Sirolimus (1) – Hyftor®

• Clinical trials
  • The NPC-12G-1 trial is a multicentre, stratified, randomised, double-blind, placebo-controlled Phase III trial with a parallel-group design in children and adults with angiofibromas associated with TSC.
  • The OSD-001-001 trial is a single-centre, stratified, randomised, double-blind, placebo-controlled dose-escalation trial with a parallel-group design in children and adults with angiofibromas associated with TSC.
  • The NPC-12G-2 study is an open-label, uncontrolled, multicentre, single-arm long-term study, which enrolled both participants from the NPC-12G-1 study following its completion and newly registered individuals.

Adults and children aged 6 years and over with facial angiofibromas associated with tuberous sclerosis

• There is a hint of a non-quantifiable additional benefit for sirolimus in the treatment of facial angiofibromas associated with tuberous sclerosis in adults, children and adolescents aged 6 years and over, as the scientific evidence does not permit quantification.
• mortality
  • No deaths occurred in any of the studies.
• Morbidity – Improvement in angiofibromas according to the Index for Facial Angiofibromas (IFA)
  • The post-hoc endpoint ‘improvement in angiofibromas according to the IFA’ is defined in the NPC-12G-1 study as an assessment of angiofibromas using the ‘Index for Facial Angiofibromas’ (IFA).
  • The responder analysis showing an improvement of ≥ 3 points (15 % of the scale range) indicates a statistically significant advantage for sirolimus.
  • Given the effect size, the results for this endpoint are taken into account in the benefit assessment, despite the significant uncertainties noted regarding the validity of the measurement tool.
  • However, it is not possible to quantify this treatment effect due to the uncertainties outlined.
• Morbidity – Combined improvement in angiofibromas (presented as supplementary data)
  • ‘Combined improvement in angiofibromas’ was the primary endpoint in the NPC-12G-1 and OSD-001-001 studies.
  • The ‘combined improvement in angiofibromas’ measurement tool has limitations in each of the different operationalisations used in the NPC-12G-1, NPC-12G-2 and OSD-001-001 studies.
  • Overall, the measurement tool is therefore not taken into account in the benefit assessment, but is presented here for supplementary information.
• quality of life
  • In the NPC-12G-1 and NPC-12G-2 studies, the DLQI (Dermatology Life Quality Index) and the CDLQI (Children’s Dermatology Life Quality Index) were assessed.
  • There was no statistically significant difference between the treatment groups in the change in the CDLQI/DLQI total score at week 12.
• Side effects
  • In the meta-analytic evaluation of the NPC-12G-1 and OSD-001-001 studies, no significant differences were observed between the treatment groups in the endpoints of severe adverse events (SAEs) and severe unanticipated events (SUEs).
  • No events occurred in either study for the endpoint ‘discontinuation due to adverse events’.
  • For the pre-specified AE of special interest (AESI) ‘symptoms of skin irritation’, the studies NPC-12G-1 and OSD-001-001 each showed a statistically significant effect to the detriment of sirolimus.
• Overall assessment / Conclusion
  • Data for the benefit assessment are available from the pivotal registration study NPC-12G-1, the dose-escalation study OSD-001-001 and the single-arm long-term study NPC-12G-2.
  • In the morbidity endpoint category, the pharmaceutical manufacturer presents data with different operationalisations for the patient-relevant endpoint of improvement in facial angiofibromas.
  • A statistically significant difference in favour of sirolimus is observed for the endpoint ‘improvement in facial angiofibromas by ≥ 3 points according to the IFA’ at week 12.
  • Given the effect size, the results for this endpoint are taken into account in the benefit assessment, despite the significant uncertainties noted regarding the validity of the measurement instrument.
  • However, it is not possible to quantify this treatment effect given the uncertainties outlined.
  • Overall, an additional benefit of sirolimus is identified for adults, children and adolescents aged 6 years and older with facial angiofibromas associated with tuberous sclerosis, based on the endpoint of improvement in angiofibromas as assessed by IFA.
  • However, the extent of the additional benefit cannot be quantified, as the magnitude of the treatment effect cannot be conclusively assessed, particularly due to insufficient information on the development of the measurement instrument and the associated lack of clarity regarding its validity.

Courtesy translation only, please refer to the German original.