FYI - I just received this email from the folks gearing up for the AVi safety trial in Ohio. Lindsay Arnott is no longer with the institution, but they are up to date with their files.

Hello,

You contacted Lindsay Arnott who used to work in our institution, back in April and she had a chart open for your child. We have his name, date of birth and mutation and he is included in our list of potential candidates.
However, we are not ready to start the trial yet. The sponsor, AVI, will give his “go”, hopefully in a few months, and we will start enrolling patients. We will contact at this time to proceed to enrollment and screening. We would be very happy to have Liam in the trial and we will make sure to contact you back.
In the meantime, if you have questions about the trial, please feel free to email me.
Thank you very much.
Best regards,

Laurence

Laurence Viollet, PhD
Clinical Research Coordinator
Team Project Leader
Center for Gene Therapy
The Research Institute at Nationwide Children's Hospital
700 Children's Drive
Columbus, OH 43205
Phone: (614) 355-2695
Fax: (614) 355-5247
Laurence.Viollet@nationwidechildrens.org

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More info is provided in the latest AVI presentation: http://www.avibio.com/events.php

A few quotes: At the WMS meeting it was concluded that exon skipping for DMD is no longer a matter of IF but of WHEN! AVI went up to 10 mg/kg in the UK trial (one more cohort with 20 mg/kg will follow soon); no significant side efffects were observed; dystrophin expression data to be presented shortly.

What I find great is that at the dose of only 1 mg/kg, 50% reduction in the CK levels was observed!

In the US trial, starting "early" next year, they plan to test both IV and subcutaneous administration. The dose level found working in the UK trial will be used in the US trial.
Did you receive this email out of the bluen or had you sent a follow up email? I contacted lindsay as well about my two sons, and now I wonder if they will be included in the trial. I hate feeling so anxious about this. ( My boys have a deletion of exon 52, that is one of the targets with skipping 51 right?)
Does anyone know......My understanding is that the boys must be at least 5 to be in the study, is that correct?
Correct.

Wyatt's Mommy, Melissa said:
Does anyone know......My understanding is that the boys must be at least 5 to be in the study, is that correct?
The inclusion/exclusion criteria is not completely determined as of yet. I sent in a follow up email to Lindsay and found she has left her with job with them, but if you sent information regarding your child, it's still on file - as was the case with us.
My understanding is that the current dose being administered in the UK through IV is low and they expect no earth shattering results. We already know the straight injections work, we know the drugs work, but it's getting the correct higher dose delivered IV wise that is not toxic is the real point. Prosensa is doing higher doses than AVI with wonderful results that are not posing toxic harm to the kids. I don;t get this though - AVI's IV delivery at a low dose - yes, safe, but yielding no positive results other than being safe - which is highly important! Why do the same dosing here in the US if it's been done already. Up the doses higher and higher - if it remains safe YIPPIE!!!!!!! Prosensa is taking this step with the higher dosing. Ck levels aside, I would rather see more dystrophin produced!!! CK levels rise prior to heart attack and a host of other ailments.
We have to just keep our kids strong and do all we can until this comes to fruition - of which I feel it will.

I did learn that children will not be excluded based on how the disease is progressing in each child. A child in a wheelchair at age 8 has as much as chance of getting on the trial as a kid who is 10 and still running. Now, this was talk through the grapevine, but if the method is double blind, it may be say 12 weeks of placebo and then another 12 weeks of the drug - so every trial patient gets something. None of this has been determined. I mean you can look at the criteria for the current trials in the uK and get a baseline of what you MAY expect, but don;t be put off as some bullets can and will change.
WHen we get back from the exon 51 skipping conference in London next month, I feel certain that many more cats will be out of the bag!!!!! The best and the brightest working on this will all be there. Fingers crossed for ALL of us!!!!!

Ofelia Marin said:
Correct.
Wyatt's Mommy, Melissa said:
Does anyone know......My understanding is that the boys must be at least 5 to be in the study, is that correct?
Prosensa is using lower doses than AVI. Prosensa went up to 6 mg/kg while AVI goes up to 20 mg/kg. AVI expects to see efficacy at these dose levels. The dystrophin expression data from the first cohorts will be presented before the end of the year. What I find significant is a 50% reduction in CK levels at a very low dose, only 1 mg/kg, the highest will be 20 mg/kg.

The Treat-NMD meeting with EMEA, FDA, AVI, Prosensa, MDEX, Eric Hoffman etc. is in London today. Pat is attending and will let us know how it goes.

http://www.prosensa.eu/news/Press%20release%20WMS.pdf

The completed phase I/IIa open label study evaluated the systemic delivery of PRO051 in twelve DMD patients receiving weekly subcutaneous injections over a period of five weeks. Four dosing cohorts were applied (0.5 mg/kg, 2 mg/kg, 4 mg/kg, 6 mg/kg), comprising three patients each. The effect of PRO051 was assessed at the RNA level, to demonstrate specific exon 51 skipping, and at the protein level, to demonstrate novel dystrophin expression.
http://www.avibio.com/news_detail.php?newsId=0054

The currently ongoing Phase 1b/2 dose-finding clinical trial is evaluating the systemic delivery of AVI-4658. This is an open label, 12-week safety trial that includes measures of drug efficacy and pharmacokinetics. To date, four of the six dosing cohorts have been successfully completed and the fifth dosing cohort (10 mg/kg) is ongoing. Preliminary data presented at the WMS show that AVI-4658 has been well tolerated with very few mild and transient drug-related adverse events and no serious adverse events. Further, the independent Data Safety Monitoring Board (DSMB) has approved each of the trial's dose escalations and - with DSMB approval - AVI could begin dosing on the sixth and final cohort (20 mg/kg) shortly. Importantly, dosing of the fifth and sixth cohort out to 12 weeks will exceed both dose level and duration of dosing previously studied by other researchers with the alternative 2'O-Me P approach.



irishgirl said:
The inclusion/exclusion criteria is not completely determined as of yet. I sent in a follow up email to Lindsay and found she has left her with job with them, but if you sent information regarding your child, it's still on file - as was the case with us.
My understanding is that the current dose being administered in the UK through IV is low and they expect no earth shattering results. We already know the straight injections work, we know the drugs work, but it's getting the correct higher dose delivered IV wise that is not toxic is the real point. Prosensa is doing higher doses than AVI with wonderful results that are not posing toxic harm to the kids. I don;t get this though - AVI's IV delivery at a low dose - yes, safe, but yielding no positive results other than being safe - which is highly important! Why do the same dosing here in the US if it's been done already. Up the doses higher and higher - if it remains safe YIPPIE!!!!!!! Prosensa is taking this step with the higher dosing. Ck levels aside, I would rather see more dystrophin produced!!! CK levels rise prior to heart attack and a host of other ailments.
We have to just keep our kids strong and do all we can until this comes to fruition - of which I feel it will.

I did learn that children will not be excluded based on how the disease is progressing in each child. A child in a wheelchair at age 8 has as much as chance of getting on the trial as a kid who is 10 and still running. Now, this was talk through the grapevine, but if the method is double blind, it may be say 12 weeks of placebo and then another 12 weeks of the drug - so every trial patient gets something. None of this has been determined. I mean you can look at the criteria for the current trials in the uK and get a baseline of what you MAY expect, but don;t be put off as some bullets can and will change.
WHen we get back from the exon 51 skipping conference in London next month, I feel certain that many more cats will be out of the bag!!!!! The best and the brightest working on this will all be there. Fingers crossed for ALL of us!!!!!

Ofelia Marin said:
Correct.
Wyatt's Mommy, Melissa said:
Does anyone know......My understanding is that the boys must be at least 5 to be in the study, is that correct?
The conference in London that I am referring to is the one hosted by Action Duchenne in late October.
My understanding is that the current dose being administered in the UK through IV is low and they expect no earth shattering results.>> AVI scientists have stated publicly that they believe, based on extrapolation of animal model results, that 2 - 4 mg/kg will turn out to be a therapeutic dose. This dose range has already been completed in the IV studies, and they have moved on to the 10 and 20 mg/kg dose range.

Prosensa is doing higher doses than AVI with wonderful results that are not posing toxic harm to the kids.>> this infomration does not jibe with what has been made public by AVI and Prosensa. Can you provide source of info that Prosensa's results were "wonderful"?

I don't get this though - AVI's IV delivery at a low dose - yes, safe, but yielding no positive results other than being safe - which is highly important!>> I believe this to be innacurate. AVI is dosing at a higher dose range than Prosensa did, and as was mentioned by another Ofelia, saw a 50% reduction in CK levels at one of the lowest doses (1mg/kg).

Why do the same dosing here in the US if it's been done already.'>> I could be mistaken, but I believe AVI plans to file INDs for both the Exon 51 drug and a new EXON 50 drug to get the go-ahead for US trials. One major difference between these two (aside form the different exons skipped) is that the Exon 50 drug will be a new class of drugs called PPMO, which includes a peptide attached to the PMO which facilitates cellular uptake, especially by cardiac tissue.

As for upping the dose, I believe that's what they are trying to do with the 10 and 20 mg/kg dose range (i.e., to greatly exceed what they believe to be the therapeutic dose. There is also some small hope that with this very high dose range, they may also actually be able to see some dystrophin production in the heart, as was seen in a recent mouse study, even using just the naked PMO.
Prosensa - currently in a 6 month extension of their trial with a maximum dose of 6 mg/kg. The original study was to have 5 weeks of dosing followed by 13 weeks of followup. At 6mg/kg, 5 weeks of dosing would yield 30mg/kg total drug introduced. It is unclear of the regimen of the 6 week followup. Comments made by Shewsbury (presentation under events on Avi website) of Avi suggest Prosensa has seen one patient with an issue. No idea of the severity. There was also one drug related adverse effect reported in the New England Journal of Medicine paper. Does anyone know whether Prosensa intended to go higher than 6mg/kg? Prosensa has apparently released no data to support "wonderful results" other than a statement of "novel dystrophin expression."

Avi - Completing the dosing at 4 mg/kg. At 4 mg/kg dosing for 12 weeks that is 48mg/kg of total drug introduced. 50% more than the total drug introduced in the originally planned Prosensa study. Treatment has started at 10 mg/kg. 20mg/kg approved, probably dependent on safety review of 10 mg/kg data. They have released only one comment suggesting drug effectiveness. With a 1 mg/kg dose, a 50% reduction in CK levels was observed. Their intention is to study the blinded results at the completion of the first 4 cohorts - .5, 1, 2, 4 mg/kg levels. Late this year or early next year there should be results with dystrophin levels.

Today for both companies the only real results appear to be that on intermuscular injections there is dystrophin produced. The real results everyone is waiting for won't come till results of clinical markers such as 6 minute walk test are released.

Hopefully both companies will be able to develop a dosing level and regimen that will allow the next trials to demonstrate efficacy.



irishgirl said:
The inclusion/exclusion criteria is not completely determined as of yet. I sent in a follow up email to Lindsay and found she has left her with job with them, but if you sent information regarding your child, it's still on file - as was the case with us.
My understanding is that the current dose being administered in the UK through IV is low and they expect no earth shattering results. We already know the straight injections work, we know the drugs work, but it's getting the correct higher dose delivered IV wise that is not toxic is the real point. Prosensa is doing higher doses than AVI with wonderful results that are not posing toxic harm to the kids. I don;t get this though - AVI's IV delivery at a low dose - yes, safe, but yielding no positive results other than being safe - which is highly important! Why do the same dosing here in the US if it's been done already. Up the doses higher and higher - if it remains safe YIPPIE!!!!!!! Prosensa is taking this step with the higher dosing. Ck levels aside, I would rather see more dystrophin produced!!! CK levels rise prior to heart attack and a host of other ailments.
We have to just keep our kids strong and do all we can until this comes to fruition - of which I feel it will.

I did learn that children will not be excluded based on how the disease is progressing in each child. A child in a wheelchair at age 8 has as much as chance of getting on the trial as a kid who is 10 and still running. Now, this was talk through the grapevine, but if the method is double blind, it may be say 12 weeks of placebo and then another 12 weeks of the drug - so every trial patient gets something. None of this has been determined. I mean you can look at the criteria for the current trials in the uK and get a baseline of what you MAY expect, but don;t be put off as some bullets can and will change.
WHen we get back from the exon 51 skipping conference in London next month, I feel certain that many more cats will be out of the bag!!!!! The best and the brightest working on this will all be there. Fingers crossed for ALL of us!!!!!

Ofelia Marin said:
Correct.
Wyatt's Mommy, Melissa said:
Does anyone know......My understanding is that the boys must be at least 5 to be in the study, is that correct?
I know.
Pat is attending this Treat-NMD meeting:

http://www.parentprojectmd.org/site/DocServer/092509_EMEA_briefing_...

I am looking forward to hear what they discussed especially about the "platform" drug concept.

irishgirl said:
The conference in London that I am referring to is the one hosted by Action Duchenne in late October.
This is exactly my understanding too!

frankie said:
My understanding is that the current dose being administered in the UK through IV is low and they expect no earth shattering results.>> AVI scientists have stated publicly that they believe, based on extrapolation of animal model results, that 2 - 4 mg/kg will turn out to be a therapeutic dose. This dose range has already been completed in the IV studies, and they have moved on to the 10 and 20 mg/kg dose range.

Prosensa is doing higher doses than AVI with wonderful results that are not posing toxic harm to the kids.>> this infomration does not jibe with what has been made public by AVI and Prosensa. Can you provide source of info that Prosensa's results were "wonderful"?

I don't get this though - AVI's IV delivery at a low dose - yes, safe, but yielding no positive results other than being safe - which is highly important!>> I believe this to be innacurate. AVI is dosing at a higher dose range than Prosensa did, and as was mentioned by another Ofelia, saw a 50% reduction in CK levels at one of the lowest doses (1mg/kg).

Why do the same dosing here in the US if it's been done already.'>> I could be mistaken, but I believe AVI plans to file INDs for both the Exon 51 drug and a new EXON 50 drug to get the go-ahead for US trials. One major difference between these two (aside form the different exons skipped) is that the Exon 50 drug will be a new class of drugs called PPMO, which includes a peptide attached to the PMO which facilitates cellular uptake, especially by cardiac tissue.

As for upping the dose, I believe that's what they are trying to do with the 10 and 20 mg/kg dose range (i.e., to greatly exceed what they believe to be the therapeutic dose. There is also some small hope that with this very high dose range, they may also actually be able to see some dystrophin production in the heart, as was seen in a recent mouse study, even using just the naked PMO.
Deletion of exon 52 can potentially be treated by skipping exon 51(per van deutkom)

jenn said:
Did you receive this email out of the bluen or had you sent a follow up email? I contacted lindsay as well about my two sons, and now I wonder if they will be included in the trial. I hate feeling so anxious about this. ( My boys have a deletion of exon 52, that is one of the targets with skipping 51 right?)

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