Telotristatethyl (1) – Xermelo®

• Clinical trials
  • The TELESTAR study (LX1606.301) is a blinded, randomised, placebo-controlled, multicentre Phase III trial investigating the efficacy and safety of telotristat ethyl in patients with carcinoid syndrome who are inadequately controlled on SSA therapy.
  • The TELECAST study (LX1606.303) is also a placebo-controlled, multicentre Phase III RCT designed to investigate the efficacy and safety of telotristat ethyl in patients with carcinoid syndrome.

a) Treatment of diarrhoea associated with carcinoid syndrome in combination with somatostatin analogue (SSA) therapy in adults with inadequate control on SSA therapy

• Non-quantifiable
• The G-BA classifies the extent of the additional benefit of telotristat ethyl as non-quantifiable. An additional benefit exists, but is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • In the TELESTAR study, overall mortality was recorded as the number of deaths during the observation period as part of the adverse event survey. In the relevant patient population, overall mortality did not differ statistically significantly between the two treatment groups.
• Morbidity – Change in bowel movement frequency
  • Bowel movement frequency was recorded daily using an electronic patient diary. During the 12-week treatment phase, the median bowel movement frequency decreased by 0.6 bowel movements per day in the placebo arm (baseline bowel movement frequency 5.06) and by 1.3 bowel movements per day in the active treatment arm (baseline frequency 5.49).
  • The difference in medians between the two study arms is 0.8 bowel movements per day (95% CI [–1.256; –0.280], p<0.001) and is statistically significant in favour of telotristat ethyl compared with placebo.
  • Although stool frequency is a patient-relevant endpoint, the clinical relevance of the extent of the observed difference in change compared with placebo – 0.8 bowel movements per day – cannot be conclusively assessed.
  • It remains unclear whether such a difference between the study arms in the change in stool frequency represents a noticeable improvement in health status for the individual patient.
  • The difference in changes in stool frequency between the two treatment arms is statistically significant in favour of treatment with telotristatethyl from week 3 onwards (with the exception of weeks 7 and 12). This difference between the study arms ranges (from week 3 onwards) from 0.57 to 0.95 bowel movements per day and is never greater than 1 bowel movement per day at any measurement point. The clinical relevance of this difference cannot be assessed.
• Morbidity – Urgent need to pass stools
  • The median proportion of days on which patients reported an urgent need to defecate during the treatment phase did not differ between the placebo and telotristatethyl arms.
• Morbidity – Abdominal pain
  • Abdominal pain was also recorded daily by the patients. The median changes over the 12-week treatment phase are minor.
  • The difference between the changes in the two study arms is not statistically significant.
• Morbidity – Nausea
  • The median proportion of days on which study participants reported nausea during the treatment phase is approximately the same in both study arms; the difference between the medians is not statistically significant.
  • The analyses submitted by the pharmaceutical manufacturer regarding changes in the severity of nausea on a 4-point scale during the treatment phase also showed no statistically significant differences between the study arms.
• Quality of life assessed using the EORTC QLQ-C30 and EORTC QLQ-GI.NET21
  • For the EORTC QLQ-C30 scales and domains ‘Health Status/quality of life’, ‘Physical Functioning’, ‘Role Functioning’, ‘Emotional Function’, ‘Cognitive Functioning’ and ‘Social Functioning’, no statistically significant changes were observed between the study arms over the 12-week treatment phase.
  • For the EORTC QLQ-GI.NET21 scales or domains ‘Endocrine Symptom Scale’, ‘Gastrointestinal Symptom Scale’, ‘Treatment-Related Symptom Scale’, ‘Social Functioning’, ‘Muscle/Bone Pain’, ‘Sexual Function’, ‘Information/Communication’ and ‘Body Image’, no statistically significant changes were observed between the study arms over the 12-week treatment period.
  • In the “Disease-Related Worries” domain, a statistically significant disadvantage for telotristatethyl was observed in the median changes over the treatment phase (median difference: 11.11 [0.00;16.67], p=0.013).
• Side effects
  • Numerical differences in the frequency of severe AEs, SAEs and AEs leading to discontinuation of study medication or withdrawal from the study are evident between placebo and telotristatethyl in both studies. However, no statistically significant differences between treatment with placebo and telotristatethyl can be inferred from the summary of AEs, SAEs and discontinuations due to AEs based on the TELESTAR study.
  • The most frequently reported AEs were in the SOC ‘Gastrointestinal disorders’ with the PTs ‘Nausea’ and ‘abdominal pain’ in both study arms, followed by the SOC ‘General disorders and administration site conditions’ and ‘Metabolic and nutritional disorders’. With the exception of the SOC ‘Vascular disorders’, the differences between the study arms in no SOC or PT exceeded 3 patients or 10 percentage points.
• Overall assessment
  • For the benefit assessment of telotristat ethyl for the treatment of diarrhoea associated with carcinoid syndrome in combination with somatostatin analogue (SSA) therapy in adults with inadequate control on SSA therapy, results are available from the TELESTAR study for the endpoint categories of morbidity, quality of life and side effects.
  • The data submitted by the pharmaceutical manufacturer show a statistically significant advantage for telotristatethyl in the endpoint category of morbidity with regard to the change in stool frequency, as well as an improvement in the ‘diarrhoea’ domain of the EORTC QLQ-C30. However, the clinical relevance of this difference in the change in bowel movement frequency remains unclear.
  • In the morbidity endpoint category, this is offset by a deterioration in the ‘insomnia’ domain. In the quality of life endpoint category, too, there is a disadvantage for telotristatethyl in the ‘disease-related concerns’ domain.
  • Overall, given the unclear clinical relevance of the findings and the inability to weigh up the positive and negative effects of telotristatethyl, the available data do not allow for a quantification of the additional benefit.

Courtesy translation only, please refer to the German original.