PTC124 is a novel, orally administered small-molecule compound that targets a particular genetic alteration known as a nonsense mutation. Genetic disorders occur due to mutations in an individual’s DNA. Among the various types of mutations, nonsense mutations are single-point alterations in DNA that, when transcribed into mRNA, introduce a premature stop codon. This change stops the ribosomal translation process at an earlier site than normal, producing a truncated, non-functional protein; the lack of full-length, functional protein can cause disease. PTC124 is an orally administered, investigational new drug that targets disease-causing premature stop codons. PTC124 induces ribosomes to override the premature stop signal resulting in the synthesis of a full-length protein when the normal stop codon is reached. PTC is developing PTC124 for the treatment of genetic disorders in which a nonsense mutation is the cause of the disease.

Click here to read Frequently Asked Questions about PTC124.

Figure 1. Translation of an mRNA into protein: comparison of normal translation, premature translation termination, and treatment with PTC124 restoring synthesis of full-length protein.

The National Institutes of Health (NIH) Office of Rare Diseases estimates that genetic disorders are responsible for the majority of rare diseases that afflict 25 million people in the U.S.. In more than 2,400 genetic disorders, on average 5 to 15 percent of the patients have the disease due to a nonsense mutation. These genetic disorders include cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), spinal muscular atrophy, hemophilia, lysosomal storage disorders, retinitis pigmentosa, familial hypercholesterolemia and some forms of cancer, and many others.

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PTC124: PRECLINICAL STUDIES

PTC has conducted multiple in vitro and in vivo preclinical studies of PTC124.  Key findings include:

• Exposure to PTC124 resulted in the production of full-length and functionally active dystrophin in both the in vitro and mouse models of nonsense mutation Duchenne muscular dystrophy; these data were published in the May 3, 2007 edition of Nature (click on text below to download a PDF of the Nature article). 
  
  PTC124 Targets Genetic Disorders Caused by Nonsense Mutations

• Similarly, the administration of PTC124 resulted in the production of full-length and functionally active CFTR in mouse models of nonsense mutation cystic fibrosis; These data were published in the February 2008 edition of the Proceedings of the National Academy of Sciences.

• PTC124 demonstrated greater potency and activity than gentamicin in the read through of premature stop codons in in vitro studies.

PTC124: CLINICAL STUDIES

Phase 1 Clinical Trials — Results from Phase 1 healthy-volunteer clinical studies show that PTC124 is generally well tolerated, achieves target plasma concentrations that have been associated with activity in preclinical models, and does not induce ribosomal readthrough of normal stop codons. Data from these studies were published in the April 2007 edition of the Journal of Clinical Pharmacology.

Phase 2 Clinical Trials for Duchenne muscular dystrophy (DMD) - Data from Phase 2a clinical trials of PTC124 in pediatric patients with nonsense mutation DMD (nmDMD) show that administration of PTC124 is associated with production of full-length dystrophin. Statistically significant reductions in the leakage of muscle-derived creatine kinase into the blood suggest that PTC124-induced dystrophin production leads to decreases in muscle fragility. In addition, parents and teachers of several study participants noted improvements in their activity and endurance.

Phase 2 Clinical Trials for Cystic Fibrosis (CF) - Data from Phase 2a clinical trials of PTC124 in pediatric and adult patients with nonsense mutation cystic fibrosis (nmCF) show that administration of PTC124 results in production of full-length CFTR. PTC124 treatment also results in statistically significant improvements in CFTR chloride channel function in the airways. In addition, PTC124 treatment is associated with reductions in cough frequency and improvements in pulmonary function tests. Data from the Israeli Phase 2a clinical trial was published in The Lancet on August 30, 2008.

Analysis of adverse events and compliance indicates a favorable PTC124 safety profile for future development. Across all Phase 2a studies, adverse events have been largely consistent with background symptoms and have usually been mild. No concerning adverse findings have been identified based on physical examinations, vital sign measurements, ECGs, or laboratory studies. Consistent with this safety profile, mean compliance has been >90% in all studies.

Collective results from the Phase 2a studies have been reviewed with regulatory authorities. Based on the advice received, PTC has initiated registration-directed Phase 2b clinical studies to evaluate the potential clinical benefits of PTC124 for patients with nmDMD and nonsense mutation Becker muscular dystrophy (nmBMD) which is a milder form of the disease. Efficacy measures being assessed are ambulation, patient activity, and muscle integrity. In CF, pulmonary signs and symptoms will be evaluated as the major measures of efficacy; this study is expected to begin in the first half of 2009.

The FDA has granted PTC124 Subpart E designation for expedited development, evaluation, and marketing and has granted Orphan Drug designations for the treatment of CF and DMD due to nonsense mutations. PTC124 has also been granted orphan drug status for the treatment of CF and DMD by the European Commission. The development of PTC124 is supported by grants from the Cystic Fibrosis Foundation, Muscular Dystrophy Association, Parent Project Muscular Dystrophy, FDA’s Office of Orphan Products Development, and by General Clinical Research Center grants from the National Center for Research Resources. In July 2008, PTC entered into a collaboration with Genzyme Corporation for the ex-US/Canada commercialization rights for PTC124.

To receive status updates on PTC124, 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, 908-912-9256 or patientinfo@ptcbio.com.

Click here to read Frequently Asked Questions about PTC124.