Bulevirtid (1) – Hepcludex®

• Clinical trials
  • MYR202 is a multicentre, open-label, randomised Phase II trial designed to investigate the efficacy and safety of three different doses of bulevirtid (2 mg/day, 5 mg/day and 10 mg/day) in combination with tenofovir, compared with tenofovir monotherapy (245 mg/day tenofovir alafenamide) over 24 weeks (modified ITT population: n = 28 in each group) in adult patients with chronic hepatitis D infection.
  • MYR203 is also a multicentre, open-label, randomised Phase II trial. In the study phase completed at the time of the benefit assessment, study arms were included to investigate the efficacy and safety of two different doses of bulevirtide (2 mg/day and 5 mg/day) as monotherapy or in combination with peginterferon alfa-2a compared with peginterferon-alfa-2a in adult patients with chronic hepatitis D infection (full-analysis set: n = 15 in each group).

Adult patients with chronic HDV infection and compensated liver disease who tested positive for HDV-RNA in plasma or serum

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Overall, a non-quantifiable additional benefit is identified.
• mortality
  • No deaths occurred in either of the studies evaluated.
• morbidity
  • Patient-relevant endpoints in the present therapeutic indication include, in particular, the development of symptomatic liver fibrosis, liver cirrhosis or hepatocellular carcinoma. Hepatocellular carcinoma was not recorded in the studies evaluated, and the operationalisation of the assessment of fibrosis or cirrhosis is not considered adequate due to a lack of consistency in the evaluation of liver biopsy findings and differing time points of assessment in the MYR203 study.
  • Virological response is an endpoint of significance for assessing clinical course and is therefore presented as supplementary information. There is no validation of this as a surrogate parameter. In both studies, it was operationalised as a negative HDV-RNA PCR test result or a reduction of ≥ 2 log10 IU/ml at the end of the treatment phase and at the end of the follow-up phase.
  • A negative test result was achieved in only one patient in the bulevirtide/tenofovir arm of the MYR202 study and in two patients each in the control and active treatment arms of the MYR203 study at the end of the treatment phase. The results are not statistically significant.
  • Significantly more patients achieved a reduction in HDV-RNA of ≥ 2log10 IU/ml; in the MYR202 study, this resulted in a statistically significant difference in favour of bulevirtide/tenofovir (n=15; 53.6%) compared with tenofovir (n=1; 3.6%). However, this statistical significance was lost following the follow-up phase.
  • In the MYR203 study, virological response was also defined as a negative HBV DNA test result, which is likewise considered as supplementary data for the present evaluation. However, no significant differences were observed either during the treatment phase or during the follow-up phase.
• health-related quality of life
  • Health-related quality of life was not assessed.
• Overall assessment
  • In the studies presented, there are statistically significant differences in a morbidity endpoint considered as a supplementary measure (reduction in HDV RNA of ≥ 2log10 IU/ml) as well as in the incidence of individual side effects; however, no significant difference is observed in the total number of AEs or SAEs.
  • The results of the MYR203 study suggest that bulevirtide has a better adverse event profile compared with peginterferon alfa-2a. However, due to the minor number of cases and the uncertainty described above regarding the appropriateness of bulevirtide monotherapy for the patients in this study, it is not possible to quantify the extent of this advantage.
  • In summary, it is not possible to quantify the additional benefit of bulevirtide on the basis of the morbidity and adverse reaction data. Due to the methodological limitations of the studies and the overall limited evidence base, the extent of the additional benefit of bulevirtide is assessed as non-quantifiable.
  • A quantitative assessment of the extent of the effect and a classification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data presented. There is an additional benefit, but it is non-quantifiable because the scientific evidence currently does not allow for a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.
• Strength of the evidence
  • The strength of the evidence is limited due to the minor number of patients in both studies, the open-label study design in each case, and the issues with randomisation outlined above. These uncertainties result in a high potential for bias. Consequently, only a hint of additional benefit can be inferred.

Courtesy translation only, please refer to the German original.