Olezarsen (1) – Tryngolza®

• Clinical trials
  • The multicentre, double-blind, randomised, controlled Phase III Balance trial investigated the efficacy and safety of olezarsen compared with placebo in adults with genetically confirmed familial chylomicronemia syndrome (FCS) as an adjunct to a low-fat diet.

Adults with genetically confirmed familial chylomicronemia syndrome (FCS)

• Overall, based on the demonstrated advantage in the endpoint ‘confirmed acute pancreatitis’, olezarsen is found to provide an indication of a minor additional benefit for the treatment of adults with genetically confirmed familial chylomicronemia syndrome (FCS).
• mortality
  • No deaths occurred in the study.
• Morbidity – Confirmed acute pancreatitis
  • In the Balance study, there were statistically significantly fewer confirmed cases of acute pancreatitis in the olezarsen group compared with the placebo group after 12 months.
  • Cases of acute pancreatitis in the Balance study were confirmed by a blinded, independent expert committee (the ‘Acute Pancreatitis Adjudication Committee’, PAC) on the basis of pre-specified criteria.
• Morbidity – Hospitalisation
  • For the endpoint ‘total hospitalisation’, the calculations provided by the pharmaceutical manufacturer in the dossier indicate a positive effect; however, this is not statistically significant based on the confidence interval.
  • Consequently, a separate calculation was carried out using an exact test. This revealed no statistically significant differences between the treatment arms for the endpoint of total hospitalisation.
  • Due to the overlap in the operationalisation with the endpoint ‘confirmed acute pancreatitis’ – for which hospitalisation was also required for certification by the PAC – it is assumed in this case that there was double counting of the cases of acute pancreatitis that occurred in the Balance study. Consequently, the endpoint ‘hospitalisations due to AP’ is presented here only as supplementary information and is not used for the benefit assessment.
• Morbidity – Symptoms assessed using the FCS symptom scale, PGIS and PGIC
  • For the endpoint ‘worsening of symptoms’ as measured by the FCS-SIS, no statistically significant difference was observed between the treatment groups after 12 months of treatment.
  • For the endpoint ‘worsening of symptom severity’ as measured by the PGIS, there was no statistically significant difference between the treatment groups after 12 months of treatment.
  • However, the response rates for the PGIC at month 12 varied considerably between the treatment arms, meaning that these data cannot be used for the benefit assessment.
• Health-related quality of life – Impact Scale (FCS-SIS)
  • For the endpoint ‘deterioration in health-related quality of life’ as measured by the FCS-Impact, which was used for the benefit assessment, there was no statistically significant difference between the treatment groups after 12 months of treatment.
• Side effects – severe adverse events (AEs) and severe adverse events (SAEs)
  • With regard to the overall rates of severe AEs (CTCAE Grade 3 or 4), a statistically significant advantage in favour of olezarsen over placebo was observed after 12 months of treatment.
  • With regard to the overall rates of SAE, there was no statistically significant difference between the treatment arms after 12 months of treatment.
  • For both severe AEs and SAEs, a statistically significant advantage in favour of olezarsen compared with placebo was observed at SOC level within the SOC ‘Gastrointestinal disorders’.
  • Based on supplementary data from which pancreatitis events were excluded: Based on these data, a statistically significant advantage of olezarsen over placebo continues to be observed for the overall rates of severe AEs; however, no statistically significant difference was observed between the treatment groups in the overall rates of SAE or within the SOC ‘Gastrointestinal disorders’ (severe AEs/SUE).
  • Overall, it does not seem plausible that more severe AEs would occur with a sham intervention than with the study medication. In the present context, it cannot be ruled out that further possible events related to the underlying disease, in addition to the pancreatitis events, are included in the safety analyses. The effects shown can therefore only be interpreted to a limited extent.
• Overall assessment
  • In the morbidity endpoint category, a statistically significant advantage was observed for olezarsen compared with placebo for the endpoint ‘confirmed acute pancreatitis’.
  • For the endpoint ‘total hospitalisation’ and for symptoms, as assessed via the FCS-SIS and PGIS questionnaires, no statistically significant differences were observed between the treatment groups at month 12.
  • The primary endpoint ‘change in the percentage of fasting triglyceride levels’ is a clinically relevant parameter used for diagnosis and treatment monitoring in the present therapeutic indication. A statistically significant difference in favour of olezarsen compared with placebo was observed after 12 months of treatment.
  • In the overall analysis of morbidity endpoints, based on the positive effect observed for the endpoint ‘confirmed acute pancreatitis’, an advantage for olezarsen compared with placebo was identified, although the extent of this advantage was considered to be minor.
  • For the endpoint category of health-related quality of life, as assessed using the FCS-Impact and PROMIS-29 questionnaires, there were no statistically significant differences between the treatment groups in either case.
  • For the endpoint category of side effects, a statistically significant advantage for olezarsen over placebo was observed for both severe AEs and the SOC ‘gastrointestinal disorders’. Based on supplementary data, which excludes pancreatitis events, olezarsen continues to show a statistically significant advantage over placebo with regard to severe AEs. With regard to the endpoints of serious AEs and therapy discontinuations due to AEs, no statistically significant differences were observed between the treatment groups. Taken together, it cannot be ruled out in the present analysis that further possible events related to the underlying disease, in addition to the pancreatitis events, are included in the safety analyses. Overall, taking all endpoints in the side effects category into account, there are no relevant differences for the benefit assessment.
  • In the overall assessment of the available results for patient-relevant endpoints, there is an advantage in the morbidity endpoint category for the endpoint ‘confirmed acute pancreatitis’, which is central to this condition. Overall, based on the results of the Balance study, the G-BA classifies the extent of the additional benefit of olezarsen for the treatment of adults with FCS as minor.

Courtesy translation only, please refer to the German original.