Givinostat (1) – Duvyzat®

• Clinical trials
  • The EPIDYS trial is a randomised, double-blind, placebo-controlled Phase III trial designed to assess the efficacy and safety of Givinostat.

Patients aged 6 years and over with Duchenne muscular dystrophy (DMD) who are able to walk

• For ambulatory patients aged 6 years and over with Duchenne muscular dystrophy (DMD), there is a hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• mortality
  • No deaths occurred during the course of the EPIDYS trial.
• Morbidity – climbing 4 steps (4SC)
  • The endpoint ‘climbing 4 steps’ (4SC) measures the time taken by the patient to climb four steps. This endpoint is considered patient-relevant in the present therapeutic indication.
  • For the 4SC endpoint, there is a statistically significant difference between the treatment arms in week 72 in favour of Givinostat.
  • The difference between the treatment arms is minor, and the upper limit of the 95% confidence interval, at –0.15 seconds, appears too minor to classify the observed effect as clinically relevant.
  • In the sensitivity analysis using MMRM, which took into account patients who attended the visit within a ±7-day window, no statistically significant difference was observed for the Week 72 study visit (LS means difference: -0.17 (95% CI [-0.82; 0.47]), p-value: 0.60); a minor response rate at week 72 (< 70%) should be taken into account.
• Morbidity – Rising from a supine position (Rise From The Floor, RFTF)
  • For the endpoint ‘Rise From The Floor’, the time (in seconds) taken by a patient with Duchenne muscular dystrophy to rise from a supine position on the floor to a standing position is measured. The test was carried out as part of the ‘North Star Ambulatory Assessment’ (NSAA) (Item 12). This endpoint is considered patient-relevant for the present therapeutic indication.
  • For the RFTF endpoint, there is a statistically significant difference between the treatment arms in favour of Givinostat at week 72.
  • The difference between the treatment arms is minor, and the upper limit of the 95% confidence interval, at –0.16 seconds, appears too minor to classify the observed effect as clinically relevant.
  • In the sensitivity analysis using MMRM (without imputation), taking into account patients who attended the visit within the ±7-day visit window, no statistically significant difference was observed for the Week 72 study visit (LS means: -0.77 (95% CI: [-1.95; 0.42], p-value: 0.20); a minor response rate at week 72 (< 70%) should be taken into account here.
• Morbidity – 10-metre walk/run test (10-MWT)
  • The ‘10-metre Walk/Run Test’ (10-MWT) endpoint measures the time taken by a patient to walk or run 10 metres. The test was carried out as part of the NSAA (Item 17). This endpoint is considered patient-relevant for the intended therapeutic indication.
  • For the 10-MWT endpoint, there is a statistically significant difference between the treatment arms in favour of Givinostat at week 72.
  • The difference between the treatment arms is minor, and the upper limit of the 95% confidence interval, at –0.1 seconds, appears too minor to classify the observed effect as clinically relevant.
  • In the sensitivity analysis using MMRM without imputation, taking into account patients who attended the visit within the ±7-day visit window, no statistically significant difference was observed for the Week 72 study visit (LS means: -0.26 (95% CI [-0.77; 0.25]), p-value: 0.32); a minor response rate at week 72 (< 70%) should be taken into account here.
• Morbidity – 6-Minute Walk Test (6-MWT)
  • The 6-minute walk test (6-MWT) is used to assess physical functioning and measures the distance a patient can walk within 6 minutes. This endpoint is considered patient-relevant in the present therapeutic indication.
  • For the 6-MWT endpoint, there is no statistically significant difference between the treatment arms at week 72.
• quality of life
  • No data on quality of life were collected.
• Side effects
  • In the EPIDYS study, adverse events (AEs) occurred in approximately 95% of participants.
  • For the endpoints ‘severe AEs’, ‘serious adverse events (SAEs)’ and ‘AEs leading to discontinuation of study medication’, there were no statistically significant differences between the treatment groups in any case.
• Overall assessment
  • The results of the pivotal, randomised, double-blind, placebo-controlled Phase III EPIDYS study are used to assess the additional benefit.
  • No deaths occurred during the course of the EPIDYS study.
  • In the morbidity category, there was a statistically significant difference between the treatment arms in favour of Givinostat for the endpoints 4SC, RFTF and 10-MWT at week 72. However, due to the minor difference between the treatment arms, a low upper limit of the 95% confidence interval in each case and the uncertain robustness of the results, the observed effects are not classified as clinically relevant. Consequently, no conclusions regarding the extent of the additional benefit can be drawn from these results.
  • For the 6-MWT endpoint, there was no statistically significant difference between the treatment arms at week 72.
  • Due to limitations in the chosen imputation strategy and in the handling of missing values, the endpoints ‘Confirmed loss of ability to stand up’, Loss of Ability to Walk without Aids and Functional Performance (NSAA) are presented in the resolution only as supplementary information and are not taken into account for the assessment of the extent of the additional benefit.
  • The endpoint ‘Physical Functioning’ (PODCI) is not taken into account in the benefit assessment due to insufficient operationalisation and unclear validity.
  • No data were collected for the quality of life endpoint category.
  • In the side effects category, there was no statistically significant difference between the treatment groups in terms of severe adverse events (AEs), serious AEs and AEs leading to discontinuation of the study medication.
  • In summary, for Givinostat in combination with corticosteroid treatment in ambulatory patients aged 6 years and over with Duchenne muscular dystrophy (DMD), there is a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.