PTC124 is an investigational new drug, which means it is being tested as a potential treatment but that it has not yet been approved for sale by the U.S. Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMEA), nor by regulatory authorities in any other country. PTC124 targets a particular genetic alteration known as a nonsense mutation. Nonsense mutations are errors in the genetic code that cause a genetic disorder by prematurely stopping the production of a critical protein, such as dystrophin in the case of Duchenne/Becker muscular dystrophy (DMD/BMD). Approximately 10-15 percent of patients with DMD/BMD have the disease due to a nonsense mutation. In such patients, PTC124 has the potential to treat the underlying cause of the disease by causing the cellular machinery to overcome the premature stop signal in the genetic code and produce the dystrophin protein.

The trial is an international, multicenter, randomized, double-blind, placebo-controlled study that evaluates two different dose levels of the drug. The main goals of the study are to understand whether PTC124 can improve walking, activity, muscle function, and strength and whether the drug can safely be given for a long period. This study is also intended to generate the information required to support approval by the FDA, EMEA, and other regulatory authorities

To be considered for this study, patients must have had a DNA blood test to evaluate the dystrophin gene and know that a nonsense mutation is the basis for their DMD/BMD. This test is known as genotyping or full-length gene-sequencing. Patients with DMD/BMD who have not been genotyped should consider discussing gene-sequencing with their treating physician or genetic counselor. Knowing the genetic sequence of a disease-causing gene may prove useful in determining eligibility for clinical trials involving certain types of experimental therapies. Facilities that perform gene-sequencing can be located through the Gene Tests website (www.genetests.org); click "Laboratory Directory" to search for the locations of gene-sequencing facilities.

In addition to having a nonsense mutation, study participants must be at least 5 years of age and be able to walk at least 75 meters (80 yards) unassisted in a 6-minute time period. They must also have exhibited an elevated creatine kinase level in the blood and evidence of DMD/BMD based on the medically documented onset of characteristic clinical symptoms or signs (e.g., muscle weakness, waddling gait, Gowers' maneuver) by 9 years of age. Other inclusion criteria will be explained prior to trial enrollment.

Because the trial is primarily evaluating whether PTC124 will improve walking ability in boys and young men with DMD/BMB, it includes only patients who are still able to walk but have difficulty doing so. This study will compare results in participants randomly assigned to receive PTC124 for 48 weeks to results in participants who are randomly assigned to receive a placebo (a substance that looks and tastes like PTC124, but does not actually contain the drug) for 48 weeks. During this time, it is necessary to repeatedly evaluate the participants with a scientifically valid test of functioning. For this purpose, a test of walking, called the 6-minute walk test, has been selected. The 6-minute walk test has been used in other clinical trials and is expected to be the best way to demonstrate an improvement in functioning with PTC124. In this test, participants must walk as rapidly and as far as they can for 6 minutes. They will perform the test before they start the study and will continue to perform it every 6 weeks during the study period while receiving either PTC124 or a placebo. If, over the study period, PTC124 safely allows participants to walk a longer distance than the participants who receive the placebo, this may provide the necessary evidence required by the regulatory authorities to show that PTC124 improves functioning.

To ensure that that the Phase 2b study has a good chance of success, it is important that participants are old enough to perform the 6 minute walk test repeatedly and consistently. It is known from past experience that children under the age of 5 years have difficulty performing the 6-minute walk test reliably. The scientific literature bears this out. Most recently, a study reported in the April 2007 Journal of Pediatrics (Ralf Geiger MD et al, "Six Minute Walk Test in Children and Adolescents") found that only 39% of children in the 3- to 5 year-old age group were able to understand and complete the test, compared to 93% of older children. For this reason, children who are younger than 5 years of age cannot be included in the Phase 2b study.

DMD and BMD, rather than being distinct diseases, represent a continuum of the same disease. A mutation in the dystrophin gene is the cause for both DMD and BMD; however, the types of mutation in patients with BMD appear to cause less rapid loss of muscle function. Because changes in muscle function vary among patients, it is not always clear whether a particular patient should be defined as having DMD or BMD. Thus, as long as an ambulatory patient has the diagnosis of DMD or BMD due to a nonsense mutation and is having trouble walking due to the disease, there is no known reason to exclude him.

In order to be able to show improved functioning in trial participants, enrollment is limited to those patients with BMD who had medically documented signs of their disease, such as elevated creatine kinase, muscle weakness, waddling gait, and Gowers' maneuver by age 9, and are having problems with walking. These criteria indicate that they have problems due to their BMD/DMD that make it appropriate for them to consider an investigational drug like PTC124. The decision as to whether a patient is appropriate for the study is ultimately made by the principal investigator at the study site, who is best able to weigh the potential risks and benefits for each potential participant.

Before being considered for enrollment in the study and before undergoing testing or receiving study medication, a patient (and a parent or guardian, if the patient is minor) must be informed about the study by the medical researchers. They must sign a document called an informed consent form indicating a willingness to participate. This document explains the trial in great detail to allow patients to assess the risks and benefits of participation. A copy of the informed consent form is provided to each patient.

Thereafter, the patient undergoes screening evaluations to determine whether he is qualified to participate in the study. These screening procedures will usually be done at 2 separate clinic visits during the 6-week period before treatment would be started. The purpose of these screening evaluations is to determine whether a person's participation in a clinical trial meets the study entrance requirements and can contribute data that will help achieve the study goals.

In order to determine if PTC124 improves symptoms of DMD/BMD and to understand what dose level can be given safely, it is necessary to compare participants receiving different dose levels of PTC124 with participants who are not receiving PTC124. The amount of drug used is determined by body weight in kilograms (1 kilogram equals 2.2 pounds).

The participants will be divided into 3 groups of about 55 patients each:

No. Participation in the trial is open to patients whether they are taking corticosteroids or not. However, it is important that participants not make a change by starting or stopping corticosteroids or adjusting the dose during the study. Thus, participants in the study who are not using corticosteroids when they start the study should avoid starting corticosteroids for the 48 weeks of the trial period. Participants in the trial who are taking corticosteroids may continue to take them. However, patients who are taking corticosteroids must have initiated corticosteroid therapy at least 6 months before enrolling in the trial and must not have changed their dose for at least 3 months before enrolling in the trial. Dose adjustments necessitated by increased body weight are allowed.

Study sites are planned in Australia, Belgium, Canada, England, France, Germany, Israel, Italy, Spain, Sweden, and the United States. As soon as each site is open to enroll patients, contact details for the site are listed on www.clinicaltrials.gov and www.ptcbio.com/PTC124_clinical_trial_locations. The study will continue enrolling new patients until the necessary number of participants has been reached. It is estimated that enrollment will end in early 2009. The sooner patients enroll in the study, the faster the study can be completed, and the sooner the results can be known.

As soon as sites are open, contact details will be posted and participants or their families can contact a site directly to inquire about study participation. Personnel at the site will explain the study procedures and the potential benefits and risks associated with participation. Potential participants will be given an informed consent form further explaining the trial; those choosing to sign the form will be screened and considered for enrollment.

All costs of physical examinations, screening, laboratory and other tests, as well as the cost of the drug, are covered by PTC Therapeutics. Reimbursement will be made for reasonable costs of travel, meals and lodging necessary for clinic visits.

This is considered a Phase 2b trial rather than a Phase 3 trial because one of its objectives is to determine the optimal dose of PTC124 by testing 2 different dose levels. Typically, an optimal dose level is determined in a Phase 2 trial before a Phase 3 study is done. However, if the Phase 2b trial results are sufficiently positive, the data from this trial could potentially be submitted to the FDA, to the EMEA, and to other regulatory authorities for approval without the need to perform a Phase 3 trial.

PTC124 is an investigational drug that has not yet been approved for sale by regulatory authorities in any country and thus cannot be legally purchased for use by a patient. The only form of PTC124 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, PTC124 is being provided by PTC Therapeutics only for use in clinical trials.