Duchenne muscular dystrophy (DMD) is a serious genetic disorder that causes muscles to weaken over time. It also affects the heart, and most patients eventually develop dilated cardiomyopathy as the disease progresses. DMD affects approximately 1 in 3500 to 5000 male births and is usually diagnosed between the ages of three and six, often when muscle weakness first appears. Without treatment, most children lose the ability to walk between the ages of 10 and 12.
Since the mid-1980s, advances in corticosteroid use have improved life expectancy in DMD. Many patients now reach their 30s, and some live into their 40s. As patients live longer, the fully penetrant cardiac phenotype has become more apparent. Cardio-respiratory disease is now the leading cause of death, with heart disease linked to about half of all deaths.
Learning more about how DMD progresses has brought both challenges and opportunities. To help patients live longer and better lives, more cardiac trials are needed. These trials must use strong methods to track skeletal muscle changes, so researchers can see how the disease develops and whether novel cardiac treatments have a meaningful effect (either positive or detrimental) on skeletal muscle function.
Most of the assessments and clinical outcome measures for DMD were developed to evaluate ambulatory patients. These include the 30-foot walk test, the six-minute walk test, the North Star Ambulatory Assessment, the wearable-sensor derived stride velocity 95th centile (SV95C), and other functional measures like time to rise and 4 stair climb. These measures help track early disease progression, but they are much less useful once patients reach late ambulatory and non-ambulatory stages. This is where the field currently faces one of its biggest challenges.
For non-ambulatory patients, the toolbox is sparse. Quantitative muscle testing can measure strength, but it depends on patient effort. The Performance of the Upper Limb (PUL) focuses on upper-extremity function, but it is time-intensive and requires highly trained physical therapists to be accurate.
The Casimir DMD video assessment provides valuable information on the quality of patient movement, but its adoption is limited by costs and operational complexity. Skeletal muscle MRI offers an alternative method for tracking disease progression; however, its reliance on specialized expertise for interpretation limits its scalability in routine clinical trials.
There is a critical need for novel outcome measures that are applicable across the entire disease spectrum, from ambulatory to non-ambulatory stages, that impose minimal burden during clinic visits. Ideally, such a measure would need to be relatively quick to administer, reproducible, cost-effective, and sensitive enough to detect meaningful change over the course of the disease. Importantly, it must align with the FDA’s definition of a clinical outcome assessment by capturing how a patient feels, functions, or survives. Ultimately, a practical functional measure is required that can be applied reliably in clinical trials even after patients lose the ability to walk.
This unmet need has driven growing interest in digital biomarkers and wearable technologies, especially for patients whose disease progression is not adequately captured by ambulatory endpoints. A recently published study evaluated the benefits of a reliably correlated, effort-independent measure for monitoring skeletal muscle disease progression in both ambulatory and non-ambulatory patients.
The 6-minute 95th centile measurement, or 6M95C, is a wearable accelerometer-based metric that can quantify peak sustained activity in a patient’s daily life. The method has been evaluated in a prospective, multicenter cardiac natural history study, in which 102 patients were followed for two years. Participants were enrolled based on their ambulatory status, with their condition and progress assessed at baseline, one-year and two-year timepoints. While the study was primarily cardiac-focused, with cardiac magnetic resonance imaging and blood collection performed at each visit, it also incorporated skeletal muscle assessments using quantitative muscle testing and seven-day wearable accelerometry.
Wrist-worn accelerometers were used to collect continuous 24-hour activity data over a 7-day period. The device recorded raw acceleration signal at high frequency (30 Hz) and transformed the signal into ‘activity counts’ in 15-second epochs. Data analysis involved using rolling six-minute windows throughout the wear period, calculating total activity counts for each window. The 95th percentile of all six-minute totals was then determined, yielding the six-minute activity-95th percentile (6M95C), which represents activity levels exceeding 95% of all windows and captures the patient’s upper spectrum of functional movement in daily life.
The 6M95C is intended to be analogous to the 6-minute walk test in a free-living environment. This distinction matters. The 6-minute walk test is considered the gold standard for ambulatory DMD populations, but it is constrained by its dependence on participant effort, clinic conditions, and infeasibility after loss of ambulation. The 6M95C captures sustained peak activity in daily life, providing a view of how a patient is functioning outside the clinical setting. It is not effort-dependent, which may make it a more accurate reflection of disease progression. It also benefits from repeated measurements over multiple days, reducing the impact of day-to-day variability and leading to a more robust picture of function over time.
A key advantage of the 6M95C is its potential to address a longstanding gap in assessment by capturing the transition through loss of ambulation and subsequent stages. In the validation studies, investigators compared 6M95C to established DMD clinical assessments, such as quantitative muscle testing and cardiac MRI measures. They also studied its longitudinal patterns in several ways by comparing values before and after loss of ambulation, evaluating the differences between ambulatory and non-ambulatory groups, and measuring change from baseline to two-year follow-up.
The results were promising. Six-minute activity window measures declined significantly in non-ambulatory patients, demonstrating that the full distribution of daily activity behavior changes substantially after loss of ambulation. The 6M95C also demonstrated sensitivity to disease progression over time and effectively distinguished between ambulatory and non-ambulatory groups. Notably, it continued to provide meaningful data after ambulation was lost, a stage at which many traditional endpoints become obsolete. This represents a significant advancement in patient evaluation.
The field has spent decades refining tools to characterize decline in ambulatory patients with DMD. But as care improves and patients live longer, DMD research must adapt to improve our understanding of disease progression in later stages. If new cardiac or disease-modifying therapies are to show benefit across the lifespan of DMD, investigators require endpoints that remain informative as patients age and functional abilities change.
The emergence of more novel therapies means that the field of DMD is asking harder questions. How do we demonstrate that a treatment changes the natural history of DMD? How do we measure patients who are no longer able to walk? As well as how do we do this in a way that is clinically relevant, scalable, and acceptable to regulators?
Free-living, digital functional measures, such as 6M95C may help provide answers to those questions. They enable tracking of how well a patient sustains activity over time, rather than capturing a single effort-dependent performance during a clinic visit. They may be especially valuable in late ambulatory patients who struggle with standard walking tests, as well as in non-ambulatory patients for whom commonly used tests are no longer relevant. This offers considerable potential for the future of DMD clinical development.
The continued reliance on primary endpoints that exclude a substantial and growing proportion of the DMD population is not sustainable. To deliver meaningful therapies across the disease trajectory, clinical trials must incorporate outcome measures that are sensitive, feasible, and valid for both ambulatory and non-ambulatory populations. In DMD, the next major advancement may come not only from improvements in available therapeutics but also in how we measure whether those therapies are making a difference.
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