The AON meeting in Washington, DC will be streamed. And we all sit on the edge of our seats, anxious to see exon skipping in trial, analyzed, and approved. We have heard bits and pieces of the first exon trial skipping exon 51. Press releases and rumors about the presence of dystrophin and what that means are rampant, and we still wait and wait for something, some news, some information, something about the IF and WHEN this might apply to your son. I thought it might be useful to provide some detail about what happened, how this meeting was developed, and what is hoped will be the outcome.

Last year, a meeting was held with EMEA (now EMA). This is the regulatory agency for Europe and while each country has their own specific regulatory requirements and issues, the EMA makes overall regulatory decisions. There is a lot of discussion about exon skipping and the promise of this technology to ‘snip’ together our sons ‘genetic recipe’ so that it restores the FRAME or restores the cell’s ability to make sense of the genetic information (recipe) and produce dystrophin, not the original recipe, but a shortened form. Something useful. Something that would place this shortened version of dystrophin right under the cell membrane and restore its connections with all of the other associated proteins. Something that would restore integrity to the muscle cell to some extent and slow the cascade of degeneration within muscle. And early results indicate that, at least in some cases, skipping one or more exons and restoring the frame does restore integrity/stability in the muscle cell and does, in fact, slow degeneration. At least that is what we know from cell culture and from animal data.

The community (research, clinical, family, people with Duchenne) want regulatory agencies to understand that this strategy is critical for many, that this strategy is likely to preserve function longer and buy time. This strategy is HOPE. And we all wanted to impress regulatory agencies to consider ways to streamline the process. For instance, if exon 51 clinical studies prove it to have benefit (efficacy), then would they consider, for instance, approving the backbone chemistry and modifying requirements for other exons, such as modifying the toxicology package, the clinical studies, and approvals.

During this meeting researchers presented data (animal data, safety, toxicology), clinicians discussed clinical studies, ethicists discussed risk/benefit and the ethics of children in clinical studies, informed consent, and to my mind, most importantly Elizabeth Vroom presented the patient’s side, starting with a video of 4 young men with Duchenne, discussing what THEY wanted/needed, what they believed would improve their quality of life. Elizabeth’s son, Justus, talked about the accommodation required to move his hands from his lap to a table, using his fingers to ‘walk’ forward, to ‘walk’ to meet his elbow, the lever approach to lift his elbow and ultimately get his finger into his mouth, and then his head to pull that arm onto the table. This demonstration, the ‘finger walking’, the ‘lever’, the accommodation, very familiar to all of us in the world of Duchenne, but very unfamiliar to regulatory agencies, provided with a ‘library’ of documents to sift through, was heartstopping and illustrative.

The meeting in Washington is a follow-on, on this side of the ocean, to talk about the same issues. The community (research, clinical, young men, and their families) believe in this approach and are interested in pursuing methods of streamlining the process, perhaps novel new approaches for clinical studies (N=1 or a few) to accelerate exon skipping as a potential treatment, to accelerate, not just the exons in the 40-53 area that are presented at meetings, but ‘skipping’ early for rare mutations and duplications.

We cannot expect Ann Pariser (FDA) or Rusty Katz (FDA) to end the meeting with decisions. Keep in mind that FDA has to react to a sponsor’s submission and does not speak in generalities. But at the end of the day, when Dr. Pariser /Katz and others go home, we want them to dream about Justus’s accommodation, think about all boys who might benefit from this strategy, and understand TIME. Buying time is the critical factor. The stakes are high, the risk is great, and TIME is critical.

The NINDS/FDA Antisense Oligonucleotide (AON) Therapies in Neuromuscular Disease Conference will stream live on September 27 and 28. Click here for more information, including webcast details and a full agenda.

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Comment by Ofelia Marin on September 28, 2010 at 4:43pm
There are many compounds/chemistries for exon skipping in DMD. If PMO's are not effective the problem is delivery. We already are not expecting good results in the heart and apparently diaphragm might not also show high levels of dystrophin. That does not mean that exon skipping as a technology doesn't have a realistic chance only that second generation compounds have a better chance. Of course, I am hoping PMOs do show some benefit and buy us some more time until second generation and/or other drugs are approved. Just get those trials started and so we can see if the drugs are effective or not...that's all we can hope for at this point.
Comment by cheryl cliff on September 28, 2010 at 9:40am
Yea, no casual glancing at the webcast for us!! You sure got that right. We DMD parents live in a tremendous state of fear, and you certainly identified several on the list. I don't hinge my son's wellness on the decisions of FDA even though they are sitting in the drivers seat regarding this skipping approval process here in USA. Most likely it will take them much longer to come to a conclusion since personalized meds are new to them and us. But, FDA doesn't own other regulatory agencies in other westernized countries. If somehow, God willing, another country is moving faster- for those who's sons are on the edge and can't wait (incl mine) we will go there. Yea, skipping might not work. But if that happens, then all speculation is moot and we focus on the next treatment coming down the pipeline. Cause that's all we have. But I doubt exon skipping will be cast aside because I believe pharma's are using DMD as a platform to open the market and use skipping for other diseases. I really don't believe they would have risked as much as they have so far, without knowledge and consultation of experts on risk, without comprehending the entire prospect. If they stop at 51, the other skipping compounds become worthless so why couldn't a non-profit purchase rights and manufacture? I'm not realistically execting that to happen, just speculating further.
Comment by Keith Van Houten on September 27, 2010 at 11:03pm
That's just my guess for exons beyond the first ones supported by $$ from big pharma. I have no data, I'm just speculating based on reading other people's speculation - so take it for what it's worth. Truth is - I don't think anybody knows how long it'd take.

Without an expedited approval process, there may not be a business case to ever go beyond 51. 51 gets them the most bang for their buck in terms of market. Each exon (in terms of how commonly it's needed) beyond 51 drops off in terms of the percentage of the DMD population that needs it. Is pharma going to invest in a full approval process for each exon when each one brings a smaller and smaller market? By the time you get to the 10th most commonly needed skip it's on the order of 2% of additional cases that would benefit from that skip. Drop out from that number the cases occurring in countries with no modern health care delivery system and drop out from that number patients incapable of paying for the treatment (the lifetime cost of which is going to be staggering if the investments from pharma are any indication), and you're talking about a very small market. Been a while since I looked at the numbers - so don't quote me - these are my recollection.

You can bet that pharma is also lobbying hard to get an expedited process and not have to do a full approval for every exon. There's hundreds of millions - if not billions - of dollars riding on this, on DMD alone. I would imagine it has implications for the approval process for all kinds of potential "personalized medicine" in the future, as well.

The truth that nobody wants to admit is that we don't even know if this is going to work at all. It's easy to forget that part.

It's interesting that the link for the morning session link works, because the webmaster guy told me specifically that it wouldn't be archived. Maybe they'll post up the afternoon session tomorrow? Watched a little bit live at work, but it's not the kind of stuff you can casually glance at once in a while, is it !?!
Comment by Ofelia Marin on September 27, 2010 at 10:27pm
No one knows what is going to happen if skipping 51 and 44 fail...just my opinion, if they fail there is a very slim chance to continue testing the same chemistry in other exons...they will probably focus on an improved delivery chemistry (PPMO etc.).
Comment by cheryl cliff on September 27, 2010 at 8:45pm
Sadly the webcast is only showing part of today's session. The afternoon session is going to remain a mystery to me unless they repost it later.

Yes, we can talk about timelines but I'm not sure exactically what you mean Keith, when you say we're "talking 4-5 years in the best case scenario". Do you mean 4-5 years from 2010 to have treatments available and approved for use for exons other than 51? Or do you mean 4-5 years they will begin clinical trials for rare deletions? Not sure where the estimation came from as well as what it relates to regarding what is currently going on (ie skipping trials just beginning in USA for exon 51 non-ambulatories as well as upcoming trials for skipping 50). Please help the more simple minded parent such as myself :)

Good question re:obtaining bad results for 51 & 45 resulting in complete failure of exon skipping for all.
Comment by Keith Van Houten on September 27, 2010 at 7:55pm
I'd really like to hear more about Wilton's N=1 concept, discussed in Sharon's blog post.

Clearly, the best case scenario are successful exon skipping trials for the first 1-2 exons and then an expedited process for approval of the remaining skippable exons. No one will argue that, and I applaud the efforts to promote that with FDA. Thank you.

FDA won't talk about a timeline - but we can. Realistically, we're talking 4 or 5 years in the absolute best case scenario to get to the less common exon skips - aren't we? And that's if FDA decides to allow an expedited process. That's time that, obviously, many boys don't have.

Sharon's blog seemed to indicate that the first exons might not necessarily even be the most effectively skipped exons. Does the whole thing die if 51 or 45 don't produce good results? What if skipping a less commonly needed skip produced better results for those patients? Would we ever know?

Can't we bypass this whole expedited FDA approval process for the less commonly needed skips with this N=1 / non-profit concept? Maybe the concept isn't realistic. Is the cost too high? Will people accept the risk?

Personally, I like the idea of being proactive and getting something to try available quicker, rather than hoping that we can convince bureaucrats in DC (as well intentioned as I'm sure they are) to see things our way...
Comment by Keith Van Houten on September 27, 2010 at 7:27pm
I got an email back - they are not archiving the webcast for download.
Comment by cheryl cliff on September 27, 2010 at 4:56pm
I understand there is to be no "timeframe" for FDA to make decisions regarding AON's and how to expedite the process through. Paul and I are extremely grateful for your representation, thank you so much. I'll be looking for your notes following today's meeting. Really enjoy seeing short clips of the presentations and some familiar faces/voices. I love your colorful outfit and the way Annemeike (sp?) still looks like a 16yr old :) God bless you both.

Comment by Pat Furlong on September 27, 2010 at 7:24am
exactly the goal Raktim. I want all of them to focus on dmd as an urgent need and commit to do whatever is possible, whatever makes sense (with safety in mind) and whatever it is that will save time for our sons. I will take notes and post this evening on day 1.
Comment by RAKTIM SINGH on September 27, 2010 at 4:11am
Thanks Pat and PPMD for representing us in this meeting.
Understand that we may not get any decision here but if we can really partner/positively engage FDA and can put AON technology and it's potential benefit to the humanity in their mind(may be top of the mind), it will be a big job done.
Hope and PRAY that we get some positive outcome from this meeting.

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