GSK trial of exon 51 skipping on Ambulatory Boys

Does anyone know what is going on with GSK and the trial on exon 51 skipping?  They said the trial will not be conducted this year. Does that mean next year, or not at all?  Have they pulled the plug on this trial?  If they have, why the heck are they moving forward with the non-ambulatory trial which the FDA has green lighted.  
Insight????

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They reported something here (obviously since so many countries approved the next phase, I assume is nothing to worry about): http://www.cureduchenne.org/wp-content/uploads/2010/04/Sent-on-Beha...

Q. Do you have any data or insight into the potential toxicities of long term systemic delivery?
Small amounts of protein were present in intermittent urine tests during Study PRO051‐02 and need to be investigated further. Longer term placebo controlled studies are needed to understand long term systemic delivery of this investigational drug.



Laurie Paschal said:
The guy from GSK at the conference did mention some issues with kidneys at higher doses.

irishgirl said:
Has anyone heard anything like or similar to this FDA denial idea...

FDA denial might have to do with dosing and toxicity; the 2'Omethyl chemistry is known to be considerably more toxic than the morpholino (actually, the best data on morpholino toxicity was done only very recently, thanks to the DoD, FED, and CureDuchenne that footed the $3 million bill to do it). FDA is usually pretty sticky about having standard animal tox data in hand, supporting the human doses planned, or they freak (e.g. won't approve). I think I mentioned before that I ran an exon skipping workshop in DC about 3 yrs or so ago, and the key FDA rep attended and said straight out: "We don't approve the 2'Omethyl drugs; too much toxicity".
Did they not also mention that it was no big deal?????

Laurie Paschal said:
The guy from GSK at the conference did mention some issues with kidneys at higher doses.

irishgirl said:
Has anyone heard anything like or similar to this FDA denial idea...

FDA denial might have to do with dosing and toxicity; the 2'Omethyl chemistry is known to be considerably more toxic than the morpholino (actually, the best data on morpholino toxicity was done only very recently, thanks to the DoD, FED, and CureDuchenne that footed the $3 million bill to do it). FDA is usually pretty sticky about having standard animal tox data in hand, supporting the human doses planned, or they freak (e.g. won't approve). I think I mentioned before that I ran an exon skipping workshop in DC about 3 yrs or so ago, and the key FDA rep attended and said straight out: "We don't approve the 2'Omethyl drugs; too much toxicity".
He really did kinda brush it off. Now I wonder.

irishgirl said:
Did they not also mention that it was no big deal?????

Laurie Paschal said:
The guy from GSK at the conference did mention some issues with kidneys at higher doses.

irishgirl said:
Has anyone heard anything like or similar to this FDA denial idea...

FDA denial might have to do with dosing and toxicity; the 2'Omethyl chemistry is known to be considerably more toxic than the morpholino (actually, the best data on morpholino toxicity was done only very recently, thanks to the DoD, FED, and CureDuchenne that footed the $3 million bill to do it). FDA is usually pretty sticky about having standard animal tox data in hand, supporting the human doses planned, or they freak (e.g. won't approve). I think I mentioned before that I ran an exon skipping workshop in DC about 3 yrs or so ago, and the key FDA rep attended and said straight out: "We don't approve the 2'Omethyl drugs; too much toxicity".
If this will be a big deal they will not get approval in EU and Australia to do trials in children. We do know that FDA requested similar GLP tox package to AVI and everybody knows that morpholinos have NO toxicology problems whatsoever. Hence it is not surprising that they required this to GSK. What would be surprising is GSK not providing it even in the future, just giving up on US. In other words, is this just a delay before they collect additional data in animals? Either way, it is very unfortunate.
I think that it's time to give up the idea that only the FDA is vigilant about toxicology and very careful when clinical trials in children are performed. All regulatory agencies are qualified and doing THEIR job. They might have different requirements but that does not imply that EMEA or other agencies approve trials when there are tox concerns.
OK - for all those wondering why the FDA denied GSK US trial for this year - read on. This email is from Dr. Padraig Wright. The FDA is requiring more animal testing - which GSK began nearly a year ago. That will be presented to the FDA later this year and with luck, the US trial will begin in 2011.

Dear Noreen,

Thank you for contacting me. I can certainly appreciate your concern. I wish to assure you that at GSK and Prosensa we are doing everything possible to develop GSK2402968 as safely and as rapidly as we can as a potential treatment for patients with Duchenne muscular dystrophy who have mutations/deletions that can be treated with exon 51 “skipping”.

In the meantime I hope that some further explanation and information may help.

Regulatory agencies have standard requirements that pharmaceutical companies must meet before commencing long term clinical trials. These requirements are intended to ensure the safety of patients and they differ somewhat from agency to agency. The FDA require more prolonged animal testing than other agencies. Recognising this, we commenced the necessary research almost a year ago and we plan to provide results to the FDA later this year. We therefore anticipate commencing long term clinical research in the US in 2011.

I want to finish by making two points which I think are very important.

First, we will soon commence study DMD114118 in the US. This will be the first time a clinical trial of an exon-skipping oligonucleotide for DMD has been performed in US patients.

Second, although US patients will not be able to participate in the long term clinical trial, DMD114044, this trial will proceed in many other countries. Most importantly, the results of this trial will be part of the package of data that we will submit to the FDA to support our application for approval of GSK2402968 for the treatment of DMD.

I think this is all that I can usefully tell you at this stage Noreen. We will of course post all our clinical trials to www.clinicaltrials.gov as our research progresses.

Please feel free to contact me with further questions at any time.

Kind regards

Pádraig
That looks good!!!! Hopefully it happens the way that GSK is saying.
I'll believe 2011 when I see it.

If the next round in the EU hasn't started yet, is scheduled to take a year, and needs to be complete and analyzed before the US trials begin, we're looking at 2012 at the earliest....
I think he is meaning that the results of the European trial will be included in the package submitted to the FDA for approval of the drug for the clinic, it is not required for the long term trial planned for the US. My understanding is that they are waiting on the completion and analysis of long term animal safety studies to support a long term human trial. (Presumably it is a 6-9 month study, possibly with a 3 month recovery period?). Thus the "live" portion is probably complete and they are in the process of analyzing the data. These types of studies generate a LOT of data and it takes time for the data to be analyzed and conclusions reached, even when there are no adverse effects. If they plan to submit the data later this year (as he states) to support the application for a human trial, it is not unreasonable to expect a long term human trial to initiate in 2011. Having said all that, I understand the frustrations, clinical trials can get delayed for numerous reasons (I have run animal safety studies supporting human trials in the past and have experienced delays first hand), my son would benefit directly from this compound and I am acutely aware of the timing issues and how they impact my son.

Mindy said:
I'll believe 2011 when I see it.

If the next round in the EU hasn't started yet, is scheduled to take a year, and needs to be complete and analyzed before the US trials begin, we're looking at 2012 at the earliest....
This is the email we just received from our genetic counselor...

I am writing to update you with news on the exon skipping trial. Here is the update from our research coordinator Amy:

I just got off the conference call with GSK. Basically, the FDA did not approve the study, so they won’t be going forward with it. They are analyzing the data from the small study they did in Ohio and may have something at the beginning of 2011.

It sounded like they are able to do the study in Europe and will be speaking with Canada to see if performing it there is a possibility.

I wish I had better news. I will keep you posted if things change. Let me know if you have any questions. Here is the contact number for GSK to see about European or Canadian trials:
Contact: US GSK Clinical Trials Call Center 877-379-3718
The study is NOT off and plans are still underway. The FDA denied GSK's request for US trial approval because the FDA felt more in depth animal data needed to be provided. GSK has been working on those for nearly a year now and will deliver those results/data by this year's end. Again, nothing is set in stone, but plans have not been terminated - not in any way.
The following is an email of clarification from Dr. Padraig Wright MD, PhD with GSK. I received this email this morning...

I have caused a misunderstanding Noreen - FDA require the additional animal data I told you about before we can start long term clinical trials in the US - given this we will proceed with DMD114044 without the US - eventually the data from this trial will be part of the package we submit to FDA to get the drug approved in the US - but we do not need to wait for that data from 044 before we start clinical trials in US - that I hope will happen next year

I hope this helps

Padraig

Tapio said:
This is the email we just received from our genetic counselor...

I am writing to update you with news on the exon skipping trial. Here is the update from our research coordinator Amy:

I just got off the conference call with GSK. Basically, the FDA did not approve the study, so they won’t be going forward with it. They are analyzing the data from the small study they did in Ohio and may have something at the beginning of 2011.

It sounded like they are able to do the study in Europe and will be speaking with Canada to see if performing it there is a possibility.

I wish I had better news. I will keep you posted if things change. Let me know if you have any questions. Here is the contact number for GSK to see about European or Canadian trials:
Contact: US GSK Clinical Trials Call Center 877-379-3718
Included, BUT NOT NECESSARY for GSK to forge ahead with US trial plans.

Here is Dr. Padraig Wright's (GSK) response which clears things up quite a bit here...

"I have caused a misunderstanding Noreen - FDA require the additional animal data I told you about before we can start long term clinical trials in the US - given this we will proceed with DMD114044 without the US - eventually the data from this trial will be part of the package we submit to FDA to get the drug approved in the US - but we do not need to wait for that data from 044 before we start clinical trials in US - that I hope will happen next year."

I hope this helps

Padraig


Roderick Scott said:
I think he is meaning that the results of the European trial will be included in the package submitted to the FDA for approval of the drug for the clinic, it is not required for the long term trial planned for the US. My understanding is that they are waiting on the completion and analysis of long term animal safety studies to support a long term human trial. (Presumably it is a 6-9 month study, possibly with a 3 month recovery period?). Thus the "live" portion is probably complete and they are in the process of analyzing the data. These types of studies generate a LOT of data and it takes time for the data to be analyzed and conclusions reached, even when there are no adverse effects. If they plan to submit the data later this year (as he states) to support the application for a human trial, it is not unreasonable to expect a long term human trial to initiate in 2011. Having said all that, I understand the frustrations, clinical trials can get delayed for numerous reasons (I have run animal safety studies supporting human trials in the past and have experienced delays first hand), my son would benefit directly from this compound and I am acutely aware of the timing issues and how they impact my son.

Mindy said:
I'll believe 2011 when I see it.

If the next round in the EU hasn't started yet, is scheduled to take a year, and needs to be complete and analyzed before the US trials begin, we're looking at 2012 at the earliest....

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