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First long-term study in the class of innovative therapies known as CFTR correctors

At the ECFS conference in Dublin in the beginning of June 2012, PTC announced the final results of an international multicenter phase 3 study with Ataluren, formerly known as PTC 124.,the first long-term study in the class of innovative therapies known as CFTR correctors

Ataluren is designed to restore production of the CFTR protein in patients whose cystic fibrosis is due to a nonsense mutation (nmCF). In this group of mutations, an interruption in the genetic code—known as a nonsense mutation—prematurely halts the synthesis of CFTR, causing the protein to be short and non-functioning.

Nonsense mutations are Class I mutations, which are associated with a complete lack of CFTR. Persons with Class I mutations generally have more severe CF symptoms, including a higher risk for severe lung disease and a higher prevalence of pancreatic insufficiency, than persons with other classes of mutations. Class I mutations are also known as stop - or X - mutations because most of them have an X in their name.

The goals of the Phase 3 study were to determine whether Ataluren is safe for children and adults to take as a long-term treatment and whether it can:

-     Improve lung function

-     Reduce the symptoms associated with CF and decrease the number of hospitalizations and the use of antibiotics for CF-related lung infections

-     Help improve overall quality of life for people with CF.

The 48-week trial enrolled 238 people with CF ages six years and older at multiple sites in North America, Europe and Israel. Participants were randomly assigned to receive Ataluren or placebo. In the trial, patients took 10 milligrams of drug for each kilogram of body weight (mg/kg) in the morning and midday and 20 mg/kg in the evening.

The Ataluren study results demonstrate overall positive, but rather moderate trends in both the primary and secondary endpoints:

-     The primary endpoint, forced expiratory volume in one second (FEV1) measured by spirometry, compared the results of the study participants over the course of 48 weeks to what would be predicted for healthy people of similar age and height and was expressed as %‑predicted FEV1. There was a 3% difference between the Ataluren and placebo groups at Week 48 (-2.5% change on Ataluren vs. a -5.5% change on placebo).

-     The secondary endpoint was the pulmonary exacerbation rate as measured by the number of pulmonary exacerbations in 48 weeks.  Patients receiving Ataluren had 23% fewer exacerbations than those receiving the placebo.

But the Phase 3 trial demonstrated important results in certain sub-groups of patients:

-     Approximately 45% of the study population was not using chronic inhaled antibiotics (such as Tobi®) at baseline and did not receive antibiotics chronically during the study.  In this subgroup, the difference between Ataluren and placebo in mean relative change in % ‑ predicted FEV1 from baseline to Week 48 was 6.7% (-0.2% change on Ataluren vs. -6.9% change on placebo), favoring Ataluren. The frequency of pulmonary exacerbations over 48 weeks was 43% lower in these patients versus placebo.  This effect of inhaled antibiotics was largely attributable to the use of inhaled aminoglycosides.

Further analysis of the subgroup results is ongoing. 

Ataluren was generally well tolerated: 

-     The most common adverse events in the trial, such as pulmonary exacerbations, cough and infections, are typical in CF.

-     No life-threatening adverse events or deaths occurred in either treatment arm. Adverse effects that were classified by investigators as being drug-related were comparable in both the placebo and Ataluren arms.

-     Most serious adverse events (i.e., those requiring hospitalization) were cystic fibrosis pulmonary exacerbations unrelated to study treatment.

-     Based on laboratory data, it appears that Ataluren may potentiate the toxic effects on the kidneys of IV aminoglycosides and perhaps other antibiotics that can be toxic to the kidneys.  It is recommended that Ataluren not be used concomitantly with IV aminoglycoside antibiotics.  Appropriate safety monitoring procedures have been implemented in ongoing clinical trials of Ataluren.

Patients who completed the Phase 3 trial were eligible to participate in an ongoing extension study in which all patients are receiving Ataluren. This study is allowing investigators to gain additional information on the long term safety of Ataluren and to further evaluate the clinical response observed in the pivotal study.

When the company announced the study results they concluded that “The next step is to conduct discussions with our investigators, patient advocacy groups and other key opinion leaders in the CF community. We are enthusiastic about the results of this study and committed to Ataluren and people affected by cystic fibrosis. As these discussions are ongoing, we have not made any decisions about the path forward.”

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