MRI Imaging May Be Important Biomarker in DMD

Magnetic resonance imaging (MRI) appears to be able to meaningfully track functional changes in Duchenne muscular dystrophy (DMD), according to a recent analysis.

If validated in additional studies, MRI-based biomarkers could become a surrogate endpoint in future trials involving patients with DMD, the study suggests. The findings were published in Muscle & Nerve.

The study was sponsored by Pfizer Inc. and AMRA Medical. Lead author Sarah P. Sherlock, Ph.D., formerly with Pfizer, and colleagues noted that disease progression in DMD is typically tracked via functional changes using tools like the North Star Ambulatory Assessment (NSAA). Such assessments generally involve timed function tests to compare patients’ performance with their own previous performance and with healthy controls.

Sherlock and colleagues said such tests are “appealing from an interoperability perspective,” but they noted that the tests also require lengthy time horizons and large trials to detect significant changes in function.

Previous studies of MRI biomarkers in DMD have led to favorable results, but most of those studies have focused on longitudinal changes in fat fraction in a central section of individual muscles, Sherlock and colleagues noted. They said it is important to also look at changes to contractile muscle tissue volume over the whole muscle, as well as diffuse fat infiltration in still-viable muscle regions.

In the new study, the investigators sought to see how well MRI-based biomarkers could track disease progression. They looked at lean muscle volume (LMV), muscle fat fraction (MFF), and muscle fat infiltration (MFI) alongside changes in NSAA performance. Their hypothesis was that they could find an association between MRI-based parameters and NSAA scores.

The investigators pulled MRI data from a clinical trial of domagrozumab, a humanized monoclonal antibody inhibiting myostatin in patients with DMD. Pfizer terminated development of the therapy after finding that it did not result in a significant benefit for patients.

Participants in the trial were aged 6 to <16 years at screening. They were tracked by both Dixon MRI and functional tests at baseline, 49 weeks, and 97 weeks. Sherlock and colleagues tracked the relationship between MRI parameters and functional performance, the potential for MRI parameters to predict loss of ambulation, and the progression of MRI biomarkers throughout disease progression.

They found a correlation between all three MRI parameters — LMV, MFF, and MFI — and muscle strength and NSAA scores at all of the study’s time points. For example, patients with preserved ambulatory function had high total LMV but low total MFI. Patients with low ratios of LMV to MFI or with small LMV and high MFI were more likely to experience a rapid loss of function and ambulation, the authors said.

The investigators also found that MRI changes at 49 weeks correlated with NSAA-score changes at 97 weeks. In fact, they found that those correlations were stronger than comparisons at week 49. The authors said this suggests that MRI parameters may help clinicians predict future functional changes.

Sherlock and colleagues said their findings have implications for future clinical trials.

“Monitoring these muscle MRI biomarkers during an interventional clinical trial may be important to identify therapeutic benefits or patients at high risk for rapid functional decline and as such could potentially have a role in patient selection,” they wrote.

The authors cautioned that because their data come from a clinical trial of domagrozumab, the data should not be interpreted as natural history data. They added that the use of Dixon images meant that only sites with manufacturer-supplied fat/water images were included in the analysis, which reduced the overall sample size.

Still, they said the study shows that multiple MRI biomarkers appear to track with functional performance in DMD, potentially opening up avenues to better understand disease changes and the impact of future therapies.