved SVR12; of the 10 patients with cirrhosis, 100 per cent (10/10) achieved SVR 12, and of the 34 patients without cirrhosis, 91.2 per cent (31/34) achieved SVR 12.
  • Given the considerable magnitude of the SVR rate achieved, it is assumed – despite the analysis of individual study arms – that treatment with ledipasvir/sofosbuvir is equivalent to the appropriate comparator therapy with regard to this endpoint.
• Side effects
  • Taking into account the proof of the adverse effects of treatment with peginterferon, which have been sufficiently documented in studies and described in the summary of product characteristics (SmPC), the possibility of an interferon--free therapy lasting 12 or 24 weeks, as opposed to the appropriate comparator therapy containing interferon, is assessed as relevant in terms of avoiding side effects.
  • In its overall assessment, in the sense of an indirect comparison, the G-BA identifies a minor additional benefit for HCV patients (genotype 4) compared with the appropriate comparator therapy, due to the relevant avoidance of side effects.
• quality of life
  • No usable data on health-related quality of life are available for comparison with the appropriate comparator therapy.
• Overall assessment
  • In accordance with the principles of evidence-based medicine applicable to the benefit assessment of a new active substance, as set out in Chapter 5, Chapter § 18(2), fourth sentence, of the VerfO, which govern the benefit assessment of a new INN, evidence must be provided that a causal link exists between a therapeutic intervention and an effect compared with another therapeutic intervention, in order to be able to make statements regarding the benefit-risk ratio of the interventions being compared, must in principle be based on directly comparative clinical trials of the highest quality (randomised, controlled, double-blind).
  • It is, however, recognised that in particularly specific circumstances, it may be justified to make an assessment decision on the basis of qualitatively adequate documentation of a lower level of evidence (see Chapter 2, Section 13(2) of the VerfO).
  • Ledipasvir/sofosbuvir offers the possibility of interferon-free treatment as opposed to the appropriate comparator therapy containing interferon. By way of an indirect comparison, the G-BA assumes that there is an additional benefit compared with the appropriate comparator therapy due to the avoidance of interferon-related side effects.

f) Treatment-naïve patients and treatment-experienced patients with HIV co-infection, genotype 1

• For the patient group listed, an overall assessment of the results regarding mortality, morbidity, health-related quality of life and side effects suggests a hint that ledipasvir/sofosbuvir offers a non-quantifiable additional benefit compared with the appropriate comparator therapy (dual therapy with peginterferon alfa and ribavirin).
• The G-BA assesses the extent of the additional benefit of ledipasvir/sofosbuvir over the appropriate comparator therapy, 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, as non-quantifiable, because the scientific evidence does not permit this.
• mortality
  • No deaths occurred in the ERADICATE study; in the ION-4 study, there was one death (1/335; 0.3%). The mortality results in the ERADICATE and ION-4 studies are therefore in line with those observed in patients without HIV co-infection receiving ledipasvir/sofosbuvir.
  • On the basis of the available documentation, therefore, no additional benefit of ledipasvir/sofosbuvir over the appropriate comparator therapy can be identified for the endpoint of mortality.
• Morbidity – Sustained virological response (SVR)
  • The SVR12 rates observed in the ERADICATE and ION-4 studies in patients with HIV co-infection (98.0% and 95.8% respectively) for patients with HIV co-infection (genotype 1) are within the range of the rates observed in patients with genotype 1 without HIV co-infection treated with ledipasvir/sofosbuvir.
  • It should be noted that only limited data are available for the group of treatment-naïve patients (with cirrhosis) co-infected with HIV in the ION-4 study. The SVR rate is 85.0% (17/20). For treatment-experienced patients (with cirrhosis) co-infected with HIV, the SVR rate is 97.9% (46/47).
  • Given the clinical relevance of SVR and taking into account the magnitude of the SVR rates for treatment-naïve and treatment-experienced patients with cirrhosis following the 12-week course of treatment, a non-quantifiable additional benefit is identified.
• Side effects
  • In the ERADICATE study, 100 per cent (50/50) of patients experienced an adverse event and 2 per cent (1/50) experienced a serious adverse event; in the ION-4 study, an adverse event occurred in 76.7 per cent (257/335) of patients and a serious adverse event in 2.5 per cent (8/335). There were no discontinuations due to an adverse event in either the ERADICATE study or the ION-4 study.
  • There is no evidence to suggest that ledipasvir/sofosbuvir causes greater harm than the appropriate comparator therapy.
  • It is noted that Harvoni® offers the possibility of interferon-free treatment. According to the Harvoni® summary of product characteristics (SmPC), treatment of treatment-naïve patients with genotype 1 HCV infection lasts for 12 or 24 weeks.
  • Taking into account the proof of the adverse effects of treatment with peginterferon, which have been sufficiently documented in studies and described in the summary of product characteristics (SmPC), the option of an interferon--free therapy lasting 24 or 12 weeks, respectively, is assessed as relevant in terms of avoiding side effects, compared with the appropriate comparator therapy containing interferon.
• quality of life
  • No usable data on health-related quality of life are available in comparison with the appropriate comparator therapy.
• Overall assessment
  • For a 12-week course of treatment with ledipasvir/sofosbuvir, there is a statistically significant improvement in sustained virological response for treatment-naïve and treatment-experienced patients with HIV co-infection, which corresponds to a dramatic effect. Overall, however, no data are available for treatment durations exceeding 24 weeks, which is routinely recommended for patients with cirrhosis and an increased risk of clinical disease progression.
  • For the SVR endpoint, the results of the historical control for patients without HIV co-infection (genotype 1) are used for patients with HIV co-infection (genotype 1). A dramatic effect is observed for the SVR endpoint in patients with HIV co-infection (genotype 1).

g) Patients with decompensated cirrhosis, genotype 1

• For the patient group listed, an overall analysis of the results regarding mortality, morbidity, health-related quality of life and side effects provides a hint that ledipasvir/sofosbuvir (in combination with ribavirin) provides a non-quantifiable additional benefit compared with the appropriate comparator therapy (best supportive care).
• The G-BA assesses the extent of the additional benefit of ledipasvir/Sofosbuvir compared with the appropriate comparator therapy, 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, as non-quantifiable, because the scientific evidence does not permit this.
• mortality
  • In the relevant patient population of the SOLAR-1 trial, there were a total of 5 deaths (5/85).
  • It is not possible to assess the incidence of deaths due to a lack of information on the appropriate comparator therapy, namely best supportive care.
• Morbidity – Sustained virological response (SVR)
  • In the groups within the relevant patient population of the SOLAR-1 study, the SVR12 rates range between 75.0% and 88.9%. For patients with decompensated cirrhosis, ‘best supportive care’ was determined to be the appropriate comparator therapy. As no antiviral treatment is administered in this setting, the SVR rate under ‘best supportive care’ is assumed to be approximately 0%.
  • Given the magnitude of the SVR rates achieved with ledipasvir/sofosbuvir and the clinical significance of SVR for patients, the additional benefit in terms of the SVR rate is considered to be considerable.
• Side effects
  • In the SOLAR-1 study, almost 100 per cent of patients in the relevant patient population experienced an adverse event, and approximately 40 per cent experienced a serious adverse event. Treatment was discontinued due to an adverse event in approximately 8% of cases.
  • No data are available on the causality of adverse events in relation to the underlying disease on the one hand or to drug therapy on the other. A comparative assessment of the incidence of side effects, in particular the occurrence of serious adverse events, against the appropriate comparator therapy (best supportive care) is therefore not possible.
• quality of life
  • No usable data on health-related quality of life compared with the appropriate comparator therapy are available.
• Overall assessment
  • In the patient populations of the relevant SOLAR-1 study, SVR-12 rates range between 75.0% and 88.9%. For patients with decompensated cirrhosis, best supportive care was determined to be the appropriate comparator therapy. Under best supportive care, an SVR rate of virtually 0% is assumed, as no antiviral treatment is administered. Achieving these SVR rates is considered decisive.
  • This must be weighed against the findings on mortality and side effects, in particular the occurrence of serious adverse events at a rate of approximately 40 per cent. Patients with decompensated cirrhosis are in a critical condition, in which the occurrence of serious adverse events is to be expected even when treated with ‘Best-Supportive-Care’. Due to a lack of data on the appropriate comparator therapy (best supportive care), a definitive quantitative and comparative assessment of the incidence of serious adverse events is not possible.
  • Therefore, when considering the SVR rates and the findings on mortality and side effects as a whole, a non-quantifiable additional benefit is identified.

Courtesy translation only, please refer to the German original.