A common strategy for the treatment of cancer is to administer cytotoxic (or cell killing) drugs in an attempt to destroy the tumour. Cyclophosphamide is one of a group of drugs that is taken by the patient in the form of an inactive prodrug. The prodrug travels through the body to the liver, where enzymes convert it to the active, cytotoxic drug. This approach affects the whole body and leads to the familiar adverse side effects of cancer chemotherapy because the cytotoxic drug destroys normal cells on its way from the liver to the tumour. In addition, because the activating enzymes are present only in the liver, high doses of prodrug must be given to achieve therapeutic levels of the cytotoxic drug at the tumour site. Often the therapeutic effect is compromised by the toxicity.

Oxford BioMedica's MetXia^® addresses these problems by delivering the gene (CYP2B6) directly to the tumour. Once incorporated into the genetic material of the tumour cells, this gene produces the liver enzyme that converts the cyclophosphamide prodrug to its active form within the tumour. The aim is to achieve high concentrations of activated cyclophosphamide locally in the tumour while minimising circulating levels of the drug. It is anticipated that this will lead to substantially increased sensitivity of the tumour to the drug and to an ability to reduce the dose of cyclophosphamide, thereby reducing adverse side effects.

In a variety of preclinical models, BioMedica demonstrated that delivery of the human CYP2B6 gene to tumours, using MetXia^®, does indeed increase their sensitivity to cyclophosphamide and leads to enhanced tumour cell killing. The mode of action of MetXia^® does not restrict its use to one particular type of tumour, and the product is expected to be useful against a range of types of solid tumour.

In addition, the possibility exists that the induction of localised tumour cell death at the site of administration by the activated cyclophosphamide might also induce a systemic anti-tumour immune response leading to the immune destruction of tumours remote from the injection site of MetXia^®.

The Phase I/II BC1 clinical trial of MetXia^® in patients with late-stage breast cancer or melanoma, was conducted at the Churchill hospital in Oxford. The initial part of the trial was designed to assess safety and to establish that MetXia^® results in transfer of the CYP2B6 gene to patients' tumours. In November 2000 BioMedica reported results from the first part of the trial, confirming that the primary goals of the trial, namely the confirmation of safety and gene transfer, had been achieved.

In parallel with the BC1 trial, BioMedica had been developing its manufacturing technologies for gene therapy products. The primary goal of these developments was the configuration of a robust process that could satisfy market demand should the product gain approval in the future. This resulted in a process that can manufacture MetXia^® at a 100-fold higher efficiency than the prototype process used for BC1. The resultant product delivered to the patients' tumour cells is the same, as is the mode of delivery.

In July 2001 the Gene Therapy Advisory Committee approved a further Phase I/II clinical trial of MetXia^® in breast cancer patients, designated BC2, a follow-up to the successful BC1 trial. BC2 will use the MetXia^® product made from the enhanced manufacturing process.. Results from the BC2 trial are expected in the second half of 2002.