SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

October 27, 2015 07:00 ET

Threshold Pharmaceuticals Announces Preclinical Data Presentations on Tarloxotinib at the 2015 AACR-NCI-EORTC Meeting

SOUTH SAN FRANCISCO, CA--(Marketwired - Oct 27, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that it will present preclinical data on tarloxotinib bromide*, or "tarloxotinib", in two scientific posters at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, which will be held November 5-9, 2015, in Boston. Tarloxotinib is Threshold's proprietary hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor exclusively licensed from the University of Auckland, New Zealand. The data highlight preclinical rationale in support of two ongoing Phase 2 proof-of-concept trials of tarloxotinib in non-small cell lung cancer and in squamous cell carcinomas of the head and neck or skin.

Poster Presentations
Abstract A66:
Preclinical efficacy of tarloxotinib bromide (TH-4000), a hypoxia-activated EGFR/HER2 inhibitor: rationale for clinical evaluation in EGFR mutant, T790M-negative NSCLC following progression on EGFR-TKI therapy.

Abstract A67: Preclinical rationale for the ongoing Phase 2 study of the hypoxia-activated EGFR-TKI tarloxotinib bromide (TH-4000) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS).

Both posters will be presented on Friday November 6, 2015, from 12:15 PM - 3:15 PM during Poster Session A in Exhibit Hall C-D.

The abstracts are now available on the AACR-NCI-EORTC meeting website.

About Non-Small Cell Lung Cancer
Lung cancer is the most common cause of death from cancer worldwide; an estimated 1.8 million new cases were diagnosed in 2012.1 The most common type of lung cancer, non-small cell lung cancer (NSCLC), accounts for approximately 85 to 90 percent of cases.2 EGFR activating mutations occur in approximately 10 percent of NSCLC cases in Caucasian patients and up to 35 percent in Asian patients.3 Tarceva®, Iressa®, and Gilotrif® are the first- and second-generation EGFR inhibitors currently approved for patients with the EGFR activating mutations. Nearly all patients ultimately progress on these therapies due to a variety of resistance mechanisms.

One largely unexplored mechanism of treatment resistance is through expression of not only mutant EGFR but also through the emergence of normal, or "wild-type" EGFR, and its subsequent stimulation by growth factors produced in the tumor microenvironment. Hypoxia upregulates the wild-type EGFR protein and its ligand TGF-alpha, leading to elevated EGFR signaling.4,5 Tumors that are heterozygous for EGFR (containing both wild-type EGFR and mutant EGFR) are associated with worse outcomes than is the case with homozygous mutant EGFR.6 Heterozygous disease has also been proposed as a cause of resistance to EGFR inhibitors.7 Tarloxotinib, which is designed to inhibit both mutant as well as wild-type EGFR in a tumor-selective manner, may effectively address these potentially important mechanisms of treatment resistance.

About Squamous Cell Carcinomas Head and Neck
Most head and neck cancers, which include cancers of the larynx (voice box), throat, lips, mouth, nose, and salivary glands, begin in the squamous cells that line the moist surfaces inside the head and neck, and are therefore referred to as squamous cell carcinomas of the head and neck (SCCHN). SCCHN is diagnosed in approximately 59,000 people in the U.S. annually and is responsible for some 12,000 deaths.8 In the recurrent/metastatic setting, chemotherapy or cetuximab monotherapy is the standard of care with response rates of about ten percent and disease progression occurs within two to three months.9

About Squamous Cell Carcinomas of the Skin
Non-melanoma skin cancers typically resulting from chronic sun exposure or other sources of ultraviolet rays are the most common types of cancer. Twenty percent of these skin cancers originate from squamous cells normally present in the outer layers of the skin (SCCS); five percent of SCCS will become locally advanced, recur, or metastasize. In the U.S., approximately 2,000 deaths per year are attributed to SCCS.10 As with SCCHN, SCCS is associated with EGFR overexpression and appear to be responsive to EGFR inhibitor therapy.11

About Tarloxotinib Bromide
Tarloxotinib bromide, or "tarloxotinib", is a prodrug designed to selectively release a covalent (irreversible) EGFR tyrosine kinase inhibitor under severe hypoxia, a feature of many solid tumors. Accordingly, tarloxotinib has the potential to effectively shut down aberrant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the systemic side effects associated with currently available EGFR tyrosine kinase inhibitors. Tarloxotinib is currently being evaluated in two Phase 2 proof-of-concept trials: one for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR tyrosine kinase inhibitor, and the other for patients with recurrent or metastatic squamous cell carcinomas of the head and neck or skin. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.

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 (www.thresholdpharm.com).

Forward-Looking Statements
Except for statements of historical fact, the statements in this press release are forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1943 and Section 27A of the Securities Act of 1933, including all statements regarding the anticipated development activities and clinical development outlook for the two Phase 2 proof-of-concept clinical trials of tarloxotinib. 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 difficulty and uncertainty of pharmaceutical product development, including the uncertainty of clinical success (including product safety issues and efficacy results), a reliable manufacturing supply and regulatory approval; the risks that Threshold's evaluation of tarloxotinib is at an early stage and it is possible that tarloxotinib may not be found to be safe or effective in the ongoing Phase 2 proof-of-concept trials of tarloxotinib or in any other studies of tarloxotinib 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 tarloxotinib preclinical and Phase 1 clinical data may not accurately predict whether a safe and effective dose can be attained in the patient populations for tarloxotinib that Threshold is targeting; the ability of Threshold to enroll or complete planned tarloxotinib clinical trials; Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Quarterly Report on Form 10-Q, which has been filed with the Securities and Exchange Commission on July 30, 2015 and is available from the SEC's website (www.sec.gov) and on our website (www.thresholdpharm.com) under the heading "Investors". Notwithstanding changes that may occur with respect to matters relating to any forward looking statements, we undertake no duty to update any forward-looking statement made in this news release.

*Tarloxotinib bromide is the pending International Nonproprietary Name.

References

1. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
2. American Cancer Society: Lung Cancer (Non-Small Cell). http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer
3. Sharma SV, et al: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 7: 169-81, 2007.
4. Wouters A, et al: The intriguing interplay between therapies targeting the epidermal growth factor receptor, the hypoxic microenvironment and hypoxia-inducible factors. Curr Pharm Des. 19: 907-917, 2013.
5. Semenza GL, et al: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3: 721-32, 2003.
6. Taniguchi K, et al: Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib. Cancer Sci. 99: 929-35, 2008.
7. Bai H, et al: Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS One. 8: e54170, 2013.
8. Cancer.net: Head and Neck Cancer: Statistics. http://www.cancer.net/cancer-types/head-and-neck-cancer/statistics
9. de Andrade DA, Machiels JP: Treatment options for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, who progress after platinum-based chemotherapy. Curr Opin Oncol. 24: 211-217, 2012.
10. American Cancer Society: Skin Cancer: Basal and Squamous Cell. http://www.cancer.org/cancer/skincancer-basalandsquamouscell/detailedguide/skin-cancer-basal-and-squamous-cell-key-statistics
11. Maubec E, et al: Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res. 25: 1205-1210, 2005.

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