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 Paul Cliff on
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Excellent. Good catch. How long is the presentation? I'll need to schedule times to listen when the kids aren't around.
Ofelia Marin said:Please listen/read AVI's presentation. There are lots of answers to our questions!!!
Transitioning an Antisense Pioneer into a Leading RNA–based Drug Discovery and Development Company
September 10, 2008
http://www.avibio.com/pr/pr390.php
Leslie Hudson, President and CEO, AVI BioPharma mentions exons 51, 45, 44, 53, 46 and 50.
Ofelia
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Permalink Reply by Ofelia Marin on
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They are quite long. The one I found very interesing, full of info is:
Dr. Leslie Hudson
Clinical Trials of AVI–4658 and the commercial prospects for a DMD franchise
One important quote on page 15: "EU approval could be on the basis of a single pivotal trial". But there are many interesting things presented there! You could start with that one...it's shorter than Muntoni's presentation.
One other very important thing; they did not see immune response in animals or boys so far. That's really great!
Paul Cliff said:Excellent. Good catch. How long is the presentation? I'll need to schedule times to listen when the kids aren't around.
Ofelia Marin said:Please listen/read AVI's presentation. There are lots of answers to our questions!!!
Transitioning an Antisense Pioneer into a Leading RNA–based Drug Discovery and Development Company
September 10, 2008
http://www.avibio.com/pr/pr390.php
Leslie Hudson, President and CEO, AVI BioPharma mentions exons 51, 45, 44, 53, 46 and 50.
Ofelia
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Permalink Reply by cheryl cliff on
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Ofelia,
Thank you for send us to this release!! This is the best news...as fantastic as hearing from the Dr Phil show!
Somebody pinch me -
cheryl
Ofelia Marin said:They are quite long. The one I found very interesing, full of info is:
Dr. Leslie Hudson
Clinical Trials of AVI–4658 and the commercial prospects for a DMD franchise
One important quote on page 15: "EU approval could be on the basis of a single pivotal trial". But there are many interesting things presented there! You could start with that one...it's shorter than Muntoni's presentation.
One other very important thing; they did not see immune response in animals or boys so far. That's really great!
Paul Cliff said:Excellent. Good catch. How long is the presentation? I'll need to schedule times to listen when the kids aren't around.
Ofelia Marin said:Please listen/read AVI's presentation. There are lots of answers to our questions!!!
Transitioning an Antisense Pioneer into a Leading RNA–based Drug Discovery and Development Company
September 10, 2008
http://www.avibio.com/pr/pr390.php
Leslie Hudson, President and CEO, AVI BioPharma mentions exons 51, 45, 44, 53, 46 and 50.
Ofelia
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Permalink Reply by Jerry Dallapè on
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And even better for those of us in the U.S. is on page 16: Phase 1b clinical study in the UK could allow for immediate pivotal trial testing in the US.
Ofelia Marin said:One important quote on page 15: "EU approval could be on the basis of a single pivotal trial". >
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If you look at the slides here:
http://www.avibio.com/downloads/AVI-2008-09-10-04-Ryszard_Kole.pdf
It looks like PPMOs are a clear winner and PMOs do not look as good (10% dystrophin for 2 weeks, weekly 1 hr, systemic injections, not to mention the diaphragm, heart etc.)... So the question remains: why are they moving forward with PMOs as opposed to PPMOs? Is this a waste of time and money?
Ofelia
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I haven't gotten through the whole presentation, but I think it might be because the reason what Christian mentioned earlier: Prosensa got its approval for the 2'O Methyl thingies, and in response Avi rushed forward with its PMO's. Since mouse evidence seems so compelling that the PPMO's are superior, I doubt they will do more with the PMO's after they finish the existing proof of principle trial UNLESS getting the PPMO trials approved is going to require going back to square one with the FDA, in which case I hope that they contact us so that we can go medieval on the FDA.
Ofelia Marin said:If you look at the slides here:
http://www.avibio.com/downloads/AVI-2008-09-10-04-Ryszard_Kole.pdf
It looks like PPMOs are a clear winner and PMOs do not look as good (10% dystrophin for 2 weeks, weekly 1 hr, systemic injections, not to mention the diaphragm, heart etc.)... So the question remains: why are they moving forward with PMOs as opposed to PPMOs? Is this a waste of time and money?
Ofelia
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But they will start the systemic delivery trial skipping 51 in the UK with PMOs not PPMOs. They have approval to start that trial. That is why I mentioned wasting time and money... that trial is 12 week long with 16 boys. From what they presented, in the best case, those results will be out Q3 of 2009, one year from now!
I whish someone would ask Leslie Hudson this question.
Paul Cliff said:I haven't gotten through the whole presentation, but I think it might be because the reason what Christian mentioned earlier: Prosensa got its approval for the 2'O Methyl thingies, and in response Avi rushed forward with its PMO's. Since mouse evidence seems so compelling that the PPMO's are superior, I doubt they will do more with the PMO's after they finish the existing proof of principle trial UNLESS getting the PPMO trials approved is going to require going back to square one with the FDA, in which case I hope that they contact us so that we can go medieval on the FDA.
Ofelia Marin said:If you look at the slides here:
http://www.avibio.com/downloads/AVI-2008-09-10-04-Ryszard_Kole.pdf
It looks like PPMOs are a clear winner and PMOs do not look as good (10% dystrophin for 2 weeks, weekly 1 hr, systemic injections, not to mention the diaphragm, heart etc.)... So the question remains: why are they moving forward with PMOs as opposed to PPMOs? Is this a waste of time and money?
Ofelia
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WOW!!
This news is SO amazing! A few weeks ago I ran out of the "shreds of hope" I had been living on. This is MUCH more than a shred, this is a whole slice!
cheryl
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Permalink Reply by Tulika on
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Ofelia,
Some details in the paper at http://www.biochemsoctrans.org/bst/035/0826/0350826.pdf
This explains that PPMO is and enhanced verision of PMO, where PMO is attached with a cell penetrating peptide (CPP).
PMO + CPP = PPMO.
Attaching PMO with CPP allows penetration into more membranes hence the better results in mice.
However looks like the CCP compound still needs research. I am assuming that we can evaluate PMO while conducting research on the best CPP. This is my guess, couldnt find papers which detail CPP
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Thanks Tulika!
I also read some papers about different peptides attached to PMOs to create PPMOs.
My guess is that they move forward with PMOs, first because they have the pre-clinical tox studies completed and they don't have those finalized for PPMOs and also b/c they want to have another option if there are any adverse effects with one compound or the other. There is a lot to learn from these first clinical trials...
I will email the AVI people to ask some questions. Let's see if I get an answer. :-)
Tulika said:Ofelia,
Some details in the paper at http://www.biochemsoctrans.org/bst/035/0826/0350826.pdf
This explains that PPMO is and enhanced verision of PMO, where PMO is attached with a cell penetrating peptide (CPP).
PMO + CPP = PPMO.
Attaching PMO with CPP allows penetration into more membranes hence the better results in mice.
However looks like the CCP compound still needs research. I am assuming that we can evaluate PMO while conducting research on the best CPP. This is my guess, couldnt find papers which detail CPP
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Permalink Reply by MicahsDaddy on
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Paul Cliff said:...so that we can go medieval on the FDA.
NUTHIN' LIKE
!!!
It is good to see these reports. You would think that they would go in order of those 6 exons that have the highest percentage to help more patients. Instead, exon 50 is next, which is the lowest of the 6. Makes me wonder if they are going to test the ones that would have better results first so that there is less chance to delay the process.
For example, with a deletion of exon 45, one would benefit from either skipping 44 or 46. To me, even though more would benefit from skipping 44, it may be better "results wise" to skip 46 first. Why? Well, there is a promoter in Intron 44 (dp140). Since exon 45 is already missing, then skipping exon 44, the dp140 promoter would be missed when the reading frame is put back in tact by going from exon 43 to 46.
But, if they skipped 46, then the corrected reading frame would include Exon and Intron 44 and connect to Exon 47, which would include the promoter.
Dp140 expression is detected throughout the central nervous system (cerebral cortex, cerebellum, hippocampus, brain stem, spinal cord and olfactory bulb) and kidney.
http://www.dmd.nl/isoforms.html
Since this is in the brain, my understanding is that having a deletion anywhere in the exon 45 to 52 range will be cause for greater chance of Autism, ADD, mental retardation and other forms of ASD's in DMD patients.
If this is the case, then maybe for better test results, 46 would be the better option to skip. But, I'm just a DMD dad and computer geek, grasping at reasons they do things the way they do.
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From what the CEO says, exon 50 is next because they have the $2.45MM from Charley's fund to work on it. If I remember correctly, Charley has a deletion of 51 so he needs 50 skipped.
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?
MicahsDaddy said:Paul Cliff said:...so that we can go medieval on the FDA.NUTHIN' LIKE
It is good to see these reports. You would think that they would go in order of those 6 exons that have the highest percentage to help more patients. Instead, exon 50 is next, which is the lowest of the 6. Makes me wonder if they are going to test the ones that would have better results first so that there is less chance to delay the process.
For example, with a deletion of exon 45, one would benefit from either skipping 44 or 46. To me, even though more would benefit from skipping 44, it may be better "results wise" to skip 46 first. Why? Well, there is a promoter in Intron 44 (dp140). Since exon 45 is already missing, then skipping exon 44, the dp140 promoter would be missed when the reading frame is put back in tact by going from exon 43 to 46.
But, if they skipped 46, then the corrected reading frame would include Exon and Intron 44 and connect to Exon 47, which would include the promoter.
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