This year the 25th edition of the World Muscle Society (WMS) 2020 International Congress, a congress where the worldwide important updates of research on Duchenne Muscular Dystrophies (DMD) and Becker (BMD) are shown, was held virtually. Although there were many posters presented, Dr. Marisol Montolio has created short summary of the most important highlights for our community. We are very grateful for her contribution and are glad to share her report.
This is a unique time for neuromuscular disorders and especially for Duchenne and Becker Muscular Dystrophies, as an unprecedented number of therapeutic candidates is now in clinical trials. With this wave of potential treatments, the importance of Preclinical Development was discussed, since rigor during the preclinical development of drugs is very important to carefully select the best candidates and optimize treatments before going into clinical trials. Furthermore, the importance of evaluating the predictive power, reliability and relevance of current Animal Models for the evaluation of the efficacy and safety of emerging therapies was discussed.
Clinical aspects of Duchenne and Becker Muscular Dystrophies
Maintaining a healthy weight is a challenge in DMD, certainly after the loss of ambulation. The use of steroids has only limited influence. Especially during the transition period, in which ambulation is lost, specific attention is required.
One study to highlight is on the demographics of patients with nonsense mutations of DMD who receive Ataluren in the STRIDE Registry (PTC). The STRIDE Registry is the first drug registry for patients with DMD and is the largest real-world study of patients with DMD to date. As of early February 2020, a total of 279 DMD-patients had been enrolled in STRIDE at 64 sites in 13 countries and the safety results were consistent with the known safety profile of Ataluren. Analyses of data collected from patients enrolled in the STRIDE registry will provide information on the long-term and real-world efficacy and safety of Ataluren.
Different prognostic factors have been found for the loss of the ability to rise from supine position in DMD. This is an important early clinical milestone in DMD and the findings suggest that the time to loss of supine elevation can be well predicted using different characteristics, especially the speed at which patients are able to rise.
When the North Star Ambulatory Assessment (NSAA) scores were compared between siblings with DMD, it was seen that younger siblings are often diagnosed earlier (on average 2.7 years) and this causes them to start steroids 0.8 years earlier. In early stages of the disease younger siblings did not differ from their older brothers. However, after 8 years, younger siblings consistently scored higher at the NSAA. This suggests that early start of steroids likely played a role in this result.
Different Treatment Approaches:
Eteplirsen is an exon 51 skipping drug, developed by Sarepta. PROMOVI, a large multicenter phase 3 study, contributes to the growing evidence of the treatment effect and safety profile of Eteplirsen as observed in previous studies. After the study had started, it became apparent that the control group chosen in the study was inappropriate. The control group consisted entirely of patients non-amenable to exon 51 skipping, but new natural history data indicated the exact mutation influences the disease progression. As an alternative the data has been compared to data from previous Eteplirsen studies and appropriate natural history controls. This suggested that Eteplirsen treatment slowed the progression of the disease. Long-term treatment has shown to be safe, as generally mild to moderate adverse effects were seen.
Data from two others studies indicated that Eteplirsen is associated with a significant attenuation of pulmonary deterioration based on FVC% predicted and delayed need for continuous ventilation.
The first real-world evidence of the effects of Eteplirsen treatment on key health outcomes in DMD-patients was presented. Eteplirsen treatment is associated with significantly lower rates of hospital visits.
Long-term safety and efficacy of Golodirsen in male patients with DMD amenable to exon 53 skipping (Sarepta). Golodirsen treatment resulted in a significant increase in exon 53 skipping and dystrophin expression. Comparison with the natural history of a control group of patients not included in the study suggested there may be a benefit of Golodirsen treatment, as seen by the 6MWM and loss of ambulation, although these results were not conclusive. Overall, there were no signs of significant risk of renal abnormality or toxicity. The clinical benefit of Golodirsen is currently being evaluated in a phase 3 study (NCT02500381).
Treatment with Casimersen in patients with DMD: safety, tolerability and pharmacokinetics during 144 weeks of treatment (Sarepta). The exon 45 skipping drug Casimersen (30 mg/kg) was well tolerated in non-ambulatory DMD-patients amenable to exon 45 skipping. Most of the adverse effects reported were mild in severity. No significant clinical abnormalities of heart function (electro- or echocardiograms), or evidence of a significant risk of renal toxicity were seen with Casimersen. Interim results from the ongoing phase 3 study (ESSENCE) showed that Casimersen significantly increased exon 45 skipping and dystrophin expression. Together, these results support further evaluation of the safety and efficacy of Casimersen in DMD-patients amenable to exon 45 skipping.
Expression of apparent full-length dystrophin in skeletal muscle in a first-in-human gene therapy trial using the scAAV9.U7-ACCA vector (Nationwide Children’s Hospital). Aiming to improve delivery of exon skipping drugs, an exon skipping compound was inserted in a viral vector (AAV; as is used in gene therapy trials). This compound is designed to skip one of the copies of exon 2 in boys carrying an exon 2 duplication, which would lead to expression of a full-length dystrophin protein. After promising preclinical results, two boys have now been treated. No adverse events occurred, and after 3 months dystrophin protein was observed and muscle function was stabilized or improved. Further studies are needed to determine its safety and efficacy.
Ataluren delays loss of ambulation and decline in lung function in patients with DMD due to a nonsense mutation (PTC). Lung function of non-ambulatory patients treated with Ataluren was compared to patients in the CINRG natural history study. Although some delay in the deterioration of lung function was seen in Ataluren-treated patients, this was not significant. Longer follow-up will be required to assess the clinical efficacy of Ataluren in terms of lung function more fully.
SRP-9001, microdystrophin gene therapy for DMD, maintains functional improvement (Sarepta). In the first study with SRP-9001 (AAVrh74.MHCK7.microdystrophin) four DMD-patients (aged 4-7 years) received a single infusion of SRP-9001. No serious adverse effects were seen; all effects were considered mild or moderate and occurred within 90 days after treatment. Twelve weeks after administration, expression levels of around 80% of microdystrophin were measured. After two years, the trial participants showed an average improvement of 7.0 points on the North Star Ambulatory Assessment (NSAA) compared to before treatment. This is, however, a small number of patients and no controls were included in the study. A larger placebo-controlled study is ongoing (NCT03769116).
Does steroid therapy influence the deterioration of lung function in adults with DMD after loss of ambulation? (CNMD, Queen Square Institute of Neurology). Retrospective data from 92 adults with DMD, from a single center, suggest that continuation of corticosteroid treatment after loss of ambulation in men with DMD could be beneficial in delaying disease progression (respiratory function decline and onset and/or progression of scoliosis). Furthermore, continuation of corticosteroids into adulthood delayed loss of ambulation by an average of one and a half years.
Edasalonexent is a developmental NF-kB inhibitor for DMD (Catabasis). Edasalonexent is an orally administered small molecule designed to inhibit NF-kB. This inhibition has, in DMD, the potential to limit muscle degeneration, promote muscle regeneration, and reduce inflammation and fibrosis. In mouse studies, Edasalonexent prevented cardiomyopathy, and maintained bone density and strength. Side effects of corticosteroids are, among others, reduced growth and negative effects on bone quality. In the phase 1/2 trial MoveDMD, Edasalonexent treatment of young children (4-7 years old) with DMD did not affect growth, bone health or adrenal function. It was generally well tolerated. The most common side effect was diarrhea, generally mild and transient. The global phase 3 placebo-controlled PolarisDMD trial, followed by GalaxyDMD open label extension phase, in, is ongoing in children aged 4 to 7 years, who have not taken steroids for at least 6 months. First-line results are expected in the fourth quarter of 2020.
Treatment with ATL1102 improves PUL2.0 in non-ambulatory DMD children compared to natural history. Data from the phase 2 trial of ATL1102 (a drug inhibiting expression of CD49d, found in immune cells) compared to control, showed an improvement in upper arm function (PUL2.0) in ATL1102-treated patients compared to natural history controls.
Studies on biomarkers
Studies on Biomarkers were also presented, for example fast but not slow muscle troponin I is elevated in the circulation of patients with DMD and BMD; the level of dystrophin protein expression could possibly be used as a marker of muscle function DMD clinical trials; grip strength may be used as a reliable outcome measure in clinical trials throughout the life of DMD-patients.
We highlight work that demonstrates how children with DMD have increased fear responses to threat, so that physiological fear responses could be used to measure the response to restoration of dystrophin in the central nervous system.
by Dr. Marisol Montolio, DPP Spain