Teprotumumab (1) – Tepezza®

• Clinical trials
  • The TED01RV trial is a multicentre, randomised, double-blind, placebo-controlled Phase II trial to assess the efficacy and safety of teprotumumab in adults with moderate to severe endocrine orbitopathy in the acute phase of the disease.
  • The HZNP-TEP-301 trial is a multicentre, randomised, double-blind, placebo-controlled Phase III trial.

a) Adults with moderate to severe endocrine orbitopathy in the acute phase of the disease; first-line treatment

• The pharmaceutical manufacturer presents data in the dossier on the TED01RV and HZNP-TEP-301 studies, in which teprotumumab is compared with placebo.
• As studies TED01RV and HZNP-TEP-301 are placebo-controlled studies in which none of the treatment options listed in the appropriate comparator therapy—whether as first-lineor timeline therapy were used, the data submitted by the pharmaceutical manufacturer are not suitable for drawing conclusions regarding the additional benefit of teprotumumab compared with the appropriate comparator therapy in adults with endocrine orbitopathy in the acute phase of the disease.
• For adults with moderate to severe endocrine orbitopathy in the acute phase who are eligible for first-line treatment, the additional benefit is not proven.

b) Adults with moderate to severe endocrine orbitopathy in the acute phase who are eligible for second-line treatment

• The pharmaceutical manufacturer also presents data in the dossier for this patient population from the TED01RV and HZNP-TEP-301 studies, in which teprotumumab is compared with placebo.
• As the TED01RV and HZNP-TEP-301 studies are placebo-controlled trials in which none of the treatment options mentioned in the appropriate comparator therapy for first-lineor timeline therapy were used, the data submitted by the pharmaceutical manufacturer are not suitable for drawing conclusions regarding the additional benefit of teprotumumab compared with the appropriate comparator therapy in adults with endocrine orbitopathy in the acute phase of the disease.
• For adults with moderate to severe endocrine orbitopathy in the acute phase who are eligible for second-line treatment, the additional benefit is not proven.

c) Adults with moderate to severe endocrine orbitopathy in the chronic stage of the disease

• For the assessment of patient population c), the pharmaceutical manufacturer submitted the HNZP-TEP-403 study.
• Whilst the chronic stage of the disease is reflected in the inclusion criteria of study HNZP-TEP-403, the study population was not restricted to moderate to severe endocrine orbitopathy on the basis of these inclusion criteria.
• The fact that it cannot be conclusively established whether study HZNP-TEP-403 adequately reflects moderate to severe disease severity leads to further uncertainties in the assessment of the study.
• Overall, irrespective of whether the HZNP-TEP-403 study adequately reflects moderate to severe disease severity, no additional benefit for teprotumumab can be inferred from the results presented.
• mortality
  • No deaths occurred in either treatment group up to week 24.
• Morbidity – freedom from diplopia
  • For the endpoint of freedom from diplopia, there was no statistically significant difference between the treatment groups at week 24.
• Morbidity – Orbital pain (VAS)
  • For the endpoint of orbital pain, assessed using a 10-cm VAS, there was no statistically significant difference between the treatment groups up to week 24.
• Quality of life – Graves’ Ophthalmopathy Quality of Life questionnaire (GO-QoL)
  • For the visual function domain, a statistically significant difference in favour of teprotumumab compared with placebo was observed up to week 24. However, the 95% confidence interval for the standardised mean difference (SMD) does not lie entirely outside the non-significant range of −0.2 to 0.2, meaning it cannot be concluded that the effect is clinically relevant.
  • For the appearance domain, no statistically significant difference was observed between the treatment groups up to week 24.
• Side effects – SUEs, severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs
  • For the endpoints SUEs, severe AEs and discontinuation due to AEs, no statistically significant difference was observed between the treatment groups at week 24.
• Side effects – hearing impairment (SMQ, HLT, AEs)
  • For the endpoint of hearing impairment, there was no statistically significant difference between the treatment groups at week 24.
• Overall assessment
  • For adults with moderate to severe endocrine orbitopathy in the chronic stage of the disease, data from the HZNP-TEP-403 trial comparing teprotumumab with placebo are available for the endpoints of mortality, morbidity, health-related quality of life and side effects.
  • With regard to the patient-relevant endpoints in the endpoint categories of mortality, morbidity and side effects, there were neither advantages nor disadvantages for teprotumumab compared with placebo.
  • In the health-related quality of life endpoint category, a statistically significant difference in favour of teprotumumab compared with placebo was observed in the visual function domain of the GO-QoL up to week 24. However, the 95% confidence interval of the standardised mean difference (SMD) does not lie entirely outside the non-significant range of −0.2 to 0.2, so it cannot be concluded that the effect is clinically relevant.
  • The fact that it cannot be conclusively determined whether the HZNP-TEP-403 study adequately reflects moderate to severe disease severity adds to the uncertainties in the assessment of the study.
  • Overall, irrespective of whether the HZNP-TEP-403 study adequately reflects moderate to severe disease severity, no additional benefit for teprotumumab can be inferred on the basis of the results presented.

Courtesy translation only, please refer to the German original.