P129 Givinostat in DMD: results of the Epidys study with particular attention to MR measures of muscle fat fraction

• Published in: Neuromuscular disorders : NMD 2023-10, Vol.33, p.S79-S80
• Main Authors: Vandenborne, K., Willcocks, R., Walter, G., Forbes, S., Cazzaniga, S., Bettica, P., Mercuri, E., McDonald, C.
• Format: Article
• Language: English
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2023.07.064

A randomized, double blinded, placebo controlled, multicenter Phase 3 clinical trial (Epidys; NCT02851797) examined the safety and efficacy of givinostat, an orally active histone deacetylase inhibitor in development, in ambulant boys with Duchenne muscular dystrophy (DMD). A total of 179 DMD boys aged ≥6 years at baseline were enrolled and treated for 18 months. The primary efficacy assessment was the time to climb 4 standard stairs (4SC). The primary endpoint was complemented by six key secondary efficacy endpoints: NSAA, time to rise from floor, 6MWT, knee extension and elbow flexion muscle strength, and a biomarker consisting of fat fraction of the vastus lateralis (VL) measured by magnetic resonance spectroscopy (MRS) which has proven to be sensitive to disease progression in DMD and predictive of loss of ambulation. The Epidys Study met its primary endpoint and givinostat demonstrated a statistically significant difference in change from baseline at 18 months in 4SC (GLSmean ratio [SD] = 0.86 [0.071]; p=0.0345). Overall, treatment effect estimates relating to the key secondary endpoints consistently favored givinostat over placebo supporting the primary endpoint result. VL fat fraction, measured by MRS, showed significant less fat infiltration in givinostat treated subjects over 18 months compared to placebo (Difference in LS means (givinostat-placebo): -2.92%; nominal p-value: 0.035). Participants in the placebo group had an average VL fat fraction increase of 10.6% while patients treated with givinostat had an increase of 7.6%. MRS VL fat fraction results were confirmed using quantitative imaging of water and fat (Dixon Imaging). The treatment effect of givinostat was demonstrated in each of the selected 5 thigh muscles/muscle groups (VL, nominal p-value: 0.0033; biceps femoris long head, nominal p-value: 0.0235; semitendinosus and quadriceps, nominal p-value: 0.0009 each; and hamstrings, nominal p-value: 0.0026). Givinostat treatment in DMD patients showed a good tolerability profile. In conclusion, the Epidys Study met its primary endpoint with consistent results in the key secondary endpoints. Quantitative MR measures of muscle fat infiltration showed that givinostat ameliorates muscle deterioration in patients with DMD. Givinostat tolerability profile in Epidys Study was in line with results in previous studies in DMD and in other diseases. These results also support the use of quantitative MR biomarkers in clinical trials.