Those Diagnosed with Duchenne do NOT get Better

Posted by: Christine McSherry on June 18, 2013

Those who have been following my blog know that myself and several other moms (Jenn McNary and Mindy Leffler) have been meeting the FDA on a regular basis to discuss eteplirsen (Sarepta Therapeutics) and accelerated approval. In accordance with FDAISA, the FDA has taken an active role in listening to us, and for the first time ever – participated in watching videos of boys in the trial – who are doing activities that, after 2 years of living with Duchenne, they should not be able to do. Our conversations and this new “patient reported outcome videos”, just might change the way the FDA looks and evaluates outcome measures. Furthermore, it can help the community identify the outcome measures that are important to them. The quality of life and functional benefits seen through these videos provide additional color and perspective on how this drug is changing lives, the lives of 12 boys with Duchenne on eteplirsen.

While I know there is argument that some diagnosed with Duchenne stabilize for a short amount of time, just shy of age 7 – and I know it is short having lived it, I want to take a moment to highlight some of the interesting predictive factors in Duchenne that I read in a recent published paper on the natural history of the disorder. Duchenne is clearly progressive – it is not a chronic disorder. Interestingly enough, the paper was published in January, 2013 and the conclusion reads,

” These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial”.

I came across the paper while preparing the videos for our last FDA meeting, and the paper was able to help me correlate what the parents were seeing and what is known about the natural history of Duchenne. The two that stood out for me; the timed Gower Test and the 6MWT.

Gower Test:
Eight children were unable to perform the Gower test at baseline. Other 8 lost the ability to perform it within 1 year and and another 18 within 2 years. The changes in the time taken to perform the manoeuvre in the subjects who were still able to perform it showed an average overall decline of 5.05 seconds (SD 12.45) in the first year and of 7.83 (SD 16.01) in the second year.

The changes were significantly different in the two baseline age groups (test for interaction, p = 0.003): children below 7 had a mean decrease of 1.75 seconds during the first year (SD = 4.62) and of 1.79 sec during the second year (SD = 7.33). Children above 7 had a decrease of 6.88 seconds during the first year (SD = 14.87) and of 11.32 during the second years (SD = 18.59).

Here it clearly states that children above age 7 had a significant decrease – compare that with Billy. Who is clearly getting off the floor in less than 5 seconds, and he is nearly 13 years old.

While only one boy lost ambulation at one year from baseline, another 12 lost the ability in the second year.The analysis of our results suggested that a 6MWD of at least 330 meters, or a NSAA score of 18 reduced significantly the risk of losing ambulation within 2 years.
Again, let’s compare this with Billy taking a walk on uneven ground downhill. Mom reports that they had been out hiking almost “all day”. Loss of ambulation within 2 years, that is what the Mazzone paper published, yet here we are – 2 years later on eteplirsen and 10 of the boys are still walking. We know that the mean baseline for the 6MWT for trial participants in the placebo arm was 327 meters, and 388 in the miTT. It seems reasonably likely that these boys are still walking and/or have stabilized because they are all on eteplirsen.

Duchenne is predictable and more importantly for this trial and upcoming trials – measurable. The data being collected will help shape additional trials for ambulant and non ambulant boys. The data can be measured and collected in numerous ways, from a child getting up from the floor, to riding a scooter, to measuring how much dystrophin is found in a muscle biopsy to whether or not the child can walk his dog. It is the totality of all the data that should be taken into consideration. I believe that the additional patient reported outcome videos may provide the stage for helping the community and the agency decide what other measures are important while designing a trial for ambulant and non-ambulant participants in the future.

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