Letermovir (3) – Prevymis®

• Clinical trials
  • The pharmaceutical manufacturer has submitted analyses of the MK-8228-001 trial. This was a randomised, double-blind trial to investigate the efficacy and safety of letermovir compared with placebo, conducted as a multicentre study at 67 centres in 20 countries.

Adult CMV-seropositive recipients of allogeneic haematopoietic stem cell transplantation, for the prophylaxis of CMV disease

• Overall, there is a hint of a non-quantifiable additional benefit of letermovir compared with a ‘wait-and-see’ approach.
• mortality
  • At the time of analysis, 48 weeks after stem cell transplantation, there was no statistically significant difference between the study arms.
  • The first 6 months following transplantation are particularly significant in terms of potential CMV reactivation and the possible complications of infection. Although a statistically significant difference in favour of letermovir was observed in the time-to-event analysis (effect estimate using the hazard ratio) at 24 weeks for this period, this advantage was not confirmed over the entire 48-week observation period.
• Morbidity – Clinically significant CMV infection, CMV organ disease and initiation of pre-emptive therapy
  • The occurrence of CMV organ disease is of direct relevance to patients. With regard to the observed events, no statistically significant difference between the treatment arms was observed at any of the analysis time points.
  • The endpoint ‘clinically significant CMV infection’ is the primary endpoint of the study. It comprises the endpoints ‘CMV organ disease’ and ‘initiation of pre-emptive therapy’. There is a statistically significant difference in favour of letermovir at week 24, due to the advantage in the ‘initiation of pre-emptive therapy’ component. No data are available for the combined endpoint at week 48.
• Morbidity – Severe CMV reactivation / CMV disease and total hospitalisation
  • The overall hospitalisation rate does not differ statistically significantly at the same assessment point.
• Morbidity – Acute graft-versus-host disease
  • There were no statistically significant differences in the endpoint of acute graft-versus-host disease between the treatment groups.
• Morbidity – Health status (EQ-5D-VAS)
  • Patients’ health status, as measured using the visual analogue scale of the EQ-5D (EuroQoL 5 Dimensions) 3L questionnaire, is relevant to patients. Analysis of the continuous data revealed no statistically significant difference between the treatment groups.
• Quality of life – FACT-BMT
  • In the analysis of the continuous data, which was carried out on the basis of 10 items from the BTMS subscale, there were no statistically significant differences between the treatment groups, either for the total score or for the subscales (physical well-being, social/ family well-being, emotional well-being, functional well-being and the stem cell transplant-specific subscale).
• Side effects
  • With regard to the endpoints of severe adverse events and discontinuation due to adverse events, no statistically significant differences were observed between the treatment arms at week 16.
  • When examining specific adverse events in detail at week 16, there was a statistically significant disadvantage for letermovir in the endpoint ‘nervous system disorders’ and a statistically significant advantage for letermovir in the endpoint ‘kidney and urinary tract disorders’.
• Overall assessment
  • There is an advantage in terms of overall mortality after a 24-week observation period; however, this is not confirmed after 48 weeks. Furthermore, advantages of letermovir over placebo are observed in the morbidity endpoint category (in the endpoints of clinically significant CMV infection and severe CMV reactivations/CMV diseases). For other morbidity endpoints, health-related quality of life and side effects, there were neither clear benefits nor disadvantages for letermovir.
  • Overall, therefore, on the basis of the results for the endpoints of clinically significant CMV infection and severe CMV reactivation/CMV disease, an additional benefit is identified.
  • There are uncertainties regarding the results for the endpoints ‘incidence of CMV end-organ disease’, ‘severe CMV reactivation/disease’ and ‘acute GvHD’ due to the high proportion of missing values. Furthermore, uncertainties arise from the shortened observation period for the endpoints in the ‘side effects’ category.

Courtesy translation only, please refer to the German original.