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April 15, 2009 (Vol. 29, No. 8)

Firm Aims to Regulate RNA in Rare Diseases

PTC Therapeutics Focuses on Small Molecule Drugs for Genetic Disorders and Cancer

  • Non-sense Mutations

    Ataluren is an orally administered, small molecule compound that targets non-sense mutations. It enables the cellular machinery to override the non-sense mutation, allowing the translation process to override the premature stop signal. The investigational drug has restored the production of full-length, functional proteins in preclinical genetic disease models, the company reports.

    In cystic fibrosis (CF), an inherited chronic disease that affects the lungs and digestive system of about 70,000 people worldwide, a defective gene and its protein product cause the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections, and obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.

    Both Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy, caused by the lack of a protein, progressively weaken the muscles; DMD, the more potent form, confines boys and young men to wheelchairs in their early teens and ultimately affects their breathing  and heart functions. While these diseases have no treatments on the market for the underlying cause of the disease, ataluren has the potential to address the underlying cause, Dr. Peltz reports.

    Data from Phase IIa clinical trials in cystic fibrosis and DMD demonstrate that treatment with ataluren can restore the production and function of the CFTR and dystrophin protein in some patients with non-sense mutations. The drug has been well tolerated for two to four weeks.

    Currently, ataluren is in Phase IIb international pivotal trials in patients with non-sense mutation Duchenne/Becker muscular dystrophy. Clinical trials for ataluren to determine its efficacy in treating CF are planned for later this year.

    Results from a Phase IIa European study demonstrated that treatment with ataluren caused statistically significant improvements in the chloride channel function of children with CF caused by a non-sense mutation. In Israel, where the incidence of non-sense-mutation CF is especially high because of its prevalence in Jewish people of Eastern European (Ashkenazic) origin, a 12-week study showed that ataluren was well tolerated.

    According to Langdon Miller, M.D., CMO of PTC, “these data demonstrate the activity of ataluren across a broad range of patients and suggest that it could be a valuable option for many patients living with CF. There is, currently, no available therapy to correct defective CFTR production and function. Instead, available treatments for CF are designed to alleviate the symptoms of the disease.”

  • More in the Pipeline

    PTC has also developed GEMS (gene expression modulation by small molecules), a screening technology for the identification of small molecules that modulate post-transcriptional control mechanisms. Compounds identified through the GEMS technology modulate gene expression by targeting the post-transcriptional control processes that act through the untranslated regions of messenger RNA molecules.

    GEMS, which enables PTC to address a wide variety of genes as potential targets for drug discovery, was used in the discovery of PTC299 in the hepatitis C virus (HCV) program and in multiple ongoing drug discovery programs.

    PTC299 is designed to decrease vascular endothelial growth factor (VEGF) production. In studies using animal models of human cancer, including breast cancer, PTC299 has been shown to decrease tumor-derived VEGF production, leading to decreased tumor blood vessel production and strong reduction or inhibition of tumor progression, says Dr. Miller. Phase Ia trials have evaluated the safety of oral dosages of PTC299 for up to seven days. Results from these early trials indicate that PTC299 is generally well tolerated.

    Also using its GEMS technology, PTC has identified small molecules that selectively inhibit the translation of the hepatitis C virus protein without inhibiting human host cell translation in in vitro studies.

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