Teduglutid (1) – Revestive®

• Clinical trials
  • The EMA regards CL0600-020 as the pivotal trial for the efficacy of teduglutide. In this randomised, double-blind, multicentre Phase III trial, patients with short bowel syndrome were studied over a treatment period of 24 weeks. Patients were randomised to an intervention group receiving teduglutide and a control group receiving a placebo.
  • The earlier randomised, double-blind, multicentre Phase III trial CL0600-004 had a three-arm design with two different dosages (0.1 mg/kg/day and 0.05 mg/kg/day) of teduglutide and a placebo arm, and was primarily designed to investigate the efficacy of the higher dose over a 24-week treatment period.

Treatment of an orphan disease in accordance with Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan drugs (teduglutide) – adult patients with short bowel syndrome

• For adult patients with short bowel syndrome, there is a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of teduglutide as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in treating the condition. In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a moderate – and not merely minor – improvement in treatment-related benefit that has not previously been achieved.
• On the basis of these considerations, the information in the dossier, the results of the benefit assessment and the statements submitted, the G-BA concludes that teduglutide offers a minor additional benefit.
• mortality
  • No deaths occurred in either study. Consequently, no conclusion can be drawn regarding the extent of the additional benefit in terms of mortality.
• morbidity
  • Response
  • The primary endpoint of the CL0600-020 study was response, defined as a 20% reduction in the volume of weekly parenteral nutrition (pE) in weeks 20 and 24 compared with baseline. In the intervention group, approximately 63% of patients were responders, compared with approximately 30% in the control group. This difference was statistically significant in favour of teduglutide (p = 0.002).
  • Categorised response
  • The primary endpoint of the CL0600-004 study was categorised response, a score in which an earlier, more sustained and greater reduction in pE leads to higher (i.e. better) scores. The study protocol provided for a hierarchical testing procedure; thus, the higher dose (0.10 mg/kg/day) was to be tested against placebo first, and if this difference was not statistically significant, no further tests were planned. The difference between teduglutide 0.10 mg/kg/day and placebo was not statistically significant. The statistically significant difference (p = 0.007) between the intervention group receiving 0.05 mg/kg/day and the control group should therefore be regarded as exploratory only.
  • No data are available on the minimum clinically important difference (MID) for this endpoint.
  • Complete discontinuation of parenteral nutrition
  • Complete discontinuation of parenteral nutrition (pE) was not achieved in study CL0600-020 in either the intervention or the control group.
  • In study CL0600-004, complete discontinuation of parenteral nutrition was achieved in two patients in the intervention group (0.05 mg/kg/day). In the control group, no patient was able to completely discontinue parenteral nutrition. The difference was not statistically significant.
  • Overall, in the present case scenario, no conclusion can be drawn regarding the extent of the additional benefit for the endpoint ‘complete discontinuation of parenteral nutrition’.
  • Reduction in pE by at least one day per week
  • The number of patients in whom a reduction in pE of at least one day per week was achieved after 24 weeks was recorded. In study CL0600-020, more patients on teduglutide achieved a statistically significant reduction in pE of at least one day (21 (48.8%) versus 9 (20.9%); p = 0.008). In study CL0600-004, statistical significance was not achieved.
  • A reduction in the frequency of pE, without achieving complete cessation of pE, directly translates into a gain in time for patients and thus potentially an improvement in quality of life. However, the results on quality of life show no advantage of teduglutide compared with placebo.
  • With regard to the morbidity endpoints, there is therefore, overall, a minor additional benefit.
• quality of life
  • In study CL0600-020, quality of life was assessed using the disease-specific Short Bowel Syndrome – Quality of Life (SBS-QoL) questionnaire. There was no statistically significant difference between the intervention and control groups.
  • In study CL0600-004, quality of life was assessed using the generic 36-Item Short Form Health Survey (SF-36) questionnaire. After 24 weeks, there was no statistically significant difference between the intervention and control groups on any of the subscales or on either of the two total scales.
  • The Inflammatory Bowel Disease Questionnaire (IBDQ) was used as a disease-specific measurement tool in study CL0600-004. After 24 weeks, there was no statistically significant difference between the intervention and control groups in any of the four domains of the IBDQ.
• Side effects
  • In study CL0600-020, AEs were reported by 83% of patients in the intervention group and by 79% in the control group. At least one SAE was reported by 36% of patients in the intervention group and by 28% in the control group. In the intervention group, two patients (5%) discontinued treatment due to an AE; in the control group, three patients (7%) did so. The most common AEs were abdominal pain, nausea, stoma complications, abdominal distension, systemic infection of the central venous access site, peripheral oedema, urinary tract infection, catheter-associated infection, flatulence, vomiting, diarrhoea, headache and weight loss.
  • In study CL0600-004, AEs were reported by 94 per cent of patients in the intervention group and by 94 per cent in the control group. At least one SAE was reported by 37 per cent of patients in the intervention group and by 31 per cent in the control group. In the intervention group, six patients (17 per cent) discontinued treatment due to an AE; in the control group, one patient (6 per cent) did so. The most common AEs were abdominal pain, abdominal distension, nasopharyngitis, nausea, vomiting, catheter-related sepsis, urinary tract infection, fatigue and general catheter-associated AEs.
  • According to the EMA, particular attention should be paid to the potential development of neoplasms during treatment with teduglutide. The two placebo-controlled studies provide no indication of an increased risk, although the minor number of cases and the short duration of the studies must be taken into account.
• Overall assessment
  • Taking an overall view of the available results on morbidity and quality of life, whilst considering the side effects, teduglutide demonstrates a moderate—and not merely minor—improvement in treatment-related benefit that has not been achieved previously.

Courtesy translation only, please refer to the German original.