Today we completed the Phase 2 trial running at Nijmegen with the intermittent regime. The trail continues since the last participant was on boarded in Aug 2011. Doc tells that results should be published by late this year. No other information available except for the few readings we took along the year.

We lost quiet some mts in the 6MWT over the year. The way my kid has slowed down; I am pretty sure that we were on placebo. Over that there were nothing but a few instances of bacteria and WBC in the urine samples. 

However we start on the extension study in a month from now. The gap is needed to ensure that data for extension is isolated from the original study. A new baseline for the extension study, and we start with weekly shots. This time its for sure that we will gets the meds. NO MORE PLACEBO.

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Let us consider a hypothetical situation that after exon skipping has demonstrated that certain % of dystrophin is being produced but not helping the kids. How many of us will be eager to jump to get the kids enrolled into the next exon skipping trial for a sequence not yet tested. I dont need to list or provide examples of how many drugs are pulled out of the market after there is approval. What happens if such a situation arises out of a exon skipping drug.  

I think its better to spend a few month extra to be safe with exon 51. Once this has proven to work then we can nail down the approvers and FDA and others on why cannot other exon skipping trials be set at a pace that approval is reached within 6 months. If I were to wish I would ask for 51 to be treated as a case for class approval. 

My personal opinion is at this stage its better to be cautious and once we have tasted success then let the approvers face some real time music. I would say keep safety as a strategic choice for now. I will certainly not recommend this approach once we have hard data to prove the exon skipping works and is beneficial. Being extra safe probably delays Exon 51 by 4 to 6 months but wins us years with other exon skipping sequences.

During the extension period, do you still have to go to the clinic once a week to get the injection? Thanks.

Hello All,

Don't forget that we have no clue if this "new dystrophin" produced will continue to be produced (over 2 or 3 years, we just haven't had this around long enough, it's new), whether it causes longer term problems (rejection, tumors, who knows), whether it actually makes a long-term functional difference (who gives a crap if they produce 300% dystrophin if it doesn't help their bodies move), etc. I am obviously all for research, and perhaps thought to be speaking from a smug place as my child happens to fall into the category for exon skipping, and is able to participate, but god forbid if I/we are causing him harm by jumping the gun. And what if exon skipping precludes him from the future benefit of some better treatment, like utrophin up-regulation, or cure?

My boy is 11 1/2. We were given the chance and had to take it, for the benefit of all the boys.Time is not on our side, and that is most frustrating. But more time does need to be "wasted" in order to produce solid science. I think we all know what happened with Thalidomide?

No, we can't waste money on a million half-baked ideas, but we do need to explore more than one or two treatment options. We have to work together, parents and pharma.

Not sure exactly what I am trying to say with all this, but let's give each other a break, ok?

A.


Obviously they need to prove efficiency, otherwise no one will approve it. This is why we have clinical trials, and boys on placebo for a year. They have multiple trials, hundreds of boys participating and producing enough data. That data will be analyzed and sent to regulators. I see extension useful if someone thinks that there can be long term side effects hence want to follow these boys for 2 additional years. The only thing I question is the duration, why 2 years, why not one? Will this be the case for all potential treatments? AVI exon skipping, Utrophin upreg etc? What about Ataluren? Do they also have 2 year extension? Is this the case for Duchenne treatments or only this specific drug? 

I researched Myozyme (Pompe disease) and noticed that it was approved faster, so it not a requirement from regulators for all long term therapies in kids:

2003 studies intitiated (infantile-onset Pompe disease patients), 2004 submitted for approval to EMEA, 2005 submitted for approval to FDA, approved early 2006 by FDA and EMEA.

http://www.genzyme.com/components/highlights/myozyme_development.pdf 

Only one antisense drug has ever been approved by the FDA, and it is injected into the eye where it has it's action.

Myozyme is an enzyme, it's not playing with people's (our kids) genetics.

These drugs are not gene therapy, work at mRNA level and do NOT create a permanent and irreversible change at DNA level (the effect/protein production stops when the treatment stops). Moreover the 2 companies (AVI and GSK/Prosensa) have years of data in animals AND humans. Prosensa has 2-3 years of data in the first boys who started treatment (they already reported results in boys at 96 weeks) proving clearly that there are NO off target effects of the drug. Unless someone believes that off target effects start > 3 years after this treatment starts, which doesn't make sense to me. I thought that the scientists (Steve Wilton etc.) are convinced that this is not the case and so are the regulators.

What is not very clear at this point is how the kidneys will hold up in the long run and if those side effects are reversible after stopping the treatment, and I am assuming this is why additional data is required, also the reason why the design of US trial has the boys on the drug for 6 months only and off drug for the next 6? In addition they need to keep the boys in the trial on the drug until it is approved, so 2-3 years might give them enough time to file for approval I guess. 

No choice but to wait and see, first they need to release data from the 48-weeks placebo controlled trials showing efficiency. What are 2-3 more years at that point, right? :( I am just frustrated by the slow progress.

This is Steve Wilton's latest podcast about exon skipping: http://www.nationwidechildrens.org/muscular-dystrophy-podcast 


Andrea Cleary said:

Only one antisense drug has ever been approved by the FDA, and it is injected into the eye where it has it's action.

Myozyme is an enzyme, it's not playing with people's (our kids) genetics.

re:       :( I am just frustrated by the slow progress.

We are in agreement.

All I'm wondering if why the 4 week delay before starting the extension? I don't understand the need to isolate the data, scientifically speaking. How is that a "safer" way to go about things than rolling him over on to the drug right away (as AVI is doing with their extension study).

 

Because I don't see a scientific need for it, (otherwise, why wouldn't AVI be doing it - they have thought out every aspect of their trial very carefully), then it makes me angry on behalf of the boys on placebo.

 

If someone can explain to me how making the boys wait four weeks to get on the drug after sacrificing so much for an entire year makes them safer in any way, or makes the data more legitimate in any way, then I'll withdraw my point. Until then, I maintain that many of the decisions made once big pharma is involved are based on what's more convenient for big pharma.

i

My son was diagnosed 10 years ago and I would have thought by now I would understand why such delays are necessary ... but I still don't. No two companies seem to share the same protocol, and I have yet to see any of these studies actually meet the dates they set for themselves, or even get close for that matter. It was 2008 when GSK first published dates for Phase 2 trials in the US!

Since my son is not in the exon 45-55 hot zone, and there are no other trials as far along as exon-skipping trials, even if they do meet their stated deadlines it is still further away for us.

I do draw some hope from the article below, however, that the bigger companies are starting to view rare diseases as more profitable than "blockbuster" drugs. If it takes greed to finally motivate these firms to speed things up, I will gladly shed my socialist tendencies and jump on the bandwagon.

-David

http://www.genengnews.com/insight-and-intelligence/big-pharma-adopt...

So exon 51 skipping is the most advanced now and still 2-3+ years away from approval. What infuriates me most these days is when someone promises that this or that drug will be approved soon enough for our sons. I just want them to be honest and tell us that it will take 5+ years for everything that is not even in trials now. Now that we have the experience of all the delays and breaks in the existing clinical trials, on top of it the “new” concept of years of “extension trials”, like it wasn’t enough when we calculated how many years phase 1-2-3 will take, I just feel they all need to give realistic timelines so we can do the math and not wait year after year for something to change.

I still hope AVI will not take this long and will not be asked to have years of extensions after the pivotal trial, if the safety continues to be good and the current small trial shows what we are all hoping to see.



David said:

My son was diagnosed 10 years ago and I would have thought by now I would understand why such delays are necessary ... but I still don't. No two companies seem to share the same protocol, and I have yet to see any of these studies actually meet the dates they set for themselves, or even get close for that matter. It was 2008 when GSK first published dates for Phase 2 trials in the US!

Since my son is not in the exon 45-55 hot zone, and there are no other trials as far along as exon-skipping trials, even if they do meet their stated deadlines it is still further away for us.

I do draw some hope from the article below, however, that the bigger companies are starting to view rare diseases as more profitable than "blockbuster" drugs. If it takes greed to finally motivate these firms to speed things up, I will gladly shed my socialist tendencies and jump on the bandwagon.

-David

http://www.genengnews.com/insight-and-intelligence/big-pharma-adopt...

Drug for Cystic Fybrosis approved even though it only benefits 4% of the CF population (~1,200 patients) and the pricing is targeted at $294,000 per year. The drug was approved within 3 months from NDA filing.

“Kalydeco will be priced at $294,000 annually and will be shipped to specialty pharmacies starting this week. The company has set up a patient assistance program to help patients pay for the drug.”

“We note that in December last year, the regulatory body had granted priority review status to the company’s new drug application (NDA) for Kalydeco, and had set a target date of April 18, 2012. However, the FDA approved the drug within three months of the NDA filing (October 2011), as there are not adequate therapies in the market for treating CF.”

 

http://online.wsj.com/article/BT-CO-20120131-715281.html

http://www.thestreetbeat.com/street-beat-articles-29/3374-vertex-ph...

 

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