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 (http://www.treat-nmd.eu/userfiles/file/general/Exon%20Skipping%20Re...).

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 http://www.humgen.nl/lab-aartsma-rus/Table%20deletions.pdf).

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 (http://www.parentprojectmd.org/site/DocServer/Interview_with_Cote.p...), 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.

Steve

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Hi Steve,

So sorry you had to find your way to PPMD, we are glad you are here, but it is heartbreaking knowing another child/family suffers this disease. Our sons diagnosis is only 2 years ago.

You've found out a lot in a couple of weeks. As far as writing letters to Congress...you would be better serving your son and all the others if you consider going to the PPMD Advocacy Conference which takes place every winter. Dates and information can be obtained at this website or you can call the 800# at PPMD. Also, you can contact Pat (again at this website) directly to find out the current status of her relationship with the FDA because she has been working on them awhile now. That said, we parents have had many discussions here and made jokes about getting out the pitchfork and going medieval on DC and are on the edge right beside you. At this point in time the FDA is undecided regarding exon skipping and needs to get up to speed with research. If that doesn't take place and FDA should drag it's federal feet with exon skipping or any other viable upcoming treatment for DMD I won't hesitate to find treatment in another (westernized medicine of course) country if thats what it takes. We've already looked into that strategy as plan B, will use it if necessary. It may be something you and your family might want to consider too.

Try to breathe deeply, our sons are at a scientific crossroad regarding efforts to kill Duchenne. I have to believe something will work soon enough, it's what keeps me going.
best
cheryl
Hi Steve,

Please see below:

AVI BioPharma, Inc. (Nasdaq:AVII), announced that the U.S. Food and Drug Administration's (FDA) Office of Orphan Products Development has granted orphan drug designation to AVI-4658 for the treatment of Duchenne muscular dystrophy (DMD). AVI-4658 uses AVI's ESPRIT technology (Exon Skipping Pre-RNA Interference Technology) and is designed to benefit patients with certain mutations in the dystrophin gene. By "skipping" exon 51, the proper RNA reading frame can be restored in suitable patients, resulting in the production of functional dystrophin.

AVI is planning clinical development of AVI-4658 including a dose-ranging trial using systemic administration of the drug. This trial will be conducted in conjunction with the company's DMD cross-licensing and development partner, Ercole Biotech, Inc.

"The orphan drug designation for AVI-4658 is a significant step in AVI's development of this drug candidate," said K. Michael Forrest, interim CEO of AVI.

About Orphan Drug Designation

The Orphan Drug Act (ODA) provides economic incentives to encourage biotechnology and pharmaceutical companies to develop drugs for rare diseases, those affecting fewer than 200,000 people in the United States. Orphan drug designation entitles AVI to seven years of market exclusivity for AVI-4658 for the treatment of patients with DMD. Additional incentives for orphan drug development include tax credits related to development expenses, reduction in FDA user fees and FDA assistance in clinical trial design.
Hi Lisa
Orphan Drug Status is great for those who will benefit from skipping exon 51. Not sure yet if that translates to other exons yet though. Have you heard anything about the other exons Lisa? Sometimes I miss things newly released...

lisa burke said:
Hi Steve,

Please see below:

AVI BioPharma, Inc. (Nasdaq:AVII), announced that the U.S. Food and Drug Administration's (FDA) Office of Orphan Products Development has granted orphan drug designation to AVI-4658 for the treatment of Duchenne muscular dystrophy (DMD). AVI-4658 uses AVI's ESPRIT technology (Exon Skipping Pre-RNA Interference Technology) and is designed to benefit patients with certain mutations in the dystrophin gene. By "skipping" exon 51, the proper RNA reading frame can be restored in suitable patients, resulting in the production of functional dystrophin.

AVI is planning clinical development of AVI-4658 including a dose-ranging trial using systemic administration of the drug. This trial will be conducted in conjunction with the company's DMD cross-licensing and development partner, Ercole Biotech, Inc.

"The orphan drug designation for AVI-4658 is a significant step in AVI's development of this drug candidate," said K. Michael Forrest, interim CEO of AVI.

About Orphan Drug Designation

The Orphan Drug Act (ODA) provides economic incentives to encourage biotechnology and pharmaceutical companies to develop drugs for rare diseases, those affecting fewer than 200,000 people in the United States. Orphan drug designation entitles AVI to seven years of market exclusivity for AVI-4658 for the treatment of patients with DMD. Additional incentives for orphan drug development include tax credits related to development expenses, reduction in FDA user fees and FDA assistance in clinical trial design.
From my understanding, and this is in Europe, drug regulation is expected ( but not confirmed yet) for all exon skipping drugs once the first have been proven to be effective. Certainly from conversations I've had here with various geneticists, the full trial process is not expected to be needed for the exon-skip drugs subsequent to patch 51. I'm not sure how the FDA works in the US though.
Steve - if you're at all the letter writing to Congress type, you need to come to DC with us in February. It's time very well spent. Friend me if you'd like, I'll tell you all about what's involved.

Just to correct one thing you said - Ataluren is a drug that being worked with to "read through" stop codons, it's not an exon skipping drug.

As to what level of trials will be required beyond exon 51 skipping drugs - no one knows. The results of the first trials will likely play into it. Most people seem to expect that the European agency will require less than the US - but again, no one knows this at this point.
First of all, thanks everyone for your responses. It depends on the day, or maybe the hour of any given day, but we want to believe that there are reasons for real optimism. At the same time, while I get the 'live in the moment, you only have now' philosophy, we suddenly feel very hemmed in by the next few years and even panicky at times at how quickly Gus' muscles will deteriorate...I'm sure you all have been there.

Based on the responses, I have a question. First, Cheryl and Lisa, we would get to Europe if that's what it takes - but what about Canada? I know that deflazacort has been approved there - and, having grown up about a mile from the border, I am very accustomed to crossing the border for pharmaceuticals.


Keith, we are already planning how we'll get to DC in February...in the meantime, I'll write a few letters to warm up.

Thanks again everyone. Looking at the responses this morning definitely made me feel like we WILL make this happen. It's nice to have some optimistic time.

Steve
Keith Van Houten said:
Steve - if you're at all the letter writing to Congress type, you need to come to DC with us in February. It's time very well spent. Friend me if you'd like, I'll tell you all about what's involved.

Just to correct one thing you said - Ataluren is a drug that being worked with to "read through" stop codons, it's not an exon skipping drug.

As to what level of trials will be required beyond exon 51 skipping drugs - no one knows. The results of the first trials will likely play into it. Most people seem to expect that the European agency will require less than the US - but again, no one knows this at this point.
Going to Canada would be much easier than traveling to anyEuropean country, I wouldn't hesitate. Deflazacort is widely used here in USA, can be obtained through www.mastersmarketing.com. They mail the stuff to you directly. So for those of us who can't cross the border easily, Masters Marketing works. Also, you might want to find out more about using Idebenone, I believe some boys in Canada are already on it and seeing benefits. Santhera Pharma is finalizing their III phase clinical trial for FDA approval on DMD boys. Glad you are able to attend the Advocacy Conference, my husband Paul Cliff will be there. Sounds like your family is doing great Steve!! Keep up the good work!

Steve Dreher said:
First of all, thanks everyone for your responses. It depends on the day, or maybe the hour of any given day, but we want to believe that there are reasons for real optimism. At the same time, while I get the 'live in the moment, you only have now' philosophy, we suddenly feel very hemmed in by the next few years and even panicky at times at how quickly Gus' muscles will deteriorate...I'm sure you all have been there.

Based on the responses, I have a question. First, Cheryl and Lisa, we would get to Europe if that's what it takes - but what about Canada? I know that deflazacort has been approved there - and, having grown up about a mile from the border, I am very accustomed to crossing the border for pharmaceuticals.


Keith, we are already planning how we'll get to DC in February...in the meantime, I'll write a few letters to warm up.

Thanks again everyone. Looking at the responses this morning definitely made me feel like we WILL make this happen. It's nice to have some optimistic time.

Steve
Keith Van Houten said:
Steve - if you're at all the letter writing to Congress type, you need to come to DC with us in February. It's time very well spent. Friend me if you'd like, I'll tell you all about what's involved.

Just to correct one thing you said - Ataluren is a drug that being worked with to "read through" stop codons, it's not an exon skipping drug.

As to what level of trials will be required beyond exon 51 skipping drugs - no one knows. The results of the first trials will likely play into it. Most people seem to expect that the European agency will require less than the US - but again, no one knows this at this point.
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.

Thoughts?
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.

Thoughts?
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.

Thoughts?
Hi Keith,

We realize obtaining medical services in another country wouldn't be simple. Some of us can't wait but just a little while. Should FDA decide to take a few more years and mull over exon skipping or anything else on the menu we'd be forced to seek care outside the US. This is not the option we hope and advocate for (hence the pitchfork jokes started by my husband). We have formulated a plan that addresses the issues you've brought up and understand anything could end the plan along the way. Still, no matter the convenience or cost, we would do what ever it takes. I won't discuss how we plan to get around some of the issues you identify and god forbid we should even have to go try it, but we would happily supply information should the occasion arise.

I really don't expect the FDA to linger (if they linger at all) too much longer than the rest of the world with providing services and treatments, when they are available, to all our sons. Pat has been working on them for awhile. Exon skipping is just one avenue but so far it appears to be working better than anything else currently available. You are so correct in saying quick FDA approval is critical. And, although getting therapy in another country couldn't possibly be for everybody perhaps if our "plan", such that it is, appears to work, it could open a door for at least some other families. Saving even a small amount of boys is better than watching them die while waiting for FDA to get up to speed with current research.

Somebody's gotta break outa this prison alive!!

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.

Thoughts?
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...

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