Somapacitan (1) – Sogroya®

• Clinical trials
  • To assess the additional benefit of Somapacitan for children aged 3 years and over and adolescents with growth disorders due to growth hormone deficiency, the pharmaceutical manufacturer submitted the REAL 4 study, on which the marketing authorisation is based, and the REAL 3 supportive study. The REAL 4 (Phase III trial) and REAL 3 (Phase II trial) studies were randomised, open-label, active-controlled trials comparing once-weekly somapacitan with daily somatropin.
  • To assess the additional benefit of somapacitan for adults with growth hormone deficiency (AGHD) in whom replacement therapy with endogenous growth hormone is indicated, the pharmaceutical manufacturer has submitted the REAL 1, REAL 2 and REAL JP studies. These studies are all randomised, open-label, active-controlled Phase III trials comparing once-weekly somapacitan with daily somatropin.

a) Children aged 3 years and over and adolescents with growth disorders due to growth hormone deficiency

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• mortality
  • No deaths occurred in the REAL 3 and REAL 4 studies.
• Morbidity – height (z-score)
  • The anthropometric parameter of height is considered a patient-relevant morbidity parameter, particularly in children with characteristic, disease-related growth disorders. Data adjusted for age and sex (z-scores) are preferred over absolute values.
  • In the REAL 4 study, there was no statistically significant difference between somapacitan (N = 132) and somatropin (N = 68) for the endpoint ‘height (z-score)’ at week 52.
  • In the REAL 3 study, there was a statistically significant difference in favour of somapacitan (N = 14) compared with somatropin (N = 14) for the endpoint ‘height (z-score)’ at week 52. The statistically significant difference in favour of somapacitan compared with somatropin is also evident in the long-term data at week 156. However, the clinical relevance of this difference cannot be conclusively assessed.
  • Due to the high level of heterogeneity, no meta-analytic synthesis of the results from the REAL 4 and REAL 3 studies at week 52 is provided.
• Morbidity – Growth velocity
  • The primary endpoint, growth velocity, describes the annual increase in standing height [cm/year] and is presented here solely for supplementary purposes, as it does not provide any information on growth beyond standing height that is relevant to the benefit assessment.
  • For the growth rate endpoint, a statistically significant difference between the treatment groups was observed at week 52 in the REAL 3 study, but not in the REAL 4 study. By week 156, there was no longer a statistically significant difference between the two treatment groups in the REAL 3 study either.
• Quality of life – Growth Hormone Deficiency – Child Impact Measure (GHD-CIM) ObsRO
  • The GHD-CIM ObsRO is a disease-specific instrument for assessing the burden on children and adolescents aged 4 to under 13 years with GHD. The ObsRO version of the questionnaire used in the REAL 4 and REAL 3 studies is completed by the child’s parents or legal guardians, based on their observations of the child’s daily life and health.
  • In the REAL 4 and REAL 3 studies, as well as in the meta-analysis, there was no statistically significant difference between somapacitan and somatropin – neither in the total score nor in the three individual domains of the GHD-CIM ObsRO. At week 156, the REAL 3 study also showed no statistically significant difference in the GHD-CIM ObsRO.
• Side effects
  • At week 52, there were no statistically significant differences between somapacitan and somatropin for the severe AEs, SAEs and AEs leading to discontinuation of study medication, in either the REAL 4 or REAL 3 studies. Similarly, the long-term data at week 156 of the REAL 3 study show no statistically significant differences between the treatment arms for these endpoints.
• Overall assessment
  • To assess the additional benefit of somapacitan for children aged 3 years and over and adolescents with growth disorders due to growth hormone deficiency, the pharmaceutical manufacturer submitted the REAL 4 study, on which the marketing authorisation is based, and the REAL 3 supportive study. The REAL 4 (Phase III study) and REAL 3 (Phase II study) were randomised, open-label, active-controlled studies comparing once-weekly somapacitan with daily somatropin.
  • No deaths occurred in either study.
  • For the morbidity endpoint category, the ‘height (z-score)’ endpoint in the REAL 4 study showed no statistically significant difference between the treatment groups. In the REAL 3 study, there was a statistically significant advantage of somapacitan over somatropin for this endpoint at weeks 52 and 156. Overall, however, the clinical relevance of the statistically significant difference in the ‘height (z-score)’ endpoint cannot be conclusively assessed, meaning that no conclusions can be drawn regarding the extent of the additional benefit.
  • For the quality of life endpoint category, the GHD-CIM ObsRO shows no statistically significant difference between somapacitan and somatropin in either the REAL 4 or the REAL 3 study. For the GHD-CTB ObsRO endpoint, only the REAL 3 study showed a statistically significant and, based on Hedges’ g, clinically relevant effect in favour of somapacitan over somatropin in the long-term data at week 156 in the physical domain. Overall, no advantages can be identified in the quality of life category.
  • In the ‘side effects’ category, the overall review reveals neither advantages nor disadvantages for somapacitan compared with somatropin.
  • Overall, therefore, for children aged 3 years and over and adolescents with growth disorders due to growth hormone deficiency, Somapacitan offers a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.

b) Adults with growth hormone deficiency (AGHD) for whom replacement therapy with endogenous growth hormone is indicated

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• mortality
  • No deaths occurred in the REAL 1, REAL 2 and REAL JP studies.
• Morbidity – change in trunk fat percentage
  • In the REAL 1 study, various body composition parameters (including change in trunk fat percentage) were measured using whole-body dual-energy X-ray absorptiometry at screening and at week 34.
  • The primary endpoint ‘change in trunk fat percentage at week 34’ from the REAL 1 study is not included in the benefit assessment due to a lack of clinical relevance. Furthermore, there are no morbidity endpoints relevant to the benefit assessment.
• Quality of life – Health Survey Short Form 36 (SF-36), Version 2
  • The SF-36 is a generic instrument for measuring health-related quality of life, comprising eight domains and a total of 36 questions. In addition, the eight domains are combined to form a physical summary scale and a mental health summary scale. For both the domain and summary scores, higher values indicate an improved health-related quality of life.
  • The REAL 1 study found no statistically significant difference between the treatment arms on either the physical or mental health summary scales.
• Quality of Life – Treatment-Related Impact Measure – Adult Growth Hormone Deficiency (TRIM-AGHD)
  • The TRIM-AGHD is a disease-specific, patient-reported questionnaire comprising 27 items, 26 of which are grouped into 4 domains (energy, psychological/emotional, cognitive and physical). A single item not assigned to a domain relates to general energy levels. The questions refer to the present moment at which the questionnaire is being completed. Respondents rate the items on a 5-point Likert scale, either for frequency or severity. Lower scores indicate a better health status.
  • In the REAL 1 study, the TRIM-AGHD at week 34 showed a statistically significant difference to the detriment of somapacitan compared with somatropin. However, when interpreting this disadvantage, it is important to take into account the probability that patients in the somapacitan arm are under-treated. Against this background, the effect cannot be conclusively assessed.
  • No quality-of-life endpoints were assessed in the REAL 2 and REAL JP studies.
  • Overall, the data do not indicate any advantages or disadvantages in the quality of life category.
• Side effects
  • In the REAL 1 and REAL 2 studies, there was no statistically significant difference between the treatment arms for the endpoints ‘severe AEs’ and ‘SAE’, respectively.
  • In the REAL 1 study, a statistically significant advantage in favour of somapacitan was observed for the endpoint of AEs leading to discontinuation of the study medication. However, when interpreting this advantage, the probability of under-treatment of patients in the somapacitan arm must also be taken into account. It is not possible to assess to what extent a longer dose-titration period, as provided for in the SmPC, would lead to higher doses of somapacitan and whether these would cause further AEs. Overall, therefore, neither advantages nor disadvantages can be inferred in the category of side effects.
  • In the REAL JP study, no severe AEs occurred in either treatment arm. For the endpoints ‘severe AEs’ and ‘AE leading to discontinuation of study medication’, there was no statistically significant difference between the two treatment arms in either case.
• Overall assessment
  • To assess the additional benefit of somapacitan for adults with adult growth hormone deficiency (AGHD) in whom replacement therapy with endogenous growth hormone is indicated, the pharmaceutical manufacturer has submitted the REAL 1, REAL 2 and REAL JP studies. These studies are all randomised, open-label, active-controlled Phase III trials comparing once-weekly somapacitan with daily somatropin.
  • No deaths occurred in the REAL 1, REAL 2 and REAL JP studies.
  • The primary endpoint ‘change in body fat percentage at week 34’ from the REAL 1 study is not included in the benefit assessment due to a lack of clinical relevance. Furthermore, there are no endpoints relevant to the benefit assessment for the morbidity endpoint category.
  • For the quality of life endpoint category, the REAL 1 study showed no statistically significant difference between the treatment groups based on the SF-36 at week 34. Based on the TRIM-AGHD, the REAL 1 study at week 34 shows a statistically significant disadvantage of somapacitan compared with somatropin; however, this cannot be conclusively assessed due to under-treatment in the active treatment arm.
  • In the ‘side effects’ endpoint category, the REAL 1 study showed a statistically significant advantage in favour of somapacitan for the endpoint ‘AE leading to discontinuation of study medication’. However, when interpreting the results, probable under-treatment of patients in the somapacitan arm must be taken into account.
  • Overall, therefore, no advantages or disadvantages can be inferred in the categories of quality of life and side effects.
  • On balance, therefore, for adults with growth hormone deficiency for whom replacement therapy with endogenous growth hormone is indicated, there is a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Validity of the evidence
  • The potential for bias in the open-label, randomised, active-controlled studies REAL 1, REAL 2 and REAL JP is classified as high in each case due to the lack of blinding.
  • Overall, the strength of the evidence is minor; consequently, the strength of the evidence is classified as ‘hint’.

Courtesy translation only, please refer to the German original.