SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

October 13, 2015 07:00 ET

Threshold Pharmaceuticals Receives Two U.S. Patents for Tarloxotinib Bromide

SOUTH SAN FRANCISCO, CA--(Marketwired - Oct 13, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that the U.S. Patent and Trademark Office (USPTO) has issued the first two U.S. patents protecting tarloxotinib bromide*, or "tarloxotinib," the Company's proprietary hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor exclusively licensed from the University of Auckland, New Zealand. The first patent, U.S. Patent No. 9,073,916, generically covers a structural class of EGFR tyrosine kinase inhibitor prodrugs, including tarloxotinib, and pharmaceutical compositions containing this structural class of prodrugs. The second patent, U.S. Patent No. 9,101,632, specifically covers the compound tarloxotinib and pharmaceutical compositions containing it. 

"These two patents provide fundamental intellectual property protection for tarloxotinib, which is the subject of two ongoing Phase 2 clinical trials for the treatment of patients with mutant EGFR-positive non-small cell lung cancer and patients with squamous cell cancers of the head and neck or skin," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "Currently, treatment with EGFR inhibitors has limited efficacy because side effects can prevent effective doses from being achieved. We believe that more effective dosing may be achievable with tarloxotinib, which is designed to release an irreversible EGFR tyrosine kinase inhibitor selectively under hypoxic conditions commonly found within solid tumors. Tumor-selective activation of tarloxotinib may allow for greater inhibition of EGFR signaling within the tumor while limiting systemic side effects, potentially leading to better outcomes for patients with EGFR-dependent cancers."

*Tarloxotinib bromide is the proposed International Nonproprietary Name.

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 are 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 (

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 Company's licensing activities, legal strategy and prospects, expectations regarding enhancing shareholder value and the anticipated development activities and clinical development outlook for the two Phase 2 proof-of-concept clinical trials of tarloxotinib; and the ability of Threshold to build and protect the value of its two clinical assets and underlying hypoxia-activated prodrug technology. 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 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, including as a result of Threshold's potential inability to develop a formulation of tarloxotinib with adequate quality that meets the specifications previously filed with the regulatory agency and that meets the need for testing in its clinical trials; Threshold's dependence on single source suppliers for tarloxotinib, including the risk that these single source suppliers may be unable to meet clinical supply demands for tarloxotinib which could significantly delay the development of tarloxotinib; and Threshold's need for and the availability of resources to develop evofosfamide and tarloxotinib and to support Threshold's operations. 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 ( and on our website ( 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.


1. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012.

2. American Cancer Society: Lung Cancer (Non-Small Cell).

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. 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.

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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