Proteins are essential to the proper working of every cell in the body. A nonsense mutation is a premature stop signal in the genetic code that interrupts the production of an essential protein. When this happens, the protein that is created does not function properly and this in turn causes a disease or disorder. The disease caused by the nonsense mutation depends on which protein is incompletely formed. For example, in nonsense mutation Duchenne/Becker muscular dystrophy (nmDMD/BMD) a muscle protein – called dystrophin – is incomplete. As a result, patients with nmDMD/BMD have weak muscles. In nonsense mutation cystic fibrosis (nmCF) a protein in the lungs and other organs – called the cystic fibrosis transmembrane conductance regulator (CFTR) – is incomplete. As a result, patients with nmCF have problems with breathing and digestion.

Ataluren is an investigational (experimental) drug that is the first potential new therapy designed to enable the formation of a functioning protein in a patient with a genetic disorder due to a nonsense mutation. Ataluren is taken orally and has the potential to treat the root cause of the disease by overriding the premature stop signal, so that a functional protein can be formed in a patient who has a disease due to a nonsense mutation. In other words, it seems to allow the body to overcome the genetic problem. It does not alter a patient’s genetic code or introduce genetic materials into the body.

Ataluren is currently being tested in a Phase 2b trial in patients with nonsense mutation Duchenne/Becker muscular dystrophy and will soon be tested in a Phase 3 trial in nonsense mutation cystic fibrosis. These trials build on prior Phase 1 and 2 trials.

Genetic testing, also called genotyping, can determine whether a patient’s genetic disease is caused by a nonsense mutation. As ataluren and other mutation-based potential therapies are further evaluated, knowing a patient’s genetic make-up may prove useful in determining whether that person might benefit from any of these therapies. Patients may wish to discuss the possibility of genetic testing with their physician or genetic counselor. Usually, a small amount of blood is required to perform the test. The blood sample will be sent to a specialized laboratory, sometimes at a university hospital that has expertise in studying patients with a particular disease.

Ataluren is an investigational drug that has not yet been approved for use by regulatory authorities in any country and thus cannot be legally purchased for use by a patient. The only form of ataluren that meets regulatory requirements for safety and purity and is appropriate for use in humans is manufactured by PTC Therapeutics. Because it is an investigational drug, ataluren is available only in PTC Therapeutics-sponsored clinical trials.

Ataluren is being tested in nonsense mutation Duchenne/Becker muscular dystrophy (nmDMD/BMD). We expect to begin testing in nonsense mutation cystic fibrosis (nmCF) in the second half of 2009.

In nmDMD/BMD, we are conducting a Phase 2b clinical trial at multiple sites in North America, Europe, Israel, and Australia. The main goals of this trial are to understand whether ataluren can improve walking, activity, muscle function, and strength, and whether it can safely be given for a long period (at least 48 weeks).

In this Phase 2b study, participants are randomly assigned to receive one of two dose levels of the drug or a placebo (an inactive substance that looks and tastes like ataluren but does not actually contain the drug). The trial is double blinded, meaning that neither the researchers nor the participants know who is receiving the placebo or the drug or at what dose level.

This study is evaluating ataluren in 174 boys and young men with nmDMD/BMD. The trial, which is expected to be completed in early 2010, is now fully enrolled and is no longer accepting new participants. Although it is designated a Phase 2b trial rather than a Phase 3 trial, it is considered a pivotal, registration-directed trial. This means that if the trial results are sufficiently positive, the data from this trial could potentially be submitted to the US Food and Drug Administration (FDA), to the European Medicines Agency (EMEA), and to other regulatory authorities for marketing approval without the need to perform a Phase 3 trial in nmDMD/BMD.

Those participants who successfully complete the Phase 2b trial are eligible to participate in a Phase 2b extension study, which has now opened. In this Phase 2b extension study, all participants receive ataluren (no patients receive placebo). This extension study is only for those patients who participated in the original Phase 2b study.

The third clinical trial of ataluren currently being conducted in nmDMD is a Phase 2a extension study in which, like the Phase 2b extension study, all participants receive ataluren. The trial is available only to those boys who participated in a prior Phase 2a study that was completed some time ago.

In nmCF, we expect to initiate a Phase 3 clinical trial at multiple sites in North America, Europe and Israel in the second half of 2009. The main objectives of the trial are to understand whether ataluren can improve lung function and CF symptoms and whether it can be given safely for a long period (at least 48 weeks). Additional information will be available as the opening of the trial approaches.

After successfully completing two Phase 1 clinical trials in healthy volunteers, we started a Phase 2a trial in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) at three sites in the U.S. Each of the 38 patients in this trial received ataluren for 28 days at one of three dose levels.

The goal of this study was to determine whether ataluren increases the production of dystrophin in muscle cells. DMD is caused by a lack of dystrophin protein. Because ataluren is designed to increase the production of dystrophin in patients with nmDMD, we monitored dystrophin levels in muscle cells. This was accomplished by removing a small amount of muscle tissue from each participant in the trial and analyzing it using a microscope and specialized software.

A lack of dystrophin in muscle cells causes the protein creatine kinase to leak out of muscle cells into the bloodstream. Thus, another goal of this study was to determine whether ataluren reduces the concentration of creatine kinase in the bloodstream. Researchers also evaluated ataluren safety and how ataluren is absorbed into the bloodstream and eliminated from the body.

In this study, ataluren treatment 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. Reductions in the concentration of creatine kinase in the bloodstream were also observed during ataluren treatment, suggesting a decrease in muscle fragility.

Ataluren was generally well tolerated (see Question 8) and the majority of patients took all of the ataluren treatment without missing any doses. The presence of ataluren in the bloodstream was sustained and stable during the study treatment duration.

Based on the results of this study, we initiated a longer-term Phase 2b study in February 2008.

After successfully completing two Phase 1 clinical trials with healthy volunteers, we conducted three Phase 2 trials in patients with nmCF in the U.S., Israel, France, and Belgium. Each of the 77 patients (47 adults and 30 children) enrolled in these trials received ataluren in two repeated 28-day cycles, each consisting of 14 days on therapy and 14 days off therapy. In one cycle, participants received a lower dose regimen of ataluren, and in the other cycle, they received a higher dose of ataluren.

One goal of the CF clinical program was to determine whether ataluren increases the production of cystic fibrosis transmembrane conductance regulator (CFTR) in cells. CF is caused by a lack of CFTR. Because ataluren is designed to permit the production of CFTR in patients with nmCF, we monitored CFTR levels. This was accomplished by swabbing a small number of cells from out of the nose of participants in the trial and analyzing the cells for CFTR protein using a microscope.

Lack of CFTR causes abnormal movement of salt (sodium chloride) and water in and out of the cells in the nose and lung. Thus, another goal of these studies was to determine whether ataluren increases the movement of chloride molecules through the cells that line the nostrils. Such an improvement would provide evidence that the CFTR produced by ataluren is active. Researchers also evaluated ataluren safety and how ataluren is absorbed into the bloodstream and eliminated from the body.

In this study, ataluren treatment was associated with an improvement in the number of nasal cells showing CFTR protein. Improvements and normalization of chloride movement across respiratory cells were observed in many patients. Results appeared to improve with a longer time on treatment.
Ataluren was generally well tolerated (see Question 8) and the majority of patients took all of the ataluren treatment without missing any doses. The presence of ataluren in the bloodstream was sustained and stable throughout the study duration.

Building on the results from these studies we plan to initiate a Phase 3 trial of ataluren in nmCF in the second half of 2009.

As part of the Phase 1 trials in healthy volunteers, some participants received very high single doses of the drug (150 or 200 mg/kg) that are above those expected to be given to patients. At these very high levels, patients experienced transient effects of nausea, vomiting, diarrhea, headache, and dizziness. These effects were mild and disappeared rapidly (generally within minutes to hours). Some healthy volunteers received treatment for up to 14 days at doses up to 50 mg/kg twice a day and experienced no symptoms of drug related adverse events (side effects) at any dose level. Some participants had modest increases in enzymes from the liver that can be detected in blood tests. This did not require discontinuing ataluren, and the enzyme levels returned to normal after the participants stopped taking the drug.

Ataluren was also generally well tolerated among the 38 patients with nmDMD and the 77 patients with nmCF who participated in the Phase 2a studies. Adverse events were infrequent and usually mild to moderate in severity. A few patients with CF sometimes had mild burning with urination but this did not result in therapy being interrupted or discontinued. There were no safety concerns based on physical examinations, vital sign measurements, electrocardiograms, or laboratory test results.

Data from the Phase 2a studies are preliminary in nature. Studies of larger groups of patients are now being conducted over longer periods of time to more fully evaluate the safety and efficacy of ataluren.

In the second half of 2009 a Phase 3 trial of ataluren is expected to begin enrolling patients who are at least 6 years of age, have CF due to a documented nonsense mutation, 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.

All planned sites for this trial will be 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.

Trials of ataluren in nonsense mutation Duchenne/Becker muscular dystrophy (nmDMD) are ongoing but have completed their enrollment goals and thus are not currently enrolling new patients.

An extension study will be open only to those patients with nmCF who successfully complete the Phase 3 trial.  As more information becomes available, PTC Therapeutics will consider the conduct of additional trials of ataluren in patients with nmDMD, nmCF and in other patients with genetic disorders due to nonsense mutations (see Question 12).

At this time, a pre-approval access program would be premature. Although the early data in nonsense mutation cystic fibrosis and nonsense mutation Duchenne muscular dystrophy are encouraging, the results are preliminary, and were obtained from a small number of patients receiving ataluren for a short period of time.  Conduct of an expanded access program at this time might result in unacceptable risks for patients and might jeopardize the development of ataluren so that it cannot become available for all patients who might benefit if its efficacy and safety are eventually proven.

Once a clinical trial is initiated, important information is made available at www.clinicaltrials.gov (use the search term “ataluren”) , as well as in the clinical trials section of PTC’s website, www.ptcbio.com.  PTC sends e-mail updates about our clinical trials and other news from the company.  To join the mailing list, visit the “Contact Us” portion of our website.