Do Exon Skipping Compunds Fall Under the Orphan Drug Law?

To begin, I am very new at this - our son, Gus, was diagnosed about two weeks ago. I'm sure you're all familiar with the desperate attempts to find info after diagnosis - we're no different, and now I have a big question.

At this point, I know that they have created exon skipping AON's for all 79 exons in the lab (

I've also found a table online that explains which exons need to be skipped to treat Gus' specific deletions, as well as many others. (It's here

Finally, I have read the results of the exon 51 skipping trials and it appears that they have developed vehicles to deliver those compouds - both IV and, with Ataluren, in oral form.

So, it seems like all the pieces are in place for a really customized approach to the almost infinite number of possible deletions/duplications/mutations, especially once the 51 trials are complete. But my question is whether or not the FDA is going to treat MD as a singular disease of if it will acknowledge the unique nature of each case. If Exon skipping compounds do not fall under the Orphan Drug Law, it will be years and years to complete trials for each one (and most couldn't be done because there aren't enough cases of any given mutation).

I did see an earlier discussion thread that talked about this and ended up reading an interview of Tim Cote (, but that seems inconclusive.

Should I start writing letters to Congress?

Thanks everyone for any info - this community seems to be so strong. We'll need it.


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When people become parents they suddenly realize how vulnerable they are because they would throw themselves in front of an oncoming train to save their baby. I wouldn't worry about insurance not covering stuff Ofelia...thats why the world has attornies :D And, at this point the costs for exon skipping aren't realistic, more like some numbers on a page not to be frightened by. Didn't GSK already say they expect exon skipping for DMD to open more skipping therapies for other diseases? Isn't that where their profit lies?

Steve, you may want to check the current status of advocacy PPMD has been working on because they've been at it awhile and are making good progress. Better progress than any other organization out there. PPMD would be happy to tell you the history and where we are today. Still work to be done so I'm happy you can attend the conference this year.

Steve Dreher said:
So, to be quite honest, the uncertainty of how this would ever work in our current drug model is one of those haunting fears that keeps me up nights. Correct me if I am wrong, but the current trial on exon 51 is because the 15% of boys that can be helped from that is by far the highest percentage of any mutation (and that in a rare disease). The only way I could see this working is if a company developed a menu of all the compounds and was able to use them to address individual mutations. These can't be considered drugs in the conventional sense because each child presents a different need.

I go back to my original question, what advocacy is being done currently, and what groundwork can we lay to help the process move forward once the 51 trial is complete? It doesn't feel right to just wait and see.

Keith, you're probably right that going to Europe to get expensive treatments is not a realistic option...I was thinking of it as a band-aid until the FDA approved the therapies. Isn't it outrageous, though, that we are having this discussion in the allegedly most medically advanced country in the world?

Ofelia, I am not terribly concerned about insurance covering a proven therapy - they really would have little choice. My wife Tonya recently completed a pretty customized 18 month treatment for breast cancer, and it was covered - I don't even want to think about how much it cost. The challenge, I think, is twofold. First, proving the therapy (which I hope they are doing) and then advocating in such a way to make it clear that it is a moral imperative that we treat all the boys that we can regardless how rare their mutations are.

The thing that scares me is wondering how this can happen quickly enough that the individuals we are talking about (our sons) will benefit, and all of this doesn't take another 20 years to fall into place.

Ofelia Marin said:
I'm not sure about moving to EU either. I assume it might be possible to buy it from there (Prosensa's requires sub-cut injections) if you have a prescription from a neuro from here and there(?). Of course, the high price needs to be paid unless you are citizens of one of those countries where a high % of the price is paid by state (?).

I do however have a related question. If this becomes an FDA approved therapy, what are the chances that insurance covers something as expensive? Keep in mind that, hopefully, at some point in the future, more drugs can be approved for DMD and a cocktail of drugs can be the solution for slowing the disease progression. Will the insurance cover 100K+/year?

Keith Van Houten said:
Couple folks mentioning in this thread their willingness to get an exon skipping therapy overseas if need be.

A tidbit I picked up in the web conference with a Leiden researcher last month that I hadn't heard before you may be interested in...

If exon skipping ever became a therapy - which is still a significant "if" at this point - the work done thus far has shown that the effect only lasts about 3 months. You'd need repeated treatments for a lifetime.

So, if it's not FDA approved, you're talking about scenarios like frequent travel, or permanent relocation, until and if it becomes available in an oral form. You're also probably talking about paying for it yourself. The cost for this is going to be astronomical. I've read estimates of over $100k a year. For life. Keep in mind that GSK just agreed to pay $650 million if this work results in a therapy for only 4 exons. It's going to be very expensive in order to recoup that. If you travel to get a non-FDA approved therapy, your insurance in the US is not going to cover it - right? If you emigrate to a Western European country with socialized health care - are they allow an immigrant family to enter with a catastrophic illness, and cover the cost? I haven't researched it, but I'd doubt it. If so, why wouldn't every critically ill person with no insurance just move?

So - why do I bring this up?

First off, I've put a lot of thought into this subject of potentially moving overseas myself, and I wanted to see if anybody can pick any holes in my thought process.

Second, quick FDA approval is critical. Once and if it's been established through the trials that exon skipping is a viable therapy - which again, it has not been proven, a fact no one should lose sight of - the laser-like focus of advocacy should be to gain FDA approval as quickly as possible. For the reasons I cited above, I don't think that getting this therapy in another country is a viable alternative for most of us. We need it approved for use in the US. FDA approval means not only that it's available here, but that this very expensive potential therapy could potentially be covered by insurance.

"Keep in mind also that not all mutations are even potentials for exon skipping - mutations in the regions near the beginning and end of the gene cannot be skipped, and it's a question as to what the effectiveness of skipping will be for all exons."

Hey, Keith, do you have an article or the science on this? I hadn't heard that, and want to read any info I can get my hands on.

Keith Van Houten said:
As far as advocacy with FDA, I know that PPMD has an ongoing relationship with FDA. Tim Cote spoke at the the Advocacy Conference two years ago. I agree that the relationship needs to be nurtured, and FDA needs to know that there's a large group of people standing behind the effort, ready to make a lot of noise if the program doesn't move at the pace it deserves. I thought that Mr. Cote was very sincere, and he certainly seemed like he would be an ally.

I think GSK's involvement is going to help with the approval also. Big pharma is awfully connected, and they work the system on a daily basis. I believe GSK doesn't pony up the money until after a treatment is approved, but I'd assume they want it approved as soon as possible, since they think they can make money on it.

I believe that the insurance coverage of any therapy that's developed is an important issue to us as the development of the treatment itself. How cruel a world would it be if a treatment is found, but few can afford it?

These are the kinds of things that keep me up at night, especially as they relate to the health care reform debate happening in Congress. It's obviously a controversial subject, but I hope that if nothing else, we wind up eliminating the consideration of pre-existing conditions, and the elimination of lifetime maximums. Some insurers already have lifetime maximums, and as costs continue to escalate, I expect them to become more and more common. MD families could run into this, even if exon skipping never becomes a reality.

To address Steve's point about the development of therapies beyond the first 4 exons. I asked specifically about that in the web conference. It totally depends on the degree of clinical trials that are required, but the business case beyond those 4 starts to deteriorate quickly, because the rate of occurrence drops off so rapidly. That's going to substantially impact a private company's interest in funding it. We talked about options like advocacy groups funding development and trials beyond the first 4. Again, though, it totally depends on the clinical trial requirements for additional exons. If limited trials are required, it increases the likelihood that we'd get more exons covered. Keep in mind also that not all mutations are even potentials for exon skipping - mutations in the regions near the beginning and end of the gene cannot be skipped, and it's a question as to what the effectiveness of skipping will be for all exons. We already know that not all in-frame deletions produce BMD. So, even in a best case scenario, this won't work for everyone. Oh - and while it'd be a terrific therapy and welcomed by all, it's not a cure for anyone, so the fight isn't over...
Right Keith, the fight isn't anywhere near over. I do believe we are on the right path and at a good time with regard to science and previous advocacy putting PPMD and Pat specifically, in a good place. I don't really expect one therapy/medicine will fit all boys. Duchenne has too many layers therefore it will require many types of therapies/medicine/treatments to become available in order to completely wipe this disease off the face of the earth for each and every child. But we already have positive outcomes with PTC124. And, I expect 2010 will be a good year in determining (determining is aka getting information good and bad and yes folks its good to have even the bad data) the outcome of exon skipping for 51, what conclusions can currently be drawn about idebenone/dmd, and see the beginnng of utrophin upregulation, releasing the new "standards for care", and probably other stuff. Some of which might not turn out so good.

I don't want to sound like Polly-ana here but if you look at the history of DMD, PPMD and compare it to where we are with Duchenne today one can see tremendous progress recently in making our boys live, live longer, live better. This recent prgress is more than duchenne families have seen before. Does that say our work is over? is an indication that we are going in the right direction and need to keep working, no matter what happens, until its done.

I don't have the presentation in electronic format, and unfortunately, the recording that was planned didn't work. The presentation and discussion were really informative. Parent Project Australia put it on.

The part about the ends of the gene not being potentials for skipping was something I was specifically interested in and asked a couple of questions about. My son has an exon 5 deletion. The researcher likened the dystrophin gene to a chain connecting a boat with an anchor. She said that the parts of the "chain" near the boat and the anchor are critical. I asked how large that region was, and she said the first and last 10 exons were particularly important - especially the last 10. You can see a screenshot of the presentation on this webpage, it shows the anchor, chain and boat analogy.

You might also look through the documents on her webpage, which is here. I suspect the same information is included on one or more of them. I haven't gone through the whole site yet.

This is also a really comprehensive, yet understandable, recent paper on exon skipping from TREAT NMD.
Ont thing I forgot to mention is that Prosensa/GSK's Phase III PRO-051 trial will be both in the US and EU. If the results are as good as it is hoped, it is very likely to be approved around the same time here and in the EU. As soon as the first exon is approved or close to approval we need to increase the FDA pressure about the "platform" drug. I know that CINRG in DC hired Ed Connor who has some experience in related approvals. It looks like the focus, at the moment, is to launch the first exon skipping trials in the US correctly.

AVI's exon skipping trials are indeed more advanced in EU and probably obtain approval sooner than in the US.

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