Sofosbuvir / Velpatasvir (1) – Epclusa®

• Clinical trials
  • The ASTRAL-1 study was a multicentre, randomised, double-blind trial comparing sofosbuvir/velpatasvir (12 weeks) with placebo in treatment-naïve and treatment-experienced adults with HCV infection of genotype 1, 2, 4, 5, 6 or of undetermined genotype, in each case without cirrhosis or with compensated cirrhosis.
  • The ASTRAL-2 study is a randomised, active-controlled, open-label study sponsored by the pharmaceutical manufacturer, which was conducted at 51 study centres in the USA.
  • The ASTRAL-3 study is a randomised, actively controlled, open-label study sponsored by the pharmaceutical manufacturer, which was conducted at 76 study centres in Australia, Germany, France, Italy, Canada, New Zealand, the USA and the United Kingdom.
  • The ASTRAL-4 study was conducted at 47 centres in the USA. It is a randomised, open-label study comparing different sofosbuvir/velpatasvir treatment regimens in treatment-naïve and treatment-experienced adults with HCV infection of genotype 1, 2, 3, 4, 5 or 6, all of whom had decompensated cirrhosis (Child-Pugh-Turcotte [CPT] class B).
  • The GS-US-342-0102 study was conducted at 48 centres in the USA. This was a randomised, open-label study comparing different treatment regimens of sofosbuvir/velpatasvir (8 or 12 weeks) in treatment-naïve adults with HCV infection of genotypes 1, 2, 3, 4, 5 or 6 without cirrhosis.
  • The GS-US-342-0109 study was conducted at 58 centres in Australia, New Zealand and the USA. This is a randomised, open-label study comparing different treatment regimens of sofosbuvir/velpatasvir (12 weeks) in treatment-experienced adults with HCV infection of genotype 1 or 3, all without cirrhosis or with compensated cirrhosis.

a) Patients without cirrhosis, genotype 1

• The additional benefit is not proven.
• Mortality and morbidity
  • For the patient-relevant endpoints of mortality and morbidity (sustained virological response 12 weeks after the end of treatment [SVR12]) evaluated in the historical control, there are no significant differences between the treatment groups. There is no hint of additional benefit.
• quality of life
  • Health-related quality of life is not assessed in the indirect comparison. No data relevant to the assessment of quality of life are available.
• Side effects
  • There are no significant differences between the treatment groups regarding SAE or therapy discontinuation due to AEs. For the endpoint category of side effects, there is therefore no hint of additional benefit.
• Overall assessment
  • Overall, no additional benefit of sofosbuvir/velpatasvir can be identified for this patient group compared with the appropriate comparator therapy, ledipasvir/sofosbuvir.

b) Patients with compensated cirrhosis, genotype 1

• The additional benefit is not proven.
• Mortality and morbidity
  • For the patient-relevant endpoints of mortality and morbidity (sustained virological response 12 weeks after the end of treatment [SVR12]) evaluated in the historical control, there are no significant differences between the treatment groups. There is no hint of additional benefit.
• quality of life
  • Health-related quality of life is not assessed in the indirect comparison. No data relevant to the assessment of quality of life are available.
• Side effects
  • For SAE, there is a statistically significant difference with a relative risk of 0.06 (confidence interval cannot be meaningfully calculated) and p=0.004, based on 0 patients with an event for sofosbuvir/velpatasvir and 13 (9.8%) patients for ledipasvir/sofosbuvir.
  • There is no significant difference between the treatment groups for the endpoint of therapy discontinuation due to AEs. For the endpoint category of side effects, there is therefore no overall hint of additional benefit.
• Overall assessment
  • On the basis of the indirect comparison submitted by the pharmaceutical manufacturer, no additional benefit of sofosbuvir/velpatasvir compared with the appropriate comparator therapy, ledipasvir/sofosbuvir, can be inferred. An additional benefit is therefore not proven.

c) Patients without cirrhosis or with compensated cirrhosis, genotype 2

• Hint of a minor additional benefit.
• The G-BA assesses the extent of the additional benefit as ‘minor’ on the basis of the criteria set out in Section 5(7) of the AMNutzenV, taking into account the severity of the disease and the overall therapeutic objective for the disease.
• mortality
  • Two deaths occurred in the group treated with sofosbuvir/velpatasvir, and none in the comparator group. The difference is not statistically significant. There are no hints of additional benefit or of greater harm.
• morbidity
  • A statistically significant difference was observed for SVR12 (relative risk [95% confidence interval] of 1.06 [1.01; 1.11] with p=0.018) between the treatment groups in favour of sofosbuvir/velpatasvir.
  • Given the clinical relevance of SVR and the magnitude of the effect size for SVR, with an absolute risk reduction of 5.4% (99.3% vs. 93.9%), a minor additional benefit is observed in this patient group.
• quality of life
  • The SF-36 analyses show no significant differences between the treatment groups. There are no hints to suggest an additional benefit.
• Side effects
  • There are no statistically significant differences between the treatment groups for SAEs or therapy discontinuation due to SAEs.
  • For the AEs ‘fatigue’, ‘diarrhoea’, ‘vomiting’, ‘headache’, ‘fever’, ‘chest pain’, ‘dizziness’, ‘rash’, ‘rash with fever’, ‘rash with fever and chills’, there is an absolute risk reduction of 20.7% in favour of sofos 0.67] with p<0.001).
  • The extent of the additional benefit resulting from the statistically significantly lower incidence of psychiatric disorders under sofosbuvir/velpatasvir is assessed as minor.
• Overall assessment
  • An analysis of the individual endpoints SVR12 and psychiatric disorders suggests that an additional benefit can be inferred from the available data.
• Conclusiveness
  • Overall, therefore, the ASTRAL-2 study provides, at most, hints of additional benefit.

d) Patients without cirrhosis or with compensated cirrhosis, genotype 3

• Hint of considerable additional benefit.
• The G-BA assesses the extent of the additional benefit as ‘considerable’ on the basis of the criteria in Section 5(7) of the AMNutzenV, taking into account the severity of the disease and the therapeutic objective for the disease as a whole.
• mortality
  • There were no deaths in the group treated with sofosbuvir/velpatasvir, compared with three in the control group. Due to the differing observation periods, this result cannot be interpreted conclusively. There are no hints of additional benefit.
• morbidity
  • For SVR12, there is a statistically significant difference (relative risk [95% confidence interval] of 1.19 [1.11; 1.26] with p<0.001) in favour of sofosbuvir/velpatasvir, with an absolute risk reduction of 14.9% (95.3% vs. 80.4%).
  • Given the clinical relevance of SVR and the magnitude of its effect, a considerable additional benefit is considered to exist in this patient group.
• quality of life
  • The results on health-related quality of life (SF-36 questionnaire) cannot be meaningfully interpreted due to the differing total observation periods (treatment plus follow-up). There are no hints to suggest any additional benefit.
• Side effects
  • For the endpoint of therapy discontinuation due to AEs, there is a statistically significant difference in favour of sofosbuvir/velpatasvir (relative risk [95% confidence interval] of 0.05 [0.00; 0.89] with p<0.042; absolute risk reduction 3.3%).
  • Given the clinical relevance of the endpoint ‘therapy discontinuation due to AEs’ and the magnitude of the effect size, a minor additional benefit is observed in this patient group.
• Overall assessment
  • Based on an analysis of the individual endpoints SVR12 and therapy discontinuation due to AEs, an additional benefit can be inferred from the available data.
• Level of certainty
  • Overall, therefore, the ASTRAL-3 study provides, at most, hints of additional benefit.

e) Patients without cirrhosis, genotype 4

• An additional benefit is not proven.
• Mortality and morbidity
  • For the patient-relevant endpoints of mortality and morbidity (SVR12) evaluated in the historical control, there are no significant differences between the treatment groups. There is no hint of additional benefit.
• quality of life
  • Health-related quality of life is not assessed in the indirect comparison. No data relevant to the assessment of quality of life are available.
• Side effects
  • There are no significant differences between the treatment groups regarding SAE or therapy discontinuation due to AEs. There is therefore no hint of additional benefit for the endpoint category of side effects.
• Overall assessment
  • Overall, no additional benefit of sofosbuvir/velpatasvir can be identified for this patient group compared with the appropriate comparator therapy of ombitasvir/paritaprevir/ritonavir plus ribavirin.

f) Patients with compensated cirrhosis, genotype 4

• The additional benefit is not proven.
• On the basis of the non-comparative data, no additional benefit of sofosbuvir/velpatasvir compared with the appropriate comparator therapy, ledipasvir/sofosbuvir, can be inferred.

g) Patients without cirrhosis or with compensated cirrhosis, genotype 5 or genotype 6

• The additional benefit is not proven.
• On the basis of the non-comparative data, no additional benefit of sofosbuvir/velpatasvir compared with the appropriate comparator therapy, ledipasvir/sofosbuvir, can be inferred. An additional benefit is therefore not proven.

h) Patients with decompensated cirrhosis, genotype 1

• The additional benefit is not proven.
• Mortality and morbidity
  • For the patient-relevant endpoints of mortality and morbidity (SVR12) evaluated in the historical control, there are no significant differences between the treatment groups. There is no hint of additional benefit.
• quality of life
  • Health-related quality of life is not assessed in the indirect comparison. No data relevant to the assessment of quality of life are available.
• Side effects
  • There are no significant differences between the treatment groups with regard to SAE. For the endpoint of therapy discontinuation due to AEs, the pharmaceutical manufacturer reports a relative risk [95% confidence interval] of 7.68 [1.00; 58.80] with p=0.0498.
  • Conclusions regarding additional benefit based on non-adjusted indirect comparisons are only possible in cases of dramatic effects where it can be ruled out that they are due to systematic bias. This is not achieved by the observed effect. For the endpoint category of side effects, there is therefore no hint of additional benefit.
• Overall assessment
  • On balance, no additional benefit of sofosbuvir/velpatasvir can be identified for this patient group compared with the appropriate comparator therapy, ledipasvir/sofosbuvir plus ribavirin.

i) Patients with decompensated cirrhosis, genotypes 2, 3, 4, 5 or 6

• Hint for a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of sofosbuvir/velpatasvir compared with the appropriate comparator therapy, based on the criteria in Section 5(7) of the AMNutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease as a whole, as non-quantifiable, because the scientific evidence does not permit this.
• The SVR12 endpoint is achieved by between 84.6% and 100% of patients.
• Overall, the G-BA identifies an additional benefit for sofosbuvir/velpatasvir in the treatment of genotypes 2, 3, 4, 5 and 6, based on the achievement of SVR12.
• Level of certainty
  • Due to the non-comparative nature of the data analysis, the certainty of the findings is classified as a hint.

Courtesy translation only, please refer to the German original.