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.