Ataluren for Cystic Fibrosis

Ataluren is an investigational therapy developed by PTC Therapeutics for several genetic disorders.

PTC has discontinued the development of ataluren for cystic fibrosis (CF), as of March 2017, following failed Phase 3 clinical trials.

How ataluren works

Cystic fibrosis is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. These mutations can result in insufficient amounts or a faulty CFTR protein to be made. This causes an abnormally thick and sticky mucus to be produced in various organs, including the lungs, and can disrupt breathing and increase the risk of repeated bacterial infections. 

One type of mutation that causes CF is called a nonsense mutation. A nonsense mutation is when a signal to stop protein production is inserted part-way through the gene. This results in a shortened and incomplete protein that does not work to be produced.

Ataluren works by forcing the protein-making machinery of the cell to ignore the premature stop signal and continue reading the rest of the gene to produce the full-length protein.

For CF patients with nonsense mutations, it was hoped that ataluren would increase levels of the full-length and functional CFTR protein, improving mucus consistency and reducing the symptoms of CF.

Ataluren in clinical trials

Despite initial promising trials, the results of several Phase 3 studies, summarized below, suggested that ataluren was ineffective in CF.

A Phase 3 trial (NCT00803205) enrolled 238 patients to receive either ataluren or a placebo for 48 weeks, at sites across North America, Europe, and Israel. This was followed by an optional one-year extension study (NCT01140451), enrolling 191 participants who had completed the previous trial.

Results published in The Lancet Respiratory Medicine suggested that ataluren did not improve lung function compared to placebo. This was based on the change in forced expiratory volume (FEV1), or the volume of air exhaled in one second, a measure of lung function.

A second randomized, double-blind, controlled Phase 3 trial (NCT02139306), called ACT CF, failed to reach its primary goal. This trial enrolled 279 patients in North America, Europe, and Israel. After 48 weeks of treatment, there were no significant changes from baseline in patients’ FEV1 compared to placebo.

The ACT CF trial led to PTC halting further development of ataluren as a CF therapy, and the termination of an ongoing open-label Phase 3 trial (NCT02107859), the aim of which was to determine the long-term safety and effectiveness of the treatment.

Despite this, a Phase 4 trial (NCT03256968) with a single participant is listed as ongoing at the University of Birmingham, Alabama. The trial aims to assess how effective ataluren is in combination with Kalydeco (ivacaftor), over a one-year period. The trial is expected to be completed in December.

Other information

Ataluren is not approved to treat CF.

Common side effects of ataluren include vomiting, nausea, headaches, stomach aches, and flatulence.

The therapy has received conditional approval, under the brand name Translarna, to treat nonsense mutation-caused Duchenne muscular dystrophy (DMD) in Europe.


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