Hello Again,
The meeting is going well. It is clear that antisense oligonucleotides are a promising strategy in DMD. It is not simple and there will be some bumps in the road. I also realize there are a lot of questions about duplications and early exons. Steve Wilton suggested that he has developed more than 650 chemistries taregeted agains a range of exons from 2-78, but that there are massive variations in efficiency. Keep in mind, this approach is expected to slow things down,changing a duchenne presentation into a becker presentation. Also keep in mind, becker is a spectrum with severe to mild symptomatology. In developing and testing various antisense oligos, it is critical to make sure the shortened protein expressed is not making matters worse. I understand the question in all of your hearts is WHEN - sometimes I think it is the only question that matters.
Prosensa is now involved in systemic trials skipping exon 51. As mentioned, these trials are underway at 3 sites in Europe. They need to get proof of concept, that means they need to prove dystrophin is expressed. What we (or hope to achieve) about systemic (sub cu) injecti0ns distribution of the aon throughout the skeletal muscle. I think we all realize that the distribution will not be uniform across all muscle, that some muscle will have better, more widespread expression and some muscles may have only a little. This was also see in the dog study (3 dogs in japan) that received massive doses of aon. Proof of concept in the Prosensa trial is the first step. The next step for them is to expand the trials into the United States. They have not yet identified sites but are discussing ideas with specific clinicians. If all goes well, their plans are to expand the exon 51 trials and in parallel open the trial to skip exon 44.
AVI on the other hand is currently working on exon 51 in the UK. They have completed the single muscle trial and will now move to systemic (sub cu) in a cohort of boys, dose escalation. This means that small groups of boys will receive increasing doses in order to figure out the therapeutic dose. This trial will take one year and in parallel, AVI is moving forward on exon 50 (per specific contract).
There is work going on skipping exon 46, 55, 44, 45 and 50. They need to learn what works better in terms of expression of a functional protein.
There was also discussion about uptake of the chemistries. Some believe that the aon's get in because of the membrane instability, while others think inflammation drives the uptake. There is actually difficult to determine and various ways of imagining are under discussion. In general, it was thought that all boys in future trials may be required to have 3 biopsies. The first to determine response - how well their muscle responds to a specific exon skipping approach. The next two would be pre and post systemic delivery. There is also discussion about what muscles to biopsy. Imagine if the systemic is not uniformly distributed and the biopsy is taken from a muscle that did not express this shortened protein. The biopsy may be negative for dystrophin expression, when in fact, other muscles may express significant amounts. So this is where 'the devil is in the details' in trial design.
I do know those of you who have boys with early deletions are asking 'what about us' and there is work going on. I know it is really tough to hear, but I do believe with proof of concept in these early days, we will see a number the aon approach rapidly expand. Interestingly Genzyme is here as well... they are becoming interested in aon and I am sure, with proof of concept, they will become much more interested.
AVI biopharm's product is the PMO (Morpholino). They present today, but did mention that their first compound is the PMO. With proof of concept, they plan to use the PPMO (a peptide is added to increase the potency of the oligo). Without exception, all companies involved realize the need to improve the potency of the compounds. This can be done by adding peptides (such as the PPMO) and possibilty adding some approved drugs in combination. We all agree that the best treatment will be a combination approach.

There is more to come today.

Warm regards,

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Comment by Pat Furlong on October 23, 2008 at 1:28pm
As you know PTC124 was first tested in healthy adults. It will not be the case for exon skipping. Phase I safety trials (single muscle/safety) were initiated in DMD boys (both chemistries -2-0methyl and morpholino) because of the specificity of the approach. Prosensa is expected to announce expansion of trials to US sites in 2009. AVI is in ongoing discussion with FDA. The regulatory issues have not been worked out. There is some general belief that once we have proof of concept with a single exon, regulatory agencies may be amenable to discuss a strategy to accelerate the process. Any number of people have suggested that regulatory agencies may approve the 'backbone' chemistry and accept a modified tox package for other aon compounds, but all discussions are a bit premature until we get proof of concept for one. Let's hope data analysis from the Prosensa subcu systemic and AVI iv systemic trials provides a major step forward.
My guess is C1100 (summit) Phase I would be dmd, but it is always difficult to predict how regulatory agencies will react.
Comment by Ofelia Marin on October 23, 2008 at 9:46am
I think that exon skipping is in the class of "gene therapy" trials. In those cases they don't use healthy volunteers.

Also, for orphan diseases, in many cases, the 1st phase is done directly in patients in order to reduce the time. I hope that this will be the case for Summit/BioMarin's utrophin upregulation as well.
Comment by James Poysky on October 22, 2008 at 11:47pm
Have the regulatory issues been worked out here in the US? Typically in Phase I trials you give medication to healthy volunteers to monitor for safety. However, if you skip exon 51 in normal volunteers, you will potentially cause DMD (at least temporarily). I can't see the FDA agreeing to let healthy people take a drug that they know will impair their health...not to mention the difficulty recruiting volunteers to take this step...
Comment by Ofelia Marin on October 17, 2008 at 5:45pm
Hi Pat,

Any more info from the meeting that you would like to share with us?

Comment by Ofelia Marin on October 16, 2008 at 12:16pm
Thank you!


Comment by Pat Furlong on October 16, 2008 at 10:56am
Sorry, you are right about the typo. Trying to type fast. First off, AVI wants proof of concept.
PMO –resistant to metabolic degradation and remarkable safety profile after systemic adm.
PPMO (artinine-rich peptide conjugates) – greater potency due to enhanced cellular penetration and reduced efflux from the cell
They are in discussion with regulators and will need in vitro proof of concept data. And will need to get tox data on the PPMO. These studies are planned and proposed. They are proceeding with the systemic study to skip exon 51. They do not yet know what level of dystrophin is needed for functional improvement. This is a dose ranging study, IV (sorry for the typo). It is dose escalation, not to prove efficacy, rather to demonstrate (immunohistochemistry and western blot) that dystrophin is expressed. Suggestion is that the level of 22-30% expression should be sufficient for functional improvement and would switch the phenotype from DMD to a Becker. In the initial studies, we are looking for clinical design over a period of 6 mo to 1 year that demonstrates functional benefit and hopefully get the drug approved. This first approval would open the door to expand the strategy across other mutations.
On our side - if a drug is approved, we would need to strategize our advocacy. If we know something works, I could imagine we would need to figure a way to utilize our advocacy to secure a government grant (or international) that would be applied to develop aon for the more rare mutations. Just thinking ahead...
Comment by Ofelia Marin on October 16, 2008 at 10:13am
Hi Pat,

I apologize about repeating myself... Could you please provide more details about this: "AVI biopharm's product is the PMO (Morpholino). They present today, but did mention that their first compound is the PMO. With proof of concept, they plan to use the PPMO (a peptide is added to increase the potency of the oligo). "

Do they plan to have a systemic trial with PPMO skipping 51 ones they obtain proof of principle from the PMO skipping 51??? The pre-clinical published results using PPMO looked good that is why I'm so interested in any plans for clinical work with those. Also, their systemic trial using PMO to skip 51 is IV not subcutaneous (I think you have a typo there), correct? My understanding is that with PPMO they can do the sub cu but not with PMOs.

Thanks a lot!

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