Resmetirom (1) – Rezdiffra®

• Clinical trials
  • For the benefit assessment of resmetirom for the treatment of adults with non-cirrhotic, non-alcoholic steatohepatitis (MASH) who have moderate to advanced liver fibrosis (fibrosis stages F2 to F3), the pharmaceutical manufacturer presents results from the ongoing, multicentre, double-blind, placebo-controlled, Phase III MAESTRO-NASH trial.
  • In addition, the pharmaceutical manufacturer is presenting the results from a patient population of the double-blind, placebo-controlled MAESTRO-NAFLD-1 study, as well as from the completed, double-blind RCT MGL-3196-05.

Adults with non-cirrhotic, non-alcoholic steatohepatitis (MASH) who have moderate to advanced liver fibrosis (fibrosis stages F2 to F3)

• The additional benefit is not proven.
• mortality
  • Fatalities were recorded in the MAESTRO-NASH study as part of the safety assessment. Two fatalities occurred in the resmetirom arm and one in the placebo arm. There was no statistically significant difference between the treatment groups.
• Morbidity – serious adverse cardiac events (MACE)
  • In the MAESTRO-NASH study, MACE is defined as a composite endpoint comprising the three individual components: cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke. These events were recorded as part of the side effect monitoring.
  • No statistically significant difference was observed between the treatment groups in the composite endpoint MACE.
• Morbidity – Fibrosis response
  • The fibrosis response was one of the primary endpoints of the interim analysis at week 52 of the MAESTRO-NASH study. Histological improvement was assessed based on liver biopsies taken at week 52 (± 10 days) compared with baseline.
  • Endpoints such as fibrosis response, which are based on imaging or histological assessments, are not in themselves patient-relevant. Furthermore, there is insufficient evidence overall to provide proof that this endpoint is a sufficiently valid surrogate for patient-relevant endpoints such as mortality, the avoidance or delay of a liver transplant, or symptomatic progression to liver cirrhosis.
  • However, as the change in fibrosis stage is an important prognostic factor, this endpoint is presented as a supplementary measure.
• Quality of life – Short Form-36 Health Survey Version 2 (SF-36v2)
  • With regard to health-related quality of life, assessed using the SF-36v2, there was no statistically significant difference between the treatment groups for either the physical composite score (PCS) or the mental composite score (MCS).
• Quality of life – Chronic Liver Disease Questionnaire (CLDQ) NAFLD/NASH
  • With regard to health-related quality of life, as assessed using the CLDQ-NAFLD/NASH, there was no statistically significant difference between the treatment groups.
• Side effects
  • No statistically significant differences were observed between the treatment groups for the overall rates of serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3) or discontinuation due to AEs.
  • In detail, a statistically significant advantage was observed in favour of resmetirom compared with placebo for the endpoints of gastrointestinal disorders and vascular disorders. These endpoints are based on severe and serious adverse events at the System Organ Class (SOC) level.
  • Furthermore, a statistically significant difference in favour of placebo compared with resmetirom was observed for the endpoint ‘diarrhoea’. For this endpoint, there is an effect modification by the characteristic of sex. For men, there is a statistically significant disadvantage of resmetirom compared with placebo, whilst for women there is no statistically significant difference between the treatment groups. These endpoints are based on non-serious and non-severe adverse events at the PT level.
  • Overall, no differences relevant to the benefit assessment are identified for the category of side effects.
• Overall assessment
  • There is no evidence of additional benefit from resmetirom in combination with diet and exercise for the treatment of adults with non-cirrhotic, non-alcoholic steatohepatitis (MASH) who have moderate to advanced liver fibrosis (fibrosis stages F2 to F3). It is not proven.

Courtesy translation only, please refer to the German original.