On December 8, 2020 ImmunoGenesis, Inc., a clinical-stage biotechnology company developing therapeutics to catalyze effective immune responses in immunologically cold cancers such as prostate, colorectal and pancreatic cancer, reported that it has acquired the rights to the hypoxia-reducing agent evofosfamide. The company plans to initiate a Phase 2 clinical trial in 2021 investigating evofosfamide in combination with both CTLA-4 and PD-1 blockade in patients with castration-resistant prostate cancer (CRPC), pancreatic ductal adenocarcinoma (PDAC) and HPV-negative head and neck cancer (HNSCC) (Press release, ImmunoGenesis, DEC 8, 2020, View Source [SID1234651021]).
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Evofosfamide, a 2-nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM), was originally developed as a hypoxia-activated prodrug. Dr. Michael A. Curran, founder of ImmunoGenesis, discovered that evofosfamide can reduce hypoxia in solid tumors. Dr. Curran demonstrated in pre-clinical models that evofosfamide could restore T cell function and synergize with checkpoint inhibition.
Based on Dr. Curran’s work as Associate Professor of Immunology at The University of Texas MD Anderson Cancer Center, ImmunoGenesis is developing evofosfamide as a hypoxia-reversal agent (HRA) which could synergize with checkpoint blockade to drive efficacy in tumor types where checkpoint blockade monotherapy is ineffective. Dr. Curran’s financial relationship with ImmunoGenesis is managed and monitored by the MD Anderson Conflict of Interest Committee.
The planned Phase 2 trial is supported by data from a Phase 1 trial, both led by David S. Hong, M.D., Professor of Investigational Cancer Therapeutics at MD Anderson. The Phase 1 study investigated evofosfamide in combination with the CTLA-4 inhibitor, ipilimumab, in four tumor types where hypoxia is believed to be a major source of immune resistance. The combination treatment drove an overall response rate of 17 percent and a disease control rate of 83 percent across four different dose levels in 21 heavily pre-treated patients.
"Overcoming resistance to immunotherapy in immunologically cold tumors will likely require a multi-faceted approach to address diverse mechanisms of host immune suppression," said Dr. Curran, "Evofosfamide is the first drug to demonstrate success in reversing hostile tumor metabolism through reduction of hypoxia. Restoration of tumor oxygen supply facilitates T cell infiltration and persistence allowing these otherwise poorly immune checkpoint sensitive cancers to become therapeutically sensitized."
In addition to the clinical efficacy demonstrated in the Phase 1 trial, a clear biomarker picture has emerged. Pre-existing immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved cellular signatures of anti-tumor immunity.
"Our vision at ImmunoGenesis is to develop a pipeline of drugs that synergize to address the critical ingredients necessary for effective immunity against the particularly difficult-to-treat cold tumors, including the generation of sufficient anti-tumor T cells, the protection and expansion of those cells in the tumor, and finally the reduction in hostile tumor metabolism" said James Barlow, ImmunoGenesis President and CEO. "Coupled with the PD-L1/PD-L2 dual specific antibody and STING agonist the company previously licensed from Dr. Curran’s lab, the addition of evofosfamide creates an integrated suite of molecules with extraordinary potential to address the unmet therapeutic need in cold cancers."