Background about Ataluren and the phase 3 results (from June 2012):
About 10% of people with Cystic Fibrosis have a class 1 nonsense mutation. These mutations have stop codons in the middle of the protein instructions. The stop codon means that the ribosome stops making the protein at this point, so the normal protein is not produced.
Ataluren (PTC124) has completed phase 3 trials with CF nonsense mutations. It was thought that Ataluren was helping ‘read through,’ allowing the ribosome to ignore the stop codon and produce the normal protein. The results of this study were mixed; a larger FEV1 improvement was seen with those who were not on inhaled antibiotics compared to those who were on inhaled antibiotics. Overall there was a 3% relative increase in FEV1 at week 48 compared to placebo and a 5.7% relative improvement in FEV1 with those who were not on inhaled Tobramycin (p=0.008).
This image is from Twitter, it first appeared in June 2013, I am unsure of the source.
Latest Research, published June 25 in PLOS Biology:
Scientists recently investigated the method used to determine that Ataluren was helping the ribosome to read through the stop codon. They wondered if instead of Ataluren helping with read through, could Ataluren interact directly with the drug screening system, the luciferase enzyme, making it appear that the ribosome was working past the stop codon?
The scientists found that Ataluren failed to enhance read through past the 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. They found that another medication, G418, worked to varying degrees.
“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.”
“The current PLOS Biology paper takes the NIH research a step further, testing PTC124’s activity in reporter assays using β-galactosidase and human collagen as well as the two kinds of luciferase. The researchers also tested geneticin, a known read-through agent, using the same assays. In each assay, geneticin appeared to promote translation of proteins with premature stop codons, while PTC124 had no effect except in the presence of the firefly luciferase. Additionally, the researchers tested the effects of geneticin and PTC124 on different types of stop codons and on stop codons followed by various downstream nucleotides and found that only geneticin promoted read-through.” (Geniticin is G418)
“But representatives from PTC Therapeutics, the New Jersey biotech company that is developing the drug, said that it has produced strong evidence that PTC124, also called ataluren, does encourage the translation of complete proteins despite the nonsense mutations. “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,” the company said in an emailed response to questions sent by The Scientist.
David Bedwell, a microbiologist at the University of Alabama and a paid consultant to PTC Therapeutics, suggested that McElroy and colleagues may have simply not tested PTC124 under conditions that allowed it to work. “We have also had trouble detecting read-through by ataluren in various cell lines, and we don’t know the reason for those negative results,” he said in an email to The Scientist. He noted that studies in mouse models of cystic fibrosis and Duchenne’s muscular dystrophy did demonstrate PTC124’s read-through effects. Additionally, PTC Therapeutics said that studies in humans “are consistent with ataluren-mediated read-through having clinical activity.” “
The articles then mention that PTC filed for European Approval last year but the first review concluded that they didnt have sufficient efficacy data. The Cystic Fibrosis Phase III trial failed to reach statistically significant endpoints, another phase III trial is planned for later this year.