FDA grants Tocagen's glioblastoma treatment orphan drug status San-Diego based biopharmaceutical company Tocagen has secured orphan drug status for its investigational gene therapy treatment for glioblastoma. It follows hard on the heels of the combination treatment Toca 511 & Toca FC winning fast track designation just last month assisting the company in its quest to further advance the drug's development. Glioblastoma is the most common type of brain cancer, and most aggressive, with more than 10,000 new cases every year in the United States. However once diagnosed, patients have a five-year survival rate of less than 5%. Harry Gruber, CEO of Tocagen, said: "There's an extraordinary need for new treatment options for patients with this devastating disease."We believe the FDA's granting of both orphan drug and fast track designations to Toca 511 & Toca FC will enable us to more efficiently advance our programme, which we hope will ultimately offer physicians and patients a new option in the fight against brain cancer." Both components of the combination treatment are designed to programme cancer cells to convert prodrug 5-FC into the FDA-approved anticancer drug, 5-flurorouracil (5-FU), which kills tumour cells and additionally significantly boosts immune responses. Toca 511 is a retroviral replicator vector that delivers a gene, responsible for the enzyme cytosine deaminase, to the tumour. This is followed with oral doses of Toca FC which is converted within infected cancer cells into 5-FU, killing cancer cells while preserving healthy host cells. The treatment will enter phase II and III trials later this year and so far interim results have shown median survival rates of 13.8 months compared with historical benchmarks of around 7 months. This programme will be supported by companion diagnostic tests that Tocagen is working on in partnership with Siemens Healthcare Diagnostics under an agreement signed last year.
Feb 7, 2012 Tocagen is enrolling patients in its clinical trials of Toca 511 (vocimagene amiretrorepvec), for injection & Toca FC (flucytosine), extended-release tablets. These multicenter, open-label studies(3) are in patients with recurrent high-grade glioma, such as those with glioblastoma multiforme (GBM, Grade 4), who have had prior surgery and chemoradiation. Toca 511 is a retroviral replicating vector (RRV) that is designed to deliver a cytosine deaminase (CD) gene selectively to cancer cells. After allowing time for the administered Toca 511 to spread through the tumor, those cancer cells expressing the CD gene may convert the antibiotic flucytosine into the anti-cancer drug 5-fluorouracil (5-FU). In these studies, patients receive multiple cycles of oral Toca FC. Tocagen plans to work with Siemens Healthcare Diagnostics on the assays used during these clinical studies. Subject to FDA approval, Siemens may commercialize diagnostic tests capable of monitoring patient levels of Toca 511 and Toca FC."We believe that developing the necessary diagnostic tests with the right diagnostic partner is an important component for the successful commercialization of Toca 511 & Toca FC," said Harry E. Gruber, CEO, Tocagen Inc. "Siemens' capabilities in developing commercial viral assays in addition to their market presence in the diagnostics space make them an excellent complement to Tocagen's focus on the development and commercialization of viral gene transfer products to treat advanced cancer."
Toca 511 & Toca FC (www.tocagen.com/) Toca 511, the key novel component of Tocagen's first Product Candidate (Toca 511 & Toca FC), was developed using the breakthrough RRV technology that allows selective targeting of cancer cells and a selective, local and systemic antitumor immune response without off-target toxicity. Toca 511 is used in combination with Toca FC, a novel extended-release tablet containing 5-FC (flucytosine).
Our Preclinical Studies 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 anticancer drug selectively to the cancer tissue while leaving healthy tissue unharmed. In addition to the direct killing of cancer cells, we believe that the immune system is selectively activated by the local tumor killing, with resultant systemic anti-tumor immunity. Toca 511 is specifically designed to deliver the genetic instructions to produce Cytosine Deaminase (CD) protein inside cancer cells. The CD enzyme then catalyzes the conversion of the antifungal drug 5-FC (flucytosine) to the anticancer agent 5-FU (5-fluorouracil) inside the cancer cells. Thus the CD protein enables local production of a powerful, FDA approved anticancer drug (5-FU) that selectively destroys the cancer cells. 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. Yet 5-FU has a very short half-life and is rapidly cleared. 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. In multiple 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 one year, 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. In similar experiments as shown above conducted in immune deficient and immune competent mice, tumors recur after stopping 5-FC treatment in immune-deficient, but not in immune-competent animals. This suggests that the immune system is able to control any residual tumor following treatment with 5-FC in syngeneic mice with an intact immune system, resulting in long-term survival. Furthermore, as shown below, animals that had long-term survival from their brain cancer treatment with Toca 511 and 5-FC and subsequently re-challenged with the same tumor administered to their flank region were able to resist tumor growth. In contrast, animals not previously challenged and treated, allowed extensive brain tumor growth in their flank region. Finally, if PBMC are taken from syngeneic mice successfully treated for their tumor and the T cells exposed to tumor in vitro then stained for reactivation (an ELISpot assay for IFN gamma production) many more positives are observed in the cured mice compared to naïve mice. Thus memory T lymphocytes (T cells) remain active against gliomas previously treated with Toca 511 & 5-FC in mice that are in 1 year remission. The preclinical studies conducted to date have supported our ongoing clinical trials evaluating Toca 511 in combination with Toca FC in patients with recurrent high grade glioma (HGG), including recurrent Glioblastoma Multiforme (GBM) and recurrent anaplastic astrocytoma. We believe these clinical trials may allow for early conceptual validation of our RRV platform. In the future, Tocagen is considering additional studies of Toca 511 & Toca FC in patients with high grade glioma in the first line (primary) setting, and in patients with cancers that have metastasized to the brain, liver and lung from other advanced cancers including breast, lung, colorectal, prostate and melanoma.
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