TODDLER Study: Transforming Outcomes in Duchenne Muscular Dystrophy Using DigitaL Endpoints Remotely

Duchenne muscular dystrophy (DMD) is a rare muscle-wasting disease that affects boys, causing progressive disability and premature death. Our study will directly address a significant barrier to progress in the treatment of these patients.

DMD is a rare disease that globally affects ~20 per 100,000 live male births. Due to X-linked mutations in the DMD gene, these boys cannot produce functional dystrophin, a fundamental muscle protein. They develop muscle degeneration and progressive weakness, which leads to loss of ambulation in adolescence. Boys subsequently develop cardiorespiratory failure and need ventilation in their 20s. There is no cure for DMD. Multidisciplinary care is focused on delaying disease progression. At 4-6 years old these boys are offered steroids (glucocorticoids), which are the only disease-modifying drug. Their introduction dramatically increased median survival from 18 to 28 years. Nevertheless, long-term use is associated with considerable adverse effects on growth, puberty and bone health.

Despite being a rare disease, over the last two decades there have been over 80 drugs developed for the treatment of DMD. However, few drugs have received approval by regulatory agencies, and none have adequately restored dystrophin levels or improved quality of life. Unfortunately, there has been a high failure rate between early-phase and late-phase drug development. Gene-targeted therapies offer hope of an effective treatment but would only benefit ~30% of boys with specific gene mutations. Recently, Vamorolone, a next-generation steroid with fewer adverse effects, has also received regulatory approval. Its safety and efficacy have been demonstrated in patients over four years old.

Early treatment is a priority now. There is increasing pressure from patient groups, clinicians, and industry to test treatments in younger boys. Until recently, clinical trials have only included boys over five years old, in whom muscle damage has already begun. Destructive processes underlying the disease begin in utero and muscle remodelling and inflammation are detectable in infancy. Earlier treatment with potential disease-modifying drugs could transform treatment outcomes. Essentially, time is muscle. There is already evidence that boys with DMD benefit from starting steroids earlier, before the age of five. Additionally, pre-symptomatic treatment has been shown to revolutionise the outcomes of another debilitating paediatric neuromuscular disease, spinal muscular atrophy.

To treat younger children, there is a need to be able to reliably monitor motor function and treatment effects. Currently, there are no suitable measures of motor function validated in children under four. Toddlerhood is a time of significant neurodevelopment and skill acquisition. Therefore, it is not possible simply use standard tests developed and validated for older children. The 6-minute walk test is the gold standard in DMD. It predicts future decline but has low reliability in children under five. The North Star Ambulatory Assessment (NSAA) is a DMD-specific functional scale administered by physiotherapists, scoring skills like standing, walking, hopping. It has good reliability and validity and is routinely used in clinical practice and trials. A revised version is available for children 2-5 years but has not been validated. These assessments are subjective and reflect a single performance, which can be heavily influenced by motivation, mood, tiredness and illness. They require children's attention, comprehension, cooperation and maximum effort in an unfamiliar testing environment. Therefore, younger children, and children with autistic spectrum or attention deficit disorder (~30% of the DMD population) are significantly disadvantaged. Until now, these children have mostly been excluded from trials to limit unwanted noise in the data.