Fezolinetant (1) – Veoza®

• Clinical trials
  • The DAYLIGHT trial was a randomised, controlled, double-blind trial in which a total of 453 female patients were treated with fezolinetant or placebo in a 1:1 ratio.
  • The SKYLIGHT 1 and SKYLIGHT 2 studies were randomised, controlled, double-blind studies in which fezolinetant at two different doses was compared with placebo.
  • The SKYLIGHT 4 study is a randomised, controlled, double-blind study that included postmenopausal women aged between 40 and 65 years with vasomotor symptoms (associated with the menopause), regardless of their severity.

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

• The additional benefit is not proven.
• No data are available for the assessment of the additional benefit of fezolinetant compared with the appropriate comparator therapy in menopausal women with moderate to severe vasomotor symptoms who are eligible for hormone therapy and who, following an individual risk-benefit assessment, are considered for treatmentassessment have opted for hormone replacement therapy.

b) Postmenopausal women with moderate to severe vasomotor symptoms who are not eligible for hormone therapy or who, following an individual benefit-risk

• Hint for a minor additional benefit
• For postmenopausal women with moderate to severe vasomotor symptoms who are not eligible for hormone therapy or who, following an individual benefit-risk assessment, have decided against treatment, a minor additional benefit of fezolinetant compared with the appropriate comparator therapy – a ‘wait-and-see’ approach – is therefore identified in the overall assessment, taking into account the uncertainties mentioned.
• The certainty of the evidence is therefore classified as a hint.
• mortality
  • In the DAYLIGHT study, overall mortality, defined as adverse events leading to death, was recorded. No deaths occurred.
• Morbidity – moderate and severe vasomotor symptoms
  • For the endpoint of moderate and severe vasomotor symptoms (100% reduction), a statistically significant advantage in favour of fezolinetant was observed.
  • As it remains unclear whether the 100% reduction in moderate and severe vasomotor symptoms represents a complete resolution of the symptoms or a reduction to mild vasomotor symptoms, the additional analysis may provide further information on this endpoint.
• Morbidity – sleep disturbances (PROMIS SD SF 8b)
  • For the endpoint of sleep disturbances (PROMIS SD SF 8b, improvement of ≥ 7.14 points), a statistically significant advantage in favour of fezolinetant is observed.
  • For the present benefit assessment, the post-hoc responder analysis showing an improvement in the PROMIS SD SF 8b of ≥ 7.14 points is used, as this response criterion corresponds to exactly 15% of the scale range (based on transformed values).
• Morbidity – Female Sexual Function (FSFI)
  • For the endpoint of female sexual function (FSFI, improvement of ≥ 5.1 points), no statistically significant difference was observed between the treatment arms, either in the total score or in the individual domains.
• Morbidity – General symptoms of depression and anxiety disorders (PHQ-4)
  • For the endpoint ‘general symptoms of depression and anxiety disorders’ (PHQ-4, improvement of ≥ 1.8 points), no statistically significant difference was observed between the treatment arms, either in the total score or in the two subscales.
• Morbidity – Health status (EQ-5D VAS)
  • For the health status endpoint (EQ-5D VAS, improvement of ≥ 15 points), there was no statistically significant difference between the treatment arms.
• Health-related quality of life (Menopause-Specific Quality of Life, MENQOL)
  • For the health-related quality of life endpoint, assessed using MENQOL, a statistically significant advantage in favour of fezolinetant was observed for all four domains (vasomotor, psychosocial, physical and sexual; an improvement of ≥ 1.05 points in each case).
• Side effects
  • The proportion of patients who discontinued the study was higher in the control arm (17%) than in the intervention arm (8%).
  • For the endpoints SUEs and discontinuation due to AEs, no statistically significant difference was observed between the treatment groups.
  • For the endpoint of liver-related investigations, clinical signs and symptoms (SMQ, SUEs), there was no statistically significant difference between the treatment arms.
• Overall assessment
  • No events occurred in the mortality endpoint category.
  • In the morbidity category, by study week 24, a statistically significant advantage in favour of fezolinetant over standard of care was observed for the endpoint ‘reduction in moderate and severe vasomotor symptoms’ by 100 per cent and for the endpoint ‘sleep disturbances’ (assessed using PROMIS SD SF 8b), a statistically significant advantage in favour of fezolinetant compared with the appropriate comparator therapy was observed.
  • For the endpoints of sexual function (assessed using the FSFI), general symptoms of depression and anxiety disorders (assessed using the PHQ-4) and health status (assessed using the EQ-5D VAS), no statistically significant differences were observed between the treatment arms.
  • In the category of health-related quality of life (assessed using MENQOL), a statistically significant advantage in favour of fezolinetant compared with the appropriate comparator therapy was observed at study week 24.
  • In the category of side effects, no statistically significant differences were observed between the treatment arms.
  • Overall, therefore, at week 24, there were statistically significant advantages for fezolinetant over the appropriate comparator therapy in the endpoint categories of morbidity and health-related quality of life.
  • However, there are significant uncertainties regarding the assessment of the extent to which patients are affected by the vasomotor symptoms in question.
  • No data are available on the number of vasomotor symptoms broken down by severity.
  • Furthermore, the distinction between moderate and severe vasomotor symptoms is based solely on whether the activity currently being performed could be continued or not.
  • There are also uncertainties regarding the sleep disturbances endpoint, as it remains unclear whether the preferred transformation method was used for the analysis.
  • Fundamental uncertainties also arise from differences in patient characteristics in the DAYLIGHT study: the time since the onset of amenorrhoea was 72.9 months on average for patients in the intervention arm, compared with 56.9 months in the control arm.

Courtesy translation only, please refer to the German original.