Dasabuvir (1) – Exviera®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer’s dossier includes two randomised controlled trials [MALACHITE-I, MALACHITE-II] as well as non-comparative data from the PEARL-II, PEARL-III (GT1b without cirrhosis), PEARL-IV, SAPPHIRE-I, SAPPHIRE-II (GT1a without cirrhosis), TURQUOISE-II (GT1a/1b with compensated cirrhosis), CORAL-I/Cohort 1 (GT1 following liver transplantation), TURQUOISE-I (GT1 with HIV co-infection) and M14-103 (GT1 without cirrhosis receiving opioid substitution therapy).
  • The MALACHITE-I study is an open-label, randomised controlled trial (RCT) with 5 treatment arms (A to E), with treatment arms A and B investigating treatment-naive CHC patients with genotype 1a without cirrhosis, and arms D and E investigating treatment-naive CHC patients with genotype 1b.
  • The MALACHITE-II study is an open-label RCT with two treatment arms.
  • TURQUOISE-II was a multi-arm, randomised, open-label, multicentre study involving 380 adults with chronic hepatitis C infection of genotype 1 (1a/1b) and compensated cirrhosis (Child-Pugh A).
  • PEARL-II was a randomised, open-label, multicentre study involving 179 adults with chronic hepatitis C infection of genotype 1b without cirrhosis who had failed to achieve SVR following prior treatment with pegIFN/RBV.
  • The open-label TURQUOISE-I study investigated 63 patients with genotype 1 HCV infection and HIV-1 co-infection who received 12- or 24-week treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir plus ribavirin.

a) Treatment-naive patients (without cirrhosis), genotype 1a/1b: Dasabuvir in combination with ombitasvir/paritaprevir/ritonavir plus ribavirin (genotype 1a) Dasabuvir in combination with ombitasvir/paritaprevir/ritonavir (genotype 1b)

• For the patient group listed, an overall assessment of the results regarding mortality, morbidity, health-related quality of life and side effects indicates an indication of considerable additional benefit for dasabuvir compared with the appropriate comparator therapy (triple therapy).
• The G-BA classifies the extent of the additional benefit of dasabuvir 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.
• mortality
  • In the MALACHITE-I study, one death occurred in the ‘OBVT/PTV/R + DSV + RBV’ group (genotype 1a).
  • On the basis of the available documentation, no harm or additional benefit can be identified for the endpoint of mortality for OBV/PTV/R + DSV (+ RBV) compared with the appropriate comparator therapy.
• Morbidity – sustained virological response (SVR)
  • For SVR 12, a statistically significant difference was observed in favour of OBV/PTV/R + DSV (+ RBV) compared with the telaprevir-containing triple therapy, with an absolute risk reduction of 14.7% (genotype 1a) and 9.6% (genotype 1b), respectively.
  • Given the clinical relevance of SVR and the magnitude of the treatment effect observed with OBV/PTV/R + DSV (+ RBV), a considerable additional benefit is anticipated in this patient group.
• Morbidity – health status as measured by the European Quality of Life 5-Dimensions Visual Analogue Scale (EQ-5D VAS) (during treatment)
  • For the health status endpoint, a statistically significant difference in favour of OBV/PTV/R + DSV (+ RBV) was observed for both genotype 1a and genotype 1b.
  • With regard to genotype 1a, the 95% CI of Hedges’ g did not lie entirely above the irrelevance threshold of 0.2.
  • For genotype 1b, the 95% CI of Hedges’ g lay entirely above the irrelevance threshold of 0.2.
• Health-related quality of life (under treatment) – SF-36 – Physical summary score
  • When examining the differences in mean scores, a statistically significant difference was observed for the physical summary score in favour of OBV/PTV/R + DSV (+ RBV) compared with telaprevir-containing triple therapy for both genotype 1a and genotype 1b. The 95% CI of Hedges’ g was entirely above the irrelevance threshold of 0.2 in each case.
  • In the responder analysis, no statistically significant difference was observed between the treatment groups for the physical total score in the overall population for genotype 1a. However, the proportion of patients achieving a response in the OBV/PTV/R + DSV + RBV arm was numerically higher than in the TVR + PEG + RBV arm. This finding does not call into question the results of the analysis of mean differences.
  • For genotype 1b, the responder analysis revealed a statistically significant difference in the physical total score in favour of OBV/PTV/R + DSV. This result is consistent with that of the analysis of mean differences.
• Health-related quality of life (during treatment) – SF-36 – Mental health summary score
  • When examining the differences in mean values, no statistically significant difference was observed between the treatment groups for the SF-36 mental health total score in genotype 1a. For genotype 1b, there was a statistically significant difference in favour of OBV/PTV/R + DSV. The 95% CI of Hedges’ g lay entirely above the irrelevance threshold of 0.2.
  • In the responder analysis, no statistically significant difference was observed between the treatment groups for the SF-36 mental health summary score in genotype 1a. For the mental health summary score, the results based on the mean differences and the responder analysis were therefore consistent for the overall population.
  • For genotype 1b, the responder analysis revealed a statistically significant difference in favour of OBV/PTV/R + DSV for the physical summary score. Both analyses – mean difference and responder analysis – were therefore also consistent for genotype 1b.
• Health-related quality of life (during treatment) – Hepatitis C Virus Patient-Reported Outcomes (HCVPRO)
  • For the HCVPRO endpoint, a statistically significant difference was observed in favour of OBV/PTV/R + DSV (+ RBV) compared with telaprevir-containing triple therapy for both genotype 1a and genotype 1b.
  • The 95% CI of Hedges’ g for genotype 1a did not lie entirely above the irrelevance threshold of 0.2.
  • For genotype 1b, the 95% CI of Hedges’ g lay entirely above the irrelevance threshold of 0.2.
• Side effects – overall rate of serious adverse events (SAEs)
  • For genotype 1a, no SAEs have occurred in the OBV/PTV/R + DSV + RBV arm to date. In the TVR + PEG + RBV arm, at least one SAE occurred in 3 patients (8.8%). For treatment-naive patients with CHC genotype 1a without cirrhosis, the survival analysis showed a statistically significant difference in favour of OBV/PTV/R + DSV + RBV.
  • For genotype 1b, no SAE has occurred in the OBV/PTV/R + DSV arm to date. In the TVR + PEG + RBV arm, at least one SAE occurred in 6 patients (14.6 %). For treatment-naïve patients with CHC genotype 1b without cirrhosis, the survival analysis showed a statistically significant difference in favour of OBV/PTV/R + DSV.
  • This provided an indication of minor harm with OBV/PTV/R + DSV (+ RBV) compared with the appropriate comparator therapy, TVR + PEG + RBV, for the SAE, for both genotype 1a and genotype 1b.
• Side effects – therapy discontinuation due to adverse events (AEs)
  • For the endpoint of therapy discontinuation due to AEs, the analysis for genotype 1a showed no statistically significant difference between the treatment groups.
  • With regard to genotype 1b, a statistically significant difference in favour of OBV/PTV/R + DSV was observed for the endpoint of therapy discontinuation due to AEs (absolute risk reduction 9.8%). This provides an indication that, for this endpoint, OBV/PTV/R + DSV is associated with minor harm compared with TVR + PEG + RBV for genotype 1b.
• Side effects – AEs of particular interest
  • Given the available data, it was not possible to compile a comprehensive list of AEs of particular interest. However, analysis of the available data revealed no evidence of considerable harm associated with OBV/PTV/R + DSV (+ RBV) compared with TVR + PEG + RBV.

b) Treatment-naïve patients (with compensated cirrhosis), genotype 1a/1b: dasabuvir in combination with ombitasvir/paritaprevir/ritonavir plus ribavirin

• 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 dasabuvir 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.
• Morbidity – sustained virological response (SVR)
  • Among treatment-naïve patients with chronic hepatitis C infection (with compensated cirrhosis) of genotype 1a, the SVR 12 rate was 94.6% (53/56); the SVR-12 rate in treatment-naïve patients with chronic hepatitis C infection (with compensated cirrhosis) of genotype 1b was 100% (22/22).
  • Given the considerable magnitude of the SVR rates achieved, and despite the analysis being based on individual study arms, treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin is considered equivalent to dual therapy (ribavirin plus peginterferon) is assumed to be equivalent with regard to this endpoint.
• Side effects
  • According to the Exviera® summary of product characteristics (SmPC), treatment of treatment-naïve HCV patients (with compensated cirrhosis) with genotype 1a is administered over 24 weeks and with genotype 1b over 12 weeks using a combination of ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin.
  • With regard to the appropriate comparator therapy, a 48-week treatment cycle of a regimen containing peginterferon and ribavirin is specified for dual therapy in the treatment of treatment-naïve patients with cirrhosis and HCV genotype 1 infection.
  • Taking into account the adverse effects of treatment with peginterferon alfa, which have been provided with sufficient proof in studies and are described in the summary of product characteristics (SmPC), the option of an interferon--free therapy lasting 24 or 12 weeks, respectively, is considered relevant in terms of avoiding side effects, when compared with the appropriate comparator therapy containing interferon.
• Overall assessment
  • In an overall assessment in the sense of an indirect comparison, the G-BA identifies a minor additional benefit in treatment-naive HCV patients with compensated cirrhosis (genotype 1a/1b) compared with the appropriate comparator therapy, due to the significant avoidance of side effects.
  • The certainty of the findings is classified as a hint, based on the analysis of individual study arms for evidence of an adequate response in terms of SVR and the comparative analysis of the adverse effect profiles of the dasabuvir regimen on the one hand and the appropriate comparator therapy containing interferon on the other.
  • Compared with the appropriate comparator therapy, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a previously unattained moderate—and not merely minor—improvement in the therapy-relevant benefit for dasabuvir has been observed, in particular through a significant reduction in side effects due to the availability of an interferon-free-free treatment regimen, a previously unattained moderate – and not merely minor – improvement in the therapy-relevant benefit of dasabuvir has been identified.
  • Due to the lack of direct comparative studies, the G-BA was only able to carry out a limited quantitative comparative analysis of side effects by type, severity and frequency.

c) Treatment-experienced patients (without cirrhosis), genotype 1a/1b: Dasabuvir in combination with ombitasvir/paritaprevir/ritonavir plus ribavirin (genotype 1a) Dasabuvir in combination with ombitasvir/paritaprevir/ritonavir (genotype 1b)

• For the patient group listed, an overall assessment of the results regarding mortality, morbidity, health-related quality of life and side effects provides a hint of considerable additional benefit from dasabuvir compared with the appropriate comparator therapy (triple therapy).
• The G-BA classifies the extent of the additional benefit of dasabuvir 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.
• mortality
  • In the MALACHITE-II study, there were no deaths in the ‘genotype 1a’ patient population.
  • In the PEARL-II study, no patients died during the observation period. In the ‘genotype 1b’ patient population of the MALACHITE-II study, only one patient died in the OBV/PTV/R + DSV + RBV arm.
  • Based on the available data, no harm or additional benefit can be identified for the endpoint of mortality with OBV/PTV/R + DSV + (RBV) compared with the appropriate comparator therapy.
• Morbidity – sustained virological response (SVR)
  • For SVR 12, the MALACHITE II study showed the ‘genotype 1a’ patient population, a statistically significant difference was observed in favour of OBV/PTV/R + DSV + RBV compared with the telaprevir-containing triple therapy, with an absolute risk reduction of 42.9%.
  • For SVR 12, an indirect comparison of patients with genotype 1b also showed a statistically significant difference in favour of OBV/PTV/R + DSV.
  • Given the clinical relevance of SVR and the magnitude of the effect size for SVR under treatment with OBV/PTV/R + DSV (+ RBV), a considerable additional benefit is considered to exist in this patient group.
• Morbidity – health status as measured by the European Quality of Life 5-Dimensions Visual Analogue Scale (EQ-5D VAS) (during treatment)
  • For the health status endpoint, the MALACHITE-II study, ‘Genotype 1a’ patient population, showed no statistically significant difference between the treatment arms.
  • For the health status endpoint, an indirect comparison of patients with genotype 1b showed a statistically significant difference in favour of OBV/PTV/R + DSV. The 95% CI of Hedges’ g lay entirely above the irrelevance threshold of 0.2.
• Health-related quality of life (during treatment) – SF-36 – Physical summary score
  • For the physical total score, the MALACHITE-II study, ‘Genotype 1a’ patient population, showed no statistically significant difference between the treatment groups, neither for the mean differences nor for the responder analysis.
  • When examining the mean differences in the indirect comparison for patients with genotype 1b, a statistically significant difference in favour of OBV/PTV/R + DSV was observed for the physical summary score in the indirect comparison. The 95% CI of Hedges’ g lay entirely above the irrelevance threshold of 0.2. In the responder analysis, a statistically significant difference in favour of OBV/PTV/R + DSV was observed in the indirect comparison.
• Health-related quality of life (during treatment) – SF-36 – Mental health summary score
  • When examining the differences in mean scores, the MALACHITE-II study, in the ‘Genotype 1a’ patient population, showed a statistically significant difference in favour of OBV/PTV/R + DSV + RBV for the SF-36 mental health summary score. The 95% confidence interval for Hedges’ g did not lie entirely above the non-significance threshold of 0.2. In the responder analysis, no statistically significant difference was observed between the treatment groups for the SF-36 mental health summary score.
  • When examining the mean differences in the indirect comparison for patients with genotype 1b, a statistically significant difference in favour of OBV/PTV/R + DSV was observed for the SF-36 mental health summary score in the indirect comparison. The 95% CI of Hedges’ g lay entirely above the non-significance threshold of 0.2. In the responder analysis, a statistically significant difference in favour of OBV/PTV/R + DSV was observed in the indirect comparison.
• Health-related quality of life (during treatment) – Hepatitis C Virus Patient-Reported Outcomes (HCVPRO)
  • For the HCVPRO endpoint, the MALACHITE-II study, ‘Genotype 1a’ patient population, showed a statistically significant difference in favour of OBV/PTV/R + DSV + RBV compared with the telaprevir-containing triple therapy. The 95% CI of Hedges’ g did not lie entirely above the irrelevance threshold of 0.2.
  • For the HCVPRO endpoint, an indirect comparison of patients with genotype 1b showed a statistically significant difference in favour of OBV/PTV/R + DSV. The 95% confidence interval for Hedges’ g lay entirely above the irrelevance threshold of 0.2.
• Side effects – overall rate of serious adverse events (SAEs)
  • In the ‘genotype 1a’ patient population of the MALACHITE-II study, no SAEs have occurred to date.
  • For the SAE endpoint, the survival analysis showed no statistically significant difference between the treatments in an indirect comparison with regard to patients with genotype 1b.
• Side effects – therapy discontinuation due to adverse events (AE)
  • For the endpoint ‘therapy discontinuation due to AEs’, the MALACHITE-II study, ‘Genotype 1a’ patient population, showed a statistically significant difference in favour of OBV/PTV/R + DSV + RBV (absolute risk reduction 28.6%). However, this result was based on only 0 versus 2 patients who experienced events.
  • For the endpoint of therapy discontinuation due to AEs, an indirect comparison of patients with genotype 1b showed a statistically significant difference in favour of OBV/PTV/R + DSV. For this endpoint, however, the small effect size provides no hint of additional benefit from OBV/PTV/R + DSV compared with TVR + PEG + RBV.
• Side effects – AEs of particular interest
  • Given the available data, it was not possible to compile a comprehensive list of AEs of particular interest. Due to the minor number of patients in the relevant ‘genotype 1a’ patient population of the MALACHITE-II study, individual AEs were not analysed.

d) Treatment-experienced patients (with compensated cirrhosis), genotype 1a/1b: dasabuvir in combination with ombitasvir/paritaprevir/ritonavir plus ribavirin

• 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 dasabuvir 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.
• Morbidity – sustained virological response (SVR)
  • Among treatment-experienced patients with chronic hepatitis C infection (with compensated cirrhosis) of genotype 1a, the SVR12 rate ranged between 92.9% and 100% (previous non-responders: 39/42, previous partial responders: 10/10, previous relapses: 13/13); the SVR12 rate in treatment-experienced patients with chronic hepatitis C infection (with compensated cirrhosis) of genotype 1b ranged from 85.7% to 100% (previous non-responders: 25/25, previous partial responders 6/7, previous relapses: 14/14).
  • Given the considerable magnitude of the SVR rates achieved, it is assumed – despite the analysis of individual study arms – that treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin is equivalent to triple therapy (telaprevir plus ribavirin plus peginterferon alfa) with regard to this endpoint.
• Side effects
  • According to the Exviera® summary of product characteristics (SmPC), treatment of treatment-experienced HCV patients (with compensated cirrhosis) with genotype 1a is administered over 24 weeks and with genotype 1b over 12 weeks using a combination of ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin.
  • With regard to the appropriate comparator therapy, a treatment cycle of 48 or 72 weeks with a regimen containing peginterferon and ribavirin is specified for the treatment of treatment-experienced patients with cirrhosis and HCV genotype 1 infection.
  • 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 considered relevant in terms of avoiding side effects, when compared with the appropriate interferon-containing comparator therapy.
• Overall assessment
  • In an overall assessment in the sense of an indirect comparison, the G-BA identifies a minor additional benefit in treatment-experienced HCV patients with compensated cirrhosis (genotype 1a/1b) compared with the appropriate comparator therapy, due to the significant avoidance of side effects.
  • The certainty of the findings is classified as a hint, based on the analysis of individual study arms for evidence of an adequate response in terms of SVR and the comparative analysis of the adverse reaction profiles of the dasabuvir regimen on the one hand and the appropriate comparator therapy containing interferon on the other.
  • Compared with the appropriate comparator therapy, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a previously unattained moderate—and not merely minor—improvement in the therapy-relevant benefit of dasabuvir has been observed, in particular through a significant reduction in side effects due to the availability of an interferon-free-free treatment regimen, a previously unattained moderate – and not merely minor – improvement in the therapy-relevant benefit of dasabuvir has been identified.
  • Due to the lack of direct comparative studies, the G-BA was only able to carry out a limited quantitative comparative analysis of side effects by type, severity and frequency.

e) Treatment-naive patients and treatment-experienced patients with HIV co-infection, genotype 1a/1b: Dasabuvir in combination with ombitasvir/paritaprevir/ritonavir (genotype 1b without cirrhosis) Dasabuvir in combination with ombitasvir/paritaprevir/ritonavir plus ribavirin (genotype 1a, genotype 1b with compensated cirrhosis)

• 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 dasabuvir 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.
• Morbidity – sustained virological response (SVR)
  • In patients with genotype 1 HCV infection and HIV-1 co-infection, the SVR-12 rate for the 12-week treatment regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir plus ribavirin was 93.5% (29/31) and 90.6% (29/32) for the 24-week treatment regimen, respectively.
  • Given the considerable magnitude of the SVR rates achieved, and despite the analysis of individual study arms, treatment with ombitasvir/paritaprevir/ritonavir in combination with dasabuvir plus ribavirin is considered equivalent to dual therapy (ribavirin plus peginterferon alfa) with regard to this endpoint.
• Side effects
  • According to the Exviera® summary of product characteristics (SmPC), treatment of patients with genotype 1 HCV infection and HIV-1 co-infection is based on the genotype (genotype 1a or 1b) and the presence of compensated cirrhosis (yes/no) for 12 weeks or 24 weeks with a combination of ombitasvir/paritaprevir/ritonavir plus dasabuvir, plus ribavirin where appropriate.
  • With regard to the appropriate comparator therapy, a 48-week treatment cycle of a regimen containing peginterferon and ribavirin is specified as the standard dual therapy for patients with genotype 1 HCV infection and HIV-1 co-infection.
  • 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 12 or 24 weeks, as opposed to the appropriate comparator therapy containing interferon, is considered relevant in terms of avoiding side effects.
• Overall assessment
  • In an overall assessment in the sense of an indirect comparison, the G-BA identifies a minor additional benefit in patients with genotype 1 HCV infection and HIV-1 co-infection compared with the appropriate comparator therapy, due to the significant avoidance of side effects.
  • The certainty of the findings is classified as a hint, based on the analysis of individual study arms for evidence of an adequate response in terms of SVR and the comparative analysis of the adverse effect profiles of the dasabuvir regimens on the one hand and the appropriate comparator therapy containing interferon on the other.
  • Compared with the appropriate comparator therapy, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a previously unattained moderate—and not merely minor—improvement in the treatment-related benefit of dasabuvir has been observed, in particular through a significant reduction in side effects due to the availability of an interferon--free treatment regimen, a moderate and not merely minor improvement in the therapy-relevant benefit for dasabuvir has been identified, which has not been achieved to date.
  • Due to the lack of direct comparative studies, the G-BA was only able to carry out a limited quantitative comparative analysis of side effects by type, severity and frequency.

Courtesy translation only, please refer to the German original.