Threshold Pharma Offers Preclinical Data Suggesting TH-4000 Could Overcome Resistance to Conventional EGFR Tyrosin Kinase Inhibitors

Threshold Pharmaceuticals, Inc.

today announced preclinical data on TH-4000, its proprietary, molecularly-targeted, hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) suggesting that TH-4000 may overcome resistance to therapy with convention al EGFR-TKIs. In a xenograft model of non-small cell lung cancer (NSCLC) in which both wild-type (normal) EGFR and mutant EGFR are present (a heterozygous model), TH-4000 was more active than the conventional EGFR-TKI erlotinib. Complete tumor control was observed in this model using human-equivalent doses of TH-4000 that were less than 15% of the maximum-tolerated dose defined previously in a Phase 1 clinical trial. The company believes the data support its planned Phase 2 clinical trials of TH-4000, including one in patients with EGFR-positive, T790M-negative NSCLC and the other in patients with recurrent/metastatic head and neck (H&N) cancer. The data were reported at the annual meeting of the American Association for Cancer Research (AACR) on Wednesday, April 22, 8 AM - 12 PM EDT (Abstract #5358 in Poster Section #28) in Philadelphia, Pennsylvania. Aberrant EGFR signaling is implicated in the growth and spread of certain tumor types including NSCLC and H&N cancer. Clinical studies indicate that mutant EGFR-positive NSCLC with wild-type EGFR present (heterozygous) is associated with reduced response rates, progression free survival and overall survival outcomes on conventional EGFR-TKIs. In H&N cancer, wild-type EGFR signaling drives tumor growth. Both types of tumors are known to be hypoxic; thus, hypoxia-induced activation of wild-type EGFR signaling may be a mechanism of current EGFR-TKI resistance. "Cer tain tumor types are addicted to EGFR signaling and current EGFR-TKI therapies are ineffective in shutting down that signaling due to dose-limiting toxicities of rash and diarrhea," said Adam Patterson, Ph.D., Head of Translational Therapeutics Team at the University of Auckland in New Zealand, and co-inventor of TH-4000. "At the same time, we know that these tumors are hypoxic, and hypoxia drives the overexpression of EGFR. Therefore, a molecularly-targeted, hypoxia-activated irreversible EGFR-TKI may deliver greater efficacy with fewer side effects than currently available treatments." "Leveraging knowledge that the hypoxic tumor microenvironment enhances aberrant, wild-type EGFR signaling, we designed TH-4000 to selectively release an irreversible EGFR inhibitor upon encountering tumor hypoxia," said Jeff Smaill, Ph.D., Senior Medicinal Chemist, at The University of Auckland, New Zealand, and co-inventor of TH-4000. "Given Threshold's expertise in developing therapies that target tumor hypoxia, it's exciting for us to be working together on this next-generation approach of combining molecular and hypoxia targeting in a single drug candidate." Preclinical data reported at AACR demonstrated that TH-4000 is a pan-ErbB inhibitor, releasing a potent irreversible TKI of wild-type EGFR, mutant EGFR and HER2. In the PC9 xenograft model of NSCLC, which is heterozygous for wild-type and mutant (deletion 19) EGFR, a single dose of TH-4000 (equivalent to 20 mg/m2 in humans) showed prolonged prodrug residency and EGFR shutdown in tumor tissue for a week. In addition, while treatment with erlotinib alone resulted in only modest benefit, treatment with TH-4000, resulted in 9/9 complete responses, suggesting an ability to prevent or overcome resistance to TKI treatment. Furthermore, the PC9 model was determined to be only 8% hypoxic, suggesting that the complete responses observed with TH-4000 were due to the ability of TH-4000, once hypoxia-activated, to diffuse into the surrounding normoxic tumor tissue. Preclinical data presented also demonstrated that TH-4000 is highly active against WT EGFR-driven tumors, whereas approved EGFR-TKIs are substantially less active. It is believed the 'masked' design of TH-4000 allows WT EGFR signaling in tumor tissue to be targeted via hypoxia while sparing normal tissue signaling in the skin and GI tract, providing a potential therapeutic window. Data from a previous Phase 1 clinical trial of patients with advanced solid tumors were also reported at AACR. The maximum tolerated dose of TH-4000 administered as a 1-hour weekly intravenous infusion was established at 150 mg/m2. The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhea and fatigue. "We believe the data presented at AACR support our clinical development plans for TH-4000 in patients with tumors that are not candidates for conventional EGFR-TKI therapy," said Tillman Pearce, MD, Chief Medical Officer of Threshold. "In particular, we believe the data support the development of TH-4000 in patients with mutant EGFR-positive, T790M-negative non-squamous non-small cell lung cancer after conventional EGFR-TKI therapy has failed as well as in patients with head and neck cancer for which EGFR over-expression is associated with worse outcomes, both of which represent a significant unmet medical need. We are delighted to join forces with our friends and experts in the field of tumor hypoxia and Hypoxia-Activated Prodrug technology at the University of Auckland, and look forward to our collaborative efforts in the development of TH-4000 as potential new therapy that has potential to overcome the limitations of currently available EGFR-TKI therapies."