The Optimal Cohort for Clinical Trials in DM1
Choice of a cohort for interventional clinical trials of a candidate therapy can be challenging for any neuromuscular disease. For diseases with onset at a variety of life stages, comprehensive understanding of natural history of each patient subgroup is critical in being able to define biomarkers and endpoint measures capable of assessing safety and efficacy within the normal duration of a clinical trial. Such information, in turn, informs the choice of an appropriate trial cohort that offers the best opportunity to assess the candidate drug or biologic.
For diseases like SMA and Pompe disease, the rapid progression and clear endpoints seen for the youngest patient subgroups can lend clarity to clinical trials and, indeed, choosing these subgroups may accelerate drug discovery, development, and regulatory approval. Alternatively, disease properties, current level of understanding, and/or regulatory considerations (see FDA guidances for pediatric studies) may mandate choice of an adult cohort for the initial clinical trials.
Experience to date in DM1/CDM suggests that choice of study cohort for interventional clinical trials remains an unresolved issue—sufficiently thorough and well-powered natural history studies can clarify this decision. An adequate understanding of natural history also has value as a fundamental baseline for the DM field to move from current experienced-based to potentially more effective evidence-based patient management.
Better Resolution on the Natural History of Pediatric DM1
Data in the French DM-Scope registry (currently including 2,697 patients with genetically confirmed DM1) has already been used to achieve important advancements in understanding of DM1 (De Antonio et al., 2016; Dougan et al., 2016), particularly in the refinement of DM1 subgroups and gender differences. Such a registry of well-characterized study subjects offers a multitude of opportunities to understand the disease; mechanisms have been established for access to registry data by qualified individuals.
In a new examination of data in DM-Scope, Dr. Emmanuelle Lagrue (CHRU Tours and INSERM) and colleagues report out in Neurology on the natural history of 314 children with pediatric-onset DM1 (Lagrue et al., 2019). The cohort was 52% female and included children with congenital- (55%), infantile- (31%), and juvenile-onset (14%) forms. Although phenotypic assessments were broad spectrum, neurodevelopmental consequences received particularly detailed attention from the study team.
CTG repeat size ranged from 74 to 3,000 and generally correlated with severity. Hypotheses have been offered regarding the primarily maternal transmission of CDM (Barbé et al., 2017); in the current study, paternal transmission in CDM was higher than anticipated (13%), but increased in the other pediatric DM1 subtypes. As previously reported for adult DM1 subtypes (De Antonio et al., 2016), the pediatric cohort exhibited a phenotypic continuum, but with highly prevalent neurodevelopmental symptoms. Most common among these were cognitive slowing (83%), attention deficit (64%), written (64%) and spoken (63%) language disorders, difficulties in fine motor skills (60%), and dyspraxia (47%). 5% were on the autism spectrum.
Musculoskeletal impairment was considered to be mild (proximal weakness in ~12%, primarily in CDM; inability to walk seen only in CDM (but <4%)), and clinical myotonia observed in 66% of children. Cardiorespiratory impairment was also not highly prevalent (15% exhibited cardiac abnormalities and 27% altered pulmonary function), but when present could be life-threatening. The research team also described a constellation of other organ system involvement, from cataracts (7%, mainly in CDM) to GI disorders.
Moving Toward Evidence Based Medicine for DM1
In a process facilitated by MDF, consensus-based care recommendations have been published for adult DM1 (Ashizawa et al., 2018). None have yet been published for pediatric DM1. As yet, the care recommendations are based upon experiences of professionals who most frequently see DM1 patients, and there is not yet a body of work on which to generate evidence-based standards of care. Natural history studies, such as that provided by the DM-Scope team here, provide important data to guide the type and timing of medical specialty engagement/clinical examinations that patients should receive. The pedDM-Scope study is cross-sectional and longitudinal studies of this patient population are likely to improve both clinical trial readiness and clinical management of patients living with pediatric DM1.
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