Exon skipping – waiting, worrying, and limited information

AVI issued a press release earlier this week. If you read the press release you will read that the DMD program AVI 4658 is on “clinical hold”. This means that the FDA’s position is that they do not have sufficient data to agree it is safe to move forward. In the past months, AVI has changed its leadership, recruiting individuals who have experience in drug development in rare disease. Several of these individuals came from Genzyme. AVI is currently in discussions with FDA in an effort to provide sufficient information to lift the clinical hold.

In parallel AVI is moving forward internally, developing protocols and identifying sites for clinical trials. NO recruiting can take place for exon 51 until the ‘clinical hold’ is removed. It is illegal and unethical. I understand that many of you contacted Jerry Mendell and other sites about the trial but at the moment there are no trials and there can be no recruiting.

Here’s what we know about the current status of exon skipping:

Prosensa has completed their dose escalation trial. We know that their chemistry is safe thus far and that the subcutaneous injection of the chemistry resulted skipping exon 51 and production of a shortened (truncated) form of Dystrophin. We do not know if this protein is efficient – if it results in improved function.

The AVI chemistry (PMO) has been injected IV in the UK trial. Again, we know that thus far it is safe and that it successfully skipped exon 51 and resulted in a shortened form of the protein. We do not know if this shortened protein is efficient at this time.

There is a basic assumption that skipping a single exon, restoring the frame with expression of the shortened protein will result in stabilization of function, slowing degeneration, and functional improvement. This is the reason for clinical trials (human studies). We have mouse data, human muscle data (in culture), and dog data (PMO – 2 dogs). I realize we have our hearts on this strategy and with good reason, but we cannot put the cart before the horse at this moment.

We can expect Prosensa will move forward in multi-site trials, hopefully this year. They will need sufficient numbers of patients (exon 51) for proof of concept. They also plan to skip exon 44 with trials in the US.

Hopefully AVI’s discussions with FDA will result in lifting the clinical hold and clinical trials with exon 51. There is discussion about additional exons to include 50, 53, and 46, as well as discussions about second generation compounds, adding a peptide( PPMO) to the chemistry to improve efficiency.

Seems we have been hearing about exon skipping for years. Duchenne Parent Project (the Netherlands) and PPMD initially invested in this strategy in 1998. Statistically, it takes about 10-12 years for drug development, so we are at the forefront of trials and (cross fingers and pray) the trials will provide proof of concept. BUT we have to have trials and those trials are going to take some time - and it will be nerve racking, frustrating, and difficult. There are no shortcuts and no one gets in line before another. Once FDA gives the green light, the trials will be public knowledge and boys that are potential candidates will be screened. ALL potential candidates will be screened – blood work, genetic testing (re-testing), biopsy, functional testing. They will need sufficient boys in each trial in order to ‘power’ the trials and hopefully demonstrate proof of concept.

Once there is ‘proof of concept” on at least one or more exons, we are all hopeful FDA and EMEA will agree to streamline the process to accelerate chemistries for other mutations.

To me, the really good news is that both companies have recruited leadership from Genzyme, individuals experienced in the drug development process in rare disorders. My interpretation is that industry leaders see that antisense oligonucleoties are very promising and very likely to provide benefit to Duchenne.

The most difficult thing is the wait...and we have all been waiting since that word Duchenne entered our homes.

Things to think about:
1. Don’t make guesses. There are loads of rumors, try your very best not to get caught up in them.
2. Register on DuchenneConnect (www.duchenneconnect.org). The moment a trial is open for recruitment, you will be notified.
3. Understand that boys who qualify will be screened. For proof of concept, large numbers of boys will be needed for the trials. Those who fit the mutation criteria and fit the protocol will be screened and included.

The community feels fractured, the ‘haves’ and the ‘have –nots’ with so many feeling their sons might be on the outside of treatment and cure. The field is ripe with possibilities. Please (I’m begging here) understand that we are going to do everything possible to accelerate every opportunity. Discussions based in anger, rumor, or guesses divide us…just when we need to stick together and watch the sun rise for our boys.

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Comment by cheryl cliff on May 13, 2009 at 1:08pm
Hi Pat,

Your expertise and wisdom regarding this extremely complicated issue is very much appreciated, thank you. Would it be possible for you to comment a bit further on the possiblity that Prosensa may seek trials in the US, specifically you mentioned skipping exon 44 (Alexander's mutation)? I was wondering if they might possibly have some idea as to (sorry, I know, the $60 Mil question) when this may take place...are they aiming for some timeframe, and if so what might that be?

Also, is there anything we parents could or should be doing to help things move along with the FDA?

thanks again-
cheryl

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