Hello,
I just got off the phone with Lindsay, the clinical trials coordinator for Dr. Mendell. She asked me to post that anyone whose son is between 5-15 who would benefit from skipping 51 who is interested in participating in a systemic trial should contact her at arnottl@ccri.net.

The trial will have a placebo arm. It will take place in Columbus. I don't know the dosage.

Take care, all,
Mindy

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I was thinking about moving to the UK yesterday when listening to AVI's conference call :-).

When the question about the cost of treatment came, he estimated it at 200K/patient/year. So assuming that this works and is approved by EMEA sooner than the FDA (which is very likely!), going for treatment there one would need to pay all this out-of-pocket. So our best strategy would be to push the FDA somehow to approve it here as soon as it's approved in Europe (assuming that it comes to that!) and then hope that our insurance pays a good chunk of it. After all, isn't this an orphan disease, why are these people creating all these hurdles when it should be totally different? AVI-4658 has been in boys (in the UK) for 5 months already w/o any side effects, why are we spending money on 3-mths tox data in mice here in the US? I would be very interested in hearing the reasoning behind this waste of time and money. OK, if they tell me that they plan to increase the dose levels significantly up to a level close to what Hoffman used in dogs, then I agree that we need more preclinical data to support this. After all, a jump from 4 mg/kg/week to 200 mg/kg/week is quite scary.

One more thing I forgot to mention from yesterday's CC. AVI's ceo mentioned that in their opinion the cumulative effect is most important, so during the 12 week treatment with 4 mg/kg for a 30 kg boy that would be 1500 mg/patient which they think will induce a decent dystrophin expression (not as high as in the IM trial, but the plan is to increase the dose after seeing those results).
I listened to most of the call, and I think they were also planning to use "non-human primates" (why can't they just call them monkeys?) for more tox data. By way of explanation, not justification, I think it's numbers game, and the FDA requires more data so that at least some bad events are more likely to occur in order for them to have a handle on how common or uncommon they will be. This is all because the FDA is more afraid of adverse drug reactions than they are of excess deaths and permanent crippling caused by delaying the release of effective treatment. Cheryl, I am sure you know where the pitchfork is in the garage, but the correct sharpening tool is the file known as a #2 bastard which is on a hook next to the paintbrushes.
Don't quote me on the 200 mg - what Dr. Hoffman told me exactly was that the highest UK dosage was 1/10th the dose that worked in the dogs. I thought the highest UK dosage was 20 mg, so I just assumed.

Ofelia - since the money came from the DOD grant, I'm guessing they didn't have it otherwise. Which makes it even more stupid to waste money repeating existing trials.

On another note, Paul - can you please come and organize our garage?
In the dog results published by Hoffman they used 120 mg/kg/week and 200 mg/kg/week on two of the dogs. I quote from the article, they also have the movies showing the highest improvement in the dog treated with 200 mg/kg :
The duchenne dog study shows that:

• Multiple-exons (three) had to be skipped in order to compensate for the deletion in the duchenne dog.
• Doses were 120-200 mg/kg delivered weekly or bi-weekly for 7 to 11 doses. (A similar dose will likely be required to be effective in clinical trials.)
• Intravenous morpholino cocktail showed no toxicity.
• The dogs treated with morpholino therapy ran faster than they did before the treatment while their untreated litter-mates ran slower.
• 26% increase in dystrophin expression levels in average compared to normal animals.


In the UK trial design the dose levels are:

0.5, 1.0, 2.0, and 4.0 mg/kg

I asked Steve Wilton about the discrepancy b/w the dose levels. Since AVI-4658 was created by Steve (AVI purchased the patent from Steve this year) I thought that he might be the best person to ask. He said:

Hi Ofelia, the Hoffman canine AOs were not optimized and they relied on high concentrations to make it work. The UK trials have to be safe, hence doses will be much lower. They may not work, but they will be safe.

Hope this helps.

Cheers, Steve


Again different people provide different information, I cannot imagine that Hoffman doesn't know that the PMO used in his dog experiments was not optimized... No idea what is right or wrong at this point... I asked Mendell about the dose discrepancy and he just said that different species require different dose level, for example mouse dose 36 to100 mg/kg -human equivalent dosing 2.5 to 8.3 mg/kg, but I would assume that dogs and humans are not that different...







Mindy said:
Don't quote me on the 200 mg - what Dr. Hoffman told me exactly was that the highest UK dosage was 1/10th the dose that worked in the dogs. I thought the highest UK dosage was 20 mg, so I just assumed.

Ofelia - since the money came from the DOD grant, I'm guessing they didn't have it otherwise. Which makes it even more stupid to waste money repeating existing trials.

On another note, Paul - can you please come and organize our garage?
Good info in this recent AVI presentation:
http://www.antivirals.com/downloads/AVI_BioPharma_Corporate_Present...

Slide 15: AVI-4658 –US status

•Responses to US IND hold sent March 2009
•Two multi-dose GLP IND-enabling studies (mice/NHPs): 3m in-life
•Plan to submit final toxicology findings 4Q09
Advanced discussions + protocol with leading US site for initial study under US IND
Current planning for start in 4Q09
I'll try to schedule a garage organizing thing Mindy...just after we finish sharpening a few things :)

Mindy said:
Don't quote me on the 200 mg - what Dr. Hoffman told me exactly was that the highest UK dosage was 1/10th the dose that worked in the dogs. I thought the highest UK dosage was 20 mg, so I just assumed.

Ofelia - since the money came from the DOD grant, I'm guessing they didn't have it otherwise. Which makes it even more stupid to waste money repeating existing trials.

On another note, Paul - can you please come and organize our garage?
I’m sorry I have not been available to partake in this robust discussion. Please take a look at my current blog when you have a moment. Hopefully it will add some clarity to the conversation.
This is actually a good article, a little older (Dec 2008) but good: http://www.parentprojectmd.org/site/DocServer/PennisiScienceexonski...

I like this very much; many people forget that Steve is a pioneer and he worked on exon skipping for DMD long before other people were even interested in the subject. Not to mention the fact that he is such a great person and even though he is so busy, he answers all our questions (every time I emailed him I received an answer to my questions!):

“There are lots of issues,” says Hoffman. Nonetheless, “you have to give Wilton and others a
lot of credit for doggedly pursuing this and having it emerge as [the] winning horse.”
More delays...

http://www.avibio.com/duchenne_muscular_dystrophy.php

In addition, AVI has now started the comprehensive series of preclinical tests necessary before a US study with AVI-4658 can be undertaken. The results from these studies will need to be reviewed by the FDA before a US study can start. It is hoped that the US study could start in early 2010.

AVI is advancing a second product, targeting exon 50, and has now started a similar series of preclinical studies with AVI-5038. While these studies are underway, AVI anticipates having discussions with the Regulatory Authorities about plans to start clinical work with AVI-5038. This additional regulatory dialog could help with planning for candidates to skip other common deletions. The early results from our PMO program (with AVI-4658) should help us to streamline this PPMO program; we hope to start a clinical study in mid 2010.

AVI is examining other target deletions with the hope of developing the best candidates for treating these target deletions.
Time to start packing for the UK. Recently we asked Dr Flanigan's opinion about who will come in first - Prosensa or AVI. He said Prosensa. Looks like he might be right.

Thanks for bringing this tidbit to our attention Ofelia. Even tho it isn't great news we still need to know how things are coming along.
cheryl

Ofelia Marin said:
More delays...

http://www.avibio.com/duchenne_muscular_dystrophy.php

In addition, AVI has now started the comprehensive series of preclinical tests necessary before a US study with AVI-4658 can be undertaken. The results from these studies will need to be reviewed by the FDA before a US study can start. It is hoped that the US study could start in early 2010.

AVI is advancing a second product, targeting exon 50, and has now started a similar series of preclinical studies with AVI-5038. While these studies are underway, AVI anticipates having discussions with the Regulatory Authorities about plans to start clinical work with AVI-5038. This additional regulatory dialog could help with planning for candidates to skip other common deletions. The early results from our PMO program (with AVI-4658) should help us to streamline this PPMO program; we hope to start a clinical study in mid 2010.

AVI is examining other target deletions with the hope of developing the best candidates for treating these target deletions.
Does this only work with deletions? My son has a duplication of 45 will he be an eligible canidate?

cheryl cliff said:
Time to start packing for the UK. Recently we asked Dr Flanigan's opinion about who will come in first - Prosensa or AVI. He said Prosensa. Looks like he might be right.

Thanks for bringing this tidbit to our attention Ofelia. Even tho it isn't great news we still need to know how things are coming along.
cheryl

Ofelia Marin said:
More delays...

http://www.avibio.com/duchenne_muscular_dystrophy.php

In addition, AVI has now started the comprehensive series of preclinical tests necessary before a US study with AVI-4658 can be undertaken. The results from these studies will need to be reviewed by the FDA before a US study can start. It is hoped that the US study could start in early 2010.

AVI is advancing a second product, targeting exon 50, and has now started a similar series of preclinical studies with AVI-5038. While these studies are underway, AVI anticipates having discussions with the Regulatory Authorities about plans to start clinical work with AVI-5038. This additional regulatory dialog could help with planning for candidates to skip other common deletions. The early results from our PMO program (with AVI-4658) should help us to streamline this PPMO program; we hope to start a clinical study in mid 2010.

AVI is examining other target deletions with the hope of developing the best candidates for treating these target deletions.
Hi Amanda,

I suspect, although I don't know, exon skipping could work for duplication cases if there was only one duplication instead of many (?). But, you could ask Duchenne Connect or contact some docs who follow exon skipping - Flanigan or Muntoni are good choices. You might even have some luck calling AVI themselves.

Please let us know what you find out if you follow this further. I will keep my fingers crossed it works for your son.
cheryl

Amanda Rudd said:
Does this only work with deletions? My son has a duplication of 45 will he be an eligible canidate?

cheryl cliff said:
Time to start packing for the UK. Recently we asked Dr Flanigan's opinion about who will come in first - Prosensa or AVI. He said Prosensa. Looks like he might be right.

Thanks for bringing this tidbit to our attention Ofelia. Even tho it isn't great news we still need to know how things are coming along.
cheryl

Ofelia Marin said:
More delays...

http://www.avibio.com/duchenne_muscular_dystrophy.php

In addition, AVI has now started the comprehensive series of preclinical tests necessary before a US study with AVI-4658 can be undertaken. The results from these studies will need to be reviewed by the FDA before a US study can start. It is hoped that the US study could start in early 2010.

AVI is advancing a second product, targeting exon 50, and has now started a similar series of preclinical studies with AVI-5038. While these studies are underway, AVI anticipates having discussions with the Regulatory Authorities about plans to start clinical work with AVI-5038. This additional regulatory dialog could help with planning for candidates to skip other common deletions. The early results from our PMO program (with AVI-4658) should help us to streamline this PPMO program; we hope to start a clinical study in mid 2010.

AVI is examining other target deletions with the hope of developing the best candidates for treating these target deletions.

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