Setmelanotid (2) – Imcivree®

• Clinical trials
  • The RM-493-023 trial is a multicentre Phase III trial comprising a 14-week randomised, placebo-controlled treatment phase, followed by a 52-week open-label treatment phase, into which participants who had been randomised to the placebo arm during the controlled phase also transitioned.

Adults, adolescents and children aged 6 years and over with genetically confirmed Bardet-Biedl syndrome, for the treatment of obesity and to control feelings of hunger

• Hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Overall, there is a hint of a non-quantifiable additional benefit for setmelanotide.
• The strength of the evidence is classified as ‘hint’, as uncertainties remain, particularly regarding the study duration of the comparative studies – which is considered short for this therapeutic indication – a minor sample size, and the questionable choice of analysis methodology.
• mortality
  • The number of deaths was continuously recorded throughout the entire study duration in study RM-493-023 as part of the safety monitoring.
  • No deaths occurred in the entire study population.
  • No conclusions regarding the extent of the additional benefit can be drawn for the mortality category.
• Morbidity – Body weight and Body Mass Index (BMI)
  • During both the placebo-controlled and the single-arm treatment phases, body weight and height were recorded at each visit as part of standardised measurements, with each measurement repeated three times.
  • The anthropometric parameters of body weight and BMI are significant in this indication, as weight gain is an early-onset, key feature of BBS.
  • These endpoints are considered significant morbidity parameters in this therapeutic indication.
  • Data adjusted for age and sex (z-scores) are preferred over absolute values.
  • That said, it would have been desirable to collect further morbidity endpoints that could demonstrate the effects of obesity on patients (such as pain, physical capacity and limitations in activities of daily living).
  • At the end of the controlled study phase at week 14, statistically significant reductions in body weight, BMI and BMI z-score were demonstrated with setmelanotide compared with placebo.
  • In general, however, the clinical relevance of the observed reduction in body weight remains questionable, given the high baseline weight at the start of the study.
• Morbidity – Hunger
  • The endpoint ‘hunger’ was assessed daily, depending on the presence of cognitive impairment, using the ‘Daily Hunger Questionnaires’ (self-reported) or the ‘Prader-Willi Syndrome Food Problem Diary’ (administered by carers).
  • In general, the endpoint ‘hunger’ is considered to be of great importance in this indication, as the patients’ extreme hunger is, on the one hand, a cause of weight gain and thus also a central feature of Prader-Willi syndrome.
  • Furthermore, the inability to control the sensation of hunger is associated with considerable psychological distress for patients.
  • Notwithstanding this, however, it is generally assumed that the sensation of hunger is a highly subjective experience with strong relevance at the individual level.
  • This limits the validity of the available questionnaires.
  • Furthermore, it remains unclear to what extent the sensation of hunger leads to impairment, for example in the performance of everyday activities or in quality of life.
  • For the placebo-controlled study phase, only results from the ‘Daily Hunger Questionnaire’ are available.
  • Due to the low response rate (< 70 %) for all patient-reported endpoints and uncertainties regarding the statistical methods used, the data presented cannot be taken into account in the benefit assessment.
• Morbidity – hip circumference and lipid profile
  • The endpoints ‘hip circumference’ and ‘lipid profile’ are not taken into account in the benefit assessment due to their lack of relevance to patients.
  • No evidence was provided to demonstrate their suitability as surrogate endpoints for patient-relevant endpoints.
• quality of life
  • Health-related quality of life was assessed in individuals with BBS using the (patient-reported) Impact of Weight on Quality of Life (IWQOL)-Lite and Paediatric Quality of Life (PedsQL) questionnaires.
  • No results on quality of life were reported for the placebo-controlled treatment phase.
• Side effects
  • Adverse events (AEs) and serious adverse events (SAEs) were recorded continuously throughout the study.
  • As no additional analyses excluding disease-related events are available, it cannot be ruled out that events related to the underlying condition were included in the AE data.
  • In the side effects category, three serious AEs and no AEs with a CTCAE severity grade ≥ 3 occurred up to week 14.
  • No effect estimators were provided. Consequently, a definitive assessment of side effects is not possible in this case.
• Overall assessment
  • For setmelanotid in the treatment of obesity and the control of hunger in adults, adolescents and children aged 6 years and over with genetically confirmed BBS, results are available on mortality, morbidity, quality of life and side effects from the 14-week randomised, placebo-controlled treatment phase of study RM-493-023.
  • In the mortality endpoint category, no deaths occurred during the 14-week placebo-controlled phase of the study. No conclusions regarding the extent of the additional benefit can be drawn for the mortality category.
  • In the morbidity category, statistically significant reductions in body weight, BMI and BMI z-score were observed with setmelanotide compared with placebo at the end of the randomised study phase at week 14.
  • No results were available for the placebo-controlled study phase in the health-related quality of life category.
  • In the category of side effects, three serious side effects and no side effects with a CTCAE severity grade ≥ 3 occurred up to week 14. Effect estimates for the side effects were not provided. Therefore, no definitive assessment of the side effects is possible in this case.
  • Notwithstanding the question of whether the study duration is sufficient for BBS, the clinical relevance of the reduction in BMI observed with setmelanotide remains unclear. The BMI, which was markedly elevated at the start of the trial, remains at a high level even after week 14 of the trial.
  • Against this background, a non-quantifiable additional benefit is identified for setmelanotide in the treatment of obesity and the control of hunger in adults, adolescents and children aged 6 years and over with genetically confirmed BBS, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.