On Friday, September 25, we met with EMEA (the European regulatory agency) to begin dialogue about accelerating exon skipping. The Steering Committee met on Thursday to rehearse. A small group of us presented and/or analyzed each presentation. We wanted to strike the right tone, provide detailed information about exon skipping and we wanted them to understand this urgent need. At the end of the day, we were energized and ready to go!

We are all aware that both companies Prosensa and AVI are working on exons 51 (Prosensa- 44, AVI -50). What happens next? Will the next exons to be skipped take as long? What about the more rare mutations? Will every chemistry for each exon have to go through the common path of taking new drugs into the clinic? If this is the case for each individual exon, it may threaten the viability of exon skipping. And for our sons, it will take too long. They have no time to wait.

We stayed at a Hilton Hotel on the Thames River. We met at 8 AM and boarded the ferry, crossing the Thames. In fact, it seemed rather symbolic. We were entering new territory. When PPMD was organized 15 years ago, we could only dream about this day.

The meeting went very well. Francesco opened the meeting, introducing AON (exon skipping) as a potential therapy for DMD. Elizabeth Vroom presented the parent’s perspective. Two videos were shown – one of Justus at 4 years old. The video was actually a commercial – the first DMD commercial, donated by a PR firm 15 years ago and filmed on the beach in S. Africa. The second was done several months back. Justus as an adult, talking about outcomes – what would make a difference in his life today. It was striking in so many ways, more than I am able to describe in this short blog. It hit home. The impact, the need, the urgency.

Additional talks included delivery to tissue, results to date, toxicology, regulatory issues, backbone chemistry, trials with small populations and conditional approval.

I wrapped up with this:
The need is urgent.
Doing nothing increases risk for our sons.
Boys, all boys have little time. For the young, we need to save what they have. For the adolescent, we need to protect/preserve what they are losing and for the young adults, we need to hold on and work to restore what is lost in order to improve their quality of life.
We recognize that laws (regulatory and otherwise) are made to protect the masses, but in certain cases, in emergencies (for instance) laws are suspended. The example Elizabeth described was that of an ambulance. Speeding limits are designed to protect all drivers. In event of an emergency, the ambulance is granted permission to ignore the laws in order to protect the individual(s), help with the emergency.
In our lives, DMD is the emergency. Regulatory agencies need to consider what ‘sirens, sounds, lights’ – modifications can/should be deveoped to expedite AON as a potential therapy.

Skipping exon 51 serves only 13% of the boys with Duchenne.
Skipping exon 44 served only 6% of the boys.
Skipping exon 50 serves only 4% of the boys.
Exon skipping has the potential to help approximately 85% of all boys, but to do that in a timely way, we need to expedite the path.

The EMEA was open, interested and willing to consider how to move forward. They ‘got it’. Elizabeth McNeil, MD (orphan products/FDA) was present as well. I am certain she will help us deliver the message in the US.

Progress! We indeed crossed the river.

Ryan has posted the briefing document. We are making small revisions and the final document will be posted.

Download Briefing Document:
Muntoni EMEA introduction.pdf

Download image:
dystrophin exons EN.pdf

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Comment by Ian Anthony Griffiths on September 30, 2009 at 5:15pm
Did the EMEA have any firm guarantees? Just being receptive isn't expediting the process, I keep getting told by medical experts to wait, and that "these things take time". I'm thankful you are highlighting this to them!
Comment by Tina on September 30, 2009 at 5:13pm
I am just curious why skipping 45 doesn't come after 51? There are more boys needing 45 vs. 44 and 50. And, it's my understanding the outcome for Beckers is better after skipping 45, Is there a problem with the outcome after a 45 skip that I'm not aware of?
Comment by Ofelia Marin on September 30, 2009 at 10:58am
I agree that we need to see efficacy before we conclude that this treatment might become therapeutic BUT the FDA clinical hold is on safety grounds correct? AVI has safety data from the UK trial at this point. Why doesn't FDA accept that data instead of requesting several more months of work for mouse & primate data? My understanding is that the clinical hold has nothing to do with the efficacy, does it? Please correct me if I am wrong. At this point, I would like to see things progressing here in the US as they are in Europe.
Comment by cheryl cliff on September 30, 2009 at 10:01am
Ok, thanks Pat.

Comment by Pat Furlong on September 30, 2009 at 9:01am
well, i think we have to learn and listen before going to FDA. The thing is that if we all call/write asking for different things, FDA will not be interested. We are working with John Keast (cornerstone) and Dr. Ed Connor (children's national - consults with the exon skipping companies). We have asked them to help us develop a strategy. While we all agree exon skipping is very promising, we have to see efficacy. What we know now is that both chemistries skipped the exon (51) in boys and the shortened dystrophin was expressed. Now we need to learn about the effect of the shortened dystrophin - and how much expression corresponds to how much benefit.
FDA and all regulatory agencies have to respond to something. They will not discuss or make rules on generalities.
So, these first trials and to be honest, the Ataluren/124 trial will help inform how much dystrophin equates with benefit.
Comment by Ana Vaish on September 30, 2009 at 8:54am
Best of luck Pat !!!! Your hard work is paying off.
Comment by cheryl cliff on September 30, 2009 at 8:52am
So, it appears Obama Admin has started the FDA machine. I understood changing administrations had something to do with halting FDA progress for what seemed to be about 6 mos.

What, if anything do you recommend we parents do to help the FDA quicken the pace? Writing letters? Calling advocates to head to DC? Perhaps you will have a better idea after todays meeting.

Comment by Pat Furlong on September 30, 2009 at 8:39am
actually both to be very honest. AVI has new leadership. Steve Shrewsbury is AVI's chief medical officer. FDA is working on changes (very very slow..... government agencies do not move quickly). They will soon release new guidance. And today I am participating in a discussion about accerlerating treatments for rare disease in Washington, DC. It is clearlly on everyone's radar, thankfully.
Comment by cheryl cliff on September 30, 2009 at 8:30am
When you say "they now have new leadership..." were you referring to AVI or FDA?
Comment by Ana Vaish on September 29, 2009 at 10:14pm
That is great news that FDA is finally getting it!!!!

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