PTC Therapeutics is developing an oral compound designed to treat the basic defect in cystic fibrosis – a faulty gene and its protein product, called CFTR.
The potential drug, called ataluren (formally known as PTC124), aims to treat CF patients who have what is known as a nonsense mutation. Nonsense mutations interrupt the production of the CFTR protein and cause CFTR to be too short and non-functioning.
Data from Phase 2 clinical trials of ataluren showed that CF patients who took the drug had improved function of the CFTR protein and a decrease in the frequency of cough. Ataluren was also associated with improved lung function.
Ataluren is currently being evaluated in a Phase 3 clinical trial. The study is designed to generate data that the U.S. Food and Drug Administration can use to determine if ataluren is safe, effective and acceptable for approval.
What is ataluren?
Ataluren (formerly referred to as PTC124) is a new investigational drug for cystic fibrosis that targets a particular type of mutation known as a nonsense mutation.
A nonsense mutation interrupts the production of the CFTR protein, the key protein associated with CF. This mutation causes CFTR to be too short and non-functioning. Overall, about 10 percent of people with CF have nonsense mutations.
For patients with CF due to nonsense mutations, ataluren has the potential to address the underlying cause of the disease by allowing a fully-functioning CFTR protein to be made.
Additional information about ataluren is available at www.ptcbio.com/ataluren.
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If a patient has only one nonsense mutation, will ataluren still have the potential to work?
Everyone has two copies of the CFTR gene, one inherited from each parent. People with CF have a mutation in both copies. Often the two mutations are different. For example, a CF patient may have a Delta F508 mutation (the most common CF mutation) and a G542X mutation (a common CF nonsense mutation). Ataluren has the potential to work even if only one of the two mutations is a nonsense mutation.
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What is the purpose of the Phase 3 trial of ataluren in CF?
The main goal of the trial is to understand whether ataluren can improve lung function in patients with CF. The trial will also determine whether the drug can be given safely for a long period of time.
The study also evaluates whether ataluren can reduce the symptoms associated with CF, decrease CF-related lung infections, reduce how often patients cough due to CF, and improve patient quality of life.
This trial is considered a pivotal registration-directed trial, meaning that it is intended to generate key information that the U.S. Food and Drug Administration (FDA) can use to determine if the drug is safe and acceptable for approval.
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What is the design of the Phase 3 trial?
The study will enroll approximately 208 CF patients who have nonsense mutations at CF research centers in North America, Europe and Israel.
Each participant in this trial will be randomly assigned to one of two treatment groups. One treatment group will receive ataluren and the other will receive a placebo. Selection on which patients will receive ataluren or placebo will be done by a computer program. Each participant will have an equal chance of being assigned to either group.
The CF patient, the CF patient’s family, the study investigators, the CF Foundation and PTC Therapeutics cannot choose which group an individual patient is assigned to. No one will not know which participants are receiving ataluren.
Both groups will take the assigned study medication (ataluren or placebo) three times per day – at morning, midday, and evening – for 48 weeks.
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Why won’t all participants in the trial receive ataluren?
In order to determine whether ataluren improves symptoms of CF, it is necessary to compare results in participants receiving ataluren with those in participants who are not receiving the investigational drug.
However, each participant who successfully completes the trial will be eligible to enter into an extension study that will last at least another 48 weeks in which every participant will receive ataluren.
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Who will qualify to participate in the trial?
To be eligible for this trial, patients must have had a DNA blood test to evaluate the CFTR gene and know that a nonsense mutation is present. This is known as genotyping.
Patients with CF who have not received this genetic test should consider discussing the test with their CF physician or genetic counselor.
In addition to having a nonsense mutation, participants must be at least six years of age and must weigh at least 35 pounds. To document that each participant truly has CF, tests of CFTR function in the nose (nasal potential difference test) and in the skin (sweat test) will be done.
Patients must be able to do a breathing test (spirometry) and must have values that are between 40 percent and 90 percent of those predicted for healthy people of similar age and height. Participants cannot have serious abnormalities of the liver, kidney, or adrenal function or life-threatening complications of CF or other diseases.
Since the effects of ataluren on a human fetus are unknown, women must not be pregnant.
Additional inclusion and exclusion criteria are provided at www.clinicaltrials.gov/ct2/show/NCT00803205 and will be explained in more detail at each research center.
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Why won’t children under age six be able to participate in the trial?
Change in lung function, as measured by breathing tests (spirometry), will be the primary indication of the potential effectiveness of ataluren. Because it is often difficult for very young patients to perform spirometry testing, and because spirometry may not be a reliable measure in children under six years of age, the trial is limited to older participants.
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Will the use of other CF treatments keep patients from potentially qualifying for participation in the trial?
Participation in the trial is open to patients who are receiving other treatments for CF or CF-related conditions. However, it is important that participants not make changes by starting, stopping or changing the doses of medications within four weeks prior to the start of the ataluren trial. Unless medically necessary, participants should avoid making changes in the type or doses of medications during the trial’s 48-week treatment phase.
For example, patients can be enrolled if they are using inhaled medications such as tobramycin, dornase-alfa, hypertonic saline, corticosteroids, or β2 agonists; or systemic drugs such as azithromycin or ibuprofen. Trial participants should remain on a stable medical regimen of treatment for CF-related conditions.
Patients cannot participate in the ataluren trial if they are participating in a clinical trial of another investigational therapy for CF.
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What will patients need to do in order to qualify to participate in the trial?
Before being considered for enrollment in the trial, and before undergoing testing or receiving study medication, a patient (and a parent or guardian, if the patient is a minor) must be informed about the trial by the medical researchers. The participant and/or parent or legal guardian must sign a document called an informed consent form, indicating a willingness to participate and follow the study requirements.
The informed consent 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.
Keep in mind that the informed consent form is not a contract. Participants can withdraw from a trial at any time.
Once the informed consent form is signed, patients must undergo screening assessments to determine whether they meet study entrance requirements and are eligible to participate. The screening procedures may be completed during a single research center visit, which can be conducted up to four weeks before the ataluren trial is started.
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What will participation in the trial involve?
During the 48 weeks of the clinical trial, participants will visit the research center at least every eight weeks. During these visits, participants will have clinical and laboratory tests of blood, urine, and sputum to evaluate treatment effects and safety. For the first six months of the trial’s treatment phase, participants will also need to visit the research center or a local laboratory every four weeks for collection of additional blood and urine for safety tests.
At the time of research center visits, participants will have spirometry tests to assess lung function and nasal potential difference testing and sweat testing to check on CFTR function. They will be asked about how they are feeling and their quality of life.
Participants will receive instructions on the use of the LifeShirt® Clinical System, a monitoring device that records the number and intensity of coughs. Patients will use the LifeShirt, which is worn like a vest, for a 24-hour period after each research center visit.
Participants will also be required to keep a daily diary to detail their CF-related symptoms and use of the study drug.
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How will treatment be administered in the trial?
Ataluren and the placebo are supplied as a powder packaged in an aluminum foil packet. Both have a mild vanilla flavor, and they are mixed in water or milk and taken three times a day for 48 weeks. The amount of drug used is determined by body weight in kilograms and is higher in the evening to account for the longer period between doses.
Enrolled patients will be divided into two treatment groups of about 104 patients each:
- Group 1: Ataluren at a dose level of 40 milligrams per day for each kilogram of body weight (10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening)
- Group 2: Placebo (inactive dry powder that looks and tastes the same as ataluren), taken in the morning, at midday, and in the evening
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Will study participants who receive placebo during the trial be eligible to receive ataluren?
Upon successful completion of the trial, participants will be eligible to enter into a planned open-label extension study in which every participant will receive ataluren.
If a participant does not wish to enter the extension study or withdraws from the trial early, a short-term follow-up visit will be performed four weeks after stopping study drug to document the general health of the patient.
In addition, each patient or parent will be asked to complete a short survey on general health at six- to 12-month intervals over a five-year period. This survey may be completed at the research center during a routine visit or by telephone.
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Will there be any cost to participate in the trial?
All costs of physical examinations, screening assessments, laboratory and other trial-related 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 study visits.
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Where is the trial being conducted and how long will it be accepting patients?
Trial research centers are located in the United States as well as in Belgium, Canada, France, Germany, Israel, Italy, the Netherlands, Spain, Sweden and the United Kingdom. As each research center is opened and ready for enrollment, center contact details will be listed on www.clinicaltrials.gov/ct2/show/NCT00803205. Participants or their families can contact a research center directly to inquire about trial participation.
The trial will continue enrolling new patients until the necessary number of participants has been reached. The sooner patients enroll in the trial, the faster the trial can be completed, and the sooner the results wil be known.
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Is there any way to get ataluren outside of a clinical trial?
Ataluren is an investigational drug that has not yet been approved for use by the FDA. Therefore, it 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.
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Updated 9/10/2009
