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 lisa burke on May 17, 2009 at 10:58am
Thanks Pat. You're very kind.

Comment by Pat Furlong on May 17, 2009 at 10:15am
Hello Again, Yes, I think we will learn a great deal about exon skipping in the next months and years. And it is my belief, that based on what we know now, it will help your son.
With regard to his progress thus far. He is meeting or exceeding the developmental milestones. This is a good sign and should tell you that he is progressing normally thus far. So this is good news. With regard to activity, our boys are the best guides. Typically they are quite good at self monitoring as they grow. I think ou encourage him in every way possible. It is finding that balance - encouraging him but not suggesting he over-exercise or at some point down the road, lift weights. It is finding that balance -encouraging activity, swimming is wonderful, but not overdoing to the point of exhaustion.
Your son is talking and that is wonderful. What we do see is that some of the boys have trouble processing large amounts of information. Issues related to learning can be 'fixed'. Jos hendriksen, James Poysky and Veronica Hinton are wonderful in this area. Jos is working on a book that will be an amazing resource for families.
Lisa, you are now surrounded by a wonderful family - experts in the field and very connected. Please do not feel you are living in ignorance or are any longer alone. We are in this together and we will make sure your beautiful son is in the best of hands and has access to promising therapies.
Warm regards,
Comment by lisa burke on May 17, 2009 at 10:00am
Thanks for your reply Pat. I know that exon skipping will not be a cure for my little boy, but I just need to know that my hope if it being a therapy is 'real'; that he may be walking and enjoying as normal a life as possible in his teens and maybe twenties and then, after that, who knows? Half of the clinicians we have 'caring' for our baby here have never even heard of the trials and research. When we received the diagnosis - at 7 weeks old - we were just told "wheelchair by 10, dead by 15. Fact. Go home and 'enjoy' what time you have left". It's only by finding out stuff ourselves that my husband and I realise that this is not necessarily the case.
You're right about the constantly 'looking' for signs. My baby is only 5 months old and is a chunky little chap. He already loves to stand all the time and I find myself wondering if this is bad for him, if it'll hasten the disease, if his chunky little legs are actually signs of muscle degeneration or just 'chubby baby'. None of our clinicians can, or will, say. He can sit up unaided already. Is this a good thing, a sign of strength, or will it weaken his core muscles? He already says "mumum" and "dada", is this a sign that his intellect is largely unaffected or does it mean nothing? No-one will, or is able, to tell us....All these questions and no answers. We live in constant anxious ignorance.
If the exon skipping research is proved to be effective, do you think it'll be in time for our little one?

Comment by Pat Furlong on May 17, 2009 at 8:32am
Hello Lisa,
That is the million dollar question. Here's what I really think. 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. There are boys walking in their teen with current interventions (steroids, pt, night splints, GH, ace inhibitors). Adding a potential therapy such as exon skipping will provide significant benefit to existing therapies. In addition, there are other potential therapies nearing trial and these could provide additional benefit. My sense is that your son's generation will live long, functional lives. I cannot guess or promise that he will never need a wheelchair for long distances or for short distances, but Duchenne will have treatments. Lisa, this is a journey and one of the most difficult aspects is the unknown and the fact that there is no guidebook. All of us want to know what tomorrow, next week, next year will look like. You find yourself staring at your son's calves, watching every move, wondering if you are seeing signs. Each fall feels like a knife in your heart, worried that it is a sign. I was just in a meeting where one of the lead experts in the field said 'treatments are on the horizon'. I asked him whose horizon and when they would be available. He gave me a strange look at first and then he realized, that 'treatment' and 'horizon' mean different things to each boy and his family.
Lisa, I will never promise what is unsure. We have good data on the antisense, but my guess is that it will need to be optimized and that will take some time. But the world of Duchenne has changed and will continue to change, thank God.
Carrie, you are right. I inadvertently forgot 45. There are a range of aon's moving forward. UPPMD is working with Prosensa to provide support on the less common mutations and double skipping.
Lisa, I understand you are frustrated by the UK researchers keeping things close to their chest, while others are out there pitching 'this will happen tomorrow'. I wish there was some middle ground so that we all could follow the process step by step, grounded in realistic hope. Often in my own journey I found I myself high on hope or falling apart with despair. I think we all have great reason to hope and I believe that if we take this journey together, our sons -your sons - will live long wonderful lives and reach for their dreams.
Comment by lisa burke on May 17, 2009 at 7:33am
Hi Pat
I'm going to ask you the million dollar question. One you've probably been asked a thousand times before. My 5 month old baby boy would benefit from patch 51. Do you really think he will have a chance of an improved life? Do you really think that this may become available and work for him? I'm asking you as you've obviously so much experience of watching emerging potential therepies. Essentially, do you think that the exon skipping is a 'real' possibility or just another hope that us parents can cling to in order to remain living??? I live in the UK and the exon skipping researchers keep their cards very close to their chests.
Comment by carrie on May 17, 2009 at 12:50am

Did you inadvertently leave 45 off your list of next exons being pursued. Given its frequency and the likelihood of creating a Beckers it would be odd for it not to be pursued along with the others in the "most frequent top 5".


Comment by Pat Furlong on May 16, 2009 at 3:20pm
Hello Again, I appreciate your feedback on DuchenneConnect. I have contacted Vanessa Rangel and discussed concerns. We developed DuchenneConnect as an interactive tool and want it to be just that. DuchenneConnect downloads data from Clinicaltrials.gov. If a study is not listed on that database, it would not be picked up. Clinical studies such as the MRI study in Florida are not listed on clinicaltrials.gov because they are clinical studies rather than clinical trials. In the future, we will expand our searches to include international sites, CRISP data (nih/lists clinical studies), clinical trials.gov, AFM (french) and international sites. We will do everything possible to keep you informed and I would ask that you keep us informed as well.

Comment by Pat Furlong on May 15, 2009 at 7:54am
I understand you are terrified that you might miss an opportunity. I have connected with Vanessa Rangel (Emory Genetics/DuchenneConnect) about the outdated information. The website intersects directly with Clinical Trials.gov so we are looking to see if there is a glitch. Kyle Brown devevloped the platform for DuchenneConnect. Kyle has been wonderful and develops technology to connect government/academic and other sources. We are working with Kyle on a number of projects to include DRCI (mda/afm/ppmd/uppmd), UPPMD (international duchenne specific organizations) and Treat NMD (international clinical trial infrastructure) and MDCC (nih committee). Please always let me know if you are having problems with DuchenneConnect or connect with Vanessa Rangel (vrangel@emory.edu) directly.
I know well the importance of being connected. To be honest, this site and the uppmd community site are amazing sources of information because the individuals connecting represent so many different groups, physicians, clinics and connections.
You are always welcome to call me or connect with me anytime. I try my best to keep up with what is going on in the field.
Julie, the mutation you described would require an exon 50 skip. That being said, mutations are not simple and close evaluation of the type of testing and flanking regions is important and would be screened prior to trial.
AVI is working on exon 50 with the intention of the parallel track - -that is, after proof of concept with 51. Your boys names are already 'out there' based on the fact that they are being seen in a clinic. As trials begin, clinics will be notified. Notification for eligible families will be done through clinics, through regisitries, through websites such as ppmd. These companies and sites will be anxious to recruit for the very simple reason that the faster they recruit individuals, the faster they can screen, conduct the trial, collect the data and move toward an approved therapy.
You are probably tired of hearing, but the 124 trial is an example. They advertised everywhere - at conferences, websites, through clinics, in press. They needed to recruit 126 patients. In families where there were two boys , they counted both as 1 participant in the trial. They were fully recruited 2 months ahead of schedule. Interim safety data was evaluated when 1/2 of the boys participating had completed 1/2 of the study and finally the efficacy data will be evalaute in the next months. Exon skipping trials will follow a similar pattern, with aggressive recruitment. ALL trials will be listed on clinical trials.gov and we will fix the glitch with DuchenneConnect. There are other databases in the US (UDP and CINRG). DuchenneConnect and UDP are intergrated with Treat NMD. Personal data/Privacy are protected, but the data is aggregated into the global database with Treat NMD. This provides Treat NMD to reach back into all databases in order to notify patients/families about opportunities for trials. I think your bases are covered. I know well the feeling of waking in the middle of the night wondering if there is something you may have missed.
Please know, I am always available, happy to help and if I don't know the answer, I will dig until I find it for you.
Julie, I love the words you quoted from Habakkuk 1.5 Strangely enough, the family that mailed me the dvd said exactly that. The dad called me to say that if he lived in fear, everyday worrying and that if he had it to do over, he would believe that he would find blessings in this journey.
Warm regards,
Comment by Julie Hathaway on May 14, 2009 at 9:43pm
I, too, have been disappointed in Duchenne Connect and the lack of communication regarding studies and trials available. Thanks to you, Pat, Brandon will be participating in an MRI study in Florida beginning this summer. I would not have know had I not sought out information. Part of the problem is not knowing where to look for information. We as parents, as you well know, are desperate to do everything we can for our boys. We want to be on the cutting edge of what's going on and how to get our boys' names out there. Personally, I'm terrified of missing out on an opportunity that could save his life potentially. What are your thoughts and your advice. Thanks so much, Pat.
Comment by Julie Hathaway on May 14, 2009 at 9:37pm

I appreciate you and am so thankful that God has sent you on this mission on behalf of my son, Brandon, and all boys with DMD. I feel so good about what will be coming down the pipeline in terms this horrible disease becoming a treatable, cronic disease that will allow our boys to live wonderful, fulfilling lives. To paraphrase Habakkuk 1:5......."I am doing things in your day that you would not believe even if you were told." Wow! Those words from our Lord give me chills and sustain me each day! I'm looking forward to meeting you in Atlanta. We are new to the duchenne community and want to be sure we are doing everything in our power. Brandon has a deletion of 51. Doesn't this mean he needs an exon skipping of 50? When do you expect a trial to begin? Thank you so much. Julie Hathaway

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