Volanesorsen (1) – Waylivra®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the results of the pivotal randomised, blinded, placebo-controlled Phase III trial APPROACH, which formed the basis for the marketing authorisation.
  • In addition, results from the randomised, blinded, placebo-controlled Phase III study COMPASS and the open-label, single-arm long-term study APPROACH OLE are presented.

Adult patients with genetically confirmed familial chylomicronemia syndrome (FCS) and a high risk of pancreatitis, in whom the response to diet and triglyceride-lowering therapy has been inadequate

• For adult patients with genetically confirmed familial chylomicronemia syndrome (FCS) and a high risk of pancreatitis, in whom the response to diet and triglyceride-lowering therapy was inadequate, there is a hint of a non-quantifiable additional benefit for volanesorsen, as the scientific data do not permit quantification.
• Overall, there is evidence of a non-quantifiable added benefit for volanesorsen in the treatment of adult patients with genetically confirmed familial chylomicronemia syndrome (FCS) and at high risk of pancreatitis, in whom the response to diet and triglyceride-lowering therapy has been inadequate, there is a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• mortality
  • In the APPROACH study, deaths were recorded as safety events. No deaths occurred during the study.
  • No conclusions regarding the extent of the additional benefit can be drawn from the mortality data.
• Morbidity – Change in fasting triglyceride levels
  • Blood triglyceride levels are a clinically relevant parameter in this therapeutic indication, used for diagnosis and to guide treatment.
  • For the endpoint ‘change in the percentage of fasting triglyceride levels’, a statistically significant difference in favour of volanesorsen compared with placebo was observed after 3, 6 and 12 months of treatment. Fasting triglyceride levels decreased by 59.6 per cent after 12 months of treatment with volanesorsen, compared with a 2.7 per cent decrease following treatment with placebo (median difference: -47.8 [95% CI -69.2; -26.4]; p-value < 0.0001).
  • However, no valid data could be identified to show what effects a specific change in triglyceride levels in FCS patients has on their individual symptoms or on the risk of acute pancreatitis.
• Morbidity – Abdominal pain
  • In the volanesorsen arm, 42.4% of study participants discontinued the treatment phase prematurely, compared with 5.9% of patients in the placebo arm. No data are available on the reporting of abdominal pain following discontinuation of treatment.
  • From week 26 onwards, the calculated response rate in the volanesorsen arm fell significantly below 70%, whilst in the placebo arm a rate of over 70% was achieved by the end of the study. The data collected therefore do not allow for valid conclusions regarding abdominal pain in relation to the entire study population. The data for the endpoint ‘abdominal pain’ are therefore not presented in the benefit assessment.
• Quality of life – change in quality of life as measured by the SF-36
  • The SF-36 is a cross-disease measurement tool for assessing health-related quality of life, consisting of 8 domains with a total of 35 items.
  • In the individual domains and the physical (PCS) and mental (MCS) summary scales, there was no statistically significant difference between the treatment arms at week 13.
  • No conclusions regarding the extent of the additional benefit can be drawn from the quality of life data.
• Side effects
  • During the treatment and follow-up phases, an AE occurred in almost all patients in both the volanesorsen arm and the placebo arm (97.0% vs. 90.9%).
  • However, an AE leading to therapy discontinuation occurred exclusively in the volanesorsen arm, affecting a total of 9 patients (27.3%).
  • Severe adverse events occurred in 5 (15.2%) patients in the volanesorsen arm and in 1 (3.0%) patient in the control arm. Serious adverse events occurred in 6 (18.2%) patients in the volanesorsen arm and in 2 (6.1%) patients in the control arm.
  • For example, disorders of the skin and subcutaneous tissue and disorders of the blood and lymphatic system occurred in 54.5% and 30.3% of patients in the volanesorsen arm, respectively, and in 18.2% and 6.1% of patients in the placebo arm, respectively.
  • A reduction in platelet count occurred in 11 patients (33.3%) in the volanesorsen arm and in one patient (3%) in the placebo arm; thrombocytopenia occurred exclusively in the volanesorsen arm in 4 patients (12.1%).
  • Bleeding occurred in 16 (48.5%) patients in the volanesorsen arm and in 4 (12.1%) patients in the control arm.
  • The pharmaceutical manufacturer has not provided suitable effect estimators for assessing the safety endpoints that take into account the difference in treatment duration between the two study arms (median treatment duration (min, max) of 346 days (57, 372) in the volanesorsen arm and 358 days (163, 379) in the placebo arm). The results on side effects are therefore potentially biased in favour of volanesorsen due to the shorter duration of treatment in the volanesorsen arm. For this reason, the data on side effects cannot be conclusively assessed.
  • No conclusions regarding the extent of the additional benefit can be drawn from the data on side effects.
• Overall assessment
  • For adjunctive treatment alongside a diet in adult patients with genetically confirmed familial chylomicronemia syndrome (FCS) and a high risk of pancreatitis, in whom the response to diet and triglyceride-lowering therapy was inadequate, results on mortality, morbidity, quality of life and side effects are available from the pivotal registration trial APPROACH.
  • In the morbidity category, a statistically significant difference in favour of volanesorsen compared with placebo was demonstrated for the primary endpoint ‘change in the percentage of fasting triglyceride levels’ after 3, 6 and 12 months of treatment. Blood triglyceride levels are a clinically relevant parameter in this therapeutic indication, used for diagnosis and to guide treatment. However, no valid data could be identified to show what effects a specific change in triglyceride levels in FCS patients has on their individual symptoms or on the risk of acute pancreatitis.
  • In summary, the available results are, on the whole, classified as non-quantifiable in terms of their extent, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.