Delaying Loss of Ambulation May Mitigate Worsening Disease Burden in DMD

Therapies that slow the loss of ambulation (LoA) in patients with Duchenne muscular dystrophy (DMD) may also mitigate worsening disease burden and overall function, according to a poster presented at the 2024 ISPOR—The Professional Society for Health Economics and Outcomes Research meeting held in Atlanta, Georgia. Another poster found a potential association between age at LoA and pulmonary outcomes in DMD.

The first poster aimed to characterize disease burden and physical function changes among boys with DMD before and after LoA, then compared the changes based on age at LoA.¹ Authors Gordish-Dressman et al identified boys with DMD with self- or parent-reported full-time wheelchair use from the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study and stratified them by age at LoA. The age ranges were younger than 10 years, 10 to 13 years, and older than 13 years.

At 6-month intervals from 5 years prior to LoA to 5 years after LoA, researchers assessed Major Adverse Dystrophinopathy Events (MADE) scores, Quantitative Muscle Testing (QMT) grip scores, and the numbers and proportions of patients who reported using a wheelchair or walker daily vs less than daily.

Patients with earlier age at LoA progressed to full-time wheelchair use faster from initiation of wheelchair use in the study | Image credit: Nana_studio - stock.adobe.com

There were 45 patients in the cohort who experienced LoA at younger than 10 years, 45 in the age 10 to 13 LoA cohort, and 32 in the cohort who lost ambulation at older than 13 years. The mean (SD) age at enrollment was 11 (3.6) years.

MADE scores increased with time in all groups, especially at about 2 years prior to LoA. The disease burden was also higher when LoA was later, with a mean MADE score of 14.1 (6.9) among the group who lost ambulation the earliest, 15.8 (7) in the group who lost ambulation between 10 and 13 years, and 17.4 (5.8) in the group who lost ambulation the latest.

In the cohort of patients who lost ambulation at younger than 10 years, wheelchair use typically began 2 years prior to LoA, and more than 50% of patients progressed to wheelchair use less than 6 months prior to LoA. Among patients who experienced LoA at older than 13 years, wheelchair use typically began 5 years prior to LoA, and 90% of these patients reported daily wheelchair use by less than 6 months prior to LoA. QMT grip strength was generally strongest at 2 to 3 years prior to LOA and decreased as time went on.

“Patients with earlier age at LoA progressed to full-time wheelchair use faster from initiation of wheelchair use,” the authors concluded. “Despite limited data availability, observed trends suggest that therapies that slow progression to LoA may also address the worsening burden and functioning in DMD regardless of timing of LoA.”

Loss of Ambulation and Pulmonary Outcomes

In a second poster, Gordish-Dressman et al explored the relationship between age at LoA and the timing of pulmonary outcomes in boys with DMD, again using the CINRG DMD Natural History Study dataset.² While pulmonary outcomes are important in DMD, the authors noted that the association between pulmonary impairment and other clinical milestones, including LoA, is not well-defined.

Researchers assessed the number of patients who experienced a pulmonary event and the estimated median time-to-event using Kaplan-Meier plots and compared via log-rank test. Forced vital capacity (FVC) of less than 1 liter and predicted FVC (pFVC) of 30% or less and 60% or less were main outcomes of interest.

Twenty patients (37%) with LoA at younger than 10 years showed FVC of less than 1 liter at a median of 19 years, the median age at event was 22.6 years among 39 events (36%) in the 10 to 13 years group, and the median age at event was 28.3 years among 12 events in the group who lost ambulation at older than 13 years (P < .0001).

Regarding pFVC of 60% or less, 27 patients (71%) who lost ambulation at less than 10 years had a median age at event of 13.5 years, 54 patients (77%) who experienced LoA at 10 to 13 years had a median age of 14.6 years at the time of the event, and 32 patients (46%) who experienced LoA at older than 13 years had a median age of 18 years at the time of the event. Regarding pFVC of 30% or less, 20 patients (38%) in the youngest LoA group, 38 patients (38%) in the LoA at 10 to 13 years group, and 14 patients (17%) in the oldest LoA group had median ages of 18 years, 20.8 years, and 25.7 years at the time of event (P < .0001).

“In this descriptive analysis, a pattern of later time-to-pulmonary-event with older age at LoA suggests a potential relationship between these outcomes,” the authors concluded. “While further analysis addressing the impact of immortal time bias will be necessary, this analysis lends support to the value of delay in LoA.”



References

1. Gordish-Dressman H, Zhang R, Kamstra R, et al. Relationship between loss of ambulation (LoA), disease burden, and physical functioning among boys with Duchenne muscular dystrophy (DMD). Poster presented at: International Society for Pharmacoeconomics and Outcomes Research 2024; May 5-8, 2024; Atlanta, GA. Poster 1029.

2. Gordish-Dressman H, Zhang R, Kamstra R, et al. Relationship between loss of ambulation (LoA) and timing of pulmonary outcomes among boys with Duchenne muscular dystrophy (DMD). Poster presented at: International Society for Pharmacoeconomics and Outcomes Research 2024; May 5-8, 2024; Atlanta, GA. Poster 1026.