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Gedeptin® Addition Expands GeoVax Immuno-Oncology Pipeline Into Clinical-Stage

In September 2021, GeoVax announced the acquisition of exclusive rights to Gedeptin, a clinical-stage, gene-directed enzyme prodrug therapy (GDEPT). Gedeptin is an adenovirus vector encoding an enzyme derived from E. coli called purine nucleoside phosphorylase (PNP) and is administered intratumorally. The purine nucleoside drug, fludarabine phosphate (Fludara®), while approved for the treatment of certain hematological tumors, has shown minimal effectiveness against solid tumors. However, when systemically administered fludarabine is taken up by tumor cells previously treated with Gedeptin, the fludarabine is converted within the tumor cell to the potent cytotoxic agent, fluoroadenine. causing tumor cell death. Preclinical and early-stage human clinical data suggest the GEDPT approach may destroy otherwise refractory cancer cells in a safe and effective manner, and its Phase 1 program demonstrated a pronounced effect on tumor volume following treatment. Importantly, Gedeptin significantly expands GeoVax’s presence in immuno-oncology.


Gedeptin is based upon a replication-deficient adenoviral vector, a well-recognized vaccine vector platform similar to that used for some of the existing COVID-19 vaccines.  Examples include the Johnson & Johnson and Astra-Zeneca Covid-19 vaccines. However, instead of coding for the SARS-CoV-2 spike protein, Gedeptin codes for the PNP. Gedeptin is first injected directly into the tumor mass three times over a period of two days and then patients are administered fludarabine phosphate intravenously, once-a-day, for three days. The fludarabine prodrug in the GEDPT system is converted by the Gedeptin-encoded PNP within the tumor cells to the cytotoxic fluoroadenine compound leading to cell death.


Fluoroadenine is particularly effective at killing refractory solid tumors dependent on DNA, RNA, and protein synthesis. While fluoroadenine is highly toxic when administered systemically, one would expect minimal systemic effects when the drug is generated within the tumor cells themselves utilizing the GEDPT approach. The PNP enzyme, by itself, has no anti-cancer activity, and because it is derived from bacteria, the enzyme is unlikely to have significant metabolic activity in humans.


Impressive Initial Data


A 12-patient, first-in-human Phase 1 clinical study (NCT01310179) evaluated Gedeptin for the treatment of refractory head and neck cancer. Results published in the Annual of Oncology in 2015 (Rosenthal EL et al., 2015) show all 12 study subjects completed therapy without dose-limiting toxicity. Tumor size change from baseline to final measurement demonstrated a dose-dependent response, with 5 of 6 patients (83%) in the higher dose cohorts (cohorts-3 & -4) achieving significant tumor regression. One patient in cohort-4 demonstrated noticeable improvement in tumor response after only one treatment cycle (14 days).


Notably, despite fludarabine’s known systemic toxic effects, the overall adverse event rate was not dose-dependent, and majority of events were deemed mild or moderate in nature. In addition, there were no treatment-related serious adverse events, and analysis of patient serum confirmed the lack of systemic exposure to fluoroadenine and the PNP enzyme.


Phase 1/2 Enrolling


Gedeptin is now in a Phase 1/2 clinical study (NCT03754933) designed to confirm the encouraging response rates demonstrated in the initial Phase 1 study noted above. Five patients have been enrolled so far at Stanford University, with GeoVax planning to expand enrollment to two additional sites in the near term. Initial funding for this study has been provided through the FDA’s orphan products clinical trial grant program. Target total enrollment will be expanded to a total of 25-30 subjects with refractory, head and neck cancer, including cancer of the mouth, lips, tongue, oral cavity, and salivary glands.


Potential Expedited Approval Pathway


In its Phase 1 study, Gedeptin demonstrated a 42% response rate in all patients and 83% in the two highest dose cohorts. Should the ongoing Phase 1/2 study confirm these encouraging results, GeoVax anticipates filing a BLA for FDA approval in 2024. The Company is now focused on completing clinical trial site expansion and enrollment during 2022, with the completion of the patient evaluation in 2023.


A Significant Market Opportunity


Worldwide, head and neck cancer accounts for approximately 900,000 cases and over 400,000 deaths annually. In the U.S., head and neck cancer accounts for 3% of malignancies, with about 66,000 patients developing head and neck cancer annually and 14,600 dying from the disease each year (source: UpToDate, 2021)


Initial treatment for locally advanced, nonresectable head and neck cancer is typically a combination of chemotherapy and radiation. Patients may receive platinum-chemotherapy along with fluorouracil, methotrexate, docetaxel, or the anti-EGFR monoclonal antibody, cetuximab (Erbitux®). Treatment options for patients with tumors that are resistant to these initial therapies are limited.


Recently, checkpoint inhibitors such as Merck’s Keytruda® (pembrolizumab) and Bristol’s Opdivo® (nivolumab) have gained approval in head and neck squamous cell carcinoma (HNSCC). Data from these checkpoint inhibitors can be used to benchmark the success of Gedeptin in the ongoing Phase 1/2 study.


Gedeptin Expands GeoVax’ I/O Focus


GeoVax continues to progress on multiple fronts, and the Gedeptin acquisition significantly enhances the Company’s immuno-oncology status and pipeline with its active Phase 1/2 program, with a possible 2024 filing.


Work also continues with the Company’s use of its modified Vaccinia Ankara (MVA) virus delivery vector to introduce tumor-associated antigens (TAA) designed to provoke the immune system. GeoVax’s initial focus with the I/O approach to its MVA platform is Mucin 1 (MUC1), an oncogenic transmembrane glycoprotein in the mucin family found to be overexpressed in a wide variety of hematologic malignancies and solid tumors, including mesothelioma, breast, lung, gastric, pancreatic, colon, ovarian, and endometrial cancers. The Company’s MVA-VLP-MUC1 candidate is designed to introduce the MUC1 antigen, which like a vaccine, activates the immune system.


Gedeptin provides GeoVax with another pillar on which to build its immuno-oncology pipeline. Furthermore, the anticipated synergy between Gedeptin and MVA-VLP presents additional opportunities for novel cancer therapies. For example, the MVA-VLP platform can be used to awaken the immune system and Gedeptin can be used to achieve direct tumor cell oncolysis. Both agents can be combined with checkpoint inhibitors to reverse immune tolerance and drive long-lasting responses.

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