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 19, 2009 at 11:56am
Ok, just remember we are here for you anytime you need.
Comment by Ian Anthony Griffiths on May 19, 2009 at 9:38am
i dont need oxygen. There would be no way of heating my food, i've never gone out with it on outings. Going for a pee is fine, i meant the "other" way. I know about vents, i have asked my respiratory team about it, am waiting on them. Big snag is a portable suction machine. The one I have is brilliant at home but we have to take a heavy battery pack if we go out and that isn't practical. I have asked my local authourity and have been told they dont have the resources, am again waiting on them. My last point is I dont want to go out with all of this bother, my computer and artwork keep me happy and are fun. Thanks for your suggestions, i am grateful.
Comment by cheryl cliff on May 18, 2009 at 7:31pm
Ok, I'm checking into a portable vent for you. I suspect your food, albiet processed, can be taken for an outing - is that correct? I have seen "relief tubes" used on small planes (for men of course) and will ask after such contraptions for guys in chairs. Does your van have a place for the oxygen to be strapped down?
Comment by lisa burke on May 18, 2009 at 6:22pm
You're right Ian. Increased assistance and independence for men with Duchenne would, indeed, benefit all. And it would give us parents of young children a certain peace of mind that our children's futures are adequately catered for also. Let's hope the lobby and press stuff highlights this.
Comment by Ian Anthony Griffiths on May 18, 2009 at 1:27pm
Travel by van, but its all the equipment needed and I cant eat "normal" food or go on the toilet without my hoist, plus I have to get back to my ventilator (not exactly portable) by a certain time. Its risking to much driving further than Cardiff. Also Wales should have the facilities here, for more than just me. Having it come to my house would be ideal, but Cardiff is ok.

I want to wait to see what the welsh lobby achieves next month. I am just saying here not to forget the so called older guys (20+ isnt old). If the scientists attempted to solve the worst problems older guys have, it would benefit all. At the same time as offering treatments aimed at the kids.
Comment by cheryl cliff on May 18, 2009 at 11:47am
I believe you Ian, and didn't mean to sound harsh at all. Just wanted you to understand we are here to help in any way possible. I don't live in Wales, thats true. I don't have DMD, but do see what it does to my son. I have no expectations for you regarding hope or anything else, I just want to assist making life easier for you if at all possible. Who can say how you should feel, not I, anger is understandable with your circumstances.

Without wanting to get too personal can I ask about your method of travel to the hospital - by car or train? What specifically makes the trip difficult - the vehicle you travel in or medical equipment needed along the way? What would make the trip easier - a better method of travel or having care come to you?

Even tho we are far away we do care:)
Comment by Ian Anthony Griffiths on May 18, 2009 at 10:58am
My hope is not lost in a treatment, only exon skipping seems a bit to late for me, that seems hopeless to me.
I'm not losing hope and not going to die quietly in the corner, like I said i'm campaigning politically for change here in Wales with the uk ppmd (ActionDuchenne).

The only thing that could make my life easier is proper healthcare in my home country. I can barely make a 40 miles trip to my current hospital. Let alone over 100 miles. The need for counselling passed me by years ago.

You do sound quite harsh when you are not living here or in my situation. Hope feels very distant for me in terms of exon skipping, and how long can I wait for the next treatment to help adults. Now how do you suggest I keep my hope in the face of that. I am not giving up though, there are other avenues coming out. If I am "doomed" then I want to make sure the next generation doesn't have to be. I am a positive, determinded person believe it or not.

Comment by Jacobs Mommom on May 18, 2009 at 10:41am
That is a great idea Cheryl! We need to stand behind our older boys too. We need to let them know that we care about them and want to help. You give us some ideas Ian and we will follow your lead.
Comment by cheryl cliff on May 18, 2009 at 9:51am
Hi Ian,

Your post clearly shows you feel you are running out of hope. I understand why those feelings exist for you as your situation sounds dire. My Welsh friend (currently she is a nurse here) confirms what you say about lack of decent medical care in Wales. Thank god your mum is there for you.

But my question to you is - is there something I/we can do for you to make your life better? Should I/we contact Dr Muntoni to find out who he recommends for DMD adults? Would it be possible to travel to London for medical care sometimes? Do you require additional medical equipment to make life easier or perhaps something than can help you have more fun? Is there something I/we can do potlitcally push for a change at the Welsh assembly? What about counseling to possibly lift the spirit?

I don't mean this to sound harsh but is there no other option out there for you except to lose hope?

Comment by Ian Anthony Griffiths on May 17, 2009 at 12:49pm
pat you said I think antisense (exon skipping) has the potential to become a therapy. I do not think it is a 'cure' or a 'fix' in the sense that your son could be free of Duchenne. I think it potentially promises to dramatically slow degeneration. I also think it will take from 2-4 years to complete the trials and prove efficacy. In parallel other exons will move through the process. BUt I also think sometimes we forget the dramatic effect of care, the 'stuff' we know right now.

So does this mean those of us older than 20 are screwed? Dramatically slowing degeneration is definitely after the horse has bolted for me. Not much muscle left in me, i'm sure of that, if waiting 2-4 years to see if its viable, i'll have even less time and muscle. Will I even see my 30th birthday? Impossible to answer I know, I want to get there and then some, but realistically looking at my body, with its increasingly already overly damaged muscles dying off, more ventilator use , heart is in "failure" mode. It seems like my hope is puffed out. I'll have to pin hope on utrophin or something like that.
Then talking about care, well here in Wales, UK theres no medical centres that know of DMD, theres ignorant dr's who know nothing DMD related, no muscle specialist to even ask for a treatment weather proved viable or not. No advice for all these "interventions", we have to teach physios (PT) what is correct, and they still might do the wrong thing. I only have a vent because I was ill and thats the only thing they could give me to save my life, when i nearly died at 16. They also did the mini trach at the same time. Nothing was done as a preventative measure it is all reactionary medicine. The lack of a spinal fusion stopped me getting a feeding tube put in. Its very lucky i can swallow supplements and puree food. The only thing offered is newborn screening, but that is irresponsible of the medical professionals here because there is no care or support.
I and ActionDuchenne are lobbying for change at the welsh assembly, the change in care could take years on top of any trial results. Yes care and support is vital, but in the UK it depends on where you live, Wales is a huge void. My mother gives me the best care, not the medical professionals.

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