New hope for patients with cystic fibrosis

New hope for patients with cystic fibrosis

Clinical trials of Ataluren

To be considered for the clinical study on the new drug Ataluren, originally called PTC124, CF patients “must know their genetic mutation,” said Teaneck resident Dr. Jay Barth, executive director of clinical development at PTC Therapeutics, Inc., the South Plainfield-based company that is beginning Phase III trials for the new drug. Barth, a Teaneck resident, explained that “many patients already know their mutation. If not, they have to have genetic testing.” Patients who carry at least one copy of a nonsense mutation (see below) may qualify. Also, patients must be at least six years of age, and have lung functioning within a certain range.

Cystic fibrosis can be caused by many different forms of mutations in the CFTR gene. The CFTR gene makes a protein that normally handles the movement of salt across membranes and the secretion of fluids and mucous. Since fluid management and mucous play important roles in many critical organs, CF can affect the lungs, liver, pancreas, reproductive structures, and sweat glands.

In the cells, genetic instructions normally direct the ribosomes – cellular protein factories – how to assemble proteins. Some mutations change genes so that a dysfunctional protein is made. Nonsense mutations are stop signals that are located in the middle of a gene; they cause the production of protein to be interrupted prematurely, so a shortened protein is made. Ataluren is a chemical that can help ribosomes ignore the stop signal and complete the protein. When the normal protein is made, normal functioning throughout the body can be restored. If this approach works, Ataluren could essentially cure the disease in patients with the nonsense mutation.

Dr. Jay Barth

“About 10 percent of CF mutations are due to nonsense mutations,” said Barth. However, within Ashkenazi Jewish CF patients, up to 60 percent of mutations are nonsense mutations.

A three-month Phase II study, led by Drs. Eitan Kerem and Michael Wilschanski and their colleagues, was conducted at Hadassah Medical Center in 2008. The results of the study, published in The Lancet, suggested that many patients had improved salt transport in their tissues. “Hadassah was always a leader in CF research, in particular because of the high percentage of nonsense mutations in the population there,” said Barth. “They are one of the sites in the Phase III study.”

“There are numerous sites in the U.S., Europe, and Israel that are actively recruiting for the Phase III study,” said Barth. Children’s Hospital in Pittsburgh is taking applications and Saint Vincent’s Hospital in Manhattan is planning to participate, although it has not started recruitment yet. Other sites are planned for Westchester and New Jersey, but they have not been finalized.

During the trial, patients will take the drug three times a day in powder form, mixed with water, juice, or milk. The drug is absorbed through the digestive system, enters the blood stream, and goes everywhere in the body, targeting the production of protein by ribosomes affected by nonsense mutations.

The double-blind randomized trial will involve dividing the patients into two groups – one of which will receive the drug and the other a placebo for 48 weeks. Barth explained that after the initial study there will be an “open label extension study where all patients who choose to may continue for another year on the drug.” If proven to be effective in correcting cystic fibrosis due to nonsense mutation, the drug would have to be taken for the rest of the patient’s life. Research has shown that the drug is generally well tolerated with few side effects and very high patient compliance (up to 99 percent of patients continue to take it).

Barth explained that numerous other diseases are caused by nonsense mutations in other genes, and they might also be helped by Ataluren. There have been clinical trials of Ataluren for Duchenne muscular dystrophy caused by nonsense mutations, and there are also studies under way for hemophilia caused by nonsense mutations. Barth said that an estimated 15 percent of all patients with 7,000 rare genetic disorders have nonsense mutations, and many of those patients could be helped by this novel therapeutic drug.

“This gives hope of treating a disease that, until now, there has been nothing to treat the underlying cause,” said Barth. He noted that there are other types of drugs being developed that may be useful for other types of mutations. “Science is advancing and hopefully there will be several different treatments for CF,” Barth said.

Information on PTC Therapeutics and Ataluren clinical trials can be found at For more information, call Diane Goetz, patient advocate, at (866) 282-5873. Information on clinical trials can be found at

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