To develop new therapies for patients living with myotonic dystrophy (DM), specific “infrastructure” needs must be addressed—this infrastructure makes clinical trials feasible. It is essential to understand how a disease manifests and progresses in a cohort of patients that is sufficiently large and representative to provide confidence in the findings. This understanding, in turn, allows the design and validation of outcome measures that are sufficiently sensitive, reliable, valid and responsive to show whether a candidate therapy is effective or not.
Considerable effort has been made to understand the natural history (how the disease presents and progresses) and to develop valid outcome measures for myotonic dystrophy type 1 (DM1). This knowledge has been put to use in clinical trials, including those by Ionis and AMO Pharmaceuticals. The Myotonic Dystrophy Foundation (MDF) is working to further advance understanding of the natural history of DM1 via the Myotonic Dystrophy Clinical Research Network in the U.S. and the PHENO-DM1 study in the United Kingdom.
Although congenital myotonic dystrophy (CDM) has genetic similarities to DM1 (both are caused by expanded CTG repeat sequences in DMPK), CDM presents and progresses differently than DM1. Thus, there is a clear need for natural history data to better understand the disease and to support the selection of outcome measures that can assess whether a drug is working or not in clinical trials of CDM.
Dr. Nick Johnson (University of Utah) and colleagues have completed a study of the disease burden and potential outcome measures for clinical trials in CDM and recently published their findings in the prestigious journal, Neurology. Their study examined a cohort of 41 children (between 0 and 13 years old) with CDM in comparison to 29 healthy controls, using objective functional measures that could serve as clinical trial outcome measures.
The team described the broad traits of children living with CDM, noting impairment of physical and cognitive function and quality of life. Their data suggests that delay of motor function milestones and daytime sleepiness are important, but previously unreported, symptoms in CDM.
They looked at outcome measures that have been used in clinical trials for other neuromuscular diseases to evaluate their feasibility for use in CDM. For the 6-minute walk test, those patients who were able to complete the test walked about 45% less distance than healthy controls. Likewise, grip and pinch strength in children with CDM was about one-third that of controls. Differences in CTG repeat length did not affect walk distance or grip/pinch strength. Children with CDM showed a substantial reduction in lip strength (12% of control value).
Cardiac testing showed cardiac conduction system abnormalities in 5 children (12%) with CDM. The authors note that this finding highlights the importance of regular cardiac monitoring in CDM children of any age. Respiratory function measures, while often compromised in neonates, improved with age in the patient group studied here. Thirty percent of CDM children in the study required use of a gastrointestinal motility agent, suggesting that monitoring GI function in CDM was essential.
Mean IQ of children with CDM was 3 standard deviations below established norms, although IQ did not improve or decline with age and did not correlate with CTG length. Daytime sleepiness increased with both age and CTG repeat length. Having parents complete a standard measure of quality of life showed a decline with age, but quality of life did not show significant differences based on CTG repeat length.
Children with CDM likely will require different outcome measures than those used in clinical trials of adults with DM1. The researchers did note that the outcome measures studied here showed good ability to discriminate and moderate consistency. More will be learned about the potential for adopting specific outcome measures in their ongoing longitudinal study.
The better understanding of the complexity of CDM that is gained through these studies, and the ability to select appropriate outcome measures, will improve clinical trial readiness and de-risk the disease for biotechnology and pharmaceutical company investments in drug development for CDM. MDF hopes that this will soon lead to more clinical trials directed toward CDM.