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Disappointing Translarna failure is an isolated event for CF pipeline

PTC Therapeutics announced the failure of its ACT CF trial of Translarna (ataluren) in nonsense mutation cystic fibrosis (nmCF) patients, bringing a halt to any further planned developmental activities in the indication. Although there was a slight treatment effect, Translarna failed to significantly improve pulmonary measures compared to placebo. This is a disappointing result for the small group of nmCF patients who otherwise have no appropriate therapy targeting the underlying pathological process, although there are no wider ramifications for other cystic fibrosis pipeline agents. Translarna is the only therapy of its type, a ribosomal readthrough stimulant, and PTC Therapeutics is continuing to support the drug in nonsense mutation Duchenne muscular dystrophy (nmDMD) patients.



Translarna failed to significantly improve lung function over a 48-week treatment period

The ACT CF trial was Translarna’s second Phase III trial in cystic fibrosis and aimed to build upon previous data suggesting that drug treatment could slow decline in pulmonary function, as measured by forced expiratory volume in one second (FEV1). The prior GD-009 CF trial had shown Translarna-treated nmCF patients had better FEV1 scores after 48 weeks of treatment, with a significant improvement noted in a subset of patients not receiving inhaled tobramycin. However, this significant treatment difference compared to placebo was not replicated in the ACT CF trial, which excluded the concomitant use of inhaled aminoglycosides. Mean FEV1 decline over the 48-week treatment period was -1.4% for Translarna patients, compared to -2.0% among the placebo group (p=0.534). There was also a non-significant trend in favor of Translarna on the rate of pulmonary exacerbations, which are important clinical deterioration events in cystic fibrosis patients. No new safety signals emerged during ACT CF. Available clinical data from Translarna’s Phase III trials are shown in the table below.





Translarna Phase III data in cystic fibrosis


Sample size  Target patients  Study design   Dosing tested and duration  Results   Reference
ACT CF NCT02139306 (Phase III) 279   Adult and pediatric patients with a nonsense mutation in at least one allele of CFTR; not receiving chronic inhaled aminoglycoside therapy  Double-blind, placebo-control, safety/efficacy study  
Arm 1: Translarna at respective morning, midday, and evening doses of 10mg/kg, 10mg/kg, and 20mg/kg 


Arm 2: Placebo


Duration: 48 weeks 
Mean relative change in FEV1 after 48 weeks:


Translarna: -1.4%


Placebo: -2.0%; PTC Therapeutics, 2017a
GD-009 CF NCT02107859 (Phase III) 238  Adult and pediatric patients with a nonsense mutation in at least one allele of CFTR and a cystic fibrosis-causing mutation in the other CFTR allele  Double-blind, placebo-control, safety/efficacy study  
Arm 1: Translarna at respective morning, midday, and evening doses of 10mg/kg, 10mg/kg, and 20mg/kg 


Arm 2: Placebo


Duration: 48 weeks 
Mean relative change in FEV1 after 48 weeks:


Translarna: -2.5%


Placebo: -5.5%;


Mean relative change in FEV1 after 48 weeks, excluding chronic inhaled tobramycin patients:


Translarna: -0.7%


Placebo: -6.4%; Kerem et al., 2014
CFTR = cystic fibrosis transmembrane conductance regulator; FEV1 = forced expiratory volume in one second
 Source: various (see above)


Checkered development in CF halted; DMD opportunity continues

This negative trial has prompted PTC Therapeutics to discontinue any further development for Translarna in cystic fibrosis and withdraw its Marketing Authorization Application, which was pending at the European Medicines Agency. The initial application containing the GD-009 CF data had been speculative and unlikely to be approved, as the trial had missed its primary endpoint, but instead relied on a post-hoc analysis excluding tobramycin patients. PTC Therapeutics had hypothesized that aminoglycoside antibiotics reduce Translarna’s ability to enable ribosomal readthrough, although it now appears that any treatment effect for Translarna is likely to be minimal anyway. Although there is huge unmet need for patients with nmCF to have an appropriate treatment targeted to their underlying genetic mutation, the magnitude of effect for Translarna appears clinically insignificant. Furthermore, PTC Therapeutics would have found it impossible to justify the reimbursement of Translarna for such an incremental improvement.


Translarna is already on the market in the EU for nmDMD, for which the drug has a list price in Germany of around €440,000 ($488,000) per year. PTC Therapeutics states that it will continue to support the development of Translarna for patients with nmDMD, with plans to file a New Drug Application over protest from the US Food and Drug Administration, despite receiving a Refuse to File letter. PTC Therapeutics estimates total sales for Translarna in nmDMD of $81m for 2016 (PTC Therapeutics, 2017b).



Pipeline still has potential to deliver targeted therapies for currently unserved patients

While the failure of Translarna in the ACT CF trial is a blow for the subset of cystic fibrosis patients with nonsense mutations, accounting for around 10% of the total, it does not have any implications for any other pipeline candidates. Translarna was the only ribosomal readthrough stimulant in development, although there are no other candidates targeting the nmCF patient group.


Attention will now turn to Vertex’s VX-661/ivacaftor (tezacaftor/ivacaftor) regimen, for which several Phase III trials are due to complete during 2017. This combination pill has the potential to bring an appropriate genotype-specific drug to patients with one copy of the F508del mutation, the most common cystic fibrosis-causing mutation. Vertex currently markets Kalydeco (ivacaftor) for patients with gating mutations and Orkambi (lumacaftor/ivacaftor) for homozygous F508del patients.


Kerem E, Konstan MW, De Boeck K, Accurso FJ, Sermet-Gaudelus I, et al. (2014) Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respiratory Medicine, 2(7), 539–47.
PTC Therapeutics (2017a) PTC Therapeutics Announces Results from Pivotal Phase 3 Clinical Trial of Ataluren in Patients Living with Nonsense Mutation Cystic Fibrosis. Available from: [Accessed 2 March 2017].
PTC Therapeutics (2017b) PTC Therapeutics Provides Corporate Update and Outlines 2017 Strategic Priorities to Maximize the Global Value of Translarna™ and Advance its Innovative Pipeline. Available from: [Accessed 2 March 2017].

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