Current clinical trials for Duchenne muscular dystrophy (DMD) drugs often utilize accelerated regulatory pathways based on studies with short durations, small sample sizes, and young, ambulatory patients. These studies, characterized as SSHY (short, small, healthy, young), may not adequately capture the long-term benefits, particularly concerning cardiorespiratory complications that manifest in older, non-ambulatory individuals.
Limitations of SSHY Studies
While SSHY studies offer the advantage of faster and less costly drug development, they primarily assess functional motor strength using measures like rise and walk tests and the North Star Ambulatory Assessment scale. The clinical implications of these functional outcomes on systemic morbidities and mortality remain uncertain. Cardiorespiratory dysfunction, a leading cause of morbidity and mortality in DMD, is rarely observed in the young, ambulatory populations typically included in these studies. Moreover, surrogate outcomes, such as increased levels of truncated dystrophin protein, are emphasized despite controversies surrounding their clinical effects.
Concerns with Historical Control Databases
The use of historical controls as comparison groups in DMD drug trials raises significant concerns. These databases, derived from a few academic consortiums, exhibit variability that allows for potential bias in judging drug efficacy. For instance, a study on pamrevlumab demonstrated varying statistical significance depending on the historical control database used. Factors such as glucocorticoid (GC) therapy, known to mitigate pulmonary function decline, are often inconsistently reported or absent in these databases, further compromising their reliability.
Suboptimal Pulmonary Function Measures
Forced Vital Capacity (FVC) % predicted is a commonly used respiratory outcome measure in DMD drug trials. However, relying on a single, constant rate of decline in FVC % predicted across an age range (typically 10-18 years) may not accurately reflect the dynamic changes in pulmonary function throughout the disease stages. In healthy individuals, lung function rises through puberty, plateaus in early adulthood, and then declines. In DMD patients, pulmonary function is influenced by both linear growth and progressive weakness, resulting in three stages: rising, plateauing, and declining.
Rideau Plots: A More Comprehensive Approach
Rideau plots, which depict absolute FVC values plotted against age, offer a more comprehensive assessment of drug effects by capturing the varying influence of linear growth and progressive weakness across the age span. Unlike FVC % predicted, Rideau plots can illustrate the impact of treatments like glucocorticoids on pulmonary function, showing how they can lead to higher peak FVC values, delayed plateau levels, and a later onset of decline. This level of detail is crucial for assessing clinical relevancy and informing the design of future drug studies.
By considering the limitations of current clinical trial endpoints and exploring alternative approaches like Rideau plots, researchers can gain a more nuanced understanding of drug efficacy and improve outcomes for individuals with DMD.
