On February 2nd, 2009 an article was published that many in the Duchenne community, especially those following the PTC124 trials and information may find confusing. The publication in PNAS (Proceedings of the National Academy of Sciences) by Auld and colleagues focuses on the difficulties of relying on a single high throughput screen (HTS) assay for the discovery of potential drugs. High throughput screens are used in the early stages of drug development to identify potential molecules that show promising therapeutic activity. The authors caution against using a single HTS assay in the identification of potential therapies.

PTC has been very thorough throughout the ten-year development of ataluren (PTC124), and has conducted extensive testing in the laboratory, in animal models and in clinical trials. As a result, there is substantial evidence, much of it published in internationally recognized peer-reviewed journals, indicating that ataluren selectively reads through nonsense mutations inducing the production of dystrophin in animal models and in Duchenne patients.

I think it is important for all of us to understand that the information being presented in the PNAS article reminds us how important and critical the entire drug development and clinical trial process is. As always, we at PPMD will keep on top of the trial results and outcomes and make sure to pass along any and all information.

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Staff
Comment by Pat Furlong on February 3, 2009 at 4:50pm
sorry paul. To answer your question "how can it be a false positive but seem to show effectiveness...". While this class of drugs may have the capability to stabilize luciferase, it is also true that, at the same time, there may be expression. This is exactly the reason why the luciferase assay (or similar) is one single step in the drug development process.

Staff
Comment by Pat Furlong on February 3, 2009 at 4:47pm
Hi Paul, The article is confusing and the paper has a number of 'holes' or inconsistencies. So the bottom line is that this chemical class of drugs can stabilize the enzyme luciferase. While this may be true, it is only one piece of the puzzle. PTC124 has been demonstrated to promote read-thru in different assay systems, in the mdx mouse and in human cells in culture and in CF. The paper is irrelevant (in this case) at the moment because of the animal and cell data. As you know, PTC 124 is in human trial at the moment and this will provide definitive evidence of effect.
Pat
Pat
Comment by Paul Johnson on February 3, 2009 at 2:35pm
You are correct, Pat... I've only read an overview of the actual article and I am confused. I'm so confused I don't even know what questions I want to ask, but I'll try.
How can it be a false positive in the screening but seem to show effectiveness in preliminary animal\human trials?

~P

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