SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

March 19, 2015 07:00 ET

Threshold Pharmaceuticals to Present Data Supporting Planned Phase 2 Trials of TH-4000, a Hypoxia-Activated, Irreversible EGFR Tyrosine Kinase Inhibitor

Data to Be Presented on TH-4000 and Evofosfamide at the AACR Annual Meeting 2015

SOUTH SAN FRANCISCO, CA--(Marketwired - Mar 19, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD), today announced it will present data on its investigational anti-cancer drugs at the annual meeting of the American Association for Cancer Research (AACR) 2015 being held April 18-22, 2015, in Philadelphia, Pennsylvania. The company will present clinical and preclinical data on TH-4000, its proprietary, hypoxia-activated irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which the company believes support its two planned Phase 2 proof-of-concept clinical trials of TH-4000. In addition, preclinical data evaluating the potential use of evofosfamide (previously known as TH-302) in a variety of tumor types will be presented by Threshold and Merck KGaA, Darmstadt, Germany, the company's partner for the development and commercialization of evofosfamide.

"We believe that the data we will present 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 that the data support the development of TH-4000 in patients with mutant EGFR-positive non-small cell lung cancer (NSCLC) 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 tumor types have been shown to be highly hypoxic. TH-4000 is designed to release an irreversible EGFR-TKI under hypoxic conditions, which are commonly found in the tumor microenvironment. Preferential activation of TH-4000 in the hypoxic tumor microenvironment may provide the basis for achieving therapeutic doses of TKI while avoiding the skin and gastrointestinal toxicities associated with currently available EGFR-TKI therapies. We look forward to sharing these data at AACR and initiating our first planned Phase 2 trial of TH-4000 in patients with EGFR-positive, T790M-negative NSCLC shortly thereafter."

In collaboration with Threshold, data on TH-4000 will be presented by its co-inventors from The University of Auckland, Adam Patterson, Ph.D., and Jeff Smaill, Ph.D., on Wednesday, April 22, 8 AM - 12 PM EDT (Abstract #5358 in Poster Section #28) at the AACR annual meeting.

Additional Research on Evofosfamide in a Variety of Tumor Types

Threshold and Merck KGaA, Darmstadt, Germany, will present preclinical data related to evofosfamide in multiple tumor types.

"Evofosfamide is our most advanced hypoxia-activated prodrug in clinical development and has been evaluated in more than 1,500 patients with cancer to date," said Charles Hart, Ph.D., Senior Vice President of Biology at Threshold. "Our development strategy is to investigate the potential therapeutic application of evofosfamide across a variety of tumor types, and the preclinical data being presented at AACR highlight potential new therapeutic areas for further investigation." 

Data being presented on evofosfamide include:

  • Association between Chk1 inhibitor AZD7762-mediated modulation of pharmacodynamic biomarkers and potentiation of hypoxia-activated prodrug TH-302 antitumor efficacy in a human tumor xenograft model (Abstract #2424, Poster Section #22, Monday, April 20, 1:00 PM - 5:00 PM EDT)
  • Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft models (Abstract #2603, Poster Section #29, Monday, April 20, 1:00 PM - 5:00 PM EDT)
  • DNA repair processes involved with the hypoxia-activated prodrug TH-302: comparison to cisplatin and temozolomide (Abstract #3867, Poster Section #5, Tuesday, April 21, 1:00 PM - 5:00 PM EDT)
  • Hepatic hypoxia-activated intraarterial therapy: effect of selective targeting of hypoxia in a rabbit liver tumor model (Abstract #5271, Poster Section #23, Wednesday, April 22, 8:00 AM - 12:00 PM EDT)
  • TH-302 potentiates the antitumor activity of topotecan in neuroblastoma and rhabdomyosarcoma preclinical models (Abstract #5333, Poster Section #27, Wednesday, April 22, 8:00 AM - 12:00 PM EDT)

The abstracts are now published on the AACR website at http://www.aacr.org.

About Evofosfamide

Evofosfamide (previously known as TH-302), an investigational hypoxia-activated prodrug, is designed to be activated under tumor hypoxic conditions, a hallmark of many cancers. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood supply as a result of aberrant vasculature. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic.

Evofosfamide is currently under evaluation in two Phase 3 trials: one in combination with doxorubicin versus doxorubicin alone in patients with locally advanced unresectable or metastatic soft tissue sarcoma (STS), and the other in combination with gemcitabine versus gemcitabine and placebo in patients with locally advanced unresectable or metastatic pancreatic cancer (the MAESTRO trial). Both Phase 3 trials are being conducted under Special Protocol Assessment (SPA) agreements with the FDA. Based on current projections, the number of protocol-specified events for both Phase 3 trials may be reached in the second half of 2015, with the results of the primary efficacy analyses for both trials to be available shortly thereafter. The FDA and the European Commission have granted evofosfamide Orphan Drug Designation for the treatment of STS and pancreatic cancer. Evofosfamide is also being investigated in a Phase 2 trial designed to support registration for the treatment of non-squamous non-small cell lung cancer, and in earlier-stage clinical trials of other solid tumors and hematological malignancies.

Threshold has a global license and co-development agreement for evofosfamide with Merck KGaA, Darmstadt, Germany, which includes an option for Threshold to co-commercialize in the U.S.

About TH-4000

In September 2014, Threshold licensed exclusive worldwide rights to a 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 a potent, 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.

About Threshold Pharmaceuticals

Threshold is a biotechnology company focused on the discovery and development of drugs targeting tumor hypoxia, the low oxygen condition found in microenvironments of most solid tumors as well as the bone marrows of some 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 (www.thresholdpharm.com).

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 TH-302; Threshold's planned Phase 2 proof-of-concept clinical trials of TH-4000 and the timing thereof; Threshold's belief that the data to be presented at AACR support Threshold's planned development of TH-4000; Threshold's development strategy related to and potential development opportunities for evofosfamide; and Threshold's expectations regarding the planned conduct of primary efficacy analyses of both of the ongoing Phase 3 clinical trials of evofosfamide and the timing thereof. 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 proof-of-concept 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 or 2 clinical trials of our product candidates 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 and Merck KGaA, Darmstadt, Germany, to enroll or complete evofosfamide clinical trials; 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; Threshold's dependence on its collaborative relationship with Merck KGaA, Darmstadt, Germany, including its dependence on decisions by Merck KGaA, Darmstadt, Germany, regarding the amount and timing of resource expenditures for the development of evofosfamide and the risk of potential disagreements with Merck KGaA, Darmstadt, Germany, regarding the commencement of additional clinical trials or milestone payments; the risk that later trials of evofosfamide may not confirm the results of earlier trials; the risk that because the timing of the availability of primary efficacy data from the ongoing Phase 3 clinical trials of evofosfamide is driven by the number of events in each trial, which neither Threshold nor Merck KGaA, Darmstadt, Germany, controls, Threshold cannot predict with certainty when the primary efficacy data from either Phase 3 clinical trial will be available; the risks that the design of, or data collected from, the ongoing Phase 3 clinical trials of evofosfamide may be inadequate to demonstrate safety and efficacy, or otherwise may be insufficient to support any marketing authorization submissions and/or regulatory approvals, and that despite the potential benefits of the SPA agreements with the FDA, significant uncertainty remains regarding the regulatory approval process for evofosfamide and that evofosfamide may not receive any marketing approvals in a timely manner or at all; issues arising in the regulatory process and the results of such clinical trials (including product safety issues and efficacy results); dependence of Threshold and Merck KGaA, Darmstadt, Germany, on single source suppliers for evofosfamide, including the risk that these single source suppliers may be unable to meet clinical supply demands for evofosfamide which could significantly delay the development of evofosfamide; 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 evofosfamide and TH-4000 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 (www.sec.gov) and on our website (www.thresholdpharm.com) under the heading "Investors". We undertake no duty to update any forward-looking statement made in this news release.

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