Key Duchenne research and clinical updates from the MDA conference
Duchenne UK's Director of Research and Development, Mike Bond, attended the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference that was held on 8-11 March in Orlando, Florida. This annual conference brings together the neuromuscular disease community, including researchers, clinicians, industry and patient organisations, to discuss progress in research, emerging treatments and collaborative opportunities.
Duchenne research highlights
Building a better understanding of muscle damage and repair
Researchers discussed new discoveries in understanding how muscle damage occurs and how this leads to loss of muscle in Duchenne, as well as the ways in which muscle naturally regenerates, and potential avenues that could be explored to reduce damage and promote regeneration. Although much of the work discussed was in the early exploratory research phases, these discoveries could help inform future therapy development in Duchenne.
Gene therapy and the immune system
Gene therapies typically use viruses to deliver genes, such as dystrophin, to muscle. Viruses are well suited to this role; however, our immune systems are also tuned to recognise viruses and try to eliminate them. This is a challenge in developing gene therapies, as the immune system can prevent gene therapies from reaching muscle and an over-active immune response to the gene therapy can cause side effects.
There was significant discussion at the conference about the best ways to monitor the immune system during gene therapy, as well as drugs and approaches that can be used in combination with gene therapy to prevent immune responses. This included approaches that are already being used in trials, as well as new approaches being developed by scientists in universities and companies.
New gene therapy strategies
There were a number of presentations at the conference discussing new ways of delivering gene therapy that do not use viruses. Many of these strategies are in very early development, requiring more research before they can be used in clinical trials. These represent interesting experimental approaches, with potential advantages in terms of allowing repeat dosing or delivering larger dystrophin genes, that could lead to future therapeutic options.
Updates from the clinic
A number of clinical updates were provided at the conference, with many ongoing studies reporting positive clinical data.
Gene therapies
Interim data were presented for the Phase I/II trials of REGENEXBIO’s investigational gene therapy RGX-202 and Solid Biosciences investigational gene therapy SGT-003.
The data presented on RGX-202 showed continued positive effects in functional tests, such as the North Star Ambulatory Assessment (NSAA), following one year of treatment when compared to existing data from untreated patients. The experimental therapy showed a favourable safety profile, with no serious adverse events reported and stable heart function seen over the year.
Updating on Solid Biosciences’ programme, a favourable safety profile for SGT-003 was reported in all participants dosed to date, alongside microdystropin expression, as well as evidence that this expression was improving muscle health, based on a reduction in markers for muscle breakdown over time. It was also reported that participants treated with SGT-003 showed stable-to-improved heart function over time in the study.
Data was also presented based on long term follow-up of three patients treated with Genethon’s investigational gene therapy GNT0004 in the first phase of an international clinical trial. Over the two years following treatment, a significant gain in muscle function, measured by NSAA, was reported compared to a matched group of untreated patients, as well as improvements in other measures, such as timed walk tests. These observations were also matched by reductions in markers for muscle damage, including blood markers and images of muscle. No serious side effects were seen.
Finally, data was reported for delandistrogene moxiparvovec (Elevidys) on three-year efficacy and safety, and compared to existing matched real-world data. Based on this comparison, functional benefit was seen in treated patients across a number of measures of muscle function, including NSAA. There were no significant updates on the safety of this gene therapy, with the safety profile remaining consistent with previous reports.
Exon skipping nucleotide therapies
Initial results were reported from the Phase I/II study of BMN-351, an investigational exon skipping therapy for patients who could be treated by skipping exon 51. Exon skipping was seen in all treated participants, leading to dystrophin expression. Decreases were seen in markers for muscle damage and, when compared to historic data, potential functional benefits were also seen over a treatment period of 18 months, when looking at NSAA. A manageable safety profile was described, with most adverse events considered mild.
Z-rostudirsen is an investigational exon skipping therapy being developed by Dyne Therapeutics, also for patients who could be treated by skipping exon 51. Updating on a Phase I/II study, good dystrophin expression was also seen following treatment with z-rostudirsen over a period of six months. Improvements were observed in a number of functional measures. Upper limb function showed a trend towards improvement with no decline in a measure of lung function also presented. An acceptable safety profile was reported.
An update was provided on trial data following 1 year of treatment with Avidity Biosciences’ Del-zota, an investigational exon skipping therapy for patients who could be treated by skipping exon 44. Good dystrophin expression was seen, alongside a rapid drop in muscle damage markers over 12 weeks following treatment, remaining low over 1 year. Trends towards improvement were seen in functional outcomes, such as NSAA and timed walk tests, as well as upper limb function in non-ambulatory patients. An acceptable long-term safety was also reported.
Data from a Phase II study of Wave Life Sciences’ WVE-N531 were presented following 48 weeks of treatment in patients who could be treated by exon 53 skipping. The company reported seeing dystrophin expression following treatment, which led to an improvement in the appearance of muscle by biopsy, suggesting regeneration of muscle fibres and reduced inflammation. Signs of functional improvement were also seen when compared to existing data.
Finally, Leaper Bio discussed initial trial activity for their ribonucleic acid (RNA) editing exon skipping investigational therapy, LE051. In a small number of patients, it was reported to be well tolerated, with exon skipping and dystrophin expression reported and some early signs of functional activity.
Other therapies in development
Satellos is developing an investigational drug, SAT-3247, designed to improve the regeneration of muscle. The company reported on completion of their Phase I study, investigating the safety of SAT-3247, in addition to a small study in adults with Duchenne looking at some muscle function tests. They reported a favourable safety profile and some early exploratory signs of activity in the adult study, where improvements in hand grip strength were seen. They also reported reductions in markers for muscle damage over 15 days.
An update was reported for Capricor’s Phase III study of deramiocel, an investigational therapy derived from human heart cells. Patients in this study were older than 10 and either late ambulatory or non-ambulatory. The safety observed was comparable between deramiocel and placebo. Significant improvements in upper limb function and heart health were seen on treatment compared to placebo, along with improvements in all other outcome measures, including video assessments of everyday activities.
Wrapping up
MDA was a busy conference, packed with updates on research and development in Duchenne. As well as promising early research updates, the number of clinical trials now reporting data within Duchenne demonstrates the breadth of work currently underway to find new effective treatments. Although more work needs to be done for most of these experimental therapies, the positive progress reported shows real promise for the future.