On October 13, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported 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 (Press release, Threshold Pharmaceuticals, OCT 13, 2015, View Source [SID:1234507703]). 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.
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"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.