Significant Pulmonary, Upper Limb Function Declines in Ambulatory Patients With DMD

The progression of pulmonary and upper-limb function decline before and after loss of ambulation (LoA) varied among a cohort of patients with Duchenne muscular dystrophy (DMD), according to a study published in PLoS One.¹ The findings suggest that clinical trials assessing treatments for patients with declining lung or upper limb function, which typically limit their populations to nonambulatory patients, could also include ambulatory patients.

DMD is a rare genetic condition that causes progressive muscle loss and weakness typically beginning in early childhood.² An estimated 6 per 100,000 individuals in Europe and North America have DMD, and there is currently no cure. Past research suggests that most patients with DMD experience similar stages of disease progression, with LoA occurring in their teenage years and upper limb and pulmonary deficits following.¹

“Alongside therapeutic advances for ambulatory patients, the development of therapeutics for DMD patients in later stages of the disease is a priority,” the study authors wrote. “To this end, drug developers have evaluated treatment effects on pulmonary and upper limb function because these functions are the next to decline in patients who have started to lose ambulatory function. Many of the trials targeting these end points have required patients to be nonambulatory at baseline, motivated in part by natural history data showing reliable declines in upper limb and pulmonary function among nonambulant patients.”

The study suggests that ambulation status may not necessarily predict early lung or upper limb function declines in DMD, with some ambulatory patients having early declines in these measures. | Image credti: Nana_studio - stock.adobe.com

In their study, they assessed and quantified trajectories of ambulatory, pulmonary, and upper limb function before LoA and of nonambulatory measurements after LoA. They also explored the sequence of pulmonary and upper limb function changes relative to LoA and assessed potentially prognostic markers for the onset of LoA. Lung function was assessed by forced vital capacity (FVC %-predicted), and scores on the performance of upper limb (PUL) 1.2 measure assessed arm function.

The analysis included 51 patients with DMD who experienced LoA during follow-up in the PRO-DMD-01 natural history study (NCT01753804). The mean age at LoA was 12.7 years, the mean FVC %-predicted was 78.6%, the mean PUL score was 64. While there were smaller mean rates of annual decline in FVC <80%-predicted and PUL 1.2 total scores prior to LoA vs after LoA, these differences were not significant (P = .21, P = .20, respectively).

Approximately half of patients already had a FVC <80%-predicted by the time of LoA, and the rest of the patients experienced this milestone by 2 years post LoA. Regarding PUL 1.2, about 75% of patients had scores lower than 6 at the time of ambulation loss, with the rest experiencing this milestone by 1.5 years following LoA. More than half of patients experienced both FVC <80%-predicted and PUL 1.2 entry scores less than 6 on the same timeline, meaning both milestones occurred either before LoA, with LoA, or after LoA.

These findings imply that ambulation status may not necessarily predict early lung or upper limb function declines, with some ambulatory patients having early declines in these measures. In terms of DMD clinical trial enrollment, the authors argue it should be based on pulmonary and upper limb function thresholds in broad populations that include patients regardless of ambulatory status.

The study’s small sample size for LoA events limited its statistical power and prevented the investigation of other factors that could impact outcomes at the same time as LoA, but it also had strengths. These included the prospective collection of natural history data and the selection of patients with comprehensive data on functional assessments, according to the authors.

“Heterogeneous ordering of milestones across functional domains and individual subjects suggests that composite end points for clinical trials, particularly composite time-to-event end points (e.g., time to first clinically meaningful progression in any functional domain) could be helpful for measuring drug effects,” the authors wrote. “Such composite outcomes would be sensitive to treatment effects across functional domains and would address the heterogeneity in rates and timing of progression across patients and domains that is characteristic of DMD.”

There is an increasing need to assess long-term milestones in DMD as patients live longer and open-label extension or post-market studies are needed for treatments granted conditional or accelerated FDA approval, the authors noted. Therefore, effort should be dedicated to developing and validating composite outcomes that can measure drug efficacy.

“There is heterogeneity across patients in age at LoA and in the ordering and magnitude of deficits in pulmonary and upper limb function before and after LoA,” the authors concluded. “Enriching trials for patients with declining pulmonary or upper limb function is achievable without restricting eligibility to non-ambulatory patients; this is particularly important when outcomes of interest evaluate parameters unrelated to lower extremity function such as pulmonary and upper limb function end points.”

References

1. McDonald CM, Signorovitch J, Mercuri E, et al. Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials. PLoS One. Published online June 3, 2024. doi:10.1371/journal.pone.0304099

2. Duchenne muscular dystrophy (DMD). Muscular Dystrophy Association. Accessed July 26, 2024. https://www.mda.org/disease/duchenne-muscular-dystrophy