Bulevirtid (4) – Hepcludex®

• Clinical trials
  • The MYR301 trial is a multicentre, randomised, open-label Phase III trial designed to assess the efficacy and safety of bulevirtide.

a) Adults with chronic hepatitis D infection and compensated liver disease

• For adults with chronic hepatitis D infection and compensated liver disease, the additional benefit is not proven.
• mortality
  • No deaths occurred during the relevant observation period (48 weeks) in the MYR301 trial.
• Morbidity – liver-related events
  • The combined endpoint of liver-related events was assessed, defined as the development of cirrhosis, the development or worsening of jaundice, coagulation disorders, ascites, hepatic encephalopathy, bleeding from oesophageal varices, the development of hepatocellular carcinoma, liver transplantation, hospital admissions due to liver-related causes, or death due to liver-related causes.
  • No events occurred in either study arm during the relevant 48-week observation period.
• Morbidity – Fatigue
  • Fatigue was assessed as a patient-reported endpoint using the ‘Fatigue Severity Scale’ (FSS) questionnaire.
  • For the benefit assessment, the responder analysis is used, defined as an improvement of at least 15% of the scale range at week 48. There is no statistically significant difference between the treatment arms.
• Morbidity – Health status
  • The health status endpoint was assessed using the EQ-5D visual analogue scale.
  • An increase in the score of ≥ 15% of the scale range compared with baseline is considered a clinically relevant improvement. There was no statistically significant difference between the treatment arms.
• Morbidity – Virological response
  • The primary endpoint of the study was the combined virological and biochemical response.
  • There are currently insufficient data available to validate this as a surrogate parameter for the prevention of liver-related, patient-relevant morbidity endpoints (e.g. the development of liver fibrosis/cirrhosis, the development of hepatocellular carcinoma) or for the endpoint of mortality.
  • However, virological response is a significant endpoint for assessing the clinical course of HDV infection and is therefore presented as supplementary information.
  • With regard to virological response, based on the criterion of ‘a ≥ 2 log10 reduction in viral load’, there is a statistically significant advantage in favour of bulevirtide compared with best supportive care. In the ‘undetectable HDV RNA’ component, however, there is no statistically significant difference between the treatment arms.
• Health-related quality of life – Hepatitis Quality of Life Questionnaire (HQLQ/SF-36)
  • Health-related quality of life was assessed using the Hepatitis Quality of Life Questionnaire (HQLQ), which measures both general and disease-specific well-being.
  • For the benefit assessment, the analysis uses the responder analysis to determine the proportion of patients showing an improvement of at least 15% of the scale range by week 48.
  • There were no statistically significant differences between the treatment arms, either for the total scores or for the hepatitis-specific domains.
• Side effects
  • In the MYR301 study, adverse events (AEs) occurred in 83.7% (bulevirtide) and 80.4% (best supportive care) of participants, respectively.
  • For the endpoints ‘severe adverse events’ and ‘serious unwelcome events’ (SAEs), no statistically significant differences were observed between the treatment arms.
  • No AEs leading to discontinuation of the study medication occurred in the trial.
  • In detail, a statistically significant effect to the detriment of bulevirtid was observed for the endpoints ‘General disorders and administration site conditions’ and ‘Nervous system disorders’.
  • Overall, however, no differences relevant to the benefit assessment were identified for the endpoint category ‘side effects’.
• Overall assessment
  • The MYR301 study, which assessed the efficacy and safety of bulevirtid, was submitted for the evaluation of additional benefit. Directly comparable data are available against the appropriate comparator therapy for the endpoint categories of mortality, morbidity, health-related quality of life and side effects over a treatment period of 48 weeks.
  • No deaths occurred in the MYR301 study.
  • In the morbidity endpoint category, there was no statistically significant difference between the treatment arms for the endpoints of liver-related events, fatigue and health status.
  • The surrogate endpoint of virological response is a key endpoint for assessing the clinical course of HDV infection and is presented for supplementary information. For virological response, based on the component ‘decrease in viral load of ≥ 2 log10’, there is a statistically significant advantage in favour of bulevirtid compared with best supportive care. In the ‘undetectable HDV RNA’ component, however, there is no statistically significant difference between the treatment arms.
  • In the health-related quality of life endpoint category, as assessed using the HQLQ-SF-36, there were no statistically significant differences between the treatment arms in the overall population, neither for the total scores nor for the hepatitis-specific domains.
  • In the ‘side effects’ endpoint category, there was no statistically significant difference between the treatment arms for either severe AEs or severe SAEs. No AEs leading to discontinuation of the study medication occurred during the trial. In detail, a statistically significant disadvantage for bulevirtid was observed for the endpoints ‘General disorders and administration site conditions’ and ‘Nervous system disorders’. Overall, however, no differences relevant to the benefit assessment were identified for the side effect endpoint category.
  • On balance, there are no advantages or disadvantages of bulevirtid compared with the appropriate comparator therapy that are relevant to the benefit assessment. An additional benefit is therefore not proven.
• Overall assessment
  • On balance, there are no advantages or disadvantages of bulevirtid compared with the appropriate comparator therapy that are relevant to the benefit assessment.

b) Children and adolescents aged 3 to < 18 years with chronic hepatitis D infection and compensated liver disease

• For children and adolescents aged 3 to < 18 years with chronic hepatitis D infection and compensated liver disease, the additional benefit is not proven.
• No data from comparative studies are available for this patient group.
• It is therefore concluded that the additional benefit of bulevirtid for children and adolescents aged 3 to < 18 years with chronic hepatitis D infection is not proven.

Courtesy translation only, please refer to the German original.