Threshold Pharmaceuticals, Inc. Initiates Phase 2 Clinical Trial Of Tarloxotinib Bromide (TH-4000) In Patients With Recurrent Or Metastatic Squamous Cell Carcinomas Of The Head And Neck Or Skin

SOUTH SAN FRANCISCO, CA--(Marketwired - August 27, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that the company has initiated a Phase 2 clinical trial of tarloxotinib bromide, or “tarloxotinib” (TH-4000), for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Tarloxotinib is Threshold’s proprietary, hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor licensed from the University of Auckland, New Zealand.

“New and effective treatment options are urgently needed for patients with squamous cell carcinomas,” said Danny Rischin, M.D., Co-Director, Division of Cancer Medicine at Peter MacCallum Cancer Centre and Principal Investigator of the Phase 2 trial. “Tarloxotinib represents a novel treatment approach that may allow effective inhibition of EGFR signaling in the tumor microenvironment with relative sparing of normal tissues.”

Elevated expression of wild-type EGFR and its stimulatory ligands occurs in the majority of squamous cell carcinomas. Aberrant EGFR signaling can lead to uncontrolled tumor cell growth. One mechanism likely to be involved is hypoxia, or low-oxygen conditions, which is a prevalent feature of solid tumors including squamous cell carcinomas. In preclinical studies hypoxia has been shown to increase EGFR signaling by upregulation, stabilization, and hyperphosphorylation of EGFR, through multiple mechanisms.(1-6) Gene expression-based profiling of clinical samples supports the observations of a strong causal link between elevation in the tumor EGFR pathway and hypoxia signatures.(7)

“We are pleased that tarloxotinib is actively being investigated in two monotherapy Phase 2 proof-of-concept trials, the other being in patients with non-small cell lung cancer,” said Tillman Pearce, M.D., Chief Medical Officer of Threshold. “These clinical settings, in which EGFR is already a validated therapeutic target, represent opportune development paths for tarloxotinib, which is designed to exploit the reported overlap between elevated EGFR signaling and tumor hypoxia. By selectively targeting the hypoxic tumor microenvironment, tarloxotinib has the potential to increase the therapeutic index and overcome limitations of current EGFR inhibitor therapy, which may lead to improved outcomes for patients with these EGFR-dependent cancers.”

About the Phase 2 Clinical Trial
The Phase 2 clinical trial is a single-arm, open label study that will enroll up to 68 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Eligible patients will receive tarloxotinib (150 mg/m2 by intravenous infusion) on Days 1, 8, 15 and 22 of a 28-day cycle. Prior anti-EGFR antibody therapy is permitted. RECIST response rate is the primary endpoint. Secondary endpoints include duration of response, progression-free survival, overall survival, safety, tolerability and pharmacokinetics. In addition to other target-specific biomarkers, hypoxia status will be measured at baseline using Threshold’s proprietary PET imaging agent [18F]-HX4. The study is planned to be opened at 10 sites in the U.S. and Australia.

About Squamous Cell Carcinoma of the Head and Neck (SCCHN)
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) Historically, tobacco and alcohol use have been the greatest risk factors; more recently, infection with the human papilloma virus (HPV) has been recognized as a risk factor with a more favorable prognosis. For patients with advanced disease who have progressed on the standard regimen of platinum-based chemotherapy with or without cetuximab anti-EGFR therapy, further therapy with chemotherapy or cetuximab monotherapy is the standard of care, but response rates are about ten percent and disease progression occurs within two to three months.(9)

About Squamous Cell Carcinoma of the Skin (SCCS)
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”, (TH-4000) is a hypoxia-activated, covalent (irreversible) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that targets the activating mutations of EGFR (L858R and Del19) and wild-type, or “normal”, EGFR. Tarloxotinib is designed as a prodrug to selectively release its EGFR TKI upon encountering severe tumor hypoxia, a feature of many solid tumors. Accordingly, tarloxotinib has the potential to effectively shut down aberrant wild-type and mutant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the toxic side effects associated with currently available EGFR TKIs and systemic wild-type EGFR inhibition. In addition to this second trial in squamous cell carcinomas, tarloxotinib is currently being evaluated in a Phase 2 proof-of-concept trial for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR TKI. 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, including all statements regarding the potential therapeutic applications for tarloxotinib and its potential benefits, including as a potential treatment option in the SCCHN and SCCS settings. 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 initiated and/or planned Phase 2 clinical 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 clinical trials of tarloxotinib 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 tarloxotinib that are active in EGFR-dependent tumor xenograft models in mice could be attained in patients with an acceptable therapeutic index 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 ongoing and/or planned tarloxotinib clinical trials; 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; 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 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 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 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”. We undertake no duty to update any forward-looking statement made in this news release.

* Tarloxotinib bromide is the proposed International Nonproprietary Name (pINN)

References

1. Franovic A, et al. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13092-7.

2. Wang Y, et al. Regulation of endocytosis via the oxygen-sensing pathway. Nature Med 2009;15:319-324.

3. Wang X, Schneider A. HIF-2a-mediated activation of the epidermal growth factor receptor potentiates head and neck cancer cell migration in response to hypoxia. Carcinogenesis 2010;31:1202-1201.

4. Minakata K, et al. Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors. Cancer Sci 2012;103:1946-54.

5. Wang Y, et al. Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1.Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4892-7.

6. 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. 2013;19(5):907-17.

7. Keck MK, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res. 2015 Feb 15;21(4):870-81.

8. Cancer.net http://www.cancer.net/cancer-types/head-and-neck-cancer/statistics accessed August 26, 2015.

9. de Andrade DA and 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. 2012 May;24(3):211-7.

10. American Cancer Society. http://www.cancer.org/cancer/skincancer-basalandsquamouscell/detailedguide/skin-cancer-basal-and-squamous-cell-key-statistics. Accessed August 26, 2015.

11. Maubec E, et al. Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Research 2005;25:1205-1210.