Therapy Analysis - Gene therapy - Still the Next Big Thing?
Current gene therapies
Despite the initiation of a large number of gene therapy projects, the majority do not make it into human trials (Graph 2), with the number at Phase III only reaching double figures for the first time in 2008. To date, only two gene therapies have actually reached the market. The first of these was Gendicine, developed by SiBiono GeneTech, which was launched in China in 2004 following 14 years of development, for the treatment of head and neck squamous cell carcinoma. Gendicine consists of a recombinant human p53 tumour suppressor gene incorporated within an adenoviral vector. Upon intratumoural injection, Gendicine binds to the coxsackie adenovirus receptor on tumour cells, entering these cells and overexpressing the encoded exogenous p53 gene. The p53 protein thus produced triggers a host of antitumoural activity including inducement of cell cycle arrest and apoptosis. The launch followed a more than threefold improvement in efficacy of chemo- and radiotherapy when coadministered with Gendicine in a Phase III trial in 120 patients with late-stage head and neck squamous cell carcinoma, with no patient relapses observed over a 3 year follow-up.
The second launch of a gene therapy occurred three years later, when Rexin-G, developed by Epeius Biotechnologies, was launched in the Philippines for a broad spectrum of intractable metastatic cancers. Similarly to Gendicine, Rexin-G is designed to bind to cancerous cells and deliver a tumour suppressor gene directly to that cell. In the case of Rexin-G this is accomplished using the Cyclin-G1 gene and a retroviral vector to introduce it. One advantage of Rexin-G is that rather than having to be delivered intratumourally, it actually targets cancerous cells whilst sparing healthy tissue, increasing efficacy and allowing simpler intravenous administration. Highlighting the potential of this agent, Rexin-G received both US orphan drug status and an FDA grant for pancreatic cancer, with Phase I/II trials now underway. Rexin-G has been available for compassionate use in Japan since 2007, and further launches are expected in the US, Europe and ASEAN countries.
As of March 2009, Pharmaprojects data indicates there are 244 active gene therapeutics in development, including three currently awaiting approval. These include Collategene (beperminogene perplasmid), which consists of plasmid hepatocyte growth factor, under development by AnGes MG and Daiichi Sankyo for the treatment of critical limb ischaemia and Buerger's disease. Collategene is awaiting approval in Japan, and launches for ischaemic heart disease are planned in the EU and the US. Also awaiting approval in the EU is Advexin (contusugene ladenovac), which, similarly to Gendicine, is a p53 adenoviral anticancer, initially indicated for the treatment of head and neck cancer. A US BLA was deemed insufficient by the FDA and refused; Introgen is currently appealing this decision. The final gene therapy, Cerepro (stimagene ceradenovac), is also filed in the EU, for the treatment of glioma, a type of brain cancer. Cerepro, developed by Ark Therapeutics, also uses an adenoviral vector, although in this case to introduce the thymidine kinase gene to healthy brain tissue following tumour removal. Soon after, the patient receives the antiviral drug ganciclovir, which reacts with the cells now expressing thymidine kinase to inhibit mitosis, thus targeting any remaining cancerous cells for destruction. Cerepro is already available on a named-patient basis in France and it could be that Europe finally sees its first gene therapeutic available for public use in the near future.
