Ataluren

Ataluren for Genetic Disorders

Ataluren (PTC124®) is an investigational new drug designed to enable the formation of a functioning protein in patients with genetic disorders due to a nonsense mutation.

A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Ataluren is currently being investigated for use in patients with nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD) and cystic fibrosis (nmCF).

Figure 1. Translation of an mRNA into protein: comparison of normal translation, premature termination of translation, and treatment with ataluren inducing synthesis of functioning protein.

Mechanism of Action
In healthy individuals, ribosomes translate the informational code in the mRNA into protein until arriving at a normal stop signal in the mRNA, at which point the ribosome appropriately stops translation and a functioning protein results.

Nonsense mutations, however, create a premature stop signal in the mRNA. This premature stop signal causes the ribosome to halt translation before a functioning protein is generated, creating a shortened, nonfunctioning protein. The resulting disease is determined by which protein cannot be expressed in its entirety and is no longer functional.

Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosome to read through the normal stop signal.

Ataluren has the potential to address the underlying cause of the disease by overriding the premature stop signal, enabling the synthesis of a functioning protein. Ataluren does not alter the patient’s genetic code or introduce genetic materials into the body.

Nonsense Mutation Genetic Disorders
The National Institutes of Health (NIH) Office of Rare Diseases estimates that rare diseases affect 25 million people in the US and that the majority of these people have genetic disorders. In more than 2,400 genetic disorders, a nonsense mutation causes the disease in an average of 5 to 15% of the patients. These genetic disorders include a range of serious diseases across multiple therapeutic areas.

Genetic Testing
To determine whether a genetic disorder is caused by a nonsense mutation, patients require genetic testing. Genetic testing is done by a simple blood test that is ordered by a physician working in concert with a genetic lab.

Laboratories performing genetic testing vary by disorder and location. The NIH-funded website GeneTests.org provides a listing of laboratories and contact information.

Completed Clinical Trials

• Phase 2b results in nonsense mutation DBMD (nmDBMD): Phase 2b efficacy data presented at the World Muscle Society Congress in 2010 suggest ataluren treatment slowed the loss of walking ability in patients with nmDBMD. The primary endpoint of the Phase 2b trial was the change in 6-minute walk distance (6MWD) from baseline to 48 weeks.
• Phase 2a results in nonsense mutation CF (nmCF): Published data from Phase 2a clinical trials of ataluren in pediatric and adult patients with nmCF showed that administration of ataluren resulted in production of functional CFTR protein and statistically significant improvements in CFTR chloride channel function. Ataluren treatment was associated with significant reductions in cough frequency and trends toward improvement in pulmonary function tests.
• Adverse Events and Safety Profile: Across clinical studies to date, ataluren has been generally well tolerated based on the adverse event profile. Mean compliance has been >90% in all studies completed to date.

Grants
The development of ataluren has also been supported by grants from:

• Cystic Fibrosis Foundation
• Parent Project Muscular Dystrophy
• Muscular Dystrophy Association
• FDA’s Office of Orphan Products Development
• National Center for Research Resources
• National Heart, Lung, and Blood Institute

Orphan Drug Status
The FDA has granted ataluren Subpart E designation for expedited development, evaluation, and marketing and has granted Orphan Drug designations for the treatment of CF and DBMD due to nonsense mutations. Ataluren has also been granted orphan drug status for the treatment of CF and DBMD by the European Commission.

To receive status updates on ataluren, please visit the Contact Us page of the website and join our mailing list. Patients, families and advocacy groups may also contact Ms. Diane Goetz, Director, Patient and Professional Relations, 866-282-5873 or 908-912-9256 or patientinfo@ptcbio.com.