Elinzanetant (1) – Lynkuet®

• Clinical trials
  • The OASIS-1 and OASIS-2 studies were both double-blind, randomised, controlled trials conducted to support marketing authorisation, comparing elinzanetant with placebo.
  • The OASIS-3 trial is a double-blind, randomised, controlled trial comparing elinzanetant with placebo over 52 weeks.
  • The SWITCH-1 trial is a double-blind, randomised, controlled trial comparing elinzanetant with placebo over 12 weeks.
  • The NIRVANA study is a double-blind, randomised, controlled trial comparing elinzanetant with placebo over 12 weeks.

a) Women with moderate to severe vasomotor symptoms associated with the menopause who are eligible for hormone replacement therapy and who, following an individual benefit-risk assessment, have opted for hormone replacement therapy

• For women with moderate to severe vasomotor symptoms associated with the menopause who are eligible for hormone replacement therapy and who, following an individual benefit-risk assessment, have opted for hormone replacement therapy, there are no data available to assess the additional benefit of elinzanetant compared with the appropriate comparator therapy.
• The additional benefit is therefore not proven.

b) Women with moderate to severe vasomotor symptoms associated with the menopause who are not eligible for hormone replacement therapy or who, following an individual benefit-risk assessment, have decided against hormone replacement therapy

• For patients with moderate to severe vasomotor symptoms associated with the menopause who are not suitable for hormone replacement therapy or who, following an individual benefit-risk assessment, have decided against hormone replacement therapy, the pharmaceutical manufacturer presents data from the SWITCH-1, OASIS-1, OASIS-2, OASIS-3 and NIRVANA.
• The data presented from the OASIS-1, OASIS-2, SWITCH-1 and NIRVANA studies are therefore not taken into account for the benefit assessment.
• The OASIS-3 study, on the other hand, provides direct comparative data over a period of 52 weeks.
• For the OASIS-3 study, the pharmaceutical manufacturer has presented data on the overall population in the dossier. However, these data are not used for the benefit assessment, as it must be assumed that a significant proportion of the patients included would still have been eligible for hormone replacement therapy and are therefore not to be classified under patient group b).
• As part of the commenting procedure and following the oral hearing, the pharmaceutical manufacturer therefore submitted data on two patient populations with adjusted operationalisations regarding ineligibility for hormone replacement therapy. These are the modified intention-to-treat (mITT) population and the mITT2 population, which is further restricted by the inclusion criteria.
• As the mITT population is considered sufficiently appropriate and this uncertainty persists even in the more narrowly defined and therefore smaller mITT2 population, the mITT population from the OASIS-3 study is considered here.
• On balance, the GBA therefore finds no additional benefit of elinzanetant compared with a ‘wait-and-see’ approach.
• An additional benefit of elinzanetant is therefore not proven.
• mortality
  • In the OASIS-3 study, no deaths occurred in either treatment arm.
• Morbidity – Vasomotor symptoms
  • Vasomotor symptoms were recorded in the OASIS-3 study using an electronic diary, in which the number of hot flushes, their severity and the number of times patients woke up at night were documented.
  • For the mITT patient population relevant here, the pharmaceutical manufacturer did not provide any responder analyses on the reduction in the frequency of moderate and severe vasomotor symptoms at the end of the study.
  • As no responder analyses were provided at the end of the study, the continuous analyses of the mean change in the frequency of moderate and severe vasomotor symptoms are considered.
  • For this endpoint, there is a statistically significant difference of –2.4 hot flushes per day between the treatment arms, with an advantage for elinzanetant.
• Morbidity – sleep disturbances
  • Sleep disturbances were assessed in the OASIS-3 study using the patient-reported questionnaire PROMIS SD SF 8b.
  • For the mITT population, no responder analyses were presented at the end of the study; instead, only time-to-event analyses were provided, which – as described for the ‘vasomotor symptoms’ endpoint – are not suitable for the present benefit assessment. Consequently, the continuous analyses of the mean change are used for the benefit assessment.
  • For the ‘sleep disturbances’ endpoint, there is a statistically significant difference in favour of elinzanetant. However, the 95% confidence interval of the standardised mean difference (SMD) does not lie entirely outside the non-significant range of -0.2 to 0.2, so it cannot be concluded that the effect is clinically relevant.
• Health-related quality of life
  • Health-related quality of life was assessed using the Menopause-specific Quality of Life (MENQOL) questionnaire.
  • For the mITT population, no responder analyses were presented at the end of the study; instead, only event-time analyses were provided, which – as described for the ‘vasomotor symptoms’ endpoint – are not suitable for the present benefit assessment. Consequently, the continuous analyses of the mean change are used for the benefit assessment.
  • In the psychosocial, physical and sexual domains, there is no statistically significant difference between the treatment arms. In the vasomotor domain, there is a statistically significant difference in favour of elinzanetant. However, the 95% confidence interval of the standardised mean difference (SMD) does not lie entirely outside the irrelevance range of –0.2 to 0.2, so it cannot be concluded that the effect is clinically relevant.
• Side effects
  • The recording of adverse events in the OASIS-3 study is potentially incomplete.
  • For the endpoint ‘serious adverse events’, there is no statistically significant difference between the treatment arms.
  • For the endpoint ‘discontinuation due to adverse events’, there is a statistically significant difference to the detriment of elinzanetant.
  • No data are available for the relevant patient population regarding the specific adverse event ‘liver-related investigations, clinical signs and symptoms’.
• Overall assessment
  • For the assessment of the additional benefit of elinzanetant in the treatment of women with moderate to severe vasomotor symptoms associated with the menopause, who are not eligible for hormone replacement therapy or who have decided against hormone replacement therapy following an individual benefit-risk assessment, the results of the randomised controlled trial OASIS-3 are used for the patient population of trial participants who are not eligible for hormone replacement therapy (mITT).
  • No deaths occurred during the study.
  • In the ‘side effects’ category, there was no statistically significant difference between the treatment arms for the endpoint ‘serious adverse events’. For the endpoint ‘discontinuation due to adverse events’, there is a statistically significant disadvantage of elinzanetant compared with placebo.
  • Overall, elinzanetant shows an advantage for the endpoint ‘vasomotor symptoms’. This is offset by a disadvantage for the endpoint ‘therapy discontinuation due to adverse events’. Furthermore, the advantage in terms of symptoms is not reflected in an improvement in health-related quality of life. On balance, the GBA therefore finds no additional benefit of elinzanetant compared with a ‘wait-and-see’ approach.

Courtesy translation only, please refer to the German original.