Our Preclinical Studies
Toca 511, the key novel component of Tocagen’s first Product Candidate (Toca 511 & Toca FC), was developed using the breakthrough Controlled Active Gene Transfer (CAGT) technology that allows selective targeting of cancer cells. Preclinical data indicate that Toca 511 can hide in the cancer environment and spread from cancer cell to cancer cell, thereby allowing targeted delivery of a potent anti-cancer drug selectively to the cancer tissue while leaving healthy tissue unharmed.
Toca 511 is intended to be used in combination with Toca FC. Toca FC is a novel extended-release tablet containing 5-FC (flucytosine). Toca FC is designed to be taken orally 3 times per day with food and is intended to achieve more consistent levels of 5-FC in the body compared to an immediate release formulation.
In preclinical brain cancer studies, the combination of Toca 511 and 5-FC was able to destroy brain tumors and prolong life in most animals treated. Based on these data, we are initially developing Toca 511 & Toca FC for the potential treatment of brain cancer, and have initiated a Phase I/II human clinical study in subjects with recurrent high grade glioma (HGG), including recurrent Glioblastoma Multiforme (GBM) and recurrent anaplastic astrocytomas.
In multiple mouse preclinical models of brain cancer, the animals treated with Toca 511 and 5-FC demonstrated statistically significant prolonged survival compared to control (non-treated and Toca 511 alone treated) animals. The control groups showed a median survival of approximately 1 month, compared to prolonged survival in the Toca 511 and 5-FC treated animals. In experiments extended out to 6 months, almost all mice treated with Toca 511 and 5-FC remained alive. No significant toxicity was observed in the animals treated with Toca 511 and 5-FC.
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Toca 511 is specifically designed to deliver the genetic instructions to produce Cytosine Deaminase (CD) protein inside cancer cells. The CD protein then catalyzes the conversion of the antifungal drug 5-FC (flucytosine) to the anti-cancer agent 5-FU (5-fluorouracil) inside the cancer cells. Thus the CD protein enables local production of a powerful, FDA approved anti-cancer drug that selectively destroys the cancer cells.
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This targeted gene delivery strategy may result in higher local concentrations of the cytotoxic drug 5-FU and its phosphorylated metabolites in the cancer cells than would be otherwise attainable under currently accepted treatment regimens. This is because 5-FU has a narrow therapeutic index and when administered systemically, it exhibits dose-limiting toxicity to the rapidly dividing cells of the GI tract and bone marrow. Additionally, 5-FU does not readily cross the blood brain barrier thereby further limiting the concentration of drug that can be delivered to cancer cells in the brain.
Our Clinical Studies
Tocagen is performing multicenter clinical studies of its novel retroviral replicating vector, Toca 511, used in conjunction with Toca FC (5-FC), for treatment of those tumors that have recurred following surgery, radiation and chemotherapy. Subjects must be at least 18 years of age and have a single tumor upon recurrence. The studies are being conducted at leading neuro-oncology centers in the United States.
In these studies, Toca 511 is given one time by either injection into the brain tumor using a standard computer-assisted procedure or into the bed of the resection cavity at the time of tumor removal. After waiting several weeks to allow Toca 511 to spread through the tumor, a course (cycle) of Toca FC is taken orally. Toca 511 may continue to infect residual tumor that is not destroyed by the first cycle of Toca FC, therefore additional cycles of Toca FC are taken.
