EVOFOSFAMIDE IS AN INVESTIGATIONAL HYPOXIA-ACTIVATED PRODRUG DISCOVERED AT THRESHOLD. TREATING CANCER BY SELECTIVELY TARGETING TUMOR HYPOXIA IS A NOVEL THERAPEUTIC APPROACH THAT MAY BE LESS LIKELY TO PRODUCE BROAD SYSTEMIC TOXICITY SEEN WITH UNTARGETED CYTOTOXIC CHEMOTHERAPIES.
Evofosfamide is a prodrug that is designed to be activated under hypoxic conditions commonly found in the tumor microenvironment. Within regions of tumor hypoxia, evofosfamide releases bromo isophosphoramide mustard (Br-IPM), a potent DNA alkylating agent.1 Br-IPM kills tumor cells by forming DNA crosslinks, rendering cells unable to replicate their DNA and divide as well as interfering with the transcription of DNA to make essential proteins. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”.2 Because of its preferential activation in the targeted hypoxic regions of solid tumors, evofosfamide may be less likely to produce broad systemic toxicity seen with untargeted cytotoxic chemotherapies.
To date, evofosfamide has been investigated both as a monotherapy and in combination with chemotherapy treatments and other targeted cancer drugs in more than 1,500 patients with a broad spectrum of solid tumor types and blood cancers. In December 2015, Threshold announced topline results from two Phase 3 trials of evofosfamide, reporting that neither trial met its primary endpoint of improving overall survival with statistical significance, however, additional analysis of the MAESTRO Phase 3 trial results indicated a 48 percent reduction in risk of death among the subgroup of patients enrolled in Japan and South Korea. Threshold is currently pursuing discussions with Japanese regulators regarding potential registration pathways in Japan and evaluating next steps for potential continued development of evofosfamide.
Threshold has a collaboration with the MD Anderson Cancer Center which recently presented preclinical data on evofosfamide in combination with immune checkpoint inhibitor antibodies. The data highlighted the promise of evofosfamide to improve the efficacy of this class of immuno-oncology therapeutics. Immune checkpoint inhibitors are potent anti-cancer therapies that unleash an immune system attack on cancer cells. The Company plans to initiate a clinical trial in various solid tumors evaluating evofosfamide in combination with one or more checkpoint inhibitor antibodies.
In addition to clinical trials that are conducted by Threshold, the Company also supports Investigator-Sponsored Trials, or ISTs, which are clinical trials sponsored, designed and implemented by a clinical investigator. There are ongoing ISTs evaluating evofosfamide in Glioblastoma, Pancreatic Neuroendocrine Tumors (PNET) and Biliary Tract Cancer.