Sebetralstat (1) – Ekterly®

• Clinical trials
  • The KONFIDENT study was conducted as a multicentre, double-blind, placebo-controlled trial with a triple crossover design between February 2022 and December 2023. The study compared the administration of 300 mg and 600 mg of sebetralstat with placebo in the treatment of acute HAE attacks in adults and adolescents aged 12 years and over.

Adults and adolescents aged 12 years and over with an acute attack of hereditary angioedema

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Due to the crossover design of the KONFIDENT study, as well as methodological limitations in the conduct and analysis of the study, there are significant uncertainties which limit the overall validity of the evidence.
• With regard to the certainty of the findings, a ‘hint’ is assumed due to the high potential for bias and other limitations.
• mortality
  • Deaths were documented as part of the safety monitoring throughout the entire study duration. No deaths occurred in the KONFIDENT study.
  • Due to its study design, the KONFIDENT study is not suitable for investigating endpoints in the mortality category.
• Morbidity – Patient Global Impression of Change (PGI-C)
  • For the endpoint of confirmed symptom improvement, assessed using the PGI-C within four hours, there was a statistically significant advantage of sebetralstat compared with placebo.
• Morbidity – Patient Global Impression of Severity (PGI-S)
  • For the endpoint of reduction in attack severity, assessed using the PGI-S within four hours, sebetralstat showed a statistically significant advantage over placebo.
• Morbidity – HAE symptoms: abdominal pain, skin pain, skin swelling
  • For the endpoint ‘HAE symptoms’ (abdominal pain, skin pain and skin swelling), assessed using a visual analogue scale within four hours, there was no statistically significant difference between sebetralstat and placebo.
• Morbidity – General Anxiety – Numerical Rating Scale (GA-NRS)
  • This approach contravenes the ITT principle. This endpoint is therefore not taken into account for the benefit assessment.
• quality of life
  • No endpoints in the category of health-related quality of life were assessed in the KONFIDENT study.
• Side effects
  • At least one AE occurred in each of the 17 HAE attacks during treatment with sebetralstat and the 17 HAE attacks during placebo treatment. One person in the sebetralstat arm experienced a severe AE as well as a severe SAE. No participant withdrew from the study due to an AE.
  • Overall, no analyses of the safety endpoints were submitted that adequately account for the interdependence of the data and also take the 2x2 crossover design into account at the individual level.
  • Furthermore, no information is available on the median duration of follow-up for the included patients.
  • Further uncertainties arise from the method of recording safety endpoints, which was linked to the occurrence of an HAE attack. Consequently, it cannot be definitively ruled out that follow-up periods for participants without qualifying attacks were not reported.
  • Furthermore, it should be noted that the premature termination of the study was criticised by the regulatory authority (EMA). As a result, of the 84 participants originally planned, only 68 patients were treated with all the assigned investigational medicinal products.
  • Furthermore, due to the crossover study design, the minor number of HAE attacks that occurred, and the insufficient duration of exposure to sebetralstat, it was not possible to maintain a long-term follow-up period for patients receiving the sebetralstat dosage in accordance with the marketing authorisation.
  • Overall, based on the available documentation, it is not possible to conclusively assess the safety endpoints due to the uncertainties mentioned.
• Overall assessment
  • No deaths occurred in the KONFIDENT study.
  • In the morbidity endpoint category, the endpoints of symptom improvement (PGI-C), reduction in attack severity (PGI-S) and the HAE symptoms (VAS) of abdominal pain, skin pain and skin swelling were used to quantify the additional benefit. For the endpoints of symptom improvement and reduction in attack severity, a statistically significant advantage in favour of sebetralstat over placebo was observed in each case. For the aforementioned HAE symptoms, however, no statistically significant difference was observed between sebetralstat and placebo.
  • Endpoints relating to health-related quality of life were not assessed in the study.
  • Safety endpoints in the KONFIDENT study were assessed at the level of HAE attacks treated with the study medication, rather than on the basis of the randomised patients. No information is available regarding the exact duration of follow-up for the treated individuals. Given this method of data collection, it cannot be reliably ruled out that AEs may not have been reported at different points during the follow-up period. Furthermore, the regulatory authority criticised the insufficient duration of exposure to sebetralstat and the minor number of attacks treated, which resulted from the premature termination of the study. The approach taken in the study meant that patients receiving sebetralstat could not be observed for a sufficiently long period. For this reason, the safety endpoints cannot be conclusively assessed on the basis of the KONFIDENT study.
  • Overall, due to the study design, relevant results regarding the additional benefit of sebetralstat are available only for a patient population included in the morbidity endpoint category. Here, a statistically significant advantage of sebetralstat over placebo is evident for the endpoints of symptom improvement (PGI-C) and reduction in attack severity (PGI-S). However, as either no data were collected for the other endpoint categories – mortality, quality of life and side effects – or a definitive assessment is not possible due to the nature of the data collection and analysis, the data presented are, on the whole, not suitable for quantifying the extent of the additional benefit.
  • For sebetralstat for the symptomatic treatment of acute HAE attacks, a non-quantifiable additional benefit is established, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.