Are their any open clinical trials for deletion 22-41?

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Hi, 

 

Currently, I believe there are three trials operating - none of them for 22-41 I'm sorry to say.  The trials that are going are:

  1. GSK2402968/PRO051 – Phase II – Exon 51 skipping
  2. PRO044 – Phase I-IIa - Exon 44 skipping
  3. AVI-4658 – Planning Phase II - Exon 51 skipping

Hopefully, when these trials prove that the treatment is effective, other exon skipping compounds would gain quick approval without having to go through the full trial process..

 

Steve is correct.  But just to clarify

 

1.  Exon 51 skipping (GSK/Prosensa and AVI) targets the following deletions: 45-50, 47-50, 48-50, 49-50, 50, 52

2.  Exon 44 skipping (Prosensa) targets deletions of exon 43, exon 45, exons 38-43, exons 40-43, exons 42-43, and exons 45-t4

 

Steve Wilton's group in Australia has been investigating skipping of other exons and AVI and Prosensa are both looking at additional exons as well, although none are in clinical testing yet.   Skipping exon 21 should theoretically put a deletion of exons 22-41 back into frame, but I don't know how functional that dystrophin would be (no reason to think it wouldn't work, but not every deletion is leaves the gene functional, even when in-frame).

 

Sharon

 

Sharon Hesterlee, Ph.D.

PPMD Research Director

For those who are interested, there's a great map on the Prosensa site that allows you to work out what exons would need to be skipped to bring your son's mutation back into frame: http://www.prosensa.eu/patients-family/duchenne-muscular-dystrophy/...

 

The key is that the ends of the exons must fit together appropriately and any pieces that you can remove to make that happen are fair game in theory. Of course for technical reasons it's not always possible to skip every exon (multiple exons are particularly tricky) and not every in-frame deletion results in a functional dystrophin, but this is a good place to start if you want to try to figure it out.

 

Sharon

Hi Sharon, 

 

I've wondered about the feasibility of these treatments becoming available in the near term - at times the approval process seems so daunting. There is a table at the Leiden Muscular Dystrophy Pages:  http://www.humgen.nl/lab-aartsma-rus/Table%20deletions.pdf - so I know what we need to skip, and I am pretty sure Steve Wilton has the AON produced in the lab, but what are the chances we'll see that in production in the next few years?

In Annemieke's web conference last year, she said AON's have been created for every skippable exon.  

 

I think the IND, indefinite trial scenario Wilton talked about last year is the most likely way to have these compounds available in the US in anything close to the near term.  That's going to be costly.  And risky.  And I haven't heard anyone talk much about it lately...

I think it all depends on whether or not the regulatory agencies will be willing to approve the AONs as a class rather than as individual drugs and I think it's likely that one or two will have to get on the market first as individual drugs before they are considered as a class.  So Exon 51 and 44 drugs might become available, if they are successful, within a few years, but it will likely be a few years after that before additional exons can be skipped.  But hopefully we can get them approved as a class at that point...

 

Sharon

Under that kind of scenario, we're talking about a couple of years until 51/44 approval, and then a couple of years on top of that to see anything beyond that - if we can get approval as a class.  If we don't - then what?  There's no business case for the less commonly needed drugs to go through a full approval.  And - those drugs may actually be more effective than 51/44.  51/44 were chosen because it helps the most people, and thus has the best business case.

 

Someone was talking late last year in the blog section about starting a biotech to go after an N=1 study for his child's deletion.  Have you heard anything more about that?

 

 

 

is exon skipping  the only option?

No, exon-skipping is definitely not the only option....drugs that build muscle mass like Acceleron's ACE-031 are good possibilities as well as drugs designed to upregulate utrophin (biglycan, the Summit drug, the Project Catalyst utrophin upregulator).  There are also drugs in development that act through the steroid pathways without stimulating the side effects and then there are things like Prothelia's laminin 111 and gene therapy  to replce dystrophin directly as well....ultimately a combination of things will likely be required.

 

Sharon

Keith, I think that 2 years+2 years is very optimistic unfortunately. I do not even see skipping 51 approved in 2 years. It takes 1-2 years AFTER the clinical trial including analysis of data is completed to obtain FDA approval (IF the results of the analysis look good). I would estimate exon 51 hits the market in the US in ~3-4 years if not more, assuming the results from the pivotal trials are good.

Best scenario probably for the boys participating in the trials, after the trials are completed, if the pharma companies continue to provide the drug at no cost before market approval... But it's going to be a LONG way until then



Keith Van Houten said:

Under that kind of scenario, we're talking about a couple of years until 51/44 approval, and then a couple of years on top of that to see anything beyond that - if we can get approval as a class.  If we don't - then what?  There's no business case for the less commonly needed drugs to go through a full approval.  And - those drugs may actually be more effective than 51/44.  51/44 were chosen because it helps the most people, and thus has the best business case.

 

Someone was talking late last year in the blog section about starting a biotech to go after an N=1 study for his child's deletion.  Have you heard anything more about that?

 

 

 

Of course to me it appears as though you all are referring to regulatory approval here in the states only (?).  I do believe approvals are going to take place in other parts of the world well before it happens here, cause it's going that way right now.  Therefore, it becomes necessary to formulate plans to take boys from the US to places where meds are available.  I realize many think this approach is nuts, but it has always been my opinion that nuts is still better than dead. 

 

It would be good that organizations such as PPMD and all the others begin formulating plans now on how they can assist US families with this and soon.  If organizations can't/won't help make this happen, then it is left to us as parents. 

 

Any thoughts?

Cheryl, I am talking about US approval o/w the majority of us do not afford to treat our sons. If exon skipping is approved in Europe one would need hundreds of thousands of dollars for one year of treatment and a doctor in the US willing to dose thier son weekly or every other week. Finding a doctor to inject the drug would probably be much easier than finding the money to pay for the drug. I do not think the DMD foundations would be able to cover the price of the drug, if they do for one boy they would need to do it for all which means millions/year.

cheryl cliff said:

Of course to me it appears as though you all are referring to regulatory approval here in the states only (?).  I do believe approvals are going to take place in other parts of the world well before it happens here, cause it's going that way right now.  Therefore, it becomes necessary to formulate plans to take boys from the US to places where meds are available.  I realize many think this approach is nuts, but it has always been my opinion that nuts is still better than dead. 

 

It would be good that organizations such as PPMD and all the others begin formulating plans now on how they can assist US families with this and soon.  If organizations can't/won't help make this happen, then it is left to us as parents. 

 

Any thoughts?

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