Trial parents Sarepta's 201/202 trial refute FDA's BD

Subject: Sarepta's Eteplirsen Briefing Documents & Addendum

January 18, 2016

Dr. Billy Dunn
Dr. Eric Bastings
Dr. Ellis Unger
Dr. Ronald Farkas
Dr. Robert Temple
Dr. John Jenkins
Dr. Janet Woodcock

My name is Terri Ellsworth, mother of Billy Ellsworth, age 15, a trial participant in Sarepta's Eteplirsen Study 201/202 trials. I am writing on behalf & with permission of the other 201/202 trial parents whose emails are cc'd above. We collectively wish to address and express our deepest concerns about several misleading and erroneous remarks in the briefing documents released on Friday, January 15, 2016. These inaccuracies will be damaging to our chances of approval and directly affect our son's mortality. Know that we plan to do everything in our power to affect positive change for the best possible outcome of our adcomm for our children and all those waiting to receive this lifeline of a drug. I will address several points of dire concern below:

Point #1 Steroid Usage: Several times throughout the FDA briefing documents it is stated that, "Patients in Study 202 appeared to be getting optimal care, including intensive physical therapy and intensive steroid regimens". Elsewhere it is stated that "corticosteroid therapy appears to have been more intensive in the eteplirsen patients compared to the natural history patients"....."and this, itself, may have been capable of affecting performance."......."doses of corticosteroids appear to have been lower in the applicant's natural history patients"....."Adherence to treatment guidelines is difficult to measure, but adherence in the Eteplirsen study was reported to be exceptional, while there is evidence that care received in the regions of origin of many of the sponsor's historical control patients was likely of lower intensity."......."differences in individual care decisions, therefore, seemingly could produce large differences in 6MWT and time to loss of ambulation between eteplirsen patients and natural history controls."......and finally FDA suggests that it is the "intensive physical therapy and intensive steroid regimen" most likely responsible for stability and not due to the Eteplirsen drug.

The study 201/202 parents want on record that we vehemently disagree to these damaging and misleading assertions. Our trial boys receive either minimal, standard, or NO physical therapy outside of the trial evals. Some comments from the parents regarding the FDA's false and misleading assertions are, "no PT at all", "same PT and steroid regimen since age 3", "same low dose since age 3", "PT NEVER changed", "daily stretches/splints, which are all SOC from MDA clinic which is same recommendations for all DMD boys", "no extra PT", "same DMD regimen as those outside of the trial", "same low steroid dose for past 8 years and no private PT in 9 years, school PT released him from all PT a year ago because he has met, maintained, and exceeded all goals". So we take issue with the damaging assertions made in the briefing documents that eteplirsen boys received "optimal intensive physical therapy and intensive steroid regimens" simply isn't true! Furthermore, only 2 out of the 12 eteplirsen boys are on the appropriate recommended steroid dosage based on age/weight....all others are therefore UNDERDOSED. In contrast, the EC (external control) boys, 10 out of 13 boys were on the recommended dosage based on age/weight. In addition, loss of ambulation at year 4 shows that 2/12 eteplirsen boys or 16.7% lost ambulation in contrast to 10/13 EC boys or 89.7% lost ambulation. Eteplirsen boys have not performed better due to 'optimal intensive physical therapy and intensive steroid regimens" as suggested in the documents because there was NO "intensive therapies" as stated above from the trial parents. Their performance is due to the eteplirsen drug......all 0.9% of it which doesn't seem to be appreciated by the FDA and is considered negligible and not meaningful but to the eteplirsen parents and, more importantly our boys, this amount of dystrophin produced is a lifeline and has added meaningful QOL and continued stability with minor decline.

These inaccuracies are both misleading and erroneous whether accidental, intentional, or simply an oversight due to perhaps a hasty review but has now tainted the advisory committee members who are supposed to be unbiased but are now in receipt of inaccurate reports. This is unacceptable and we believe deceptive!

Point #2 Internal Inconsistencies: "By age 10-14, patients become wheel chair bound' (FDA drisaperson BD page 15)
"The age range at loss of ambulation is wide, ranging from 8-16 years for most patients (FDA eteplirsen BD page 7)

Our community was outraged at this lack of inconsistency! Why the change in age at loss of ambulation since November's adcom for a different DMD drug? Again, this is unacceptable and can potentially be damaging and sends an inaccurate message to the advisory committee members.

Point #3 Historical Control: If FDA was not going to support or accept post hoc selection of the control group, why did FDA make the suggestion to pursue this path in April 2014?

Point #4 Confirmatory Study Design: "With regard to future efficacy studies, any beneficial effects of eteplirsen are unlikely to be large enough to be detectable outside of a placebo controlled trial." (FDA BD page 51) Again, the FDA is challenging Sarepta on their own provided guidance (which is same guidance given to Prosensa on confirmatory trial design) Why provide the guidance to a company only to change your mind when reviewing an NDA package that was previously agreed upon? Our community sees this as setting a company up for failure! This is unacceptable!

Point #5 Cross trial comparison: This was not a matched comparison on crucial factors such as age and baseline 6MWT using the drisaperson placebo group and therefore unable to provide persuasive results. Again, this is a contradiction as to the FDA guidance provided to Sarepta on their path forward. This is unacceptable and a setup for failure!

Point #6 Lack of Independent Confirmation: (FDA Eteplirsen BD page 31) As agreed upon with the FDA, Sarepta did obtain findings from 3 independent pathologists who provided independent confirmation of statistically significant increase of dystrophin positive fibers. This independent analysis is widely known throughout our Duchenne and scientific community. How could this be misrepresented to the advisory committee in the briefing documents? Our boys voluntarily underwent a painful 4th biopsy for this purpose in order to satisfy the FDA's concern of a single analysis; for the FDA to report that protocol wasn't followed and moreover violated guidance is deceptive. How could this happen and why?

In closing, study 201/202 trial parents & many in our community feel deceived and manipulated by provided guidance only to be led down a path of an uncertain outcome due to negligent reporting.

The FDA was created to help patients and not hurt them, but these briefing documents, much of it inaccurate, misleading, & deceptive is harming patients-not just any patients-but innocent children who are now considering and dreaming of driving, entering college, and choosing a career path. They are able to now dream of such things because they feel better and have a better quality of life and can now imagine a future because of their Eteplirsen treatment which will someday become part of a combination therapy. These misleading briefing documents can be their demise. Know that we will do everything in our power to make sure that this is not their demise. We are united, we are not a timid community, we are relentless, we will not let our boys die in vain. The law of FDASIA passed by Congress in 2012 allows for the patient voice to be heard and we will exercise that right.

We, too, look forward to a "fruitful" discussion on Friday.


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