Drugs for Stop Codon Readthrough

Application: These drugs only work for patients with a “stop signal” mutation. These mutations do not affect the genetic code, but introduce a stop signal in the middle of the gene in addition to the one at the end of the gene that signifies protein translation is complete. This is the case for ~15% of Duchenne patients. The drugs can also be beneficial for individuals with stop codons in other genes (e.g. cystic fibrosis patients).
Aim: To force the cell to ignore the mutated stop codon and produce a complete dystrophin protein.
Background: All genes have a start signal and a stop signal so the machinery that translates genes into proteins knows where to begin and where to end. Sometimes a small mutation can introduce a stop signal within the gene (in addition to the one at the end). Normal stop signals generally differ slightly from these mutated stop signals (compare it to a stop signal at a busy intersection (normal stop signal) and one on a highway (mutated stop signal). Nevertheless, the cell will follow the stop signal and will stop the translation of the protein prematurely. There are drugs that suppress the usage of these mutated stop codons, while they do not affect the normal stop codons. The first drug identified to do this in cultured cells and Duchenne mouse models was gentamicin (an antibiotic of the animoglycoside class).
Clinical trial: Gentamicin has been tested in Duchenne patients, but has never convincingly shown dystrophin restoration.
Challenge 1: In addition to its low efficiency, gentamicin is toxic when used for longer periods (it can damage the ears and the kidney).
Solution 1: Screening a large number of drugs resulted in the identification of a drug that was also able to force cells to ignore mutated stop codons, without the toxic side effects. This drug is called PTC124 or ataluren or Translarna™ and is developed by PTC Therapeutics (USA). It can be taken orally and resulted in dystrophin restoration in cultured cells and the mdxmouse model.
Clinical trials: Ataluren was safe in healthy volunteers. A first trial in Duchenne patients were patients were treated with different daily doses of Ataluren for 4 weeks showed that treatment was well tolerated and that dystrophin expression was increased for treated patients. Trials to test whether this also results in functional improvement after long term treatment have been performed in multiple centers in the USA and Europe.

Unfortunately, treatment did not convincingly lead in to a functional improvement when compared to placebo treated patients using a 6 minute walk test and therefore the trials were put on hold. Patients involved in these trials in the USA and Europe can enrol in an open label trial.

After detailed analysis of the data and further optimization of dosing, a new confirmatory phase 3 trial in 220 DMD patients has been completed in North- and South-America, Asia, Australia and Europe. Translarna treated patients on average walked 15 meters more in 6 minutes compared to placebo treated patients. In the pre-specified subgroup of patients (walking between 300 and 400 meter in 6 minutes at the start of the trial) Translarna treated patients walked 47 meters further than placebo treated patients. Translarna treated patients also performed better in other functional tests. As before, Translarna was well tolerated.

PTC filed for accelerated approval with the Food and Drug Administration (USA) in January 2016. FDA sent a ‘refusal to file’ letter to PTC in February 2016 announcing that the current data is not sufficient to permit an FDA review. PTC has appealed to this and FDA scheduled an Advisory Committee meeting, after which FDA informed PTC that ataluren will not be approved based on the currently available data.

Marketing authorization: PTC Therapeutics was granted marketing authorisation for Translarna (ataluren, formerly known as PTC124) by the European Commission in August 2014. Translarna is approved for the treatment of ambulatory patients aged two years and older who’s Duchenne muscular dystrophy is caused by a nonsense mutation in the dystrophin gene in EMA countries.

The conditional approval is evaluated annually, and was extended in 2015, and again in November 2016, at which time the data of the first confirmatory study was available. EMArequested an additional confirmatory study from PTC in November 2016.

In 2018 the indication of translarna was broadened from 5 years and older to 2 years and older, after PCT confirmed safety in DMD patients between age 2 and 5.

Within the European Union Translarna is currently available in Germany, Austria, Denmark and Norway and the UK, with France, Italy and Greece having early access schemes. Outside of Europe Translarna has received approval for use in Israel, and is also available in Turkey, Brazil and Columbia. This list of countries will increase and availability of Translarna should be checked with PTC ([email protected])

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