Ataluren Update

[GenH]

A recent study found that Ataluren failed to enhance read through past stop codons (they tested all the possible stop codon combinations in different situations), instead they suggested that Ataluren interacted with the drug screening system, the luciferase enzyme.

I've summarised the findings here: http://sixtyfiverosesblog.wordpress.com/2013/06/26/ataluren-update/

“Where does this leave us with PTC124 and its potential to tackle the 10% of cases of genetic disease that are thought to result from nonsense mutations? We should remember at this point that McElroy and colleagues only test cells (not intact animals), that they only look at the read-through activity of this drug, and that there are several publications that do suggest clinical efficacy (particularly for cystic fibrosis). The conclusion remains, however, that if PTC124 does indeed have beneficial effects on some genetic diseases, it’s more likely that this is down to serendipity than the purported mechanism of translational read-through.

Numerous groups are still working on developing effective drugs that can override premature stop codons—in case you wondered, G418 is sadly too toxic for clinical use. PTC124 aside, this manuscript also raises interesting issues for the design and interpretation of high-throughput drug screening assays, and also potentially for the consequences of an initially strong positive screen result on subsequent evaluation of drug efficacy.”

Link to the study/ source of the quote: http://www.plosbiology.org/article/...8;jsessionid=0E3838B87A8B375E6034D46E5E119EA0

 

[GenH]

Just came across this new article: http://www.fiercebiotech.com/story/...-muscular-dystrophy-drug-mechanism/2013-06-26

""From a basic mechanistic standpoint, it doesn't look like [PTC124 is causing] translational read-through, certainly in our assays," Stuart McElroy, a scientist at the University of Dundee in Scotland and an author of the paper, tells The Scientist.

The company, however, defended its work.

"Numerous independent laboratories have provided confirmation of our results, demonstrating ataluren's read-through activity in studies using reporters as well as multiple animal and cell-based nonsense mutation disease models," notes a company statement.


David Bedwell at the University of Alabama, who's done consultancy work for PTC, also said that mouse studies have shown that there's a read-through.


PTC has already had to contend with some discomforting revelations in its S-1. After touting the fact that PTC had filed for a European approval late last year, company officials stayed mum when regulators came back to say that their first review led them to conclude that the company didn't have the necessary efficacy data. And the company has had to concede that a Phase IIb as well as a Phase III study both failed primary endpoints, leaving the biotech at work on new Phase III trials for CF and DMD.


This isn't the first time investigators have failed to repeat key research work backing a lead program. But for PTC--which now has a stock price to defend--it comes at a particularly bad time."

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