What can we do NOW to get next trials for SMT C1100 (utrophin upgregulator) in the US in the future?

http://www.ox.ac.uk/media/news_stories/2011/110505_1.html

 

Considering that BioMarin has scrapped their similar program, and that Dr. Davies is at Oxford, I'm very concerned that the next phase of trials for SMT C1100 will happen in Europe or elsewhere outside the U.S.

 

In my opinion when this happens the FDA uses it as an excuse to take "wait and see" approach and for those of us with boys in their teens, that is of great concern.

 

My son in particular will likely not benefit from exon-skipping or other mutation-specific treatments. Utrophin-based treatments appear to be the most directly applicable to him.

 

What can I, as a parent, do NOW to help ensure that he can participate in the first human trials? We just don't want to wait and see any more.

 

-David

 

 

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Hi Bob,

As stated by Pat we have a proposal currently under review by PPMD.

Regarding  Phase I trials, which are usually healthy volunteers, there are generally no issues in recruiting as they are paid “volunteers”. The specialist clinical site where Phase I trials are run usually has a large registry of people offering their services so recruitment is swift.  It is also worth noting that the volunteer is essentially admitted into the Unit and remains there throughout the time of their particular dosing regimen constantly being monitored and tested. So if the protocol stipulates 12 days of dosing they will remain in the Unit ward day and night for two to three weeks depending on what additional tests are run.

Regards, Jon

we just need to  get the funding,well i have my fundraising hat on!!! thanks Jon
Exon skipping has commercial potential beyond Duchenne; utrophin does not.  That is why more money is being poured into exon skipping.  Similarly, that is why PTC-124 got money.  Duchenne is not viewed as commercially viable unless the drug has blockbuster potential in populations other than Duchenne.  I think utrophin is one of our best shots, but it is only relevant to Duchenne.
amit gupta said:

It is certain that there has been more support for exon skipping even though the % of boys who would benefit from it is low. One would think that the most money would go to support research/trials that would benefit all the boys rather than a small subgroup.

Summit is looking for funds for phase 1, possibly around a million dollars. It would seem that between MDA/PPMD/European organizations, that should be possible. The challenge for us (parents of non-exon-skipping boys) is to ensure that it happens.

I would like to clarify a couple of points which are a little misleading.

  1. Exon skipping has commercial potential beyond Duchenne; utrophin does not. That is why more money is being poured into exon skipping.

Each exon skipping drug designed for Duchenne only has use in Duchenne. The DNA sequence used in the morpholino/oligo to skip a set of dystrophin exons is only found in dystrophin so has no applicability in any other disease. The concept, the technology of exon skipping has potential use in many other diseases but the exon skipping drug, something you can administer to patients, only has use to alter a very specific gene. So all the money being poured into exon skipping to make a prescription drug for each sub-set of DMD patients will only be useful in those DMD patients.

  1. Similarly, that is why PTC-124 got money.

No - the PTC case is different. Ataluren alters a general cell mechanism which is appropriate for many disease genes where it is known that one part of the problem is where the manufacture of the protein is stopped early because of a mutation. The reason why it might be appropriate for many diseases is because it alters a cell process which is used by all proteins when they are being made. I imagine PTC got their money from Genzyme because the identical compound (drug) which can alter this cell process can be immediately tested in different clinical trials in other diseases.

  1. Duchenne is not viewed as commercially viable unless the drug has blockbuster potential in populations other than Duchenne. I think utrophin is one of our best shots, but it is only relevant to Duchenne.

In commercial terms DMD is a potential “blockbuster” drugs so please don’t think that the big drug companies aren’t really interested in DMD – they are. Very conservatively if there are 50,000 DMD patients worldwide, and you have a drug that is better than steroids and works in all DMD so even if only 50% took the drug and because it is an orphan disease you can charge say $20,000 per year then that is worth 0.5 billion dollars per year. Regarding orphan pricing I note from another thread on this Community site someone stated that Idebenone (Catena) in Canada for FA is $40,000 per person per year.

I obviously agree that utrophin upregulation is one of the best shots.

 

Jon,

 

Thank you for the informative dialogue.

 

My family has been quite active in the fund raising efforts to cure/treat Duchenne.  I keep trying to think of new ways for people to donate or promote pharma research.

 

For discussional sake, let's say someone has a rich Uncle or a family member has a large sum of money in their 401K's.   I see Summit PLC is a publicly traded company (http://www.summitplc.com/investors1.aspx).  

 

If a person is not inclined to donate cash but would rather trade a stock in the direction of finding a cure/treatment for Duchenne, how would the purchase of Summit PLC stock directly or indirectly help the chance of seeing SMT C1100 through trials to general availability?

 

Kindest regards,

 

Bob Getler

 

~~ 

 

Go to www.ParentProjectMD.org/Amazon to raise money for PPMD! 

PPMD makes approx 5% of purchase price and you pay the same price regardless.

 

 

 



Jon Tinsley said:

I would like to clarify a couple of points which are a little misleading.

  1. Exon skipping has commercial potential beyond Duchenne; utrophin does not. That is why more money is being poured into exon skipping.

Each exon skipping drug designed for Duchenne only has use in Duchenne. The DNA sequence used in the morpholino/oligo to skip a set of dystrophin exons is only found in dystrophin so has no applicability in any other disease. The concept, the technology of exon skipping has potential use in many other diseases but the exon skipping drug, something you can administer to patients, only has use to alter a very specific gene. So all the money being poured into exon skipping to make a prescription drug for each sub-set of DMD patients will only be useful in those DMD patients.

  1. Similarly, that is why PTC-124 got money.

No - the PTC case is different. Ataluren alters a general cell mechanism which is appropriate for many disease genes where it is known that one part of the problem is where the manufacture of the protein is stopped early because of a mutation. The reason why it might be appropriate for many diseases is because it alters a cell process which is used by all proteins when they are being made. I imagine PTC got their money from Genzyme because the identical compound (drug) which can alter this cell process can be immediately tested in different clinical trials in other diseases.

  1. Duchenne is not viewed as commercially viable unless the drug has blockbuster potential in populations other than Duchenne. I think utrophin is one of our best shots, but it is only relevant to Duchenne.

In commercial terms DMD is a potential “blockbuster” drugs so please don’t think that the big drug companies aren’t really interested in DMD – they are. Very conservatively if there are 50,000 DMD patients worldwide, and you have a drug that is better than steroids and works in all DMD so even if only 50% took the drug and because it is an orphan disease you can charge say $20,000 per year then that is worth 0.5 billion dollars per year. Regarding orphan pricing I note from another thread on this Community site someone stated that Idebenone (Catena) in Canada for FA is $40,000 per person per year.

I obviously agree that utrophin upregulation is one of the best shots.

 

Thanks Jon for all these informations. You clarification are very useful.

Whether utrophin upregulation ( and SMT C1100) will help becker patients also. If yes, that will increase the potential market here.

But what confuses me is that as such Utrophin upregulation ( and SMT C1100) appears to solve many of our problem. I mean,it will help all our boys, it does not seem to have safety issues, it will not cause immune reaction, FDA/other regulatory agencies should not have any new issues with this.... and much more.Also, exon skipping will convert Duchenne to BMD. 

So why many of our Duchenne groups are not devoting much attention/funds here. (I am aware of PTC utrophin project and ACTION DUCHENNE grant to Summit). But apart from that not much money/attention/debate for utrophin upregulation as a technology.Am I missing something here.   



Do we know that utrophin upregulation in humans solves any problems?  At this point, I don't think anyone's even been successful in producing utrophin in a human - and what it does once it's there in a human body outside the uterus is only speculation, as far as I understand. 

 

Someone please correct me if I've got it wrong.

Also important, how many fold increase in utrophin would be needed to make any difference. Modest increase would more likely not do much right? I remember reading that PTC's compound produced more increase than Summit's in preclinical studies. Were any of these compounds studied in a bigger animal (monkeys, dogs?) or only in mdx? I am only aware of mouse data.

Keith Van Houten said:

Do we know that utrophin upregulation in humans solves any problems?  At this point, I don't think anyone's even been successful in producing utrophin in a human - and what it does once it's there in a human body outside the uterus is only speculation, as far as I understand. 

 

Someone please correct me if I've got it wrong.

 Biglycan by Tivorsan Pharmaceuticals can upregulate utrophin.

http://www.tivorsan.com/wp-content/uploads/2011/03/020311_Biglycan.pdf

That's in mice. 

Jason Darienzo said:

 Biglycan by Tivorsan Pharmaceuticals can upregulate utrophin.

http://www.tivorsan.com/wp-content/uploads/2011/03/020311_Biglycan.pdf

In answer to some of the questions and comments about utrophin.

Utrophin is found in all tissues in children and adults. In fetal muscle, whether in mice or humans, there is only utrophin protein, with no dystrophin present.  In this case the utrophin is doing the same job as dystrophin.

As healthy muscle matures the production, or expression, of utrophin is switched off like a tap and dystrophin expression is turned on to replace utrophin. In healthy adult muscles utrophin is then only found at specialist areas; where the nerves touch the muscle and at the end of the muscles where the tendons join.

If you damage healthy muscle for example through exercise, the damaged fibers degenerate and the gaps are filled by myoblasts (expressing utrophin) which fuse to become newly formed young fibers expressing utrophin which mature to become adult dystrophin bearing fibers completely repairing the damage.

In DMD patients, and DMD animal models, the muscle fibers mature in the same way as healthy muscle with utrophin production being eventually switched off but because there is no dystrophin to replace the utrophin, the fibers quickly get torn apart and degenerate. If you look at sections of DMD muscle biopsies there is evidence of lots of utrophin present and this originates from the regenerating (young) muscle fibers present in the section at the time of cutting.

The utrophin therapy strategies being developed are trying to keep utrophin present in muscle as long as possible to allow it to do the job of the missing dystrophin.

Summit’s unique approach is to keep the utrophin RNA “tap” turned on by using a drug (SMT C1100) to interfere with the natural turning off process. With the continual expression of utrophin RNA you keep utrophin protein around all the time to allow it to do the basic job of dystrophin.

The other approaches are either looking at ways of making more utrophin protein from the natural utrophin RNA levels (e.g. PTC) or “stabilizing” the normal utrophin levels so it takes longer to degrade (e.g. Biglycan). In these approaches however the utrophin RNA tap remains turned off so no more new protein can be made. 

I believe that it is not necessary to make any more utrophin than the levels the young fibers already make – nature has already determined this level. SMT C1100 does this and more in DMD muscle cultures. The amount of human utrophin needed to improve or even cure human muscle function can only be answered through clinical testing in DMD.

All these different utrophin approaches could be complimentary to all approaches and enhance the benefit for patients.

Buying a stock on an exchange from another owner has little effect on a company's ability to finance its operations.  If this was a new stock offering - yes - but not buying it on the stock exchange.  The money you pay goes to the owner of the shares you're buying - not to the company.

 

If you had a very large sum of money, you could buy enough shares to get a seat on the board of directors and try to influence company direction.  Or, buy a controlling interest.  The company's market cap is about USD$1.6 billion, so you're talking hundreds of millions...

 


Bob Getler said:

 

For discussional sake, let's say someone has a rich Uncle or a family member has a large sum of money in their 401K's.   I see Summit PLC is a publicly traded company (http://www.summitplc.com/investors1.aspx).  

 

If a person is not inclined to donate cash but would rather trade a stock in the direction of finding a cure/treatment for Duchenne, how would the purchase of Summit PLC stock directly or indirectly help the chance of seeing SMT C1100 through trials to general availability?

 

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