SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

April 22, 2015 08:00 ET

Threshold Pharmaceuticals Reports Preclinical Data Suggesting That TH-4000 May Overcome Resistance to Conventional EGFR Tyrosine Kinase Inhibitors

TH-4000 Overcomes Erlotinib Resistance in Heterozygous (Wild-Type/Mutant) EGFR Xenograft Lung Cancer Model; Preclinical Antitumor Activity Observed With Human-Equivalent Doses Lower Than the Maximum Tolerated Dose of TH-4000 Determined in Phase 1; Phase 2 Trials in Patients With EGFR-Positive, T790M-Negative NSCLC and Patients With Head & Neck Cancer Planned

SOUTH SAN FRANCISCO, CA--(Marketwired - Apr 22, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) 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 conventional 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.

"Certain 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."

About TH-4000

In September 2014, Threshold licensed exclusive worldwide rights to a clinical development program based on TH-4000 (formerly referred to as PR610 or Hypoxin™) from the University of Auckland. TH-4000 is a hypoxia-activated epidermal growth factor receptor, or EGFR, tyrosine-kinase inhibitor (TKI). TH-4000 is designed to selectively release an irreversible EGFR-TKI in hypoxic tumors. Preclinical and Phase 1 clinical data suggest that plasma concentrations of TH-4000 that are active in EGFR-dependent tumor xenograft models in mice could be attained in patients with an acceptable therapeutic index. Threshold expects to initiate Phase 2 proof-of-concept studies in patients with EGFR-positive, T790M-negative non-small cell lung cancer (NSCLC) after conventional EGFR-TKI therapy has failed and in patients with head and neck cancer.


NSCLC accounts for approximately 85 percent of the annual 1.3 million lung cancers diagnosed worldwide. EGFR activating mutations occur in approximately 15 percent of NSCLC cases in Caucasian patients and up to 35 percent in Asian patients. Tarceva®, Gilotrif® and Iressa®, are the first-generation EGFR inhibitors currently approved for patients with the EGFR activating mutation. Nearly all patients ultimately progress on these therapies, with approximately 50% of these patients developing acquired resistance due to a second, "gatekeeper" mutation, termed T790M. Chemotherapy is the primary treatment option for patients without the T790M mutation, and TH-4000 represents a potential novel and targeted treatment option in this setting.

About H&N Cancer

The American Cancer Society estimates that more than 45,000 men and women in the United States will be diagnosed with head and neck cancers in 2015. In 2002, the World Health Organization (WHO) found that there were 600 ,000 new cases of head and neck cancer and 300,000 deaths each year worldwide. Nearly 66% of patients present with advanced disease (stage III and IV), and fewer than 30% of these patients are cured. The average survival rate for head and neck cancer is low due to the lack of early detection and the inability of current therapies to achieve a sustained response when the disease is in an advanced state. Overexpression of EGFR is recognized in more than 80% of squamous cell cancers of the head and neck, and this overexpression is associated with a poor prognosis.

About Threshold Pharmaceuticals

Threshold Pharmaceuticals, Inc. is a biotechnology company focused on the discovery and development of drugs targeting tumor hypoxia, the low oxygen condition found in the microenvironments of most solid tumors as well as the bone marrows of some patients with hematologic malignancies. This approach offers broad potential to treat a variety of cancers. By selectively targeting tumor cells, we are building a pipeline of drugs that hold promise to be more effective and less toxic to healthy tissues than conventional anticancer drugs. For additional information, please visit our website (

Forward-Looking Statements

Except for statements of historical fact, the statements in this press release are forward-looking statements, including all statements regarding the potential therapeutic applications for TH-4000 and its potential benefits; Threshold's planned Phase 2 clinical trials of TH-4000; and Threshold's belief that the data presented at AACR support Threshold's planned development of TH-4000. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Potential risks and uncertainties include, but are not limited to: the risks that Threshold's evaluation of TH-4000 is at an early stage and it is possible that TH-4000 may not be found to be safe or effective in the planned Phase 2 clinical trials of TH-4000 or in any other studies of TH-4000 that Threshold may conduct, and that Threshold may otherwise fail to realize the anticipated benefits of its licensing of this product candidate; the risk that preclinical studies and Phase 1 clinical trials of TH-4000 may not predict the results of subsequent human clinical trials, including the risks that preclinical and Phase 1 clinical data that suggest that plasma concentrations of TH-4000 that are active in tumor xenograft models in mice could be attained in patients may not accurately predict whether a safe and effective dose can be attained in the patient populations that Threshold is targeting; the difficulty and uncertainty of pharmaceutical product development, including the time and expense required to conduct clinical trials and analyze data, and the uncertainty of clinical success and regulatory approval; the ability of Threshold to enroll or complete planned TH-4000 clinical trials; Threshold's potential inability to develop a formulation of TH-4000 with adequate quality that meets the need for testing in its clinical trials; issues arising in the regulatory process and the results of such clinical trials (including product safety issues and efficacy results); Threshold's dependence on single source suppliers for TH-4000, including the risk that these single source suppliers may be unable to meet clinical supply demands for TH-4000 which could significantly delay the development of TH-4000; and Threshold's need for and the availability of resources to develop its product candidates and to support Threshold's operations. Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission on March 3, 2015 and is available from the SEC's website ( and on our website ( under the heading "Investors". We undertake no duty to update any forward-looking statement made in this news release.

Contact Information

  • Contact

    Laura Hansen, Ph.D.
    Senior Director, Corporate Communications
    Threshold Pharmaceuticals
    Phone: 650-474-8206