Abstract Details

Title Ezutromid significantly reduced muscle damage whilst maintaining utrophin in patients with Duchenne muscular dystrophy (DMD) after 24-weeks of treatment

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) ES1 - (-)

Poster/Presentation
Number 007

Objective

Background Utrophin is a naturally occurring protein that may act as a functional replacement for dystrophin. It is hypothesized that continuous expression in mature muscle fibers could modify the course of DMD (Tinsley et al, 1998).

Design/Methods PhaseOut DMD is a Phase 2 open-label study of ezutromid administered to 40 ambulatory patients with DMD. Primary endpoints (48 week) are MRS assessments. Key secondary endpoints are from muscle biopsy; to be collected at baseline (n=40) and week 24 (n=25) or 48 (n=15). Safety, pharmacokinetics and functional measures are monitored throughout. The interim analysis was planned to assess impact on muscle health, primarily by biopsy; mixed effect models were used to estimate, with 95% confidence intervals, the changes from baseline (least square means difference [LSMD]).

Results A statistically significant reduction in %fibres expressing developmental myosin (MHCd) was observed (from 11.37% to 8.76%, LSMD -2.62% CI, -4.33, -0.90); a relative reduction of 23%. Mean utrophin intensity was maintained and even increased (relative +7%) (0.370 to 0.396, LSMD 0.026 95% CI, -0.005, 0.058). MRS indicated an increase in mean fat fraction (vastus lateralis: from 14.7% to 18.5% n=37) but a decrease in relaxation time (T2) (soleus: from 31.85 to 30.99 msec, n=38). No patient lost ambulation and there were no meaningful decreases in functional performance (eg 6MWD: baseline 404m, 24 week: 395m, n=39). All patients achieved plasma levels sufficient to modulate utrophin. Ezutromid continues to be safe and well tolerated.

Conclusions Decreased MHCd, a marker of regeneration, indicates reduction in muscle damage. Utrophin levels were maintained and even increased which, with decreasing MHCd, provides evidence of target engagement. These results support the utrophin hypothesis and the potential for universal treatment for DMD. With PhaseOut DMD StudyGroup

Authors/Disclosures
Francesco Muntoni, MD (UCL Institute of Child Health)	Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sarepta. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. The institution of Dr. Muntoni has received research support from European Commission. The institution of Dr. Muntoni has received research support from Medical Research Council. The institution of Dr. Muntoni has received research support from Biogen. The institution of Dr. Muntoni has received research support from Muscular Dystrophy UK. The institution of Dr. Muntoni has received research support from MDA USA. The institution of Dr. Muntoni has received research support from Sarepta. The institution of Dr. Muntoni has received research support from Association Francoise Myopathies. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving as a Clinical expert with UK NICE Committee.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Anne Heatherington	No disclosure on file
	No disclosure on file
Jon Tinsley	No disclosure on file
	No disclosure on file

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