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My email to Federal Drug Administration

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A personal perspective on the U.S. Federal Drug Administration’s Advisory Committee meeting for Sarepta Therapeutics exon 51 skipping Drug Eteplirsen by Alex Johnson mother of eight year old Jack Johnson who suffers with Duchenne Muscular Dystrophy.

As I sit here waiting for my delayed flight back to London I feel close to tears, I am completely exhausted and emotionally drained. I feel like the whole trip has been a bad dream and in a minute someone is going to wake me and tell me everything is ok and the Ad Comm just didn’t happen, but it did.

Having diligently read the briefing documents I didn’t go into the ad comm with high hopes of a favourable review. I expected negativity but what I didn’t expect was bias. I expected a fair review, surely our community deserved that, right?

During the course of the meeting it was alluded to that the sponsor, Sarepta Therapeutics and the FDA had previously had strained relations. I can’t help but feel that the bad blood between the sponsor and the Federal Drug Administration (FDA) shaped the discussions that took place. The one thing I am sadly and frequently learning as a member of this community is that it is always the patients that suffer and lose out. This is an open plea with the FDA to not allow your disagreements with the sponsor cloud your judgement in this New Drug Application (NDA) review for eteplirsen.

Watching the distress of the Columbus 12 boys during the final vote are memories that will haunt and stay with me for the rest of my life. I am sure this is a sentiment shared by everyone present at the meeting and we must work together to make sure this never happens again.

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Dr Farkas’s bizarre behaviour as he excitedly and erratically jumped around his presentation are also memories that will never leave me. His awful and at times insensitive commentary has cut deep into our community. He seemed to take delight in having his opportunity to try to take down the sponsor. This makes me feel very sad. Considering what is at stake from the result of this review I would have expected his presentation to have been more professional and prepared. His presentation went considerably over time and this in my opinion was one of the factors that led to bias being created that led the committee towards his negative stand point. He should have been made to stick to time this was poor chairmanship from the chairman. I truly believe Dr Farkas should apologise for his behaviour and I hope the FDA will also address this internally.

At this point I want to highlight I do not tar everyone within the division of neurology with the same brush. I want to thank Dr Janet Woodcock for coming out and taking the time to speak with members of the Duchenne community after the meeting and listening intently to our concerns. We are grateful for the time, respect and compassion Dr Woodcock has shown our community. I hope others in the division will follow her lead and reach out to us in the coming days.

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I make no attempt to shy away from the limitations of the data set presented. It was a small trial but it is important to understand that Duchenne is a rare disease and this is a drug been developed from an even smaller subset of boys within the disease. It is roughly estimated that eteplirsen could benefit 13% of the Duchenne population. I would ask that the division of neurology is made to sit and re-watch the ad comm objectively and looks at the negative bias they presented through the meeting.

I would also request that this analysis for bias is evaluated by an independent expert. In my opinion Dr Farkas unashamedly leads the committee to a negative review. I did not count the exact number of times the sponsor was ignored when trying to make comments to clarify points but it appeared frequent to me. The FDA on the other hand did not receive this same treatment. I honestly thought there would be a fair and open debate, there was not.

One thing I will take home from the meeting and intend to learn from is that the meaningful outcomes that patients testified about weren’t being reflected in the data. As a community this is something we need to address. I will be attending a clinical outcomes workshop measures in May and will work with other patient organisations, researchers and clinicians to look at how we can best address this issue. I would ask that the division of neurology meets and interviews the Columbus 12 boys and listens to them and understands how eteplirsen has dramatically improved their quality of life. They are the real Duchenne experts.

In my testimony I talked about how I would be willing to move to the US to be able to have access to a drug like eteplirsen that has a life changing treatment effect for those lucky enough to be receiving it. I am now glad that I live in Europe and will be relying on the European Medicine Agency (EMA) to grant drug approvals for the Duchenne community which has a clear and desperate unmet medical need.

In Europe the EMA has used the regulatory tools available to them and granted conditional approval for Translarana, this is our first approved drug to treat Duchenne. Similarly to eteplirsen it is a drug that treats a small sub population, although a different sub population of patients with a premature stop codon. NICE our Health Technology Assessment body in England has just reimbursed the drug and is making it available to patients on a managed access basis. The EMA and NICE have acknowledged our unmet medical need, looked at the phase two data set, seen that it is slowing the disease progression for a sub population of boys and acknowledged that it is safe and have rightly made the decision to make it available to patients while the company collects more data. They have understood the risk/benefit equation involved for Duchenne patients and their families and thankfully made the treatment available.

The sponsor PTC have now collected more data and have submitted it to the EMA and we hope to hear later this year that the drug will receive full marketing authorisation. I implore the FDA to look at this example and use the tools it has available and grant patients not currently enrolled in studies access to eteplirsen, helping you avoid the type 2 error that was frequently mentioned in the meeting yesterday. Amongst the testimonies we heard yesterday were harrowing examples of what has happened to boys who have been excluded from the eteplirsen trials because they did not meet the entry criteria. Their devastating loss of function is not reversible. Like with translarana we will get more data in the coming years from the phase three confirmatory trials that Sarepta has already begun for eteplirsen. You can use the tools available to you and rightly grant accelerated approval now.  

I understand the FDA wanted a double blinded randomised placebo controlled trials. I share Mitch Leffler’s view, who testified in the OPH that this is no longer statistically possible in this small sub-population. I ask that you to re review Mitch Leffler’s testimony from the OPH. I also want to highlight this historically was not possible due to companies financials position, they simply did not have enough money to make the drug. I also want to highlight part of my group’s testimony and repeatedly request that you filter the Drisapersen placebo data appropriately and match it to the eteplirsen data, please continue to compare the two groups even when the patients cross over on to drisapersen drug. I am convinced this will be an appropriate control that will satisfy all parties and demonstrate that eteplirsen works. Can you confirm to me this analysis will be done?

I think it’s important for you to understand that most people in the audience did not understand the voting questions or discussion points due to the wording chosen by the FDA. I strongly believe the Ad Comm panel shared this same problem. They were ambiguous and leading. I am sure you are aware of the voting questions for the Parkinson Disease Ad Comm. They are clear and will give the division the answers they need on whether to approve the drug. The two sets of questions are incomparable.  

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Although the AdComm and the FDA’s final decision has no bearing on drug approvals in Europe it sucked all the hope I had that an exon skipping drug could ever be developed in time to benefit my son from me. He has a rare mutation. It would not be possible for a large placebo controlled trial to be carried out for his exon. I had hoped to leave the US with a shining example of how the FDA intended to use the powers and tools available to you to do the right thing and grant Accelerated approval to eteplirsen and put a pathway forward for other kids to benefit from personalised medicine. I don’t leave feeling that way. I leave feeling we are stuck in traditional drug development model where drugs typically take 10 to 15 years to develop. Time my son and the rest of the Duchenne community do not have.

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