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

Click here to read Frequently Asked Questions about ataluren.

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 (eg, the dystrophin protein in nmDBMD or the CFTR protein in nmCF).

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 ribosomes to read through the normal stop signal.

Ataluren, taken orally, 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.

Click on the video below to listen to Dr. Langdon Miller, Chief Medical Officer of PTC Therapeutics explain how ataluren (PTC124®) works.

Nonsense Mutation Genetic Disorders
The National Institutes of Health (NIH) Office of Rare Diseases estimated 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. Besides nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD) and nonsense mutation cystic fibrosis (nmCF), these genetic disorders include a range of serious diseases across multiple therapeutic areas including, spinal muscular atrophy, hemophilia, lysosomal storage disorders, and some forms of cancer.


Genetic Testing
Ataluren has the potential to treat any genetic disorder caused by a nonsense mutation. Although current clinical trials involve only nonsense mutation DBMD and nonsense mutation CF, future trials are anticipated in other genetic disorders caused by a nonsense mutation. 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, www.genetest.org provides a listing of laboratories and contact information.

Ongoing Clinical Trials
Ataluren has demonstrated proof of concept in Phase 2a clinical trials in nonsense mutation DBMD (nmDBMD) and nonsense mutation CF (nmCF). PTC has initiated registration-directed clinical studies to understand whether ataluren can improve how patients with nmDBMD and nmCF feel and function and to determine if the drug can be given safely over a long period.

• nmDBMD: PTC has fully enrolled a Phase 2b clinical study of ataluren in nmDBMD. The trial is a multi-center, randomized, double-blind, placebo-controlled study to determine whether ataluren can improve walking activity, muscle function, and muscle strength. It is being conducted at 37 centers around the world with approximately 165 patients.
  
• nmCF: PTC has initiated a longer-term, Phase 3 clinical study of ataluren in patients with nonsense mutation CF. The main goals of this study are to understand whether ataluren can improve how nmCF patients feel and function and whether the drug can safely be given over a long period. The trial is a multi-center, randomized, double-blind, placebo-controlled study.
  
• nmHA/B: PTC has initiated a Phase 2a clinical trial of ataluren in patients with nonsense mutation hemophilia type A and B (nmHA and nmHB). The trial is a multi-center, open label, dose escalation study. The main goals of the trial are to determine whether treatment with ataluren can result in an increase in Factor VIII or IX levels and whether the drug can safely be given to people with severe hemophilia due to a nonsense mutation.

Completed Clinical Trials

• Phase 2a Data nonsense mutation DBMD (nmDBMD): Data from Phase 2a clinical trials of ataluren in pediatric patients with nmDBMD show that administration of ataluren is associated with production of functional dystrophin. Ataluren treatment has also been associated with statistically significant reductions in the leakage of muscle-derived creatine kinase into the blood.
  
• Phase 2a Data nonsense mutation CF (nmCF): Data from Phase 2a clinical trials of ataluren in pediatric and adult patients with nmCF show that administration of ataluren results in production of functional CFTR and statistically significant improvements in CFTR chloride channel function in the airways. Ataluren treatment was associated with reductions in cough frequency and improvements in pulmonary function tests.
  
• Adverse Events and Safety Profile: Across all clinical studies to date, including Phase 1 healthy-volunteer studies, ataluren has been generally well tolerated. In Phase 2a studies, adverse events based on physical examination, vital sign measurements, ECGs or laboratory studies have been largely consistent with background symptoms and have usually been mild. Mean compliance has been >90% in all studies.

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

The FDA has granted PTC124® (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. PTC124® (ataluren) has also been granted orphan drug status for the treatment of CF and DBMD by the European Commission.

Partnership with Genzyme
PTC Therapeutics, Inc. and Genzyme Corporation have an exclusive collaboration to develop and commercialize ataluren. PTC will commercialize ataluren in the United States and Canada and Genzyme will commercialize ataluren in all other countries.

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.

Click here to read Frequently Asked Questions about ataluren.

PTC124 Targets Genetic Disorders Caused by Nonsense Mutations