Duchenne Muscular Dystrophy gene therapy trial highlights complexity of disease

The first large-scale trial of gene therapy for the debilitating neuromuscular disease, Duchenne Muscular Dystrophy (DMD) has been carried out by an international group of researchers, including Great Ormond Street Hospital (GOSH) and University College London (UCL).

DMD is a genetic condition which causes progressive muscle weakness, most commonly in boys.

The results, published in Nature Medicine, explored the used of the gene therapy Delandistrogene moxeparvovec (DM), which was developed by Sarepta Therapeutics and acquired by Roche for commercialisation in Europe.

The results suggest that the gene therapy could halt or slow down the progression of the disease in boys and, at the same time, provides important lessons for design of future studies.

The therapy was approved in 2023 in the USA for boys affected by DMD over four years old, combining data from a small trial involving four boys with DMD aged four and five who were still able to walk, and a subsequent study in 41 boys with DMD.

However, the new EMBARK trial is a large, global, multi-centre trial that explored the treatment over 52 weeks for a much larger group of boys (125 enrolled) with a wider age range, from 4-7 years old, who were still able to walk.

In this study boys with DMD were split into two arms (63 received the gene therapy and 62 the placebo), with neither the affected boys nor clinical team aware of which arm of the trial they were in. The boys were assessed every 12 weeks for 36 weeks and again at 1 year. The data was then analysed to see if there was a difference between the two groups.

DMD is caused by a variant in the X-linked DMD gene. Females have two X chromosomes, so they have a healthy version that can typically compensate in case they carry a deleterious copy, but males only have a single X chromosome so the condition mainly affects them.

The variant in the DMD gene leads to a lack of a protein called dystrophin. This causes muscle fibres to break down and be replaced by fibrous or fatty tissue in muscles across the whole body, leading to gradual deterioration of muscle strength and full-time wheelchair use.

Advances in management and treatment have led to boys with DMD remaining mobile for longer and living with a better quality of life. While most boys will reach adulthood, they are still more likely to die from heart or respiratory failure before or during their 30’s due to muscle damage.

By using a modified virus, the gene therapy delivers the genetic instructions into cells needed to make dystrophin via a single intravenous infusion. The specific adeno-associated viral vector (AAV) used in this study is known to target and accumulate in muscle tissue, making it an ideal candidate to deliver the therapy for a neuromuscular disease.

In June 2024 in the USA, the US Food and Drug Administration (FDA) granted approval for use of the treatment in children over four years old who could still walk if they had a confirmed mutation in the DMD gene, and accelerated approval in those older children with DMD who have already lost the ability to walk.

In the UK, the National Institute of Health and Care Excellence (NICE) opened the scoping stage of an appraisal in January 2024 and these trials results will likely form part of the body of evidence for the full appraisal process.

The standard assessment grades 17 different activities from zero to two, including hopping, running, jumping and standing (North Star Ambulatory Assessment). This scale is also influenced by developmental gain in the younger patient population and because of this and other factors, this important outcome measure failed to demonstrate a statistically significant difference between treated and untreated group of children.

In more sensitive measurements involving precise timings, there were improvements seen. For example, the time taken for the patient to rise from the floor (time-to-rise) and how fast they could walk or run 10 metres didn’t deteriorate as much for the treated group as those who received the placebo, over the year of the study. These detailed measurements indicate that the gene therapy could reduce the odds of a time-to-rise worsening to more than five second by up to 91% and has the potential to modify the course of the disease.

As disease progresses, boys with DMD require more and more assistance and care. With such a large and progressive undertaking for families, improvement in quality of life for the patients can have far reaching implications for all involved in care.

The gene therapy was well tolerated with only short-lived nausea and vomiting and no serious immune reaction requiring additional prolonged treatment. Analysis of biopsies from 31 treated boys showed healthy dystrophin due to the gene therapy 12 weeks post treatment.

Professor Francesco Muntoni, Honorary Consultant at GOSH and Professor of Paediatric Neurology at UCL and Director of the Dubowitz Neuromuscular Centre, said: “While these results are complex, we are pleased to see that, overall, the treated boys did experience a benefit from receiving the gene therapy. The study suggests that we need to pay attention to a wide array of endpoints and longer studies to see the full picture.

“DMD is an extremely complex disease. It’s different for every child that has it. We must remember this when we try to measure effects in a relatively short amount of time – especially when this has implications on approval and licensing decisions. We’ll continue to follow all our EMBARK boys with DMD and establish what the long-term benefits may be and we are so grateful to them for going on this journey with us.”

Next steps for this research will be to explore the benefits and disadvantages in younger and older boys, and whether the impact of the gene therapy could go beyond mobility symptoms. For example, in improving cardiac and respiratory function.

Separate research at GOSH and its partners at UCL and Imperial College London is also exploring if wearable technology could help understand the progression of complex diseases that affect movement in a way that is hard to measure with conventional assessments.

All research at GOSH is underpinned by support from the NIHR GOSH Biomedical Research Centre.