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New Hope for Duchenne Muscular Dystrophy Patients and Their Families

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Duchenne muscular dystrophy is an inherited neuromuscular disorder primarily occurring in boys and caused by mutations in the dystrophin gene. New treatments other than the classic glucocorticoids have started phase 2 testing. This brings hope to patients and families currently dealing with Duchennes.


This medication is administered orally and is designed to inhibit a small molecule that is activated in infancy and is central to causing muscle damage and preventing regeneration in Duchenne muscular dystrophy. Duchenne is the most common form of neuromuscular disease of childhood. It is progressive with muscle weakness and degeneration being the first noted symptoms that is always fatal; usually from cardiopulmonary complications.

Treatment options are limited for Duchenne victims with eteplirsen approved for those patients who exon 51 skipping would benefit, usually a small percentage. Glucocorticoids is approved for use in muscular dystrophy patients greater than five years old. And while it can help cardiopulmonary function and delays loss of motor milestones there are serious side effects as well. Some of these are osteoporosis, behavioral changes, growth inhibition (delay in puberty), and weight gain.

This study in pediatric patients with Duchenne showed that edasalonexent was well tolerated and inhibited the small molecule that was its target. But the test was only for one week of dosing. In order for these results to be validated, a larger number of participants are needed for further research. It has been suggested that a study of at least 12 weeks, double-blind, placebo-controlled be done (Finanger et al, 2019).

Hurdles of new treatments

There was a recent world workshop on dystrophin quantification methodology. The purpose was to provide an overview of methods used to quantify dystrophin levels in human skeletal muscle and their applicability to clinical trials. This workshop also discussed the potential and limitations of techniques currently used in the field of translational research and emerging techniques. The group agreed on the need for a common reference sample. The group was from six countries and cleared up misconceptions over some results of research.

The US FDA suggests objective and automated capturing of images so consistent analysis can be performed by independent laboratories. One up and coming method is making use of the mass spectrometry that is able to detect 1% dystrophin. Previous versions could only detect 5% of dystrophin. In recent years much progress has been achieved in the quantification of dystrophin. Researchers understanding of the role of this protein plays has increased as well as techniques to reproduce small increases in dystrophin. In the US, one drug has received accelerated approval based on the surrogate endpoint of dystrophin increase with confirmatory studies and trials ongoing (Aartsma-Rus et al, 2019).

There has been rapid development and approval of new medicines for neurological disease indications in children. This includes multiple FDA approvals in just the past two years. Conditions targeted by novel therapies have significant morbidities and high mortality. Children with Duchenne face a chronic progression of loss of muscle ability eventually leading to death by the early 20s. Costs of medications are often high; third-party payers’ may not be familiar with the medicine and patients who might benefit from therapy denied coverage.

This study was to develop a strategy to address the challenges in deploying these new therapeutics. Since this study was completed, the same strategy of including concerns of families, facilitate peer review by treating doctors and assisting payers unfamiliar with the complex nuanced decisions about drug approval. In addition, another entity in the building with the study members has adopted the strategy for the evaluation of treatments for cystic fibrosis as new drugs require specialized considerations. Insurance companies and other third-party payers have concerns related to the novel therapeutics. High costs and balancing resources to treat one child versus the resources allocated to more basic health-care needs such as preventative health visits and immunizations.

As novel treatments increase, the Neurology Therapeutics Committee approval rates may decrease. The committee does not solve other ethical and financial issues associated with these therapeutics. Third-party payers and government regulators will need to develop infrastructure and guidelines to address these issues (Clark et al, 2019).

New organizations to help families

CPCHILD-Caregiver Priorities and Child Health Index of Life with Disabilities, this was used as a basis for a muscular dystrophy version. Nineteen parents and children with muscular dystrophy were interviewed and an index was made for these children called MDCHILD. Duchenne is among the most common as a severe neuromuscular disorder affecting one in 3500-6000 male births. It results in death usually due to cardiopulmonary difficulties.

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These children undergo many procedures and interventions in the effort to prolong life and preserve quality of life. Unfortunately, many of the interventions focus mainly on physical limitations and neglect important psychosocial aspects of the disorder.

There are many new and promising treatments for Duchenne being investigated but little focus is investigating the health-related priorities of parents and/or children with this disease. Their priorities are different from most ill children so a new assessment tool was devised. This addresses the unique issues patients with Duchenne and their families have identified as important for them and their quality of life (Propp et al, 2019).

HOPE-Halt Cardiomyopathy Progression-Duchenne is a clinical trial in patients with Duchenne muscular dystrophy that have established cardiomyopathy. This study was to evaluate the safety and explore the efficacy of intracoronary CAP-1002 in these patients. In early-phase clinical trial to evaluate cell therapy for Duchenne cardiomyopathy with no serious safety issues and several indications that intracoronary CAP-1002 may benefit the heart as well as skeletal muscle. Unlike most clinical trials with Duchenne which target younger ambulatory patients, this study had an older population with more advanced disease process. The HOPE population were predominately non-ambulatory, had substantial cardiomyopathy but no heart failure. In addition, they had severe shoulder limitation placing their upper limbs function between severe losses of function; recovery would be extraordinary and normal function that would be impossible.

Patients treated with CAP-1002 showed improvement in regional cardiac function. This is consistent with the distribution of scarring caused by muscular dystrophy and the use of CAP-1002 showed improvements in regions where the cardiac burden of scarring by Duchenne. This decrease in scar burden is the opposite of the natural course of Duchenne muscular dystrophy. This was a one time dosing in humans of CAP-1002 showing this encouraging outcome. The next step studying of rats and mice are being conducted to explore improvements, if any, by multiple doses of this substance can be elicited. Then arrangements can be devised for the next phase of human study (Taylor et al, 2019).

Duchenne is a rare genetic disorder that presents with progressive muscle weakness and is caused by either an absence of or a greatly decreased amount of muscle protein dystrophin. Currently, there are two groups of therapies being researched to halt or prevent the disorder.

One group, focusing on restoration of dystrophin in the muscle and the other one is focusing ways to compensate for the lack of dystrophin. To date, there are several studies being conducted to find ways to treat Duchenne. Exon-skipping, gene therapy, and cell therapy are being investigated for this purpose. Of all the therapies exon-skipping applies to about 80% of total Duchenne mutations.

There are two trials exploring the use of gentamicin to increase the dystrophin. So far the biggest issue with long-term use of gentamicin is the already documented side effects of this medicine; kidney toxicity and hearing/balance issues from otic toxicity. Animal studies have shown great promise and have since led to human trials. Two drugs have been conditionally approved for use. Testing the efficacy of medications for Duchenne is difficult as studies involving control groups are not feasible with muscular dystrophy. In addition, analyzing real-world data may provide information on the true benefit of innovative drugs can only be assessed after long-term usage (Shinizu-Motohashi et al, 2019).

Work Cited
Aartsma-Rus, A.et al. (2019). Report of a TREAT-NMD/World Duchenne Organization. Meeting on dystrophin quantification methodology. Journal of Neuromuscular Diseases, 6(1).

Clark, E. B. et al. (2019). Development implementation and use of a Neurology Therapeutics Committee. Child Neurology Open.

Finanger, E. et al. (2019). Phase one study of edasalonexent (CAT-1004) an oral Nf-ĸB inhibitor in Pediatric patients with Duchenne Muscular Dystrophy. Journal of Neuromuscular Diseases, 6(1).

Propp, R. et al. (2019). Development and content validation of the muscular dystrophy child health index of life with disabilities questionnaire for children with Duchenne muscular dystrophy. Developmental Medicine & Child Neurology, 61(2).

Shimizu-Motohashi, Y. et al. (2019). Restoring dystrophin expression in Duchenne muscular dystrophy: Current status of therapeutic approaches. Journal of Personalized Medicine,9(1).

Taylor, M. et al. (2019). Cardiac and skeletal muscle effects in the randomized HOPE-Duchenne trial. Neurology, 92(8).