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 JUAN PEDRO ARBULU on May 14, 2009 at 1:38am
Keep on focused Pat, we support you from backstage for what ever you need.

Thank you!!!
JP & Juan
Comment by Char Burke on May 14, 2009 at 12:47am
Hi Pat,
Great to see you in Seattle. I know you mention how important it is for all of us to band together. Ok - I hear you. Tell me though - is the exon skipping only available for the deletions and not the duplications? If only for deletions, can you tell me some thing that will help the duplications that I can hang on to? Thank you - Char Burke
Comment by Ofelia Marin on May 13, 2009 at 7:44pm
Right, the dose levels can be significantly lower with PPMOs. One other very important fact (maybe more important than the dose level (?)) is that they can be delivered to the heart and the PMOs cannot. The question is, if it takes such a long time to advance the PMOs, how many more years would it take for the PPMOs? Also, will they have the funding to go through trials with both PMOs and PPMOs? Unfortunately the window of time a boy can be treated with an exon skipping treatment is quite short.

Comment by Pat Furlong on May 13, 2009 at 5:32pm
Ofelia, clearly there is a major gap between the dose range in the UK trials and the dog study. It is for this reason they are working on the second generation compounds (ppmo). I have participated discussions related to dose as well as regulatory issues.
These early trials (prosensa and avi) will give us a significant amount of information for sure and I am also certain it will take some time to work all this out.

Comment by Pat Furlong on May 13, 2009 at 5:27pm
First we need proof of concept. It will do no good to go to FDA about accelerating exon skipping until that time. The FDA is not the 'bad guys' , rather wants to be assured the produce is safe and effective. Once those first exons get through trial and provide evidence of benefit, i am certain FDA will work with industry and advocacy in order to accelerate trials/proof of concept on other exons.
Comment by Tagni McRae on May 13, 2009 at 4:16pm
Is there anything we can do to try to influence the FDA decision at this point? Or does it all depend on AVI? Thanks so much for the update.
Comment by Ofelia Marin on May 13, 2009 at 3:47pm
One more question...I know, I have many, sorry about that!
Have you participated/attended any discussion/presentation where they mentioned something about the huge discrepancy in the dose levels used by Hoffman in dogs (120 mg/kg/week-200 mg/kg/week) and the systemic UK trial (highest dose 4 mg/kg, 30-50 times lower than those used in dogs)? I do know that they plan to increase the dose levels in the systemic PMO trial, but they are very far from 200 mg/kg. Anything you can clarify about this matter? I am just trying to understand if we can have any hope to see clinical improvement at this stage (using those dose levels).
Comment by Ana Vaish on May 13, 2009 at 3:04pm
Thanks Pat for the great input. Ryan needs skipping 51. He has 48-50 deletion. You made my day.

Comment by Pat Furlong on May 13, 2009 at 1:48pm
Both AVI and Prosensa have done formal inquiries via existing databases (duchenne connect and others)
the PRO systemic trial may not be made public, though my guess is both prosensa and avi will have something to say at the world muscle society meeting in September.

The 'WHEN" part depends on regulatory issues. Everyone has their heart on later this year for US trials.
Comment by Ofelia Marin on May 13, 2009 at 1:42pm
Thanks for the blog. Do you have an estimate for when the results of PRO51 systemic trial will be made public? Was the dose level in this trial high enough to expect improvement or this Phase was mainly Safety?

Also, maybe it wasn't clear enough in our discussion. There was no type of recruiting done by Mendell's group. After several discussions with AVI their intention was to size the possible candidate population. As expected, they received a very high number of replies from US and abroad. As mentioned, GLP tox studies need to be completed before the clinical hold is lifted and the trial gets green light to begin screening candidates.

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