Duchenne Destroys, Causes Devastation and Death

Posted by: Christine McSherry on April 30, 2013




While there seems to be a debate related to the dystrophin being produced by eteplirsen and whether or not it has proven to be correlated with a clinical benefit, I believe the FDA guidance on accelerated approval requires that the dystrophin production only be “reasonably likely to predict” clinical benefit.  All of the arguments related to the size of the eteplirsen study, the statistical analysis or the debate about the natural history of the disease doesn’t seem to recognize the fact that eteplirsen is producing dystrophin in all patients after 48 weeks of treatment and has led to a stabilization of all ambulatory patients in the study over 74 weeks in the early treatment arm and now over 38 weeks in the placebo patients who were on a steep decline before eteplirsen produced dystrophin in their muscles.

To those who do not have to live with the personal devastation, as my family has with Jett, and what it brings families, I am here to tell you that we cannot wait any longer while those who are not living with Duchenne (Devastation, Destroys, Degenerate, Death) debate the need for a more precise and definitive correlation of dystrophin and stabilization of the disease.  The fact that eteplirsen has proven to be safe in all of these patients, including those who have now received high doses of the drug over a 74 week period puts an exclamation point on the need for this drug today based on the risk-benefit ratio of making the drug available for this rapidly progressive and irreversible disorder.

“The Correlation Between Dystrophin Levels And Clinical Benefit Is Poor” – Cowen Research Report dated April 22, 2013

I find it interesting that this sentiment that the correlation between dystrophin and clinical benefit is “poor” has only started to gain traction AFTER we have drug that is producing dystrophin at statistically significant levels with a drug that is designed to produce dystrophin in Duchenne patients.  No one was questioning the need to restore dystrophin when it was made clear that the milder disease that affects Becker muscular dystrophy patients is based on the same type of dystrophin that eteplirsen is producing.  There have been a number of animal studies that have demonstrated clear functional improvement, even with the same chemistry that eteplirsen is produced, in mouse and dog models of the disease.  Subpart H, accelerated approval doesn’t require a “proven and confirmed correlation,” it requires the data to suggest that the drug is “reasonably likely to predict” a clinical benefit – what does reasonably likely mean? Does it mean it has to mirror or correlate 100%?  No, it means what it says -  “the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.”

All of the patients, all 12 patients showed positive dystrophin fibers in their biopsies.  All ambulatory participants demonstrated stabilization of their walking in the 6MWT after dystrophin was produced by the drug.  The two twins who rapidly lost ambulation before dystrophin was produced have surprisingly shown stability on pulmonary function and muscle strength.  This means all patients seem to demonstrate positive effects associated with the drug after dystrophin is produced.  Not some patients, all patients.  Is it reasonable to think that there was variability in quantifying all 12 of the muscle biopsies?  Is it reasonable to think that there is a sampling error in all 12 of the muscle biopsies?  Even though there might be variation in the amount of dystrophin in the individual patient, the data shows that all dystrophin increased with time.  Despite the limitations of dystrophin variability, it is quite encouraging that all the boys displayed dystrophin production.  This bolsters confidence that the drug is working.  Slides presented at the MDA conference this week show stabilization in the 6MWT along with an increase in dystrophin positive fibers, around the same time.

If the numbers confuses anyone, there is visual evidence of the dystrophin production as well.  Take a look at the slide below showing the progression of dystrophin production with eteplirsen.  If you look at the 48 week biopsy slide and the dystrophin positive fibers, do you believe this looks closer to the normal healthy patient biopsy (on the far right) or does it look closer to an untreated Duchenne patient’s muscle biopsy (on the far left)..  I’ll bet if you asked any 5-year-old Duchenne patient which muscle biopsy looked closer to the 48-week eteplirsen biopsy, they would pick the normal non-Duchenne slide.



Do you have to require trials with hundreds of children to satisfy the system or can you show a large effect and significant benefit with a smaller cohort, which suggests that this drug could change those diagnosed with Duchenne and their families’ lives forever?

During discussions with the FDA, specifically Commissioner Hamburg, this is a direct counter to what we were told. We were told repeatedly to tell industry that the FDA wanted smaller, innovative trial designs that targeted the underlying cause of the disease, they are aware of how these patients progress and don’t want large scale trials in this indication. It was my sense that there was a willingness to be flexible, that this FDA wanted the change it was advocating for, and this might be the opportunity to demonstrate their proactive demeanor.

At the end of the day, the data speaks for itself.  The natural history data is undeniable.  Those diagnosed follow a projected decline, there are few outliers.  The average patient follows a predictable course – this we know.  The dystrophin data is there, the clinical benefit is evident.  There is anecdotal data circulating in the community that further strengthens the case – patients in the trial are beginning do to things that they never could prior.  That rarely, if ever, happens in Duchenne – in this age group.  These are important and measurable patient reported outcomes where parents are seeing gains and stabilization.  These gains have an enormous impact across the board; psychologically, sociologically, economically – they are simply immeasurable.  This is something the Duchenne “experts” have not taken into consideration, but is an important consideration and must be highlighted.  These participants and their families are being spared – perhaps temporarily – the costly move to a one story house, the purchase of a handicap van, the fitting for a power-chair, the alteration of installing a ramp to their home and many more.  Instead, they are celebrating things like, making a basket in basketball for the first time, participating in a 5k, trying on ice skates, and jumping over a bike rack – to impress a girl, and many more.

My family is living with this horrible progressive disorder.  We hope the community will have a clear understanding of the key issues and successfully navigate any diversions.  We finally have the opportunity to impact this disease.  How much further devastation and loss could result if this drug is not approved in the upcoming months?   Far too many “experts” have lost sight of the bigger picture because they are lucky enough not to have to deal with it every day of their lives – but to be clear Duchenne equals death and this drug needs accelerated approval now.

Perhaps readers might think that I am biased and over emotional because I want this drug to work for my son – but actually, I am capable of evaluating trials just like anyone else, I have been doing this for 12 years, I have evaluated many potential treatments. I wouldn’t be as passionate about this drug if I wasn’t convinced it works, and I have seen it with my own skeptical eyes, and from what I have seen, it works.




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