Maribavir (1) – Livtencity®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted data from the Phase III multicentre, open-label, randomised controlledstudy SHP620-303, in which maribavir is compared with an anti-CMV therapy assigned by the study staff, comprising the active ingredients ganciclovir, valganciclovir, foscarnet and cidofovir.

Adults who have undergone haematopoietic stem cell transplantation or solid organ transplantation, with a cytomegalovirus infection and/or disease that is refractory to one or more previous therapies (including ganciclovir, valganciclovir, cidofovir or foscarnet)

• In summary, the additional benefit of maribavir is assessed as follows: For adults who have undergone haematopoietic stem cell transplantation or solid organ transplantation, with a cytomegalovirus infection and/or disease that is refractory to one or more previous therapies (including ganciclovir, valganciclovir, cidofovir or foscarnet), there is a hint of a minor additional benefit.
• Overall, there is a hint of a minor additional benefit from maribavir.
• The certainty of the evidence is therefore classified as ‘hint’.
• mortality
  • The endpoint of all-cause mortality was defined as death from any cause and was recorded at all study visits from the time of randomisation throughout the entire study duration.
  • No statistically significant differences were observed between the study arms.
• Morbidity – Infection control
  • The infection control endpoint at week 8 is the primary endpoint of the study. It was defined as a CMV DNA concentration of < 137 IU/ml in blood plasma, confirmed in two consecutive samples taken after baseline, with at least five days between them.
  • Although the CMV-DNA concentration is a laboratory parameter that does not reflect symptoms and is therefore not directly relevant to patients, the infection control endpoint is used for benefit assessment due to the potentially life-threatening situation for patients and its clinical relevance in treatment decision-making.
  • For the endpoint of infection control at week 8, as well as for the maintenance of infection control at week 20, there is a statistically significant advantage for maribavir compared with the control arm.
• Morbidity – Symptom control
  • The ‘symptom control’ endpoint is a composite endpoint which is assessed, depending on the presence of symptoms at baseline, by evaluating tissue-invasive CMV disease and CMV syndrome.
  • Due to the overall lack of clarity regarding its relevance to patients, as well as the unclear added value of the information on clinical relevance compared with the ‘infection control’ endpoint, the combined ‘symptom control’ endpoint is not used for the benefit assessment and is presented here solely for supplementary purposes.
• quality of life
  • Health-related quality of life was assessed in the study using the Short Form 36 Health Survey (SF-36). Due to minor response rates (< 70 %) and large differences (> 15 %) between the study arms on the SF-36, no usable data are available regarding quality of life.
  • The visual analogue scale of the European Quality of Life 5-Dimension (EQ-5D-VAS) was used to assess general health status via an electronic study diary. Due to minor response rates (< 70 %) and large differences (> 15 %) between the study arms of the EQ-5D-VAS, no usable data are available for this endpoint.
• Side effects
  • According to the protocol, the a priori planned follow-up period for all adverse events (AEs) was to extend up to 30 days after the last dose. At this data collection point, the pharmaceutical manufacturer did not provide any statistical analysis. The results are presented descriptively in the resolution.
  • The analyses submitted showed a clear, statistically significant advantage of maribavir for the endpoint ‘AEs leading to discontinuation of study medication’, which is also supported by the descriptive results over the entire study period.
  • In the overall rates of severe AEs, a statistically significant advantage of maribavir was observed within the treatment period; however, due to the uncertainties in the results associated with the smaller effect size, this cannot be taken into account over the entire study period.
  • No statistically significant difference was observed between the study arms in the overall rates of serious AEs.
  • Furthermore, at the SOC level, a statistically significant advantage for maribavir was observed in disorders of the blood and lymphatic system (severe AEs and AEs) and disorders of the kidney and urinary tract (AEs) whilst a statistically significant disadvantage of maribavir was observed for the endpoints disorders of the nervous system (AEs) and disorders of the skin and subcutaneous tissue (AEs).
  • Overall, despite the uncertainties described, maribavir shows advantages in the category of side effects.
• Overall assessment
  • For the benefit assessment of maribavir for the treatment of adults who have undergone haematopoietic stem cell transplantation or solid organ transplantation, with cytomegalovirus infection and/or disease that is refractory to one or more previous therapies (including ganciclovir, valganciclovir, cidofovir or foscarnet), evaluable results on mortality, morbidity and side effects are available based on the SHP620-303 study.
  • In the mortality category, no statistically significant differences were observed between the study arms for the endpoint of overall mortality.
  • In the morbidity endpoint category, a statistically significant advantage of maribavir was observed for the patient-relevant endpoints ‘infection control at week 8’ and ‘maintenance of infection control at week 20’. The ‘symptom control’ endpoint and the graft-related endpoints could not be used for the benefit assessment.
  • No usable data on health-related quality of life are available from the study.
  • In the side effect category, despite remaining uncertainties, a statistically significant advantage of maribavir was observed for the endpoint ‘AE leading to discontinuation of study medication’. In detail, both advantages and disadvantages of maribavir were observed for specific AEs. In the overall rates of ‘serious AEs’ and ‘severe AEs’, no advantage of maribavir was observed in the overall analysis.
  • Taking the available results as a whole, a minor additional benefit of maribavir is identified on the basis of advantages in the endpoints ‘infection control’ and ‘AE leading to discontinuation of study medication’.

Courtesy translation only, please refer to the German original.