(Filing, 10-Q, Seattle Genetics, JUL 30, 2015, View Source [SID:1234506783])

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On July 31, 2015 Takeda Pharmaceutical Company Limited ("Takeda") reported the completion of the study to fulfill the post-marketing commitment and submissions of data to regulatory authorities from the Pan European Multi-Database Bladder Cancer Risk Characterization Study, a large (n= 112,674), multi-database retrospective matched cohort study, conducted in four European countries, for pioglitazone containing medicines, including ACTOS (pioglitazone HCI) with up to 10 years of follow-up (Press release, Takeda, JUL 30, 2015, View Source [SID:1234506785]). Findings demonstrate that there is no association between the use of pioglitazone and the risk of bladder cancer, (hazard ratio [HR] 0.99 [95% CI: 0.75, 1.30]). These results are consistent with those of a 10-year, prospective cohort study, conducted by the University of Pennsylvania (U. of Penn.) and Division of Research at Kaiser Permanente Northern California (KPNC), which demonstrated no increased risk of bladder cancer among patients ever exposed to pioglitazone ([HR] 1.06 [95% CI 0.89-1.26]).1 Additionally, both studies found no association between the risk of bladder cancer and cumulative dose of pioglitazone, or duration of pioglitazone exposure.

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"ACTOS is an important treatment option for patients with Type 2 diabetes. These data further reinforce the positive benefit/risk profile for ACTOS," said Alfonso Perez, MD, vice president, clinical research, Takeda. "These long-term studies underscore Takeda’s commitment to ensuring physicians have the best available information to make treatment decisions."

The data from the Pan European Multi-Database Bladder Cancer Risk Characterization Study also shows a mortality decrease with ever use of pioglitazone (adjusted HR 0.67 [95% CI: 0.64, 0.70]).This study was completed as part of the post-marketing request from the Committee for Medicinal Products for Human Use (CHMP). In addition to the European Medicines Agency (EMA), the results from the Pan European study were also submitted to the U.S. Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA). The data will be shared with additional regulatory authorities in accordance with local requirements around the world.

"Patient safety remains a top priority for Takeda," said Perez. "Throughout a product’s lifecycle we continue to monitor and conduct additional research to further our knowledge. This milestone is an important example of Takeda’s commitment to conducting further research and sharing the outcomes with regulatory agencies, physicians, and others."

About the Study
The retrospective cohort study of the European Union (EU) medical record databases was conducted using six medical records databases across four countries, including Finland, The Netherlands, Sweden, and the United Kingdom. Type 2 diabetes patients treated with pioglitazone were matched equally with patients with similar characteristics who were not treated with pioglitazone. Patients were matched based on diabetes duration, diabetes complications, cardiovascular complications, and previous antidiabetic drug use. This study design was developed to minimize treatment allocation bias, an issue seen in some previous epidemiological studies of pioglitazone.

About Pioglitazone
Pioglitazone is a thiazolidinedione for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise.

Unlike many oral antidiabetic drugs, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Therefore, pioglitazone is a medication that depends on the presence of insulin for its mechanism of action, and it decreases insulin resistance in muscle and the liver, resulting in increased insulin-dependent glucose disposal as well as decreased hepatic glucose output.

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with Type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with sulfonylurea, metformin, or insulin.

Important Safety Information
Contraindications
Initiation of ACTOS is contraindicated in patients with NYHA Class III or IV heart failure.

ACTOS is contraindicated in patients with known hypersensitivity to pioglitazone or any of its excipients so as to avoid inducing a potentially serious hypersensitivity reaction.

Warnings and Precautions
Fluid retention and cardiac failure: Thiazolidinediones, including ACTOS, can cause dose-dependent fluid retention, which may exacerbate or precipitate heart failure. After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, discontinuation of ACTOS must be considered. ACTOS should be used with caution in patients with cardiac dysfunction whose physical activity is markedly limited. Combination use with insulin may increase risk.

Hepatic effects: Post-marketing reports of hepatitis and hepatic dysfunction have been received. Very rarely these reports have involved hepatic failure, with and without a fatal outcome, although causality has not been established. Obtain liver tests before starting ACTOS and periodically thereafter. Pioglitazone therapy should not be initiated in patients with increased liver enzyme levels (ALT> 2.5x upper limit of normal) or with any other evidence of liver disease. Existing pioglitazone therapy should be discontinued if ALT levels are persistently higher than 3x the upper limit of normal, and symptoms suggesting hepatic dysfunction should cause the liver enzymes to be checked. Pending the results of laboratory investigations, the decision as to whether pioglitazone therapy should continue must be based on clinical judgment; in the presence of jaundice, drug therapy should be discontinued.

Weight gain: Weight gain was observed in clinical trials and has been seen in post-marketing experience with pioglitazone, so patient weight should be closely monitored.

Fractures: An increased incidence of bone fracture has been noted in female patients.

Bladder cancer: Some data suggest there may be an increased risk of bladder cancer in ACTOS users and also that the risk increases with duration of use. Do not use ACTOS in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.

Hypoglycemia: When ACTOS is used with insulin, a sulfonylurea or other oral hypoglycemic agents, hypoglycemia may occur.

Ovulation: Ovulation in premenopausal anovulatory women or women with polycystic ovarian syndrome may occur with ACTOS.

Macular edema: Post-marketing reports of new-onset or worsening diabetic macular edema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Physicians should consider the possibility of macular edema if a patient reports decreased visual activity.

Drug interactions: Use of ACTOS with CYP2C8 inducers or strong inhibitors may require dose adjustment.
Please refer to the Summary of Product Characteristics (SmPC) for ACTOS before prescribing.

ACTOS should be used according to the indication, posology and method of administration described in the SmPC.

Please consult with your local regulatory agency for approved labeling in your country.

(Filing, 10-Q, Sunesis, JUL 30, 2015, View Source [SID:1234506784])

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On July 30, 2015 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported financial results for the second quarter ended June 30, 2015. Loss from operations for the three and six months ended June 30, 2015 was $10.6 million and $19.4 million, respectively (Press release, Sunesis, JUL 30, 2015, View Source;p=RssLanding&cat=news&id=2072752 [SID:1234506755]). As of June 30, 2015, cash, cash equivalents and marketable securities totaled $39.6 million.

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"We remain committed to moving vosaroxin forward as an important new therapy for patients with AML, and to realizing the value of this product candidate for all our constituents," said Daniel Swisher, Chief Executive Officer of Sunesis. "As part of this effort, we are moving forward rapidly toward the filing of a marketing authorization application in Europe and are carefully evaluating and refining our plans to gain marketing approval in the U.S. As we continue to advance these strategies and work toward key milestones with our kinase inhibitor pipeline, we are also evaluating and prioritizing our spending to ensure our ability to realize the value of our portfolio."

Second Quarter 2015 Highlights

Received European regulatory guidance regarding potential marketing authorization application for Vosaroxin in AML. In July 2015, Sunesis announced that, following pre-submission advisory meetings to discuss the potential submission of a Marketing Authorization Application (MAA) for vosaroxin in Europe, the company is proceeding with an MAA filing. The MAA will focus on the indication of relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older, a population with the greatest medical need and for whom the greatest benefit was observed in the vosaroxin/cytarabine treatment arm of VALOR, the company’s pivotal Phase 3 study of vosaroxin in adult patients with relapsed or refractory AML.

Received feedback from FDA regarding NDA filing for Vosaroxin in AML. In July 2015, Sunesis announced that, following a recent meeting with the U.S. Food and Drug Administration (FDA), the FDA recommended that the company provide additional clinical evidence to support a future NDA submission. The company is currently evaluating and refining its plan to gain marketing approval in the U.S. based on this feedback.

Announced presentation of new data at EHA (Free EHA Whitepaper) 2015 from predefined subgroup of patients age 60 years and older enrolled in VALOR. In June 2015, Sunesis announced the presentation of results from predefined subgroups of patients age 60 years and older enrolled in VALOR. The results were presented at the 20th Congress of the European Society of Hematology in Vienna, Austria. The poster, titled "Improved survival in patients ≥60 with first relapsed/refractory acute myeloid leukemia treated with vosaroxin plus cytarabine vs placebo plus cytarabine: results from the Phase 3 VALOR study," as well as an additional poster presented at the meeting, titled "Allogeneic transplant in patients ≥60 years of age with first relapsed or refractory acute myeloid leukemia after treatment with vosaroxin or placebo plus cytarabine: results from VALOR," are available on the Sunesis website as www.sunesis.com.

Announced presentation of VALOR trial subgroup analysis at ASCO (Free ASCO Whitepaper) 2015. In May 2015, Sunesis announced the presentation of results from a post hoc subgroup analysis of patients age 60 years and older who underwent allogeneic hematopoietic cell transplant (HCT) in the VALOR trial. The poster, titled "Allogeneic hematopoietic cell transplant (HCT) in patients (pts) ≥ 60 years of age with first relapsed or refractory acute myeloid leukemia (R/R AML) after treatment with vosaroxin plus cytarabine (pla/cyt): results from VALOR", is available on the Sunesis website at www.sunesis.com.

Financial Highlights

Cash, cash equivalents and marketable securities totaled $39.6 million as of June 30, 2015, as compared to $43.0 million as of December 31, 2014. The decrease of $3.4 million was primarily due to $19.8 million of net cash used in operating activities and $1.6 million of principal payments against notes payable, partially offset by $18.0 million raised from the sale of common stock through the company’s at-the-market facility with Cantor Fitzgerald & Co. and from option exercises. A further $0.4 million was raised in July through this facility, resulting in a pro-forma June 30, 2015 cash balance of $40.0 million. This capital is expected to be sufficient to fund the company to the middle of 2016.

Revenue for the three and six months ended June 30, 2015 was $0.9 million and $1.7 million as compared to $2.0 million and $4.0 million for the same periods in 2014. Revenue in each period was primarily due to deferred revenue recognized related to the royalty agreement with Royalty Pharma.

Research and development expense was $6.3 million and $10.8 million for the three and six months ended June 30, 2015 as compared to $7.2 million and $14.8 million for the same periods in 2014. The decreases between the comparable three and six month periods were primarily due to reductions in clinical trial expenses in each case.

General and administrative expense was $5.2 million and $10.3 million for the three and six months ended June 30, 2015 as compared to $6.4 million and $9.8 million for the same periods in 2014. The decrease between the comparable three month periods was primarily due to decreases in personnel costs and outside services costs. The increase between the comparable six month periods was primarily due to an increase in outside services costs.

Interest expense was $0.2 million and $0.5 million for the three and six months ended June 30, 2015 as compared to $0.5 million and $1.0 million for the same periods in 2014. The decreases in the 2015 periods were due to the reduced principal balance outstanding on notes payable.

Net other income was $1.9 million and $1.8 million for the three and six months ended June 30, 2015 as compared to $0.3 million of net other income and $4.8 million of net other expense for the same periods in 2014. The amounts for each period were primarily comprised of non-cash credits or charges for the revaluation of warrants issued in 2010.

Cash used in operations was $19.8 million for the six months ended June 30, 2015 as compared to $21.6 million for the same period in 2014. Net cash used in the 2015 period resulted primarily from the net loss of $18.1 million and changes in operating assets and liabilities of $3.4 million, partially offset by net adjustments for non-cash items of $1.7 million.

Sunesis reported loss from operations of $10.6 million and $19.4 million for the three and six months ended June 30, 2015 as compared to $11.6 million and $20.6 million for the same periods in 2014. Net loss was $8.9 million and $18.1 million for the three and six months ended June 30, 2015 as compared to $11.8 million and $26.4 million for the same periods in 2014.
About QINPREZO (vosaroxin)
QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.
The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.

On July 30, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported financial results for the second quarter 2015 (Filing, 8-K, Threshold Pharmaceuticals, JUL 30, 2015, View Source [SID:1234506757]). Revenue for the second quarter ended June 30, 2015 was $3.7 million. The operating loss for the second quarter ended June 30, 2015 was $8.9 million. The net loss for the second quarter ended June 30, 2015 was $8.3 million, which included the operating loss of $8.9 million and non-cash income of $0.6 million related to the changes in fair value of the Company’s outstanding warrants and was classified as other income (expense). As of June 30, 2015, Threshold had $67.0 million in cash, cash equivalents and marketable securities, with no debt outstanding.

"We are pleased with progress being made in the development programs for both of our product candidates, evofosfamide and tarloxotinib," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "We expect to announce top-line results from the two pivotal Phase 3 clinical trials of evofosfamide in patients with advanced soft tissue sarcoma and in patients with advanced pancreatic cancer (MAESTRO) around the end of this year. We are initiating two proof-of-concept Phase 2 clinical trials of tarloxotinib this year in patients whom we believe may benefit from treatment with our proprietary and novel hypoxia-activated EGFR tyrosine kinase inhibitor."

Second Quarter 2015 Financial and Operational Results

Revenue of $3.7 million was recognized for both the second quarter of 2015 and 2014. Revenue is related to the amortization of the aggregate of $110 million in upfront and milestone payments earned in 2013 and 2012 from Threshold’s collaboration with Merck KGaA, Darmstadt, Germany. The revenue from the upfront and milestone payments earned under the agreement is being amortized over the relevant performance period, rather than being immediately recognized when the upfront and milestone payments are earned or received.

The net loss for the second quarter of 2015 was $8.3 million compared to a net loss of $0.8 million for the second quarter of 2014. Included in the net loss for the second quarter of 2015 was an operating loss of $8.9 million and non-cash income of $0.6 million compared to an operating loss of $7.5 million and non-cash income of $6.7 million included in the net loss for the second quarter of 2014. The non-cash income is related to the change in fair value of the Company’s outstanding warrants and was classified as other income (expense).

Research and development expenses were $10.1 million for the second quarter of 2015 compared to $8.7 million for the second quarter of 2014. The increase in research and development expenses was due primarily to a $1.2 million increase in clinical development expenses, net of reimbursement from Merck KGaA, Darmstadt, Germany related to their 70% share of total development expenses for evofosfamide (previously known as TH-302).

General and administrative expenses were $2.5 million for both the second quarter of 2015 and 2014.

Non-cash stock-based compensation expense included in total operating expenses was $1.9 million for the second quarter of 2015 versus $1.5 million for the second quarter of 2014. The increase in stock-based compensation expense was due to the amortization of a greater number of options with higher fair values.

As of June 30, 2015 and March 31, 2015, Threshold had $67.0 million and $83.1 million in cash, cash equivalents and marketable securities, respectively. The net decrease of $16.1 million in cash, cash equivalents and marketable securities during the second quarter of 2015 was primarily due to the Company’s operating cash requirements for the second quarter of 2015.

Second Quarter and Recent Key Achievements

Evofosfamide

In May, Threshold announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation to the Company’s partner Merck KGaA, Darmstadt, Germany, for the development of evofosfamide (TH-302), administered in combination with gemcitabine, for the treatment of previously untreated patients with locally advanced unresectable or metastatic pancreatic cancer. This is the second Fast Track designation for evofosfamide, the first having been granted to Threshold in November 2014 for the development of evofosfamide in combination with doxorubicin for the treatment of patients with locally advanced or metastatic soft tissue sarcoma.

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Also in May, Threshold presented data from the Phase 2 component of an ongoing Phase 1/2 trial of evofosfamide in combination with the proteasome inhibitor Velcade (bortezomib) and low-dose dexamethasone ("EBorD") in patients with relapsed or refractory multiple myeloma at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Abstract 8579). A clinical benefit rate of 29% (one complete response, two partial responses, and one minimal response) was observed in 4 of 14 patients treated at the recommended Phase 2 dose of evofosfamide (340 mg/m2) in EBorD. These patients had already received multiple types of treatment prior to enrollment including a median of 3 prior bortezomib-containing regimens. The most common adverse events were thrombocytopenia and anemia and no patients discontinued treatment due to an adverse event.

In April, preclinical data evaluating the potential use of evofosfamide in a variety of tumor types were presented by Threshold and Merck KGaA, Darmstadt, Germany, at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Abstract Nos. 2424, 2603, 3867, 5271, and 5333).

Tarloxotinib bromide* ("tarloxotinib")

In April, data on tarloxotinib (TH-4000; previously referred to as PR610 or Hypoxin), Threshold’s proprietary, hypoxia-activated irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, were presented in collaboration with the molecule’s co-inventors from The University of Auckland at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting (Abstract 5358). The Company believes the data presented support its planned Phase 2 proof-of-concept clinical trials of tarloxotinib in patients with EGFR-positive, T790M-negative NSCLC after conventional EGFR-TKI therapy has failed as well as in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or skin.

Clinical Development Outlook for Threshold- and Merck KGaA, Darmstadt, Germany-Sponsored Trials of Evofosfamide

The development plan for evofosfamide is designed to investigate its safety and efficacy across a broad range of solid tumors and hematologic malignancies. Evofosfamide is being developed in therapeutic areas supported by preclinical and clinical data and where there is high unmet need for new anti-cancer agents. To date, evofosfamide has been evaluated in more than 1,500 patients with cancer. Threshold anticipates the following development activities related to Threshold- and Merck KGaA, Darmstadt, Germany-sponsored clinical trials for evofosfamide in 2015:

· Continue to efficiently execute the two Phase 3 clinical trials of evofosfamide to allow for timely data analyses and to prepare for the potential submission of marketing applications, assuming the data from the trials are supportive;
· Continue enrollment in the Phase 2 clinical trial of evofosfamide designed to support registration for the treatment of patients with non-squamous non-small cell lung cancer;
· Complete enrollment in the Phase 2 clinical trial of evofosfamide in combination with bortezomib (Velcade) and low-dose dexamethasone in patients with relapsed or refractory multiple myeloma; and
· Threshold is in the process of closing the Phase 2 clinical trial of evofosfamide in patients with melanoma due to a slower than anticipated enrollment rate in light of the evolving treatment landscape and new therapeutic options for patients with melanoma since the trial began.

About Evofosfamide

Evofosfamide is an investigational hypoxia-activated prodrug that is designed to be preferentially activated under severe tumor hypoxic conditions, a feature of many solid tumors. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood vessel supply. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic.

Evofosfamide is currently in two Phase 3 trials, both of which are fully recruited: one in combination with doxorubicin versus doxorubicin alone in patients with locally advanced unresectable or metastatic soft tissue sarcoma (STS) (the TH-CR-406 trial), 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. The FDA and the European Commission have granted evofosfamide Orphan Drug designation for the treatment of STS and pancreatic cancer. The FDA has also granted Fast Track designation for evofosfamide for both 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 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 hypoxic conditions, a feature of many solid tumors. Accordingly, it 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. Threshold expects to initiate two Phase 2 proof-of-concept trials with tarloxotinib in 2015: one in patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR-TKI, and the other in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or skin. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland in September 2014.