Setmelanotid (3) – Imcivree®

• Clinical trials
  • The pharmaceutical manufacturer has submitted the single-arm, open-label, multicentre registration trial RM-493-033 for the benefit assessment.

Children aged 2 to < 6 years with genetically confirmed Bardet-Biedl syndrome, POMC, PCSK1 or LEPR deficiency, for the treatment of obesity and to control feelings of hunger

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• mortality
  • The number of deaths was recorded as part of the safety monitoring. No deaths were reported during the 52-week observation period.
• Morbidity – Body Mass Index (BMI)
  • Body weight (kg) was measured at the study centre each morning, where possible at the same time each day. Three measurements were to be taken at each study visit, and the average calculated from the measurements taken during that visit.
  • BMI-z was calculated using the 2007 WHO Child Growth Standards as a reference.
  • The anthropometric parameters of body weight and BMI are significant in this indication, as weight gain is a key characteristic. These endpoints are considered to be significant morbidity parameters in this therapeutic indication. Data adjusted for age and sex (z-scores) are preferred over absolute values.
  • For the benefit assessment, the mean absolute and percentage change in the BMI z-score at study week 52 compared with baseline is used.
  • At the start of the study, the median BMI-z in the overall study population was approximately 7 standard deviations above the population mean of the WHO Child Growth Standards 2007 reference population. Over 52 weeks, there was a change in the median BMI-z of –3 standard deviations. This corresponds to a percentage change of 40.2% at week 52 compared with baseline. The percentage change was more pronounced in the PPL population (52.3%) than in the BBS population (32.9%).
  • With regard to the natural course of the disease, it should be noted that affected patients continuously gain body weight and consequently develop severe obesity. This is associated with a significantly increased risk of mortality and morbidity. In particular, cardiovascular, metabolic, respiratory and orthopaedic complications are relevant, which can already occur in childhood. Against this background, relative weight loss or a reduction in BMI is of significant clinical importance in this therapeutic indication.
  • Overall, however, it is severe to interpret the significance of the data presented, as it is not possible to assess them in comparison with the natural course of the disease in the patient population under consideration. In principle, however, relative weight loss or a reduction in BMI should be regarded as a therapeutic goal in this therapeutic indication, as these represent the relevant manifestation of the genetically determined obesity in question and are the cause of the associated comorbidities.
  • Taken together, the present data show a significant reduction in the BMI-z-score at week 52 compared with baseline following administration of setmelanotide; however, the extent of this reduction is non-quantifiable.
• quality of life
  • The pharmaceutical manufacturer has submitted data on the ‘PROMIS Global Health Parent Proxy Questionnaire’ and the ‘PROMIS Global Health Questionnaire’.
  • The results from the ‘PROMIS Global Health Parent Proxy Questionnaire’ are not used for the benefit assessment due to insufficient validation in the therapeutic indication. The PROMIS parent proxy instruments have been developed and validated for the parent-reported assessment of quality of life in children aged 5 to 17 years. However, a clear majority of the children included in study RM-493-033 (at least n = 10 out of N = 12) were under 5 years of age.
  • The ‘PROMIS Global Health Questionnaire’ was used to assess the quality of life of parents/carers, which is not relevant for the purposes of the benefit assessment.
  • Consequently, no suitable data are available for the endpoint category of health-related quality of life for the present benefit assessment.
• Side effects
  • The median duration of treatment was 52.2 weeks. According to the study documentation, safety was monitored for up to 30 days following the last administration of the study medication.
  • No serious or severe adverse events were observed in study RM-493-033. There were also no therapy discontinuations due to adverse events.
• Overall assessment
  • The pharmaceutical manufacturer has submitted the single-arm, open-label, multicentre registration trial RM-493-033 for the benefit assessment. The trial covered a period of 52 weeks. A total of 12 participants were included in the study (7 with PPL and 5 with BBS).
  • No deaths were reported during the 52-week observation period.
  • For the morbidity endpoint category, a significant reduction in the BMI-z-score was observed at week 52 compared with baseline following administration of setmelanotide. Given the natural course of this genetic condition, which is associated with a continuous increase in body weight in affected patients and the development of severe obesity—and which is the cause of the associated comorbidities— the reduction in BMI is of significant clinical importance in this therapeutic indication.
  • No suitable data are available for the endpoint category of health-related quality of life.
  • For the endpoint category of side effects, neither serious nor severe adverse events were observed. There were also no cases of therapy discontinuation due to adverse events.
  • Overall, by week 52, administration of setmelanotide resulted in a relevant reduction in the BMI z-score compared with baseline. However, as the presented, single-arm data do not allow for a comparison with the natural course of the disease, the extent of the advantage is non-quantifiable. Against this background, no quantifiable additional benefit has been established for setmelanotide in the treatment of obesity and the control of hunger in children aged 2 to < 6 years with genetically confirmed Bardet-Biedl syndrome, POMC, PCSK1 or LEPR deficiency, as the scientific evidence does not permit quantification of the additional benefit.

Courtesy translation only, please refer to the German original.