FDA Approval of Exon Skipping
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.
Replies to This Discussion
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Permalink Reply by Ofelia Marin on
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Hopefully they will start a clinical trial with one of these PPMOs soon...it looks better than the PMO used in the UK trials.
http://www.mda.org/research/080915dmd-exon-skipping.html
Does anyone know what the plan is? Will the USA systemic trial skipping 50 be the first one using a PPMO? That one seems to take a while until it begins (end of 2009?).
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Permalink Reply by MicahsDaddy on
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Hi Cheryl,
Please don't take me wrong. I am not trying to be controversial or prove a point...nor do I think I know everything…though I’m sure many feel that I think I do. I don’t. Everything I write is how I understand it and is definitely wrong more so than right.
When I post, I am hoping someone can clarify what my thoughts are. Or, at the least, get all of us thinking. If one person writes what they believe is right and no one responds, then we will all head down the wrong path of thinking.
For example, I used to think that an intron, say 45, came before an exon, in this case exon 45. Because of forums like this, I was informed that no, intron 45 follows exon 45…and the same goes throughout genes. This is a case where I am glad we have these forums because I learned that I was wrong and what is correct. Because of parents and biologists from PPMD sites and other sites, I have been able to get a better understanding of things. Key word being “better” not “all”.
So, basically, all I am doing when I see a post that is different to my thoughts, I put up my understanding…err, 2 cents…and hope that someone (a third party) responds in agreement of one or the other, or, even a completely different thought to get me thinking even more.
All of us can read the exact same document on something (for example, how exon skipping works) and all of us, except the professionals, will interpret it differently. That’s why we are here, right? To help each other better understand and/or maybe even think outside of our own thoughts. That’s all I am doing and all I want in return.
I apologize if I was taken differently, that was not my intention.
BTW, where did you hear this news about Prosensa? This would be devastating if true.
Thanks and take care,
Christian
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Permalink Reply by cheryl cliff on
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Hey Christian,
How'd you get those smiley faces to drink beer?
I completely understand everything you just said and am glad you are around! I think Paul mentioned something recently about Prosensa, althought I don't know where he got that information or if it was just his own conclusion. I'll hafta ask...
cheers,
cheryl
MicahsDaddy said:Hi Cheryl,
Please don't take me wrong. I am not trying to be controversial or prove a point...nor do I think I know everything…though I’m sure many feel that I think I do. I don’t. Everything I write is how I understand it and is definitely wrong more so than right.
When I post, I am hoping someone can clarify what my thoughts are. Or, at the least, get all of us thinking. If one person writes what they believe is right and no one responds, then we will all head down the wrong path of thinking.
For example, I used to think that an intron, say 45, came before an exon, in this case exon 45. Because of forums like this, I was informed that no, intron 45 follows exon 45…and the same goes throughout genes. This is a case where I am glad we have these forums because I learned that I was wrong and what is correct. Because of parents and biologists from PPMD sites and other sites, I have been able to get a better understanding of things. Key word being “better” not “all”.
So, basically, all I am doing when I see a post that is different to my thoughts, I put up my understanding…err, 2 cents…and hope that someone (a third party) responds in agreement of one or the other, or, even a completely different thought to get me thinking even more.
All of us can read the exact same document on something (for example, how exon skipping works) and all of us, except the professionals, will interpret it differently. That’s why we are here, right? To help each other better understand and/or maybe even think outside of our own thoughts. That’s all I am doing and all I want in return.
I apologize if I was taken differently, that was not my intention.
BTW, where did you hear this news about Prosensa? This would be devastating if true.
Thanks and take care,
Christian
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"How'd you get those smiley faces to drink beer?"
here you go:
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Permalink Reply by Polly Sundeen on
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Hey - how'd you find a smiley that looks like my husband? LOL
MicahsDaddy said:"How'd you get those smiley faces to drink beer?"
here you go:
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Permalink Reply by Paul Cliff on
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Something got a little lost in translation. I've been going nuts looking for it, but I could swear that I read in one of Scheuerbrandt's interview with Platenburg that Prosensa did not have enough dough to take its exon skipping compounds to market, and would need a partner. I'm sure that's the case for all of these little start ups. Nothing devastating; just biotech business as usual.
MicahsDaddy said:Hi Cheryl,
Please don't take me wrong. I am not trying to be controversial or prove a point...nor do I think I know everything…though I’m sure many feel that I think I do. I don’t. Everything I write is how I understand it and is definitely wrong more so than right.
When I post, I am hoping someone can clarify what my thoughts are. Or, at the least, get all of us thinking. If one person writes what they believe is right and no one responds, then we will all head down the wrong path of thinking.
For example, I used to think that an intron, say 45, came before an exon, in this case exon 45. Because of forums like this, I was informed that no, intron 45 follows exon 45…and the same goes throughout genes. This is a case where I am glad we have these forums because I learned that I was wrong and what is correct. Because of parents and biologists from PPMD sites and other sites, I have been able to get a better understanding of things. Key word being “better” not “all”.
So, basically, all I am doing when I see a post that is different to my thoughts, I put up my understanding…err, 2 cents…and hope that someone (a third party) responds in agreement of one or the other, or, even a completely different thought to get me thinking even more.
All of us can read the exact same document on something (for example, how exon skipping works) and all of us, except the professionals, will interpret it differently. That’s why we are here, right? To help each other better understand and/or maybe even think outside of our own thoughts. That’s all I am doing and all I want in return.
I apologize if I was taken differently, that was not my intention.
BTW, where did you hear this news about Prosensa? This would be devastating if true.
Thanks and take care,
Christian
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http://www.treat-nmd.eu/userfiles/file/general/2008%20Prosensa%20In...
Christian saw the same quote I did earlier in this thread: "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." I interpreted that as they were going to be out of money after proving up the compound for skipping exons 51 and 44. Now that I read it, it's not exactly clear what he's saying here.
Paul Cliff said:Something got a little lost in translation. I've been going nuts looking for it, but I could swear that I read in one of Scheuerbrandt's interview with Platenburg that Prosensa did not have enough dough to take its exon skipping compounds to market, and would need a partner. I'm sure that's the case for all of these little start ups. Nothing devastating; just biotech business as usual.
MicahsDaddy said:Hi Cheryl,
Please don't take me wrong. I am not trying to be controversial or prove a point...nor do I think I know everything…though I’m sure many feel that I think I do. I don’t. Everything I write is how I understand it and is definitely wrong more so than right.
When I post, I am hoping someone can clarify what my thoughts are. Or, at the least, get all of us thinking. If one person writes what they believe is right and no one responds, then we will all head down the wrong path of thinking.
For example, I used to think that an intron, say 45, came before an exon, in this case exon 45. Because of forums like this, I was informed that no, intron 45 follows exon 45…and the same goes throughout genes. This is a case where I am glad we have these forums because I learned that I was wrong and what is correct. Because of parents and biologists from PPMD sites and other sites, I have been able to get a better understanding of things. Key word being “better” not “all”.
So, basically, all I am doing when I see a post that is different to my thoughts, I put up my understanding…err, 2 cents…and hope that someone (a third party) responds in agreement of one or the other, or, even a completely different thought to get me thinking even more.
All of us can read the exact same document on something (for example, how exon skipping works) and all of us, except the professionals, will interpret it differently. That’s why we are here, right? To help each other better understand and/or maybe even think outside of our own thoughts. That’s all I am doing and all I want in return.
I apologize if I was taken differently, that was not my intention.
BTW, where did you hear this news about Prosensa? This would be devastating if true.
Thanks and take care,
Christian
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AVI BioPharma’s Drug for Duchenne Muscular Dystrophy Recommended for Orphan Drug Status in EU and Receiving Provisional GTAC Approval for Clinical Trial in UK
For Immediate Release
CORVALLIS, OR — October 14, 2008 — AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA–based drugs, today announced that the European Medicines Agency (EMEA) Committee for Orphan Medicinal Products (COMP) adopted a positive opinion recommending orphan medicinal product designation for AVI–4658 to treat Duchenne muscular dystrophy (DMD). Additionally, the Company received notification from the Gene Therapy Advisory Committee (GTAC) in the UK granting provisional approval for the Company’s planned clinical trial for systemic delivery of AVI–4658 to treat DMD. The conditions for final GTAC approval include certain wording changes in the patient and parent information documents and completion of normal site specific assessments. AVI expects to comply with the conditions for final approval this quarter.
http://www.avibio.com/pr/pr393.php
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AVI BioPharma to Co-Host Exon Skipping Conference for Duchenne Muscular Dystrophy
Therapeutic Strategies using Oligonucleotide–Directed Splicing
For Immediate Release
CORVALLIS, OR — October 14, 2008 — AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA–based drugs, today announced that the Company — along with The Foundation to Eradicate Duchenne, the CureDuchenne Foundation, and Prosensa — will co–host an exon skipping conference for Duchenne muscular dystrophy (DMD) from October 14–17, 2008 at the Banbury Center of Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Invited participants will be drawn from all over the world and from all areas of research, clinical development, regulatory affairs and key DMD disease foundations to review the advances in oligonucleotides as therapeutic agents for DMD.
http://www.avibio.com/pr/pr394.php
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Permalink Reply by irishgirl on
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Do you not want to buy more time?
cheryl cliff said: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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Permalink Reply by ronald singh on
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Hello Paul
My son has recently been diagnosed requiring exon 43 skipping and I wanted to know how your son is doing since you posted this in 2008 How close are we to the two exons you require for your son?
Ronald
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Ronald,
In 2008, when I started this discussion, Alex had just turned 10. He is now 14, and will be 15 this summer. He has been in a wheelchair full time since 2011, and has been on various cardiac meds since about that same time. I have also learned more about his specific mutation. He has two missing nucleotides on exon 44, and these create a premature stop codon. This means that he has to skip both exon 44 and exon 45. The good news is that Prosensa's exon 44 compound is in clinical trials now, and the exon 45 compound should be starting this year. Of course, none of this can happen fast enough. Please friend me on Facebook, and I can point you to some more current discussions.
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