Muscle MRI outcomes in patients with Duchenne Muscular Dystrophy treated with delandistrogene moxeparvovec: Findings from EMBARK Part 1

Topic:

Clinical Trials

Poster Number: P168

Author(s):

Krista Vandenborne, PhD, Department of Physical Therapy, University of Florida, Gainesville, FL, USA, Glenn A Walter, PhD, University of Florida, Volker Straub, PhD, Newcastle University, JWMDRC, Rebecca J Willcocks, PhD, University of Florida, Sean C Forbes, PhD, University of Florida, Sravya Ennamuri, MD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Kai Ding, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Carol Reid, PhD, Roche Products Ltd, Welwyn Garden City, UK, Alexander P Murphy, MD, PhD, Roche Products Ltd, Welwyn Garden City, UK, Marianna Manfrini, MD, PhD, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Jacob S Elkins, MD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Louise R Rodino-Klapac, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA

Background: Delandistrogene moxeparvovec, an rAAVrh74 vector-based gene transfer therapy, delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered, functional form of dystrophin shown to stabilize or slow disease progression in Duchenne muscular dystrophy (DMD). It is approved in the US and in other select countries. The Phase 3 EMBARK trial did not meet its primary endpoint (NSAA); however, multiple secondary functional endpoints showed stabilization of DMD disease progression.

Objective: We report prespecified, exploratory analyses of muscle health and changes in muscle pathology assessed by magnetic resonance (MR) in EMBARK Part 1 (Week 52) to further evaluate the effect of delandistrogene moxeparvovec on DMD disease progression.

Methods: A subset of patients who received delandistrogene moxeparvovec (1.33×10^14 vg/kg; n=19) or placebo (n=20) underwent quantitative muscle MR, including 8-point Dixon MR imaging (MRI) and proton MR spectroscopy (MRS) to measure muscle fat fraction (FF) and multi-slice spin echo imaging to measure transverse relaxation time (T2). MRS FF was measured in the soleus and vastus lateralis, while MRI FF and T2 were measured in 5 preselected leg muscles/groups with important roles in ambulation. A post hoc global statistical test (GST) combining all muscles and modalities assessed overall treatment effect.

Results: Overall, treated patients showed less disease progression vs. placebo. In all muscles, MRI FF and MRS FF magnitudes of change favored the treated group vs. placebo. The placebo group also showed increases (worsening) in T2 (all muscles) compared with reductions (improvement) in treated patients (4/5 muscles; baseline to Week 52 change ranged from −1.05 to 0.05 msec [delandistrogene moxeparvovec] and 1.11 to 3.02 msec [placebo]). GST supported overall treatment benefit (P=0.0328).

Conclusions: Muscle MRI changes were consistent with secondary functional outcomes from EMBARK Part 1 showing stabilization or slowing of disease progression in delandistrogene moxeparvovec-treated patients and progression in placebo-treated patients, demonstrating treatment efficacy.