G.O.11: Longitudinal quantitative muscle MRI in 5 Duchenne boys treated with exon 51 skipping – A pilot study

Abstract

Exon skipping in Duchenne muscular dystrophy (DMD) aims to restore dystrophin expression and maintain muscle function. The largest RCT so far targeting exon 51 failed to reach its primary endpoint despite promising results from preceding studies. It underscores the need for biomarkers. Quantitative MRI (qMRI) is promising as it is a non-invasive method which can be repeated easily. qMRI was used in 5 boys from the 48week RCT (DMD114044) and open label extension (OLE) study (DMD114349) assessing exon 51 skipping with weekly subcutaneous dosing at 6mg/kg drisapersen. T1w, 3-point Dixon and quantitative fat suppressed T2 scans were acquired from the left lower leg at 3T at 3 occasions: n =5), around the start of the OLE phase ( n =5) and n =4). Two boys were on placebo during RCT. Outcome measures were % fatty infiltration, contractile cross-sectional area (cCSA), and mean and standard deviation (SD) of T2 relaxation times in five lower leg muscles. Results were compared to three DMD controls from our natural history study. Interval between scans on treatment varied between 322 and 825days. cCSA and fat% did not show a clear pattern. However, in treated boys, a reduction in mean value and SD of the T2 relaxation time was visible especially in the tibialis anterior muscle. In contrast, T2 values of controls increased. The oldest boy with the highest initial fat% showed a large reduction in fat% and increase in cCSA for all lower leg muscles during 10.5months on treatment. Nonetheless he lost ambulation during the extension phase. The observed shift in T2 values opposite to that of controls may point towards less damaged muscle tissue. Subclinical improvement in muscle structure can provide a base for developing more potent drugs or studying prolonged treatment in younger patients as disease progression may lead to a point of no return regarding ambulation. qMRI should be considered as a biomarker in DMD trials.