Daclatasvir (1) – Daklinza®

• Clinical trials
  • These studies investigate morbidity endpoints such as sustained virological response (SVR) and the occurrence of side effects.
  • To demonstrate additional benefit, the pharmaceutical manufacturer’s dossier draws on two randomised controlled trials (AI444042, AI444010) as well as non-adjusted indirect comparisons involving individual study arms of the open-label, randomised trial AI444040.
  • The AI444040 study is a multi-arm (10 study arms in total) open-label, randomised Phase II trial in which daclatasvir in combination with sofosbuvir, with or without ribavirin, was investigated over a treatment duration of 12 or 24 weeks for the treatment of chronic infection with HCV genotype 1, 2 or 3 in 211 adults without cirrhosis.
  • The AI444010 study was a randomised, placebo-controlled, double-blind, multicentre study that enrolled treatment-naïve patients with CHC genotype 1 or 4.
  • The ALLY 3 study investigated treatment-naïve and treatment-experienced HCV patients with genotype 3 infection (with and without cirrhosis) over a 12-week treatment period.
  • The ALLY 2 study included HCV patients with genotype 1, 2, 3, 4, 5 or 6 infection and HIV co-infection (treatment-naïve, treatment-experienced). The combination of daclatasvir (30, 60 or 90 mg) and sofosbuvir (400 mg) was investigated over a treatment period of 8 or 12 weeks.

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

• 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 daclatasvir 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 consideration of a single study arm for demonstrating an adequate response in terms of SVR and the comparative analysis of the adverse reaction profiles of the daclatasvir regimen and, on the other hand, the interferon-containing appropriate comparator therapy on the other, is classified as a hint.
• Morbidity – sustained virological response (SVR)
  • In the AI444040 study, 41 treatment-naïve patients without cirrhosis and with genotype 1 HCV infection were treated for 12 weeks with a combination of daclatasvir and sofosbuvir. Of these patients, 100 per cent (41/41) achieved SVR 12.
  • Given the considerable magnitude of the SVR rate achieved, it is assumed – despite the analysis being based on a single study arm – that treatment with the combination of daclatasvir and sofosbuvir is equivalent to the appropriate comparator therapy with regard to this endpoint.
• Side effects
  • Taking into account the adverse effects of treatment with peginterferon, which have been provided with sufficient proof in studies and are described in the summary of product characteristics (SmPC), the possibility of a 12-week course of interferon--free therapy lasting 12 weeks compared with 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 in treatment-naïve HCV patients without cirrhosis (genotype 1) compared with the appropriate comparator therapy, due to the relevant avoidance of side effects.
• Overall assessment
  • For the patient group listed, there is a hint of a minor additional benefit compared with the appropriate comparator therapy. Reasoning: 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, the principles of evidence-based medicine applicable to the benefit assessment of a new INN require that proof of a causal link between a therapeutic intervention and an effect, compared with another therapeutic intervention, in order to be able to draw conclusions 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).
  • 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 daclatasvir has been observed, in particular through the significant avoidance of side effects due to the availability of an interferon-free-free treatment regimen, a moderate—and not merely minor—improvement in the therapy-relevant benefit of daclatasvir has been observed, which had not previously been achieved.

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

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

c) Treatment-experienced patients, genotype 1

• Morbidity – sustained virological response (SVR)
  • In the AI444040 study, 21 HCV patients (without cirrhosis) who had not responded to prior treatment with a protease inhibitor regimen (boceprevir or telaprevir), were treated with daclatasvir in combination with sofosbuvir for 24 weeks in accordance with this recommendation. These 21 patients achieved an SVR12 of 100 per cent.
• Due to the lack of statistical significance arising from the minor number of study patients who had failed triple therapy containing boceprevir or telaprevir, as well as the lack of data for patients who had failed peginterferon/ribavirin therapy, the additional benefit is not proven for the group of treatment-experienced HCV patients with genotype 1 infection.

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

• For the patient groups listed, the additional benefit is not proven compared with the appropriate comparator therapy. There are insufficient data available for these patients to assess the additional benefit.
• For treatment-naïve patients (with compensated cirrhosis) and treatment-experienced patients with genotype 3, the Daklinza® summary of product characteristics (SmPC) contains a recommendation for a treatment duration of 24 weeks. This treatment regimen was not investigated in the ALLY 3 study. The ALLY 3 study is therefore not suitable for assessing the additional benefit for this patient group.

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

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

f) Treatment-naïve patients, genotype 4

• For treatment-naïve patients (genotype 4), an overall analysis of the results on mortality, morbidity and side effects provides a hint of a considerable additional benefit of daclatasvir in combination with peginterferon alfa and ribavirin compared with the appropriate comparator therapy [peginterferon alfa + ribavirin].
• The certainty of the findings from study AI444042, particularly with regard to the possible uncertainty of the SVR 24 results, is classified as a ‘hint’.
• mortality
  • No deaths occurred in the AI444042 study.
• Morbidity – sustained virological response (SVR)
  • The AI444042 study shows a statistically significant result in favour of daclatasvir + peginterferon alfa + ribavirin for SVR 24. Taking into account patients who discontinued the study but for whom the treatment itself was completed, there is a statistically significant advantage for daclatasvir + peginterferon alfa + ribavirin in terms of SVR 24 (reference value: without imputing missing values), there is a statistically significant advantage for daclatasvir + peginterferon alfa + ribavirin (RR 1.54; CI [1.12; 2.11]; p = 0.008) with an absolute risk reduction (ARR) of 30.2 %.
  • The sensitivity analysis using the imputation strategy ‘all patients with missing values are classified as responders’ is also statistically significant (RR 1.32; CI [1.02; 1.71]; p = 0.036; ARR = 21.3%).
  • Given the clinical relevance of SVR, a considerable additional benefit is observed in this patient group.
• Side effects
  • In the AI444042 study, there were no statistically significant differences in the incidence of serious adverse events or therapy discontinuations due to adverse events.
  • The overall shorter follow-up period in the daclatasvir arm works in favour of daclatasvir. The higher frequency of therapy discontinuations due to discontinuation criteria in the control arm works in favour of the control group.
• Overall assessment
  • For treatment-naive patients (genotype 4), an overall analysis of the results on mortality, morbidity and side effects provides a hint of a considerable additional benefit of daclatasvir in combination with peginterferon alfa and ribavirin compared with the appropriate comparator therapy [peginterferon alfa + ribavirin].
  • Reasoning: The G-BA classifies the extent of the additional benefit of daclatasvir 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, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, there is a considerable improvement in the therapy-relevant benefit, resulting from a statistically significant improvement in sustained virological response (SVR).
  • There are no statistically significant differences with regard to side effects. However, due to methodological shortcomings, the results concerning side effects can only be interpreted to a limited extent.
  • There are no sufficiently robust results available for an assessment of health-related quality of life. No deaths occurred in the study.
  • The randomised controlled trial AI444042, which is used to assess this patient group, has methodological shortcomings that result in differing proportions of missing values in the two treatment arms. This results in potential uncertainty regarding the treatment effect for the morbidity-related endpoint SVR.
  • The sensitivity analyses for the SVR 24 endpoint, which incorporate different imputation strategies for missing values, show that the effect estimator is predominantly statistically significant. The only result that is not statistically significant is found in the analysis using the imputation strategy ‘all patients with missing values in the daclatasvir arm are classified as non-responders; for the control arm, the observed risk is assumed’. However, this analysis represents the most conservative approach.
  • Taking the sensitivity analyses into account, the results for SVR 24 are nevertheless considered sufficiently robust, albeit subject to a high degree of uncertainty.

g) Treatment-experienced patients, genotype 4

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

Courtesy translation only, please refer to the German original.