Advancements in Duchenne Muscular Dystrophy Clinical Trials: Strategies for Successful Development

Representing Duchenne muscular dystrophy clinical trials
Representing Duchenne muscular dystrophy clinical trials

Duchenne muscular dystrophy (DMD) is a rare genetic disorder that disproportionately affects males, with an incidence of 1 in 3600 male infants. The disorder is characterized by a gradual loss of strength and mobility as a result of muscle fiber degeneration. DMD is not only an X-linked recessive hereditary disorder, caused by mutations in the dystrophin gene, but it is one of the most common and severe types of congenital muscular dystrophies. Disease progression typically shortens the lifespan as a result of cardiac, respiratory, and orthopedic complications, and can cause death at a young age. In this article, we explore high attrition rates in clinical development and five approaches to avoid common challenges with Duchenne muscular dystrophy clinical trials.

High Attrition Rates in Clinical Development

The current treatment options available to DMD patients are limited to disease-management therapies such as glucocorticoids, beta blockers, and physiotherapy to alleviate symptoms. Although the gene therapy, Eteplirsen, has been approved by the Food and Drug Administration (FDA), drug discovery for DMD has not seen much success despite several leads being studied, pre-clinically and clinically, for over 30 years. Considering the high attrition rates associated with its clinical trials, discovering disease-modifying treatments for DMD will require targeted strategies for success. We discuss five approaches sponsors and contract research organizations (CROs) can take to avoid common challenges with Duchenne muscular dystrophy clinical trials.

1 | Refining Preclinical Research Models

Like with other rare disease trials, the success of a molecule can be linked back to the extent of animal data gathered prior to clinical development. Although mouse models are common for simulating DMD, they aren’t considered comparable representations of human DMD. Because these mice have faster regeneration speeds, any muscle deterioration would not present as severely as it would in real patients. Preclinical researchers may benefit from selecting larger, more relevant animal models, such as dystrophin-deficient rats, to address the issue of inter-animal variability in early DMD studies.

2 | Improving Sample Size Limitations

Although large sample sizes are integral for collecting accurate clinical trial data, this becomes a restrictive criteria in the case of rare disease research. The regulatory pressure of including a placebo arm is also not widely supported by those studying conditions like DMD. To overcome these limitations, some proposed solutions include adopting digital platforms through which to share historical placebo arm data, stratifying inclusion criteria by disease trajectories, and adopting Bayesian statistical modeling to account for the heterogeneity in DMD clinical presentations and progression.

3 | Embracing Adaptive Clinical Trial Designs

Similar to the benefits Bayesian statistics can have on DMD research, adaptive clinical trial designs are uniquely suited to the restrictive nature of recruiting rare disease patients. As opposed to traditional controlled clinical trial designs, which may also require more DMD patients than sites may have access to, alternative designs can be adopted by a sponsor’s or CRO’s protocol development team. These include considering cross-over studies, randomized placebo-phase design (RRPD) trials, or enriched-enrollment randomized-withdrawal studies to discover disease-modifying treatments and ensure all included patients are responding to the investigational product. Considering the high attrition rate associated with DMD trials as it is, adaptive designs allow scientists to change course if a therapy doesn’t work as expected. Read more about adaptive clinical trial designs in our article here.

4 | Improving Outcome Measures

As a genetic disorder, one of the challenges of studying DMD is accounting for its numerous variabilities, which can present across the whole disease population. Researchers can tailor their eligibility criteria to target particular disease severity or patient age to help select more specific endpoints. For example, because younger patients have a greater baseline capacity for functional mobility than older individuals affected by DMD, they would make more ideal participants to test disease-modifying treatments. Additionally, the trial’s expected duration would also determine which endpoint is most appropriate. Whereas quantification of dystrophin expression can take months, detecting clinical endpoints related to improvements in muscle function may not appear for years.

5 | Controlling Inter-Site Variability

Considering how rare DMD incidence is, collecting a large sample size that is representative of the general population is a significant challenge. CROs are a valuable resource for sponsors conducting DMD trials because many will offer their own network of highly qualified investigator sites, such as Vial’s Preferred Investigator Network. However, sometimes even this may not be enough, and sponsors may require a large number of clinical research sites globally to build up the required sample size. As a result, there is a need to control for variability in differing standards of care between sites. This can be addressed by implementing standardized evaluator training, ensuring site staff are highly experienced and well-trained to follow protocol procedures, as well as ensuring the study endpoints are independent of investigator site quality.

Rare Disease CRO for Duchenne Muscular Dystrophy Trials

Duchenne muscular dystrophy clinical trials have considerable obstacles for sponsors and CROs to overcome, but taking the five approaches above can improve the chances of achieving success in clinical drug development.

Vial is a full-service CRO that recognizes the central role of technology in advancing our understanding of rare diseases and is paving the way for modernized clinical research through digital innovation. Trusted by leading sponsors, our specialized teams deliver shorter study timelines, quality affordable services, and a clinical trial experience that puts you first. Contact a team member today to discover how we can help you with your Duchenne muscular dystrophy clinical trials!

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