Relugolix / Estradiol / Norethisteronacetat (1) – Ryeqo®

• Clinical trials
  • For the present benefit assessment procedure pursuant to Section 35a of the German Social Code, Book V (SGB V), the pharmaceutical manufacturer has submitted the two studies LIBERTY 1 and LIBERTY 2 (hereinafter referred to as LIBERTY 1/2), which have an identical study design. These are randomised, double-blind, multicentre Phase III trials comparing the free combination of relugolix and oestradiol (E2)/norethisterone acetate (NETA) with placebo over 24 weeks.

a) Adult women of childbearing age with moderate to severe symptoms of uterine fibroids, for whom a ‘watch-and-wait’ approach is deemed most appropriate on a case-by-case basis

• For adult women of childbearing age with moderate to severe symptoms of uterine fibroids, for whom a ‘watch-and-wait’ approach is deemed most appropriate on a case-by-case basis, there is a hint of considerable additional benefit for relugolix/E2/NETA.
• Overall, there is a hint of considerable additional benefit.
• mortality
  • No deaths occurred during the course of either study.
• Morbidity – Menstrual blood loss assessed via ‘confirmed clinically relevant reduction in MBL volume’ and ‘confirmed amenorrhoea’
  • To assess the effect of relugolix/E2/NETA on the core symptom of hypermenorrhoea, the confirmed clinically relevant reduction in menstrual blood loss volume (referred to in the dossier as sustained normalisation of MBL volume) and confirmed amenorrhoea are used as patient-relevant endpoints.
  • The meta-analysis of the LIBERTY 1/2 studies shows a statistically significant advantage for relugolix + E2/NETA for this endpoint.
  • This is consistent with the results for confirmed amenorrhoea (amenorrhoea that persisted from at least the previous assessment point until the end of the study). The vast majority of patients who suffered from heavy menstrual bleeding at the start of the study were no longer experiencing bleeding at the end of the study in the relugolix-E2/NETA arm. This represents a significant improvement in core symptoms.
• Morbidity – Pain (NRS)
  • In the LIBERTY 1/2 studies, patients assessed the maximum intensity of their uterine fibroid-related pain daily using an 11-point Numerical Rating Scale (NRS).
  • The meta-analysis of the studies revealed a statistically significant advantage for relugolix + E2/NETA for this endpoint. The 95% confidence interval for the standardised mean difference lies entirely outside the non-significant range of –0.2 to 0.2, suggesting a clinically relevant difference.
• Morbidity – Symptoms (Symptom Severity Scale of the UFS-QoL)
  • In the meta-analyses based on the responder analyses submitted as part of the commenting procedure, with a clinical relevance threshold of 15%, a statistically significant advantage in favour of relugolix/E2/NETA compared with a ‘wait-and-see’ approach is evident for this endpoint.
  • However, it is unclear whether there are effect modifications, particularly due to disease severity (MBL volume < 225 ml / ≥ 225 ml), as no subgroup analyses for relevant subgroup characteristics were submitted for the responder analyses presented.
• Morbidity – Health status (EQ-5D VAS)
  • Health status was assessed in the LIBERTY 1/2 trials using the EuroQoL 5-Dimensional (EQ-5D) visual analogue scale. The meta-analysis showed no statistically significant difference between the treatment groups in the changes observed between the start of the study and week 24.
• quality of life
  • In the meta-analyses based on the responder analyses submitted as part of the commenting procedure, with a clinical relevance threshold of 15%, a statistically significant advantage was observed for this endpoint in favour of relugolix/E2/NETA compared with a ‘wait-and-see’ approach.
  • As with the ‘symptoms’ endpoint, no subgroup analyses are available here either that would allow conclusions to be drawn, in particular, regarding effect modifications due to disease severity.
• Side effects
  • For the present benefit assessment, the overall rates of adverse events (AEs) and serious adverse events (SAEs) are used. The meta-analysis of the studies revealed no statistically significant differences between the treatment groups for the endpoints of SAEs, severe AEs (CTCAE grade ≥ 3) or discontinuation due to AEs.
  • Vasomotor and skeletal-related events were considered as specific AEs. Here too, the meta-analysis revealed no statistically significant differences between the study arms.
  • However, the interpretability of the findings regarding skeletal-related events is limited, as the duration of the LIBERTY trials (24 weeks) is too short to allow for an adequate assessment of skeletal-related events, and comparative long-term data would be required for this purpose.
• Overall assessment
  • In the mortality endpoint category, no deaths occurred in either of the two studies.
  • In the morbidity category, there were statistically significant, clinically relevant benefits in favour of relugolix/E2/NETA for the patient-relevant endpoints of menstrual blood loss (confirmed clinically relevant reduction in MBL volume, confirmed amenorrhoea), pain and fibroid-associated symptoms (UFS-QoL Symptom Severity Scale) statistically significant, clinically relevant advantages for Relugolix/E2/NETA compared to No statistically significant change in health status was observed for relugolix/E2/NETA compared with a ‘wait-and-see’ approach.
  • With regard to health-related quality of life, the UFS-QoL total score indicates an advantage for relugolix/E2/NETA.
  • For the endpoint category of side effects, there are neither advantages nor disadvantages. However, at 24 weeks, the duration of the LIBERTY trials is too short to allow for an adequate assessment of skeletal-related events.
  • In summary, the existing statistically significant and clinically relevant advantages of relugolix/E2/NETA compared with a watch-and-wait approach, in terms of the endpoints of menstrual blood loss (confirmed clinically relevant reduction in MBL volume, confirmed amenorrhoea), symptoms (UFS-QoL Symptom Severity Scale) and health-related quality of life (UFS-QoL total score) are, on balance, considered to be of considerable extent. The advantages observed for the pain endpoint support this assessment.
• Conclusiveness (probability of additional benefit)
  • The assessment of additional benefit is based on the randomised, controlled, multicentre, Phase III LIBERTY 1/2 trials, which investigated the efficacy and safety of relugolix/E2/NETA compared with a ‘wait-and-see’ approach.
  • However, the assessment of certainty of evidence primarily focuses on the uncertainties surrounding the implementation of the appropriate comparator therapy. It is unclear whether a ‘watch-and-wait’ approach was the most appropriate treatment option for individual patients in the LIBERTY 1/2 trials, or whether other therapies within the appropriate comparator therapy might have been more suitable. Overall, therefore, with regard to the reliability of the findings, there is a hint of additional benefit.

b) Adult women of childbearing age with moderate to severe symptoms of uterine fibroids, for whom a ‘watch-and-wait’ approach is not the most appropriate option on an individual basis

• For adult women of childbearing age with moderate to severe symptoms of uterine fibroids, for whom a ‘wait-and-see’ approach is not the most suitable option on an individual basis, the additional benefit is not proven.
• The pharmaceutical manufacturer has not submitted any study data on relugolix/E2/NETA compared with the appropriate comparator therapy. An additional benefit is therefore not proven.

Courtesy translation only, please refer to the German original.