Wow! Interesting. :) Low dose "working" better than high? Have they looked at that dystrophin expression already?

 

http://www.parentprojectmd.org/site/DocServer/2010-04-16_Final_Summ...

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This is great news! I have a little ray of hope, now. :) Thank you so much for posting this.
I agree Cosmin, RANCOVA was the right procedure. I would put the boys on low dose for one more year if I would be PTC/Genzyme.
If we only look at the statistics results with RANCOVA method, can we say the low-dose Ataluren might be working for the boys with non-sense mutation? I am still very confused about efficacy results part of the article. Can you explain it a little bit more without math statistics terms?Thank you very much!
Melanie.
It is interesting..one mom I know has some of the drug left and has been weaning her son off of it. She posted on her caringbridge site in the last few days that "she would swear her son is doing better on the lower dose!"...I bet she was stunned to see this confirming what her eyes are seeing!!!
I do not know who made those summaries, PTC or Dr. Wong.

Either way, the results using RANCOVA (which was specified in the protocol and in my opinion the good approach to analyzing this data) satisfy 85% significance level (this means that the finding has a 85% chance of being true.)...usually one wants to see a 95% level.

Just based on the results presented yesterday, it is too early to say that the low dose works, more data analysis needs to be done, it might work for a subgroup. It would be good to put the kids on low dose and collect more data while completing the analysis including biopsy data BUT that might not be doable due to protocol (regulatory agencies might not allow this).

What we can say with certitude at this point is that the high dose does not work. That in itself needs to be explained before they move forward.

Melanie Sunny said:
If we only look at the statistics results with RANCOVA method, can we say the low-dose Ataluren might be working for the boys with non-sense mutation? I am still very confused about efficacy results part of the article. Can you explain it a little bit more without math statistics terms?Thank you very much!
Melanie.
Ofelia.Thank you so much for the detailed explanation and I get it now. Melanie.

Ofelia Marin said:
I do not know who made those summaries, PTC or Dr. Wong.

Either way, the results using RANCOVA (which was specified in the protocol and in my opinion the good approach to analyzing this data) satisfy 85% significance level (this means that the finding has a 85% chance of being true.)...usually one wants to see a 95% level.

Just based on the results presented yesterday, it is too early to say that the low dose works, more data analysis needs to be done, it might work for a subgroup. It would be good to put the kids on low dose and collect more data while completing the analysis including biopsy data BUT that might not be doable due to protocol (regulatory agencies might not allow this).

What we can say with certitude at this point is that the high dose does not work. That in itself needs to be explained before they move forward.

Melanie Sunny said:
If we only look at the statistics results with RANCOVA method, can we say the low-dose Ataluren might be working for the boys with non-sense mutation? I am still very confused about efficacy results part of the article. Can you explain it a little bit more without math statistics terms?Thank you very much!
Melanie.
Ofelia

How are you certain that high dose does not work for any of the boys?

Brenda Wong's report states that Ataluren may have a bell-shaped dose-response curve so this means that the high dose could be effective for some. Many of the best responders to Ataluren may have been randomized into the placebo group so they will not show in the stats. As you probably know, the effectiveness of Ataluren depends on factors such as the gene sequence and then the location of a pyrimidine etc. I'm pretty sure that the high dose will work for some of the boys as there have been reports of it doing so from the 2a trial.

Is there some other information regarding the trial that I have missed which categorically says the high dose does not work for any?

Kenny
The summary is brief and there will be a lot more data to come from this which will give more insight.
Still there is something to be taken from this in that they have a better idea on dosing structure. What will be more interesting now is the breakdown of the low dose group to see if the nonsense codon structures plays a bigger part in the results.
As for the statistical side of things, I think it is too early to be getting worked up over them. They are based on broad grouping, and as has been pointed out, genetic structure has been shown to have different results with ataluren.
Kenny,

All statistics aside, based on the summaries presented about the 6MWT, one does not see a difference b/w the placebo and the high dose groups. There is no indication that the high dose has any beneficial effect. We do not have access to individual data and the regulatory agencies are looking at group results. I am not sure I understand what you mean by "many of the best responders to Ataluren may have been randomized into the placebo group so they will not show in the stats."

There are many other sub-analyses and a lot more data to be reported. I think the results of the low dose are promising and I would like to see more data about that.

This is from the summary:

Conclusions
The safety and efficacy results from the trial lead to the following conclusions:
• Overall, the study was well conducted
• Ataluren was well tolerated across both treatment arms compared to placebo
Variability of the change in 6MWD was greater than expected
The high-dose ataluren group did not show a treatment effect (a difference in outcome from the placebo
group)

The low-dose ataluren group showed a mean improvement in 6MWD compared to the placebo group

Kenny Munro said:
Ofelia

How are you certain that high dose does not work for any of the boys?

Brenda Wong's report states that Ataluren may have a bell-shaped dose-response curve so this means that the high dose could be effective for some. Many of the best responders to Ataluren may have been randomized into the placebo group so they will not show in the stats. As you probably know, the effectiveness of Ataluren depends on factors such as the gene sequence and then the location of a pyrimidine etc. I'm pretty sure that the high dose will work for some of the boys as there have been reports of it doing so from the 2a trial.

Is there some other information regarding the trial that I have missed which categorically says the high dose does not work for any?

Kenny
I think you may have mis-understood what they meant by the bell shaped curve. The curve is to do with the effect given vs the dosage. What this means is that there will be a dosage level which gives the best results. Going higher will decrease the effect given.
I would say that this is a mechanism of the drug itself meaning that it will be the same for all boys to an extent.
hi

as parent of a kid on ataluren trial, I'm very surprised to see that the difference between the target and the results on the low dose were only 1 yard on the 6MW! is it a good reason to give up? I asked the details of the sample and the calculation of the statistic level of confidence because I am afraid the real reason is a disagreement between the different partners of the company.
Can all the parents whose sons participated at the trial communicate in the group "ataluren following up" on this web site
best
It is important that PTC publish the detailed data as soon as possible. Perhaps the type of nonsense mutation is a factor here - UGA, UAG, UAA - but let's hope that the scope for a follow-up trial or trial extension is fully explored.

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