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Toca 511 and Toca FC, developed by Tocagen, is a combination treatment currently being investigated in phase I/II trials for recurrent high grade glioma including the notoriously difficult to treat glioblastoma multiforme. Toca 511 (vocimagene amiretrorepvec) is a nonlytic retroviral replicating vector (RRV) that encodes the transgene cytosine deaminase (CD). This enzyme is used to catalyze the conversion of Toca FC, a novel oral extended-release prodrug 5-fluorocytosine (5-FC) to the active 5-fluorouracil (5-FU). Intravenous or intracranial injection of Toca 511 takes place during initial treatment and 3-7 weeks later the patient starts cyclic administration of Toca FC.1,2,3 The phase I/II trials in humans have shown similar results of patients exceeding the average life expectancy of high grade gliomas.4
Clinical stage immuno-oncology company, Tocagen, Inc., announced the US Food and Drug Administration has granted its primary immuno-oncology candidate orphan drug designation as a promising and much-needed treatment of glioblastoma, the most common form of primary brain cancer. Every year, over 10,000 people are diagnosed with glioblastoma in the United States. The new designation brings the company’s Toca 511 & Toca FC closer to helping patients suffering with this type of tumor. Tocagen is preparing to proceed with a pivotal clinical trials later this year.
Glioblastoma is known to be extremely aggressive, with newly diagnosed patients expecting a mere five-year survival rate of less than 5 percent, along with a high likelihood of tumor recurrence despite completion of standard treatment. Once the tumor recurs, the average survival is only 8 months.
Toca 511 is a retroviral replicating vector (RRV) that selectively delivers a gene for the enzyme cytosine deaminase into the tumor. Patients then take oral cycles of Toca FC, a novel formulation of an antifungal drug, which is converted within infected cancer cells into the FDA-approved anticancer drug, 5-fluorouracil (5 FU). Toca 511 & Toca FC work by programming cancer cells to convert the prodrug 5-FC into the anticancer drug 5-FU, effectively causing tumor cell death and stimulating the immune system through a combination of mechanisms.
“There’s an extraordinary need for new treatment options for patients with this devastating disease,” said Harry Gruber, M.D., chief executive officer of Tocagen. “We believe FDA’s granting of both orphan drug and Fast Track designations to Toca 511 & Toca FC will enable us to more efficiently advance our program, which we hope will ultimately offer physicians and patients a new option in the fight against brain cancer.”
ImmunoCellular Therapeutics, Ltd., announced it has come to an agreement with the US Food and Drug Administration (FDA) on a Special Protocol Assignment (SPA) for the Phase III registrational study of its investigational immunotherapy, ICT-107, indicated for patients with glioblastoma.
ICT-107 is a dendritic cell-based immunotherapy targeting multiple tumor-associated antigens on glioblastoma stem cells. The trial will be a randomized, double-blind, placebo-controlled, and will aim to enroll around 400 HLA-A2 positive patients. The study will be conducted across 120 sites in the US, Canada, and the European Union.
Mechanism of action
Retroviruses, once inside the target cell, use reverse transcriptase to produce DNA from the RNA present in the virus. Toca 511 is based on the gamma retrovirus, murine leukemia (MLV).5 The virus has many innate properties that are suitable for targeted cancer treatment. One of the most important properties is the reproduction mechanism that occurs without cytolysis of the host cell. In non-lytic reproduction, the infected cell continuously forms small buds that are pinched off containing the virus to allow rapid infection. Another property is the requirement for cell division. Infection is limited to mitotically active cells. These two properties present an ideal candidate vector for modification. The lack of cytolysis in the host cell prevents an immune response and the necessity for the cell to be dividing allows localization to cancerous tumors. As an oncolytic agent, the mechanism uses the rapid mitotic activity of the cancerous tumor cells to spread the therapeutic gene in an effective and controlled manner.5 In Toca 511, the insertion of the CD transgene into the active tumor catalyzes the treatment. The expression of CD by the tumor allows intratumoral conversion of 5-FC to 5-FU.6 This allows the cytotoxic 5-FU to be maintained within the tumor cell. A second mechanism of action is proposed based upon recent data. Post-treatment, a systemic anticancer immune response is present that selectively acts against the cancerous cells.4,7
The design of the Toca 511 RRV is based upon the vector design by Logg et al.5 Multiple changes facilitated selection of a clinically efficacious RRV. The original ecotropic envelope was changed to an amphotropic sequence. In the IRES-CD cassette, multiple small repeats were removed to allow for decreased instability during homologous recombination. A restriction site Psi I was placed at the 3′ of IRES for the insertion of the CD transgene. The resulting vector consists of the following, 5′ to 3′: CMV-R-U5, PBS, 5′ SS, gag, pol (with a 3′ SS), 4070A env, IRES, Psi I, yCD2, Not I, PPT, and the U3-R-U5.8
Toca 511 and Toca FC combination therapy is currently being investigated for recurrent and progressive Grade III or IV glioma.1,2,3 The initial clinical study is the first to use a RRV to facilitate gene transfer into gliomas. In a recent presentation by Tocagen, researchers expressed the safety and efficacy of the therapy in the first two trials. Minimal treatment toxicity was reported. The landmark six and twelve month survival rates were higher than previously published data in both studies.4 Following positive results with the initial two trials, investigation into the intravenous efficacy is currently being determined.7
Two important discoveries that led to the creation of Toca 511/FC treatment are the optimization of yeast CD and modifications to the vector backbone for genomic replication stability. The optimization of the yeast CD involved the modification of the codon sequence at three amino acids to a known preferred human codon sequence. This did not change the amino acid sequence. This resulted in stability at 37°C compared to the previous 26°C. The vector backbone modification at the env-3′ untranslated boundary created a vector with higher fidelity than the wild type.8 In studies of mice with implanted gliomas, Toca 511 and Toca FC therapy resulted in an unprecedented survival rate.6,8 Furthermore, when the mice were re-implanted with the same glioma post-treatment, memory T lymphocytes remained active and the growth was inhibited.6 The combination of these findings led to the clinical candidate that is currently undergoing trials.
1. Tocagen Inc. A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 June 12]. Available from: http://clinicaltrials.gov/show/NCT01156584 NLM Identifier: NCT01156584.
2. Tocagen Inc. A P1 Ascending Dose Trial of Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered to Subjects at the Time of Resection for Recurrent High Grade Glioma & Followed by Treatment With Toca FC, Extended-Release 5-FC. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 June 12]. Available from: http://clinicaltrials.gov/show/NCT01470794 NLM Identifier: NCT01470794.
3. Tocagen Inc. A P1 Ascending Dose Trial of the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered Intravenously Prior to, and Intracranially at the Time of, Subsequent Resection for Recurrent HGG & Followed by Treatment With Extended-Release 5-FC. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 June 12]. Available from: http://clinicaltrials.gov/show/NCT01985256 NLM Identifier: NCT01985256.
4. Interim Clinical Data for Tocagen’s Toca 511 & Toca FC in Patients with High Grade Glioma Presented at American Association of Neurological Surgeons Annual Meeting. Tocagen Inc., 10 April 2014. Web. 10 June 2014. .
5. Logg, C. R.; Robbins, M. J. Retroviral Replicating Vectors in Cancer. Methods in Enzymology 2012, 507, 199-228.
6. Ostertag, D.; Amundson, K. K.; Espinoza, F. L.; Martin, B. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-flurouracil using a nonlytic retroviral replicating vector. Neuro-Oncology 2012, 14(2), 145-159.
7. Tocagen Doses First Patient Intravenously in Clinical Trial of
Selective Cancer Therapy, Toca 511 & Toca FC. Tocagen Inc., 11 March 2014. Web. 10 June 2014. http://www.tocagen.com/press/tocagen-doses-first-patient-intravenously-in-clinical-trial-of-selective-cancer-therapy-toca-511-toca-fc/
8. Perez, O. D.; Logg, C. R.; Hiraoka, K.; Diago, O. Design and Selection of Toca 511 for Clinical Use: Modified Retroviral Replicating Vector With Improved Stability and Gene Expression. Molecular Therapy 2012, 20(9), 1689-1698.
Anna Tan, RN
SDVYCEVCEFLVKEVTKLIDNNKTEKEILDAFDKMCSKLPKSLSEECQEVVDTYGSSILSILLEEV SPELVCSMLHLCSG [SEQ ID NO: 2].
Cincinnati Children’s Hospital ……..innovator
Bexion Pharmaceuticals……….under license
In February 2015, the US FDA granted saposin C Orphan designation for the treatment of glioblastoma multiforme
Recombinant human Saposin C (SapC) bound to a liposomal formulation of the dioleoylphosphatidylserine
Bexion’s Saposin C – the active ingredient in the brain tumour therapy BXQ-350 – has been awarded Orphan Drug status by US regulators.
Bexion Pharmaceuticals, under license from the Cincinnati Children’s Hospital, is investigating a human saposin C (SapC)/liposomal dioleoylphosphatidylserine (DOPS) conjugate, SapC-DOPS (BXQ-350), a nanovesicle-formulated pro-apoptotic sphingomyelinase activating molecular imaging agent and anticancer agent, for the potential diagnosis and treatment of cancer , . In October 2013, Bexion was planning a phase I first-in-human trial for the therapy of glioblastoma multiforme
Bexion Pharmaceuticals LLC announced today that the U.S. Food and Drug Administration (FDA) has granted the company Orphan Drug designation for Saposin C, active ingredient in its proprietary drug BXQ-350 for the potential treatment of glioblastoma multiforme.
The FDA’s Office of Orphan Drug Products Development reviews applications for Orphan Drug status to support development of medicines for underserved patient populations, or rare disorders that affect fewer than 200,000 people in the United States. The successful application submitted by Bexion and the FDA granting of Orphan Drug status entitles the company to a seven-year period of marketing exclusivity in the United States for BXQ-350, if it is approved by the FDA for the treatment of glioblastoma multiforme. Orphan Drug status also enables the company to apply for research grant funding for Phase I and II Clinical Trials, tax credits for certain research expenses, and a waiver from the FDA’s application user fee, as well as additional support from FDA and a potentially faster regulatory process.
Bexion was previously awarded a prestigious Phase II Bridge Award (Small Business Innovation Research Grant; SBIR) from the National Cancer Institute (NCI) to support the manufacture and clinical testing of BXQ-350.
“Orphan Drug status for BXQ-350 is an important milestone in the development of this new treatment modality,” stated Dr. Ray Takigiku, founder and CEO of Bexion. “Few treatment options are available for patients suffering from glioblastoma multiforme and this designation recognizes the unmet need that exists with this disease, as well as the unique attributes of BXQ-350. In addition, orphan designation allows Bexion to benefit from important financial, regulatory and commercial considerations and we have seen recently that products with orphan designation have become sought after assets.”
About Orphan Drug Designation
Orphan Drug designation is a status assigned to a medicine intended for use in rare diseases. In the U.S., the Orphan Drug Designation program confers Orphan Drug status to successful applicants for medicines intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. or that are not expected to recover the costs of developing and marketing a treatment.1
The approval of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval for investigational use. Sponsors must establish safety and efficacy of a compound in the treatment of a disease through adequate and well-controlled studies. However, the FDA review process may be speedier for Orphan Drugs than those which do not receive Orphan Drug designation.
In pre-clinical studies, Bexion’s first-in-class biologic, BXQ-350 has shown promising results in selectively inducing cell death in the laboratory. BXQ-350 is a proprietary nanovesicle formulation of Saposin C (sphingolipid activator protein C, or SapC) and the phospholipid dioleoylphosphatidylserine (DOPS).
About Bexion Pharmaceuticals
Bexion Pharmaceuticals is a privately held biotech company focused on the development and commercialization of innovative cures for cancer. Initial products are based on a proprietary platform technology licensed from Cincinnati Children’s Hospital Medical Center. The technology has demonstrated potential for development as a therapeutic, diagnostic and surgical imaging reagent, and as a carrier for other pharmaceutical agents, such as oligonucleotides. For more information, visit www.bexionpharma.com or contact Margaret van Gilse firstname.lastname@example.org.
1 U.S. Food and Drug Administration web site. “Regulatory Information: Orphan Drug Act.”http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/orphandrugact/default.htm.
Margaret van Gilse859email@example.com
SOURCE Bexion Pharmaceuticals LLC
Glioblastoma is the most common primary CNS malignant neoplasm in adults, and accounts for nearly 75% of the cases. Although there has been steady progress in their treatment due to improvements in neuro-imaging, microsurgery, and radiation, glioblastomas remain incurable. The average life expectancy is less than one year from diagnosis, and the five-year survival rate following aggressive therapy, including gross tumor resection, is less than 10%. Glioblastomas cause death due to rapid, aggressive, and infiltrative growth in the brain. The infiltrative growth pattern is responsible for the un-resectable nature of these tumors. Glioblastomas are also relatively resistant to radiation and chemotherapy, and therefore post-treatment recurrence rates are high. In addition, the immune response to the neoplastic cells is mainly ineffective in completely eradicating residual neoplastic cells following resection and radiation therapy.
One problem in treating glioblastoma is the tumor’s protection behind the blood-brain tumor barrier (BBTB). A significant obstacle in the development of therapeutics for glioblastoma is the inability of systemic therapies to efficiently cross the BBTB. Saposin C (SapC) is a sphingolipid- activating protein that functions to catabolize glycosphingolipids. SapC-DOPS forms stable nanovesicles which can efficiently cross the blood-brain tumor barrier and fuse with GBM cells inducing cell death.
Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus, which was discovered first for its properties as an antifungal agent. Streptomyces hygroscopicus has also been implicated as a cancer agent.
There remains a need in the art for new therapeutics for the treatment of glioblastoma.
Example 1Purification of Recombinant Saposin C
 Recombinant saposin C was overexpressed in E. coli cells by using the isopropyl-1-thio-β-D-galactopyranoside inducing pET system (Qi et al. (1994) J. Biol. Chem. 269:16746-16753, herein incorporated by reference in its entirety). Expressed polypeptides with a His-tag were eluted from nickel columns. After dialysis, the polypeptides were further purified by HPLC chromatography as follows. A C4 reverse phase column was equilibrated with 0.1% trifluoroacetic acid (TFA) for 10 minutes. The proteins were eluted in a linear (0-100%) gradient of 0.1% TFA in acetonitrile over 60 minutes. The major protein peak was collected and lyophilized. Protein concentration was determined as previously described (Qi et al. (1994) J. Biol. Chem. 269:16746-16753).
Example 2Bath Sonication of Sanosin C and Dioleoylphosphatidylserine
 Dioleoylphosphatidylserine (DOPS) was obtained from Avanti Polar Lipids (Alabaster AL). Twenty to thirty imoles of DOPS in chloroform were dried under N2 and vacuum to lipid films. Five to ten μmoles saposin C polypeptide was added to the dried films and suspended in 50 μl McIlvanine buffer (pH 4.7). The suspension was then brought to a 1 ml volume with either cell culture medium or phosphate buffered saline (PBS) (Ausubel et al. (2002) Current Protocols in Molecular Biology. John Wiley & Sons, New York, New York, herein incorporated by reference). The mixture was sonicated in a bath sonicator for approximately 20 minutes. Ice was added as needed to prevent overheating the samples.
The SapC-DOPS composition comprises a phospholipid, an isolated saposin C-related polypeptide, wherein the polypeptide comprises an amino acid sequence at least 75% identical to the entire length of SEQ ID NO: 2, and a pharmaceutically acceptable carrier, wherein the phospholipid forms a nano vesicle incorporating the polypeptide. In certain embodiments, the polypeptide comprises an amino acid sequence at least 85% identical to the entire length of SEQ ID NO: 2. In certain embodiments, the polypeptide comprises an amino acid sequence at least 95% identical to the entire length of SEQ ID NO: 2. In certain embodiments, the polypeptide comprises an amino acid sequence at least 99% identical to the entire length of SEQ ID NO: 2.
The Sequence Listing, filed electronically and identified as SEQ_LIST_OSIF-2013- 102.txt, was created on November 12, 2013, is 5,548 in size, and is hereby incorporated by reference.
 SEQ ID NO: 1
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SEQ ID NO: 2
ABT-414 is in phase I/II clinical development at AbbVie for the treatment of squamous cell carcinoma. The product is also in early clinical development for the treatment of glioblastoma multiforme.
In 2014, orphan drug designation was received in the U.S. and E.U. by AbbVie for the treatment of glioblastoma multiforme.
EGFR antibody-drug conjugate (cancer), Abbott; ABT-414; EGFR antibody-drug conjugate (cancer), AbbVie; EGFR-ADC (cancer), AbbVie; ABT-806-MMAF conjugate; anti-EGFR antibody-MMAF conjugate, AbbVie; EGFR-ADC (cancer), Abbott
AbbVie’s glioblastoma multiforme therapy receives orphan drug designation
AbbVie has obtained orphan drug designation from the European Medicines Agency (EMA) and the US FDA for its anti-epidermal growth factor receptor monoclonal antibody drug conjugate, ABT-414, as a treatment for glioblastoma multiforme.
AbbVie has obtained orphan drug designation from the European Medicines Agency (EMA) and the US FDA for its anti-epidermal growth factor receptor monoclonal antibody drug conjugate, ABT-414, as a treatment for glioblastoma multiforme.
AbbVie’s ABT-414 Receives FDA and EMA Orphan Drug Designation
AbbVie announced that the EMA and the FDA have granted orphan drug status to its investigational compound ABT-414, an anti-epidermal growth factor receptor antibody drug conjugate. It is currently being evaluated for safety and efficacy in patients with glioblastoma multiforme. Glioblastoma multiforme is the most common and most aggressive type of malignant primary brain tumor. Each year in the United States and Europe, two to three out of every 100,000 people are diagnosed with glioblastoma multiforme, which has a five-year survival rate of approximately 4 percent.
“The orphan drug designation is an important regulatory advancement as we further our development in recurrent glioblastoma multiforme, a disease that is uniformly fatal with limited treatment options,” said Gary Gordon, M.D., vice president, oncology clinical development, AbbVie. “We are pleased to continue developing ABT-414 in Phase II trials in patients with glioblastoma multiforme based on the results of our Phase I program.” Read the press release
AbbVie oncology clinical development vice-president Gary Gordon said: “The orphan drug designation is an important regulatory advancement as we further our development in recurrent glioblastoma multiforme, a disease that is uniformly fatal with limited treatment options.
“We are pleased to continue developing ABT-414 in Phase II trials in patients with glioblastoma multiforme based on the results of our Phase I programme.”
AbbVie is currently evaluating the safety and efficacy of ABT-414 in patients with glioblastoma multiforme, the most aggressive type of malignant primary brain tumour.
In May, the company presented results from the Phase I clinical trial evaluating ABT-414 in combination with temozolomide in patients with recurrent or unresectable glioblastoma multiforme.
The Phase I trial was designed to assess the toxicities, pharmacokinetics and recommended Phase II dose of ABT-414 when administered every other week in combination with temozolomide.
Other important assessments included adverse events, pharmacokinetic parameters, objective response and tumour tissue epidermal growth factor receptor biomarkers.
The study results showed four objective responses, including one complete response.
AbbVie has developed ABT-414 with components in-licenced from Life Science Pharmaceuticals and Seattle Genetics.
ABT-414 is also being evaluated in clinical trials for the treatment of patients with squamous cell tumours.
ABT-414 is an anti-EGFR (epidermal growth factor receptor) monoclonal antibody drug conjugate (ADC). As an ADC, ABT-414 is designed to be stable in the bloodstream and only release the potent cytotoxic agent once inside targeted cancer cells. Developed by AbbVie researchers with components in-licensed from Life Science Pharmaceuticals, ABT-414 is currently being investigated for the treatment of glioblastoma multiforme, the most common and most aggressive malignant primary brain tumor. ABT-414 is also in clinical trials for the treatment of patients with squamous cell tumors. ABT-414 is an investigational compound and its efficacy and safety have not been established by the FDA.
About Glioblastoma Multiforme
Glioblastoma is the most common and most aggressive type of malignant primary brain tumor. Each year in the U.S. and Europe, two to three out of every 100,000 people are diagnosed with glioblastoma, which has a five year survival rate of less than 3 percent. Prior to diagnosis, most patients experience a serious symptom of glioblastoma, such as a seizure. Typically patients succumb to the disease approximately 15 months after diagnosis. Treatment for glioblastoma remains challenging and no long-term treatments are currently available. Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy. More than 8,700 patients are enrolled in industry-sponsored clinical studies.
A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectable glioblastoma (GBM)
50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2021
ABT-414: An anti-EGFR antibody drug conjugate for the treatment of glioblastoma patients
18th Annu Sci Meet Soc Neuro-Oncol (November 21-24, San Francisco) 2013, Abst ET-079
ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors
25th EORTC-NCI-AACR Symp Mol Targets Cancer Ther (October 19-23, Boston) 2013, Abst A250
A Phase I/II Study Evaluating the Safety, Pharmacokinetics and Efficacy of ABT-414 in Subjects With Advanced Solid Tumors Likely to Over-Express the Epidermal Growth Factor Receptor (EGFR) (NCT01741727)
ClinicalTrials.gov Web Site 2012, December 07