A nonsense mutation is a premature stop signal in the genetic code that interrupts the production of an essential protein. Proteins are essential to the proper working of every cell in the body. Nonsense mutations result in incomplete proteins that do not function properly and in turn cause a genetic disorder. The disorder caused by the nonsense mutation depends upon which protein is incompletely formed. Nonsense mutations occur across a broad range of serious, life-threatening genetic disorders.

For example, in cystic fibrosis, a protein in the lungs and other organs – called the cystic fibrosis transmembrane conductance regulator (CFTR) – is incomplete. As a result, patients with nonsense mutation cystic fibrosis (nmCF) have problems with breathing and digestion. In nonsense mutation Duchenne and Becker muscular dystrophy (nmDBMD), a muscle protein called dystrophin is incomplete. Consequently, patients with nmDBMD have weak muscles. In nonsense mutation hemophilia A and hemophilia B (nmHA and nmHB), factor VIII protein and factor IX protein, respectively, are incomplete. This results in the inability of blood to clot properly.

In nmCF, we are conducting a Phase 3 clinical trial at multiple sites in North America, Europe and Israel to evaluate the impact of ataluren on lung function and other CF symptoms. For more information please see our cystic fibrosis clinical trial overview.

Additionally, we are conducting a Phase 2a clinical trial to evaluate the safety and activity of ataluren in patients with nonsense mutation hemophilia type A and B. For more information please see our hemophilia clinical trial overview.

A Phase 3 trial of ataluren is currently enrolling patients who are at least 6 years of age, have CF due to a documented nonsense mutation (those that end in X, such as G542X), and have lung function (FEV1) between 40% and 90% of normal. Additional inclusion/exclusion criteria are available at www.clinicaltrials.gov. Interested patients may want to discuss potential participation with their CF physician.

CF trial sites are listed on www.clinicaltrials.gov and on the related page on PTC’s website. As each study site is opened and ready to enroll, site contact details will be added to these listings. People with nonsense mutation CF or their families should contact a site directly to inquire about trial participation. Personnel at the site will explain the study procedures and the potential benefits and risks associated with participation. Potential participants will be given a consent form further explaining the trial; those choosing to sign the form will be screened and considered for enrollment.

A Phase 2a trial of ataluren is currently being conducted in patients with nonsense mutation Hemophilia A and Hemophilia B (nmHA and nmHB) at multiple sites in North America. Several trial sites in Europe are to be opened. The main goals of the trial are to determine whether treatment with ataluren can result in an increase in Factor VIII or IX levels and whether the drug can safely be given to people with severe hemophilia due to a nonsense mutation. The trial is open to males at least 18 years of age with nmHA/nmHB who are not receiving or are willing to forgo prophylactic factor. For more information please see the hemophilia clinical trial overview.

Hemophilia trial sites are listed on www.clinicaltrials.gov and on the related page on PTC’s website. As each study site is opened and ready to enroll, site contact details will be added to these listings. People with nonsense mutation HA and HB or their families should contact a site directly to inquire about trial participation. Personnel at the site will explain the study procedures and the potential benefits and risks associated with participation. Potential participants will be given a consent form further explaining the trial; those choosing to sign the form will be screened and considered for enrollment.

We conducted a Phase 2a trial in patients with nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD) at three sites in the U.S. The goal of this study was to determine whether 28 days of ataluren treatment increased the production of dystrophin in muscle cells. The results showed that treatment with ataluren was associated with an improvement in the production of dystrophin in muscle cells. In total, 23 of the 38 patients (61%) showed a positive change in the production of dystrophin in muscle cells over 28 days of ataluren treatment. In addition, muscle cells from 35 of the participants were grown in culture dishes and treated with ataluren. The production of dystrophin was observed in cultured muscle cells from all of these boys.

Based on the results of this study, we initiated a longer-term Phase 2b study in February 2008. This randomized, double-blind, placebo-controlled Phase 2b trial was designed to evaluate the safety and efficacy of 48 weeks of ataluren therapy in patients with nmDBMD. The study enrolled 174 participants in North America, Europe, Australia and Isreal. The primary outcome measure was the total distance walked during a 6-minute walk test, a standardized test of ambulation.  Other outcome measures in the study evaluated activity at home, muscle and heart function, strength, cognitive ability, muscle integrity, and muscle dystrophin expression.  Safety parameters, compliance, and ataluren blood levels were also monitored.

The primary outcome measure of 6-minute walk distance proved feasible in assessing ambulation in patients with nmDBMD.  However, variability was greater than expected and statistical significance within the 48-week duration of the study was not observed. Additional efficacy analyses are underway in patient subgroups. Study results showed that ataluren was well tolerated and no clinical trial patients discontinued treatment due to an adverse event.