Setmelanotid (1) – Imcivree®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from two open-label, multicentre, single-arm, non-randomised Phase III trials, 012 and 015, for the benefit assessment.
  • The two trials investigate the efficacy and safety of setmelanotide in patients with POMC/PCSK1-deficient obesity (trial 012) and LEPR-deficient obesity (trial 015), respectively.

Adults, adolescents and children aged 6 years and over with 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 in studies 012 and 015 as part of the safety monitoring. There was one death in study 015.
• Morbidity – body weight and body mass index (BMI)
  • The primary endpoint in both studies was the proportion of patients achieving ≥ 10 % weight loss by week 52 compared with baseline. In both studies, a significant proportion of patients achieved a weight loss of ≥ 10 % after 52 weeks (Study 012: 12 out of 14 patients; Study 015: 8 out of 15 patients).
  • As only patient lists are available for the BMI-z-score in the age group < 18 years, the data cannot be used for the benefit assessment.
  • In both single-arm studies, a reduction in body weight compared with baseline was observed after 52 weeks; in Study 012, a reduction in BMI was also observed. However, no usable data on age-adjusted BMI (BMI-z-score) are available.
  • Whilst the baseline values suggest a significantly higher body weight and an increased BMI in children, adolescents and adults compared with the general population, by the end of the study after 52 weeks, although the anthropometric values are not yet within the range of individuals of the same age in the general population, the results nevertheless indicate a significant reduction in body weight and BMI.
  • Overall, however, it is severe to interpret the significance of the data presented, as it is not possible, on the basis of the data provided, to assess the findings in comparison with the natural course of the disease in this patient population.
  • Taken together, the present study shows a significant reduction in body weight and BMI following administration of setmelanotide, in each case at week 52 compared with baseline; however, the extent of these reductions is non-quantifiable.
• Morbidity – Hunger
  • The endpoint ‘hunger’ was assessed in the studies using the ‘Hunger Score’ questionnaire. Data were collected using the ‘Daily Hunger Questionnaire’ and the ‘Global Hunger Questionnaire’.
  • The ‘Daily Hunger Questionnaire’ assessed daily hunger before breakfast. For patients aged ≥ 12 years, an 11-point Likert scale was used, ranging from 0 (= not hungry) to 10 (= as hungry as possible). For children aged 6 to < 12 years, a 5-point Likert scale with a smiley face system was used.
  • The “Global Hunger Questionnaire” comprised the Patient Global Impression of Severity (PGIS), which assessed overall hunger status with four response options (none, mild, moderate and severe), and the Patient Global Impression of Change (PGIC) regarding changes in hunger status, with five response options (significantly less hungry, slightly less hungry, no change, slightly hungrier, significantly hungrier), each assessed at week 52 compared with baseline.
  • Overall, it is questionable to what extent the study population included, particularly children, with this clinical presentation characterised by intense feelings of hunger or hyperphagia, are able to quantify an assessment of both their current state and the baseline state of hunger and thereby perform a mental subtraction.
  • With regard to the ‘Daily Hunger Questionnaire’, more than half of the patients aged ≥ 12 years in both studies showed an improvement in their sense of hunger of ≥ 25 per cent.
• quality of life
  • With regard to health-related quality of life, the two studies used the (patient-reported) questionnaires Impact of Weight on Quality of Life (IWQOL)-Lite, Paediatric Quality of Life (PedsQL) and Short Form 36 (SF-36). However, due to the low response rates at baseline and during the course of the studies, and the lack of analyses at an aggregated level, the data presented cannot be taken into account in the benefit assessment.
• Side effects
  • Adverse events (AEs) and serious adverse events (SAEs) were recorded in studies 012 and 015 during the period from the first administration of setmelanotide up to 30 days after the last dose of setmelanotide.
  • In study 012, no patients experienced an AE of grade ≥ 3, and approximately 40% of patients experienced a SAE. In study 015, approximately 20% of patients experienced an AE of grade ≥ 3, and approximately 20% experienced a SAE. Only one patient discontinued study 015 due to an AE.
• Overall assessment
  • In the morbidity endpoint category, a significant reduction in body weight was observed in both single-arm studies after 52 weeks, and in study 012 a significant reduction in BMI was observed, in each case compared with baseline. However, no usable data on age-adjusted BMI (BMI z-score) are available.
  • The data on health-related quality of life cannot be used for the benefit assessment due to low response rates.
  • With regard to the results on side effects, treatment with setmelanotide was associated with some severe (grade ≥ 3) and serious adverse events (AEs), as well as therapy discontinuation due to AEs. With regard to depression, Study 012 showed no statistically significant differences compared with baseline at 52 weeks; the results of Study 015, as well as those on suicidal ideation in both studies, cannot be used for the benefit assessment due to low response rates.
  • Overall, administration of setmelanotide resulted in a significant reduction in body weight and BMI at week 52 compared with baseline; however, the extent of these reductions 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 adults, adolescents and children aged 6 years and over with POMC, PCSK1 or LEPR deficiency, as the scientific evidence does not permit quantification of the non-quantifiable additional benefit.

Courtesy translation only, please refer to the German original.