Efficacy and Safety of Golodirsen and Casimersen Compared With Placebo in Duchenne Muscular Dystrophy (ESSENCE): Phase 3 Topline Results

Topic:

Clinical Trials

Poster Number: 22 S

Author(s):

Francesco Muntoni, MD, Dubowitz Neuromuscular Centre, UCL and Great Ormond Street Hospital Trust, London, UK, Emma Ciafaloni, MD, FAAN, University of Rochester Medical Center, Rochester, NY, USA, Fernando Chloca, MD, Favaloro Foundation - Neurosciences Institute, Buenos Aires, Nicolas Deconinck, MD, PhD, Hôpital Universitaire des Enfants Reine Fabiola, Ameneh Masud, MD, MHA, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Ihor Sehinovych, PharmD, Sarepta Therapeutics, Kerri Drummond, RN, Sarepta Therapeutics, Inc., Weijian Liu, MPH, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Pamela Magistrado-Coxen, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Andrés Nascimento, MD, Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain, Sheffali Gulati, FRCPCH (UK), FAMS, FIAP, FIMSA, AIIMS, Maria Judit Molnar, MD, PhD, Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary, Maria Mazurkiewicz-Beldzinska, MD, PhD, Department of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Gdańsk, Eugenio Mercuri, MD, PhD, Paediatric Neurology, Catholic University, Rome, Italy, Centro Clinico Nemo, IRCCS, Rome, Italy, Craig McDonald, MD, Department of Physical Medicine and Rehabilitation, University of California Davis, CA, USA

Background: Golodirsen and casimersen are phosphorodiamidate morpholino oligomers (PMOs) used for treatment of Duchenne muscular dystrophy (DMD). Objectives: To report topline efficacy and safety results from the phase 3 ESSENCE trial (NCT02500381).
Methods: Eligible ambulatory males with DMD amenable to exon 53 (aged 6-13 y) or exon 45 (aged 7-13 y) skipping were randomized 2:1 to the combined treatment group (30 mg/kg golodirsen or casimersen; PMO) or placebo (PBO). A 96-wk double-blind period was followed by a 48-wk open-label period. The primary endpoint was change from baseline (CFB) in 4-step ascend velocity (step/s) at wk 96 vs PBO. Secondary functional, biological, and safety endpoints were reported. A prognostic scoring approach identified patients at high risk of 4-step ascend velocity decline (prognostically relevant subgroup [PRS]) for post hoc analysis. Results: 225 patients were enrolled from 2016 to 2022, including through the COVID-19 pandemic, across 24 countries. Baseline characteristics were well matched. At wk 96, the primary endpoint in the PMO group (n=138) showed a numerical mean (SD) change of −0.27 (0.39) steps/s vs PBO (n=74; −0.34 [0.37]), least squares mean (LSM) difference 0.06 (95% CI, −0.05 to 0.16; =0.309). Although not statistically significant, most secondary endpoints favored PMO. At wk 144, 4-step ascend velocity was −0.004 (−0.123 to 0.115). At wk 96, 6-minute walk test distance was 5.34 (−23.32 to 34.00), 10-meter walk/run velocity was 0.020 (−0.097 to 0.137), rise from floor velocity was −0.003 (−0.020 to 0.014), and North Star Ambulatory Assessment was 0.61 (−0.90 to 2.12). At wk 96, dystrophin expression by western blot had a mean difference of CFB of 0.69 (0.28 to 1.10; <0.001; unadjusted) and 1.25 (0.20 to 2.31; =0.020; muscle-content adjusted). Dystrophin fiber intensity by immunohistochemistry had a mean difference of CFB of 0.023 (0.015 to 0.031; <0.001). Through wk 144, no new safety signals were reported. Most treatment-emergent adverse events were mild or moderate and resolved without treatment. The PRS (PMO, n=74; PBO, n=35) suggested a meaningful change in 4-step ascend velocity at wk 96 for the PMO group (LSM difference vs PBO, 0.186 steps/s; =0.010).Conclusions: ESSENCE confirms the established safety profile of golodirsen and casimersen. The primary endpoint was not met in ESSENCE. A post hoc analysis and the totality of PMO evidence suggest the clinical benefits of golodirsen and casimersen.