I realize that this is a little premature, but since I have a 10 year old who is predicted to benefit from skipping either exon 43 or 45, but not 51, I am more than a little concerned that he'll be on a ventilator and gi tube before completion of clinical trials for a compound that will skip exon 43 or 44. I spent a godawful amount of money on a book on FDA law, and reached the conclusion that the FDA probably has discretion to treat the Prosensa compounds as one drug, even where they are designed to skip different exons, and the would apply to AviBioPharma's compounds. However, there is nothing in the law that would require the FDA to do so. Does anyone know whether these two companies or any of the patient advocacy organizations have begun talking to the FDA about whether they will require separate trials for each compound? I have heard a great deal of rumor and speculation, but I really want to know whether there is any reason to be optimistic, short of going to Congress for a legislative change. If we need a legislative change, then that ball needs to get rolling next year, assuming that the Phase I/II's for ProSensa and AviBioPharma come in as expected in December and are positive.

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Paul and Cheryl,

After going to conference, I have kind of stopped putting my hopes into exon skipping as a treatment right away. There is still plenty of room for error because they have only tested it in small worthless locations of the human body....worthless meaning in the foot where if something goes wrong, no big deal.

Besides, if it is found to be perfectly sound, at the pace they will be testing on specific exons, it would take time before they decide to finally start testing the rest simultaneously. At this time, we know they are testing 51 and next will be 50. After that, w/o having 100% knowledge on the matter, 46 may be the next. Whatever the 3rd one is, how long until they start? I wouldn't know. The thing that sucks is that Dr. Wilton told me at conference that they have a drug that can skip every possible exon. But, they have to wait to test on humans. Once a few exons have been successful, then you (well, we) can start banging on the FDA doors to open up more trials for more exons.

Another thing Wilton is working on is the ability to skip multiple exons. For example, 46 thru 52 (i'm just pulling random exons out of my woo hoo here). Something like this would be of benfit for anyone with a deletion in the 45 to 52 range, single exons and mulitiple exon deletions....I think this would even help those with duplications in this range as well.

So, anyway, my point of not having immediate hope on exon skipping. I think trials for Losartan (already FDA approved), Utrophin (or Biglycan (UTR is already accepted by the human body)), and BBIc (Haelan is a legal suppplement) would be faster.

This cocktail:
1. Would help everyone with DMD, not just a specific percentage.
2. Shouldn't need steroids.
3. Would save the need for approximately 4 exon skipping treatments a year for an individual DMD patient.
4. Would allow research to focus on a cure instead of just a treatment.

That's my take on the matter. What do you think?

Take care,

Christian
Paul,

If interested, here's the presentation that Elizabeth McNeil from the FDA gave at conference:

Click Here

What bother's me is all the review time the FDA needs. They should have FDA members that work side by side with companies so that they know what is going on during the entire process. In the software development world, we call this process "Agile".
Christian,

About the multiexon skipping... my understanding is that Steve has 4 consecutive exons targeted that work well. I quote here: "trying for more but it is hard; more exons you target, the more inefficient."

I agree that there are many things they need to clarify, for example what chemistry to use (PMOs or PPMOs) before a possible exon skipping treatment becomes reality. Even for skipping 51 or 50, it is not clear to me how this will work. Will they wait for both trials to be completed so they can compare the results? How else can they know if PMO or PPMO is better? And let's assume that PPMOs give better results, than what happens to the skipping 51 trial that is using PMOs? Do they have pre-clinical toxicology work completed for other exons using both chemistries? It is not clear at all at this point.

Ofelia
Ofelia Marin said:
And let's assume that PPMOs give better results, than what happens to the skipping 51 trial that is using PMOs? Do they have pre-clinical toxicology work completed for other exons using both chemistries?

If PPMO ends up being better, then it sounds to me that they would have wasted valuable money/time testing PMO.

seems like a corporate tug of war....you got one company (x) with only PMO, so trying to get there first, then another company (y) that has both PMO/PPMO, trying to find the best treatment possible.

I wonder if (y) was forced to jump in early with their version of PMO since (x) was already ahead of the game instead of waiting until (y's) PPMO was ready?

Again, though, I think the cocktail I mentioned is closer to reach and would possibly be better than us hoping for exon skipping. Exon skipping, if proven to work, to me would be a good back-up plan. I may be wrong, but that's not the vibes i got at conference.
I think that AviBioPharma is doing both the PMO, which is currently in clinical trials in the UK [ http://www.clinicaltrials.gov/ct2/show/NCT00159250?term=duchenne+mu... ] and the PPMO compounds. http://www.parentprojectmd.org/site/DocServer/Oligo_and_MDX_Mouse.p...


Lastly, ProSensa's trial, for which I can't easily find details online, is for systemic delivery; I think they did the foot injections and published their results last year. http://www.prosensa.eu/Pdf/NEJM%2027DEC07.pdf Maybe you're right that their early EU approval of their clinical trials caused AviBioPharm to invest in its PMO strategy before its PPMO strategy was available, though I suspect that the problem is that the FDA does not do agile development; they respond [slowly] to New Drug Approval applications from people who have developed compounds. Thus, a company needing to cover its bases submits an application for a drug approval while still improving the drug.

On the other hand, I suspect that there will be a number of medications for a "cocktail," including the ones you mentioned and Idebenonne that will all come on line at about the same time which should have a cumulative protective effect.

MicahsDaddy said:
Ofelia Marin said:
And let's assume that PPMOs give better results, than what happens to the skipping 51 trial that is using PMOs? Do they have pre-clinical toxicology work completed for other exons using both chemistries?

If PPMO ends up being better, then it sounds to me that they would have wasted valuable money/time testing PMO.

seems like a corporate tug of war....you got one company (x) with only PMO, so trying to get there first, then another company (y) that has both PMO/PPMO, trying to find the best treatment possible.

I wonder if (y) was forced to jump in early with their version of PMO since (x) was already ahead of the game instead of waiting until (y's) PPMO was ready?

Again, though, I think the cocktail I mentioned is closer to reach and would possibly be better than us hoping for exon skipping. Exon skipping, if proven to work, to me would be a good back-up plan. I may be wrong, but that's not the vibes i got at conference.
Paul,

These are details about Prosensa's systemic trial:

http://www.prosensa.eu/news/Start%20trial%20Phase%20I%20II.pdf

The exon skipping trials planned and/or in progress are:

AVI exon 51 intra-muscular UK using PMO (in progress)
AVI exon 51 systemic UK using PMO (planned)
AVI exon 51 systemic USA using PMO (planned)
AVI exon 50 USA systemic USA using PPMO (planned)

Prosensa exon 51 systemic EU using 2'O-methyl (in progress)
Ofelia,

Thanks. Were there representatives of either Prosensa or AviBiopharma at the conference?

Ofelia Marin said:
Paul,

These are details about Prosensa's systemic trial:

http://www.prosensa.eu/news/Start%20trial%20Phase%20I%20II.pdf

The exon skipping trials planned and/or in progress are:

AVI exon 51 intra-muscular UK using PMO (in progress)
AVI exon 51 systemic UK using PMO (planned)
AVI exon 51 systemic USA using PMO (planned)
AVI exon 50 USA systemic USA using PPMO (planned)

Prosensa exon 51 systemic EU using 2'O-methyl (in progress)
"Were there representatives of either Prosensa or AviBiopharma at the conference?"

From Prosensa: Gerard Platenburg, Chief executive officer

From AVI: _____________________________?
Cheryl, my understanding is that compounds for several other exons have been worked up and will go into full scale production for clinical trials should exon 51 be everything we think it will. These other few chemistries will probabyly run concurrently, though I've not heard for sure, and should be suficient to argue "platform" status. Someone please correct me if this doesn't seem right.

The good thing for you and me is that exon 45 is one of the chemistries being tested next. Does that mean two years? Five years? Ten years? That much, I don't know.

cheryl cliff said:
PS
And...can we find out how much time is involved in what Steve Wilton referred to as a "few"? Ofelia- will he answer that question for you?

And...if, by chance, a "few" turns out to be a huge amount of time (again, our son just turned 10 and we want to keep him walking) does anyone out there know ways to speed this thing up?

cheryl
Hi All-

Thank goodness you guys are available to keep Paul and I straight on all this very confusing stuff.

Every single step of the testing/trial process is important, ultimately, to most of the boys. Even the trials where it looks like they are injecting a mere foot. It will eventually bring us closer to knowing if exon skipping might be ok for our son and how much more possible waiting there could be.

As we inch along Paul and I are attempting to calculate some (even if wrong) type of time frame for exon skipping to reach our child, realizing there are elements which can not be controlled. Our son, having just turned 10 and still walking, is right on the line between possibly managing the entire wait and not making it. It is in his best interest to attempt to gauge what that could possibly mean. If it turns out wrong...at least we tried. If one type of exon skipping is better than the other it doesn't matter much to us. Even if the not-as-good exon skipping becomes available in the UK it might be best to get treatments there while waiting for the FDA to process here and work to speed that process up here if we can.

If by chance you guys come across any "time" estimates, have any best guesses, or become proficient at reading tea leaves please don't hesitate to offer it up.

We appreciate your help,
cheryl
here's some not so good numbers for calculations...i apologize in advance:

1. Each exon skipping treatment without insurance will cost $250,000
2. They estimate treatments being needed quarterly.
3. Cost of flights to the UK 4 times a year.

ok, better news:

1. When they get to the exon you need, it will most likely be available here in the US as well.

So, what to do? As I said previously, the cocktail is closer than exon skipping and I honestly feel that our focus and stress should be on that.

Reason I say this is because I want someone who has a deletion that includes either the very 1st exon or the very last exon to be saved (exon skipping wont help them) as much as i want my own son to be saved. That said, my son needs exon 46 skipped, which is right there with regards to one of the first few that they will test against. But, if the cocktail was ready before hand, then none of us would need skipping.
Hi Christian-

My understanding (limited as it might be) is that one cocktail that fits all isn't as efficient a medication as say, something customized to fit each child's needs, regarding exon skipping. Boutique medicine, I have heard this called. Despite the awful trend name - this personalized treatment method is what I have been hearing about, which would encompass all boys who qualify for exon skipping.

I don't worry about the cost (yet) for each treatment since I don't see that particular number sticking permanently. Quarter of a mil is a lot but I don't let big numbers frighten me too badly. Frankly, I'd sell everything I own to let him have a simple weekend with no DMD. In the UK the medical system is socalized so they wouldn't be billing insurance companies in the US - those traveling abroad for treatments will have to find the means to get into the system. The cost for flights- thats what air miles are for.

cheryl

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