Clinical condition
Malignant glioma is a cancerous tumour that is confined to the brain and only rarely spreads further. The current standard therapy involves surgically removing the solid tumour mass and initiating radiotherapy and/or chemotherapy. Even when the solid tumour mass has been removed, pre-cancerous or isolated cancerous cells can exist in the brain. In the majority of these patients a new tumour grows and a repeat operation is frequently required. Currently most available cancer medicines are generally very toxic and many do not readily reach the brain tumour. They often cause severe side effects that can reduce the patient's quality of life significantly and it is these side-effects that can often limit their use. Mechanism of action
Cerepro® is comprised of a gene encased in a virus 'shell' (a "vector"). Vectors transfer their gene 'payload' into target cells, a process known as transfection, which use this new genetic material as a blueprint for the production of new beneficial proteins. Cerepro® uses a well-established adenoviral vector (Ad5) to introduce the gene that causes cells to express a protein called thymidine kinase ("TK"). Following the standard surgery to remove the solid tumour mass, Cerepro® is injected through the wall of the cavity left behind by the surgical removal of the solid tumour, into the surrounding healthy brain tissue. In the following days, the healthy cells in the wall of the cavity express TK. Five days after surgery, the drug ganciclovir ("GCV") is given to the patient as part of the overall Cerepro® treatment regimen. Neither TK nor GCV is individually active but they react together to produce a substance which destroys cells when they try to divide. Since cell division is a key characteristic of cancer and the normal brain cells are not dividing, cells that try to divide to form a new tumour around the site of the removal of the original tumour are targeted for destruction by the Cerepro® treatment.
Cerepro® thus works by harnessing healthy cells to produce the substances necessary ultimately to destroy newly growing cancer cells. This is in contrast to other historical gene-based approaches to treating cancer, where the cancer cells themselves are the targets for transfection of genes which then kill them. This historical approach is self-limiting, because as the cancer cells are killed, the treatment gene within them is lost. In addition, to kill the complete cancer tumour these approaches need to achieve gene transfer in the majority, if not all, of the cancer cells. It is widely accepted that 100% transfection is difficult to achieve with current viral vectors, leaving many existing cancer cells unaffected by the treatment. Ark’s novel use of healthy cells does not require high levels of transfection because cancer cell killing substances continue to be produced by these healthy cells even after the first new cancer cells are destroyed thereby continuing to kill surrounding cancer cells.
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Development status
Cerepro® has been granted Orphan Drug Status by the European Committee for Orphan Medicinal Products and by the Office of Orphan Products Development, FDA.
Cerepro® is manufactured in the Group's facility in Kuopio, Finland, which was previously licensed by the Finnish National Agency for Medicines in 1998, 2000 and 2004 for the manufacture of injectable gene-based medicines for Phase I, II and III trials.
Ark is working with the regulatory authorities to ensure its enlarged manufacturing facility meets US and European certification standards for Phase III/commercial gene medicine production. All manufacture has been, and the Group intends that all manufacture will be, performed in accordance with applicable European and US regulatory standards and guidelines.
The Cerepro® development programme has completed four clinical trials to date. The first, published in Human Gene Therapy in 1998, established the dose and method of administration. Results of the second, an open label efficacy and safety study, were published in Human Gene Therapy in 2000 and showed that Cerepro® doubled mean survival time and was well tolerated.
The results of the third study were presented at the American Society of Gene Therapy (ASGT) meeting in Minneapolis on 5 June 2004, and published in Molecular Therapy in 2004.
Reference: Immonen et al, Nov 2004; Mole Therapy:10 No. 5, 967-972.
The most recent clinical study, called the ASPECT study (904), was a Phase III, randomised, controlled, multicentre evaluation that recruited 250 patients. The results from the ASPECT study were recently presented during an oral presentation at the 3rd Quadrennial meeting of the World Federation of Neuro-Oncology in Yokohama, Japan. These preliminary results showed a statistically significant outcome for the primary endpoint. Complete results of the ASPECT study are expected to be published during the course of 2010.
A Marketing Authorisation Application (MAA) was submitted to the EMEA in November 2008. This submission was accepted for review by the EMEA at the end of 2008 and the evaluation completed in December 2009. Following a refusal by the CHMP to approve Cerepro® for commercial use, Ark entered request for the application to be reevaluated. The reevaluation began with an Oral hearing with the Scientific Advisory Group for Oncology (SAG-O). Following this SAG-O meeting Ark decided to withdraw from the appeal process.
Ark is currently investigating the next steps for the development of Cerepro®. Further information will be published on the website once available.
Approvals for named patient supply of Cerepro® have been given by the French Medicines Control Agency (AFSSAPS) in February 2009 and also by the Finnish Medicines Authorities (NAM) in May 2009.
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Selected Publications
- Puumalainen A-M, Vapalahti M, Agrawal RS, Kossila M, Laukkanen J, Lehtolainen P, et al. b-galactosidase gene transfer to human malignant glioma in vivo, using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 1998; 9: 1769-1774.
- Sandmair AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M, et al.
Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther 2000; 11: 2197-2205.
- Immonen A, Vapalahti M, Tyynelä K, Hurskainen H, Sandmair A, Vanninen R, et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 2004; 10: 967-972.
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