Ledipasvir / Sofosbuvir (2) – Harvoni®

• Clinical trials
  • The pharmaceutical manufacturer presents results from a patient population (n=80) of Study 1116 (interim report) for treatment-naïve patients with genotype 1 infection. This is an open-label, single-arm study investigating ledipasvir/sofosbuvir in treatment-naïve and previously treated children aged 3 to 18 years.
  • The pharmaceutical manufacturer submits results for a patient population (n=20) from the open-label, single-arm Study 1116 (interim report) for treatment-experienced patients with genotype 1 infection.

a) Treatment-naïve patients with chronic hepatitis C aged 12 to < 18 years, genotypes 1, 4, 5 or 6

• For treatment-naïve patients aged 12 to < 18 years with chronic hepatitis C infection of genotype 1, 4, 5 or 6, there is a hint of a non-quantifiable additional benefit.
• Overall, there is a hint of a non-quantifiable additional benefit for treatment-naïve patients aged 12 to < 18 years with chronic hepatitis C infection of genotypes 1, 4, 5 or 6.
• Morbidity – Sustained virological response (SVR)
  • A sustained virological response at 12 (SVR12) or 24 weeks (SVR24) was achieved in study 1116 with LDV/SOF in 78 out of 80 (97.5 per cent) treatment-naïve patients.
  • In view of the findings from previous benefit assessments for the indication of chronic hepatitis C, it cannot be assumed that similarly high response rates will be achieved with the appropriate comparator therapy, peginterferon alfa plus ribavirin.
  • For the endpoint category of morbidity, there is therefore an additional benefit compared with the appropriate comparator therapy; however, the extent of this benefit in the adolescent population cannot be quantified in more detail due to the lack of comparative data.
• Health-related quality of life
  • An assessment of health-related quality of life was not included in the interim report of Study 1116 and was not addressed by the pharmaceutical manufacturer.
• Side effects
  • There were no deaths, no serious adverse events, nor any adverse events that led to therapy discontinuation due to adverse events.
  • 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 possibility of an interferon--free therapy lasting 8 or 12 weeks, as opposed to the appropriate comparator therapy containing interferon, is considered relevant in terms of avoiding side effects.
  • The certainty of the evidence must be regarded as limited due to the single-arm study design.
• Conclusion
  • The results from the interim report of the open-label, single-arm study 1116 are available for the assessment of additional benefit in the patient group of treatment-naïve patients with chronic hepatitis C aged 12 to < 18 years with genotype 1 infection.
  • The results of the single-arm study show that advantages in terms of morbidity can be inferred for the endpoint of sustained virological response (SVR12) and for adverse events.
  • Due to the single-arm study design, it is not possible to quantify the extent of the additional benefit in the adolescent population.
  • As no patients with genotype 4, 5 or 6 infection were included in Study 1116, the derivation of additional benefit is only possible through evidence transfer.
  • For patients with genotype 4, additional benefit can be extrapolated from studies in adults, in which ledipasvir/sofosbuvir demonstrated an advantage in terms of SVR12 and in avoiding the side effects of peginterferon therapy.
  • For patients with genotype 5 or 6 infection, an additional benefit compared with the appropriate comparator therapy is also derived on the basis of the SmPC and the treatment standards established in clinical practice.

b) Treatment-naïve patients with chronic hepatitis C and compensated cirrhosis aged 12 to < 18 years, genotype 3

• An additional benefit is not proven for treatment-naive patients aged 12 to < 18 years with chronic hepatitis C infection of genotype 3.
• An additional benefit is therefore not proven for treatment-naïve patients aged 12 to < 18 years with chronic hepatitis C infection of genotype 3 and compensated cirrhosis.
• The pharmaceutical manufacturer has not provided any data for patients with genotype 3 infection.
• Consequently, no data are available to assess any additional benefit compared with the appropriate comparator therapy.
• As no additional benefit has been demonstrated in adult patients with genotype 3, it is not possible to extrapolate such a benefit to the adolescent population.
• Furthermore, it can be inferred from the current evidence base and the written and oral statements that genotype 3 exhibits different response rates and – consequently – requires different treatment regimens; even in adults, treatment with ledipasvir/sofosbuvir should not be regarded as the standard treatment for genotype 3 infection.

c) Previously treated patients with chronic hepatitis C aged 12 to < 18 years, genotypes 1, 4, 5 or 6

• For previously treated patients aged 12 to < 18 years with chronic hepatitis C infection of genotypes 1, 4, 5 or 6, there is a hint of a non-quantifiable additional benefit.
• Overall, there is a hint of a non-quantifiable additional benefit for previously treated patients aged 12 to < 18 years with chronic hepatitis C infection of genotypes 1, 4, 5 or 6.
• Morbidity – Sustained virological response (SVR)
  • A sustained virological response at 12 (SVR12) or 24 weeks (SVR24) was achieved in study 1116 with ledipasvir/sofosbuvir in 20 out of 20 (100 per cent) treatment-experienced patients.
  • In view of the findings from previous benefit assessments for the indication of chronic hepatitis C, it cannot be assumed that similarly high response rates will be achieved with the appropriate comparator therapy, best supportive care.
  • For the endpoint category of morbidity, there is therefore an additional benefit in the adolescent population compared with the appropriate comparator therapy; however, the extent of this benefit cannot be determined more precisely due to the lack of comparative data.
• Health-related quality of life
  • Assessments of health-related quality of life were not included in the interim report on Study 1116 that was submitted and were not addressed by the pharmaceutical manufacturer.
• Side effects
  • There were no deaths, no serious adverse events, nor any adverse events that led to therapy discontinuation due to adverse events.
  • Consequently, the endpoint categories of quality of life and side effects provide no further hints on which to base a conclusion regarding the additional benefit.
• Conclusion
  • The results from the interim report of the open-label, single-arm Study 1116 are available for the assessment of additional benefit in the patient group comprising treatment-experienced patients with chronic hepatitis C aged 12 to < 18 years with genotype 1 infection.
  • The results of the single-arm study show that advantages in terms of morbidity can be inferred for the endpoint of sustained virological response (SVR12) and for adverse events.
  • Due to the single-arm study design, it is not possible to quantify the extent of the additional benefit in the adolescent population.
  • As no patients with genotype 4, 5 or 6 infection were included in Study 1116, the derivation of additional benefit is only possible through evidence transfer.
  • For patients with genotype 4, additional benefit can be extrapolated from studies in adults, in which ledipasvir/sofosbuvir demonstrated an advantage in terms of SVR12.
  • For patients with genotype 5 or 6 infection, an additional benefit compared with the appropriate comparator therapy is also derived on the basis of the summary of product characteristics (SmPC) and the treatment standards established in clinical practice.

d) Previously treated patients with chronic hepatitis C aged 12 to < 18 years, genotype 3

• Additional benefit is not proven for treatment-naive patients aged 12 to < 18 years with chronic hepatitis C infection of genotype 3.
• An additional benefit is therefore not proven for previously treated patients aged 12 to < 18 years with chronic hepatitis C infection of genotype 3.
• The pharmaceutical manufacturer has not provided any data for patients with genotype 3 infection.
• Consequently, no data are available to assess any additional benefit compared with the appropriate comparator therapy.
• Nor was any additional benefit established for adult patients in the resolution of 21 May 2015, as insufficient data were provided.
• As no additional benefit has been demonstrated in adult patients with genotype 3, it is not possible to extrapolate such a benefit to the adolescent population.
• Furthermore, it can be inferred from the current evidence base and the written and oral submissions that genotype 3 exhibits differing response rates and – consequently – requires different treatment regimens; therefore, even in adults, treatment with ledipasvir/sofosbuvir should not be regarded as the standard treatment for genotype 3 infection in adults either.

Courtesy translation only, please refer to the German original.