In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases.
Today’s pick is by Sherlock et al from Journal of Neurology about MRI measurements in patients in the Pfizer domagrozumab trial in Duchenne (myostatin inhibition). Doi 10.1007/s00415-022-11084-0.
Duchenne is a severe progressive muscle wasting disease. For therapeutic development in clinical trials sensitive outcome measures to detect efficacy are important. Functional measures are usually a primary endpoint but this requires long trials (usually 2 years).
MRI can measure muscle volume, fat fraction and T2 relaxation times will increase with inflammation and edema. Domagrozumab is an antibody against myostatin. As such it inhibits the inhibitor of muscle growth. In mice this increased muscle mass and function.
In a phase 2 placebo controlled clinical trial in Duchenne patients domagrozumab did not result in functional efficacy as measured by the 4 stair climb scale after 2 years of treatment. Most patients also had MRI analysis at different timepoints in the first year of the trial.
Here authors present these results, trying to also assess if MRI results at week 49 predicted functional effects at week 96. The thigh muscle volume was increased for domagrozumab treated patients compared to placebo at week 49 and T2 relaxation times were decreased.
No differences were observed in fat fractions, except after 17 weeks where it was lower in domagrozumab treated patients. This difference was not present at week 33 or 49. MRI measures at week 49 did correlate with the 4 stair climb and NSAA outcomes at week 96.
An increase in muscle volume of 2.45% and 7.92% predicted a better result on the 4 stair climb and the NSAA respectively. Muscle volume was very variable also for patients of similar ages. However with time it declined for individual patients as expected for Duchenne.
Authors discuss that the increase of muscle volume in domagrozumab treated patients fits with the working mechanism. While MRI differences were found at week 49, suggesting more muscle function, this did not result in functional effects at week 96.
At the same time MRI measures did correlate with future function within patients (treated and untreated). However apparently the difference in volume was not enough to effectuate a functional change. We have to bear in mind that likely this is not extrapolatable to other drugs.
Domagrozumab increases muscle fiber size and the number of type 2 fibers. Fiber integrity is still poor lacking dystrophin. Compounds that restore dystrophin or act on other pathological processes may have a different correlation between muscle volume and function.
Authors discuss doing MRI analysis in a multicenter trial with standard equipment is feasible. I’m no MRI expert but imagine insisting on a specific MRI machine may limit choice of trial sites. With different machines image analysis is more challenging but doable.
Authors discuss MRI analysis was feasible in their trial cohort of 6-16 year old Duchenne patients. Failed images were generally due to motion. However, I commend authors for analyzing & sharing data. Even though the functional endpoint was not achieved we can still learn a lot.
Pictures by Annemieke, used with permission.