Ataluren

Ataluren for Genetic Disorders

Ataluren is our lead product candidate for the treatment of patients with genetic disorders that arise from a type of genetic mutation known as a nonsense mutation. Ataluren is currently being investigated for use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) and cystic fibrosis (nmCF).

A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Nonsense mutations create a premature stop signal in the translation of the genetic code contained in mRNA and prevent the production of full-length, functional proteins. We believe that ataluren interacts with the ribosome, which is the component of the cell that decodes the mRNA molecule and manufactures proteins, to enable the ribosome to read through premature nonsense stop signals on mRNA and allow the cell to produce a full-length, functional protein.

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.

We believe that ataluren interacts with the ribosome, which is the component of the cell that decodes the mRNA molecule and manufactures proteins, to enable the ribosome to read through premature nonsense stop signals on mRNA and allow the cell to produce a full-length, functional protein. As a result, we believe that ataluren has the potential to be an important therapy for muscular dystrophy, cystic fibrosis and other genetic disorders for which a nonsense mutation is the cause of the disease

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. A significant number of rare genetic disorders are monogenic disorders that occur as a consequence of the absence of a single protein. The restoration of the production of that single protein has the potential to treat the genetic disorder. We estimate that, on average, 11% of patients with any monogenic disorder have a nonsense mutation as the cause of the disease.

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.

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 EMA has designated ataluren as an orphan medicinal product and the U.S. Food and Drug Administration, or FDA, has granted orphan drug designation to ataluren for the treatment of both nmDMD and nmCF.

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.