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 able to listen today's CC. They will post the audio within approximately 24 hours at www.avibio.com/events.php.

The Q&A session was very interesting.

A few key points:

- DMD is a national priority for Dept. of Defense along with breast and prostate cancer hence the funding;

- $ 2.5 MM will be used on preclinical GLP tox work, from what I got this is NOT a new request from FDA; it is the original request for completing toxicology 3-months exposure in animals (after the 3 months, they need to analyze the data, write the report and send to the FDA for a 30-day review); 2 of the GLP tox studies already started in non-human primates and mice; they plan to send the clinical trial protocol to the FDA at the same time;

- the 1st Phase of the US trial will be Safety with dose escalation design probably (the guy did not seem very convinced which shows that they did not finalize their plans);

- when asked directly about timeline they did not give a clear answer about the start of the US trials;

- when asked about milestones for 2009 they only mentioned the UK trial, when they hit 2-4 mg/kg dose level (during Q4 2009) they will give a full update; they still hope that the therapeutic range will be close to 4 mg/kg, for a 30 kg boy, that means 1500 mg/12 weeks/patient; they plan have an amendment to increase this dose to obtain higher % dystrophin (he said something like, if 4 mg/kg could give us half of the IM's 40% we would still like to increase the dose w/i safety limits);

- about the PPMO skipping 50, IND data package expected to be available in the 2nd half of 2010
Ofelia,

Any speculation or information as to why the FDA isn't accepting the preclinical data already done from the UK trials? My understanding, such as it is, is that FDA CAN accept their data (preclinicals too perhaps but I don't know for sure) if they want to.

Ofelia Marin said:
I was able to listen today's CC. They will post the audio within approximately 24 hours at www.avibio.com/events.php.

The Q&A session was very interesting.

A few key points:

- DMD is a national priority for Dept. of Defense along with breast and prostate cancer hence the funding;

- $ 2.5 MM will be used on preclinical GLP tox work, from what I got this is NOT a new request from FDA; it is the original request for completing toxicology 3-months exposure in animals (after the 3 months, they need to analyze the data, write the report and send to the FDA for a 30-day review); 2 of the GLP tox studies already started in non-human primates and mice; they plan to send the clinical trial protocol to the FDA at the same time;

- the 1st Phase of the US trial will be Safety with dose escalation design probably (the guy did not seem very convinced which shows that they did not finalize their plans);

- when asked directly about timeline they did not give a clear answer about the start of the US trials;

- when asked about milestones for 2009 they only mentioned the UK trial, when they hit 2-4 mg/kg dose level (during Q4 2009) they will give a full update; they still hope that the therapeutic range will be close to 4 mg/kg, for a 30 kg boy, that means 1500 mg/12 weeks/patient; they plan have an amendment to increase this dose to obtain higher % dystrophin (he said something like, if 4 mg/kg could give us half of the IM's 40% we would still like to increase the dose w/i safety limits);

- about the PPMO skipping 50, IND data package expected to be available in the 2nd half of 2010
Ofelia,
This is what I don't understand. They are currently doing safety dose escalation studies in the UK. Why would AVI spend tons of money just to repeat the same exact study in the US? It makes no sense at all.

I'm not too psyched about moving to Columbus to participate in a safety study. That absolutely won't happen.

Also - Dr. Hoffman told me that 200 mg/kg is what worked in the dogs. I wonder why they think that 4 mg/kg will work in the boys?
I agree with Mindy. Why should AVI spend money on something that is already being done in UK? Safety study is not something I am looking for. I thought the Columbus trial would be more than a safety study.


Mindy said:
Ofelia,
This is what I don't understand. They are currently doing safety dose escalation studies in the UK. Why would AVI spend tons of money just to repeat the same exact study in the US? It makes no sense at all. I'm not too psyched about moving to Columbus to participate in a safety study. That absolutely won't happen.

Also - Dr. Hoffman told me that 200 mg/kg is what worked in the dogs. I wonder why they think that 4 mg/kg will work in the boys?
The standards for clinical trials are different in the UK than they are are in the U.S. It is easier and cheaper to get approval to administer an experimental medication in the U.K. than it is in the U.S. However because the standards for collecting data are supposedly quite similar, I wouldn't assume that this is an exact duplication of effort; it may be that they can do a smaller trial in the U.S. than they otherwise would have had to do by using the data from the U.K.
Mindy,

About the preclinical data, from my understanding, EMEA approved the start of the UK trial w/o this GLP package requested by FDA. I really hope that they will not repeat the dose levels used in the UK trial, but use that knowledge and increase the levels, o/w it would not make any sense to pay twice to test the same dose levels. In fact, I hope that they will use a placebo group, modify the design and make it safety/efficacy. I think that they really need a Safety phase, I guess FDA requires this for any drug.

When I asked Steve Wilton about the high dose level used by Dr. Hoffman in dogs he only said that the PMOs used in dogs were not optimized and of course in humans they need to make sure that it is safe...so I assume that they will try the lowest possible dose. One other thing that comes to my mind is that the PMO used by Hoffman was a cocktail used to skip 3 exons 6,7,8 -- should this require a higher dose (?), I do not know, but I really hope that they do not need to go as high as 200 mg/kg/week...that seems so huge. Oh, I have so many questions and no answers... and if we ask different people, we get different answers. This is very frustrating!

Ofelia


Mindy said:
Ofelia,
This is what I don't understand. They are currently doing safety dose escalation studies in the UK. Why would AVI spend tons of money just to repeat the same exact study in the US? It makes no sense at all.

I'm not too psyched about moving to Columbus to participate in a safety study. That absolutely won't happen.

Also - Dr. Hoffman told me that 200 mg/kg is what worked in the dogs. I wonder why they think that 4 mg/kg will work in the boys?
One thing that I really cannot understand is why they spend $2.5 MM on preclinical data when, by Q4 2009, they will have more than 3 months of clinical data at the highest dose level from the UK trial. How does spending the money on preclinical in mice accelerate developing this treatment when AVI-4658 is already tested in boys since Jan 2009? It would make sense if the completion of these GLP tox studies would be much earlier than obtaining the data from the UK trial, but that doesn't seem to be the case. What is the reasoning for not looking at human data when it's available and waiting for animal data instead, not to mention spending $2.5 MM for this animal data?
Exactically!!

So, the question in my mind is what do we do about this? Who can we question...AVI?...They are building a relationship with DOD so can we expect an honest answer? Then there is maybe Pat?...MDEX?...I already know nobody is talking at FDA so we can forget about that route.

Paul once said if FDA doesn't move things fast enough we should "sharpen our pitchforks and plan to go medieval on Washington". @*^# (insert swear word) the FDA, I'm sharpening ours right now.

Anyone have any other suggestions?

Ofelia Marin said:
One thing that I really cannot understand is why they spend $2.5 MM on preclinical data when, by Q4 2009, they will have more than 3 months of clinical data at the highest dose level from the UK trial. How does spending the money on preclinical in mice accelerate developing this treatment when AVI-4658 is already tested in boys since Jan 2009? I would kind of understand if the completion of these GLP tox studies would be much earlier than obtaining the data from the UK trial, but that doesn't seem to be the case anymore. What is the reasoning for not looking at human data when it's available and waiting for animal data instead, not to mention spending $2.5 MM for this animal data?
my apologies for the outburst. I do get tired of the merry-go-round this diagnosis puts us on.
Cheryl - if we lived in the same area, we could sit together and have a really, really good outburst.

Columbus told me that this was indeed an efficacy study, not a safety study, and I trust the people I talked to, so that means AVI isn't being forthright with the clinicians who are conducting the trial.

I get that the FDA wants a round of safety studies, but then wouldn't they just say, OK - wait for the results of the UK systemic trial? Why repeat them? It's not like anyone's got that deep of pockets these days.

I, too, am very frustrated.
Hi Mindy,
It's funny how a communication can change as it travels around. Could there have been a misunderstanding of some kind? Or perhaps AVI is being jerked around by the FDA down a different path than what they first planned to go...I expect we will never know.

With all the current changes at FDA (breaking into two possibles: Fed Drug then another Fed Food) why can't someone go and speak for us regarding this unnecessary, expensive, time wasting duplication of research science?

Skip thinking of moving to Columbus...start packing for London! Let me know when you get there Mindy so we can schedule a real good outburst:)!!



Mindy said:
Cheryl - if we lived in the same area, we could sit together and have a really, really good outburst.

Columbus told me that this was indeed an efficacy study, not a safety study, and I trust the people I talked to, so that means AVI isn't being forthright with the clinicians who are conducting the trial.

I get that the FDA wants a round of safety studies, but then wouldn't they just say, OK - wait for the results of the UK systemic trial? Why repeat them? It's not like anyone's got that deep of pockets these days.

I, too, am very frustrated.
Exactly! I am very sure that AVI told Mendell that it will be an efficacy study. He seems convinced about it. He just spoke with AVI last week, after the $2.5 MM announcement and they did not tell him about any delay in the start of the trial. AVI should hold all these answers but who can talk to them and get some honest answers out of these people? I emailed AVI last week but of course I did not get any answers.

Why spend all that money to wait until next year for mice tox data when human data will be available sooner it's also beyond my understanding!

At this point, I really hate this!



Mindy said:
Cheryl - if we lived in the same area, we could sit together and have a really, really good outburst.

Columbus told me that this was indeed an efficacy study, not a safety study, and I trust the people I talked to, so that means AVI isn't being forthright with the clinicians who are conducting the trial.

I get that the FDA wants a round of safety studies, but then wouldn't they just say, OK - wait for the results of the UK systemic trial? Why repeat them? It's not like anyone's got that deep of pockets these days.

I, too, am very frustrated.

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