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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Ofelia Marin said:
The only things I found about the brain were that the incidence of learning disabilities etc. is higher if exons after 55 are missing, when dp116 is not produced. Have you found any papers about the 45-52 range and autism and mental retardation?

Here are some links:

http://snps3d.org/search/?q=Dp140+consists&limitShow=20

http://www.ncbi.nlm.nih.gov/pubmed/9800909?dopt=Abstract

Mental Retardation (has autism as a form, though it may be reclassified): http://en.wikipedia.org/wiki/Mental_retardation

There is one other abstract that i know of, but i can't find it...argh!
who cares what my concerns are...this is why they are the researchers:

http://www.treat-nmd.eu/userfiles/file/general/2008%20Prosensa%20In...

Guenter:
The next exons to be skipped. All the boys who take part in this systemic trial need skipping of exon 51. Which exons will be the next whose skipping you will develop?

Gerard Platenburg (Prosensa (company x))
We have two antisense molecules in development for skipping exons 51 and 44. As long as we can financially do it, we will develop them up to the concept stage, that one sees benefit. And then we have also identified AONs for skipping other exons that need to be developed in addition to the two. On this initial list are the exons 43, 45, 46, 50, 52 and 53. We already have made the AONs for each of them.

Ya think company x is trying to get there first with PMOs? hey, doesn't bother me...someone has to be first. besides, there's meds out there to help the heart until PPMOs would be ready.

So, there's a race...exon skipping vs. pill cocktail....at least it's something. 5 years ago, only steroids....today, only steroids....and all the other stuff you gotta take to counter against the pitfalls of steroids.
not sure what to make out of this:

The price of the AONs.

Do you know anything about the cost? You will need kilograms of the AONs in pure form. For instance, how much will one injection cost, or a treatment for one month or one year?


The price depends on many factors: on the way you introduce the products, on how much money we have invested, and on many more things. It would hard for me to give figures. But it will not really be a cheap treatment. You have to be realistic. I mean, we are investing a lot, but if the benefit is there, a high price will be worth it.

But as far as I understand, our health insurance system in Germany, if a treatment is proven to be effective and has been approved, the insurances have to pay, even if it is very, very expensive.

It is the same in many other countries, too, also in the Netherlands.
Christian,

I don't think it's a race. I think our sons are going to be needing both strategies, and I think that the biotech business has awakened to the idea that there are money in our hills. While I share your concerns about cost, when you listen to Leslie Hudson's 9.10.08 presentation at the links to Avi's site that Ofelia posted it's pretty apparent that Avi Bio Pharma is literally betting its publicly traded, for profit existence on exon skipping. It's difficult to picture some executive who doesn't want to spend the next decade hanging around lawyers (the horror!!) making that bet on a drug family that he knows will never be bought by anyone. In Scheuerbrandt's interview with Dr. Platenburg, it's interesting how Dr. Platenburg seems very sanguine about getting FDA approval of multiple exon skipping compounds based only upon the clinical data of two.

MicahsDaddy said:
who cares what my concerns are...this is why they are the researchers:

http://www.treat-nmd.eu/userfiles/file/general/2008%20Prosensa%20In...

Guenter:
The next exons to be skipped. All the boys who take part in this systemic trial need skipping of exon 51. Which exons will be the next whose skipping you will develop?

Gerard Platenburg (Prosensa (company x))
We have two antisense molecules in development for skipping exons 51 and 44. As long as we can financially do it, we will develop them up to the concept stage, that one sees benefit. And then we have also identified AONs for skipping other exons that need to be developed in addition to the two. On this initial list are the exons 43, 45, 46, 50, 52 and 53. We already have made the AONs for each of them.

Ya think company x is trying to get there first with PMOs? hey, doesn't bother me...someone has to be first. besides, there's meds out there to help the heart until PPMOs would be ready.

So, there's a race...exon skipping vs. pill cocktail....at least it's something. 5 years ago, only steroids....today, only steroids....and all the other stuff you gotta take to counter against the pitfalls of steroids.
"Christian,

I don't think it's a race.
"

Paul,

no, to me it is a race. i don't care which one is ready first...exon skipping or pill cocktail...does not matter...which ever one comes first, that's the one i use...that one wins...so does my boy.
Christian,

I suspect that your son, like mine, is going to need a number of drugs. Your body stops making utrophin for a reason, and we're all about to find out why. Maybe it's not a big deal, but maybe it is. Exon-skipping is not going to be 100% efficient and will never do more than make a DMD boy able to grow up to be a Becker's man. I'm sure it's news to the Becker's patients that Becker's is a picnic. The one man whom I know casually who has it had scoliosis surgery in his late teens, has struggled with a number of health problems since then and is now confined to a wheelchair. Yes, he's a alive in his 40's, but this first generation of treatments is not going to do anything more than buy us time.

On the other hand, if you (meaning evey parent with a deletion mutation shown on slide 6 of Dr. Hudson's second presentation) sit through Leslie Hudson's second presentation you'll see that they're expecting that if the intravenous test that they are starting now works well, they could be in the market in Europe by 2010. They plan to charge $100,000/year for the medication on the grounds that it will save the $500,000 in treatment costs that a non-ambulatory DMD patient imposes on his insurance company (if he has one, I doubt that many do after age 18) Medi-Care, Medi-Caid, and the various European health ministries. In my business, we call this value pricing.

He argues that because of the huge size of this revenue stream (he estimates $1.7BILLION each year for those mutations amenable to Avi's six exon skipping compounds) and because Genzyme paid $100MM up front to PTC for the exclusive rights to license PTC 124, a drug that only treats about 18% of our boys, his company with a medication family designed to treat 50% of DMD boys can surely expect a similarly sized capital infusion, and with that they will be well enough funded to pursue US approval of all six exon skipping compounds simultaneously if they have to.
I think , that only PCT 124 would bring big yearly revenue for investors and for company. PCT124 will treat not only DMD/BMD but about 180 (or 1800?) diseases where nonsense mutations are involved.
Someone posted this on another website. Very interesting article.
Here is a link to Karl Bettelheim's latest blog:

http://www.actionduchenne.org/blog/265/99/Recent-Publications-deali...

It discusses the problems that exist in taking discoveries from the lab to the patient.
----------------------------------------
good point.

Bozena Sporna said:
I think , that only PCT 124 would bring big yearly revenue for investors and for company. PCT124 will treat not only DMD/BMD but about 180 (or 1800?) diseases where nonsense mutations are involved.
"Exon-skipping is not going to be 100% efficient and will never do more than make a DMD boy able to grow up to be a Becker's man......but this first generation of treatments is not going to do anything more than buy us time."

This is sooooooooo true. A while back, 8-12 months ago, i did some investigation on Beckers and the progression of it. On record, there have been patients who seen their 80th birthday. On the flip side, there are cases that fail to make it to 25....the progression can be identical to DMD.

That said, with exon skipping, who's to say which end of the statistics our children end up on. At the minimum, exon skipping gives the chance that our children will get a slow progressing form of BMD.

I met a gentleman in Oregon back in June who has BMD. He is 29 and confined to a wheelchair full time since he was 21. He can't lift his arms to eat, but he had no problem drinking champagne through a straw with his Sunday brunch. ;-)

Your body stops making utrophin for a reason, and we're all about to find out why.

Is this completely true? I know it is sort of true for you and myself, though we still do have UTRN in our bodies…I believe in smooth muscle. But what about in our boys? If they have 0% dystrophin, then they should still have a lot of UTRN in their systems since there is not any dystrophin to take it over.

http://en.wikipedia.org/wiki/Utrophin

“Utrophin expression is dramatically increased in patients with Duchenne's muscular dystrophy (and female carriers), both in those muscle fibers lacking dystrophin and in rare, revertant fibers that express dystrophin.”

With what is available today, I think a good place to start with our boys is to preserve muscle how ever as a parent we feel possible and do what we can to protect the lungs and heart. If nothing comes in time to keep our children walking, at least we know we have kept close tabs on the function of their lungs and hearts.
Hi Christian,

I understand your position about exon skipping and appreciate your input. Paul and I make sure to always find your posts because not only have you been at this longer than we have but you do have loads of really great information. Yes, turning a DMD kid into a BMD patient isn't ideal. Exon skipping will just buy some time and nobody knows how much that will amount to since each child has different elements evident in their individual mutations. For our son, already 10, with treatments of exon skipping until something better comes along, we are at least hoping a little we might have a chance to preserve his ability to walk. My understanding, such as it is, is that walking itself helps preserve heart, lungs, soft muscle...I realize there are treatments and medications for conditions related to body organs but we are right on the edge with Alexander's walking and the onset of exon skipping. Or so we thought.

When Paul started this post he and I had taken the summer "off" reading this website in order to "press the reset button" with our boys. Stuff here can be stressful and we felt the kids needed a fun summer. When we returned, expecting not much to have changed, it appears we got behind because I thought Prosensa was still in the exon skipping business and am told they are going out(?). And, this announcement with AVI is great except it puts us behind at least another year (or more) from where we estimated to be with exon skipping (based on previous info).

We also continue hoping and working for treatment choices beyond exon skipping. Upregulation of Utrophin is clearly a very important for an option. If by chance upregulation and exon skipping become available at the same time then comparing pros and cons of each would be magnified before starting either.

cheryl

MicahsDaddy said:
"Exon-skipping is not going to be 100% efficient and will never do more than make a DMD boy able to grow up to be a Becker's man......but this first generation of treatments is not going to do anything more than buy us time."

This is sooooooooo true. A while back, 8-12 months ago, i did some investigation on Beckers and the progression of it. On record, there have been patients who seen their 80th birthday. On the flip side, there are cases that fail to make it to 25....the progression can be identical to DMD.

That said, with exon skipping, who's to say which end of the statistics our children end up on. At the minimum, exon skipping gives the chance that our children will get a slow progressing form of BMD.

I met a gentleman in Oregon back in June who has BMD. He is 29 and confined to a wheelchair full time since he was 21. He can't lift his arms to eat, but he had no problem drinking champagne through a straw with his Sunday brunch. ;-)

Your body stops making utrophin for a reason, and we're all about to find out why.

Is this completely true? I know it is sort of true for you and myself, though we still do have UTRN in our bodies…I believe in smooth muscle. But what about in our boys? If they have 0% dystrophin, then they should still have a lot of UTRN in their systems since there is not any dystrophin to take it over.

http://en.wikipedia.org/wiki/Utrophin

“Utrophin expression is dramatically increased in patients with Duchenne's muscular dystrophy (and female carriers), both in those muscle fibers lacking dystrophin and in rare, revertant fibers that express dystrophin.”

With what is available today, I think a good place to start with our boys is to preserve muscle how ever as a parent we feel possible and do what we can to protect the lungs and heart. If nothing comes in time to keep our children walking, at least we know we have kept close tabs on the function of their lungs and hearts.

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