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ºÚÁÏÍø., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “ºÚÁÏÍø”) announced today that its U.S. subsidiary ºÚÁÏÍø Inc. has received approval of its in-house developed novel anticancer agent Lenvima™ (lenvatinib mesylate) as a treatment for locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC) from the U.S. Food and Drug Administration (FDA). Lenvima was granted priority review status by the FDA, and was ultimately approved six months from the submission of the New Drug Application in August 2014, two months ahead of the FDA priority review action date. This marks the first country in the world where the agent has received marketing authorization.

Lenvima is an orally administered molecular targeted agent that selectively inhibits the activities of several different molecules including VEGFR, FGFR, RET, KIT and PDGFR. In particular, the agent simultaneously inhibits VEGFR, FGFR and also RET which are especially involved in tumor angiogenesis and proliferation of thyroid cancer. Furthermore, Lenvima has been confirmed through X-ray crystal structural analysis to be the first compound to demonstrate a new binding mode (Type Ⅴ) to VEGFR2, and exhibits rapid and potent inhibition of kinase activity, according to kinetic analysis¹.

The approval was based on the results of a multicenter, randomized, double-blind, placebo-controlled Phase Ⅲ study (the SELECT study) of 392 patients with progressive RAI-R DTC. In the study's primary endpoint of progression-free survival (PFS), Lenvima demonstrated a statistically significant extension in PFS compared to placebo (p<0.001; median PFS in the Lenvima group: 18.3 months, median PFS in the placebo group: 3.6 months; Hazard Ratio (HR) 0.21 [99% CI: 0.14-0.31]). In addition, Lenvima demonstrated a statistically significant improvement in response rate (sum of complete and partial responses) compared to placebo (p<0.001; Lenvima: 64.8% vs placebo: 1.5%). In particular, complete response was observed in 1.5% (4 patients) of the Lenvima group and zero in the placebo group. The most common Lenvima treatment-related adverse events of any grade, which occurred in more than 40% of patients in the Lenvima group, were hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), weight loss (46.4%) and nausea (41.0%).

Currently, the agent is undergoing regulatory review in Japan and the EU, as well as Switzerland, South Korea, Canada, Singapore, Russia, Australia and Brazil, and Lenvima was also granted accelerated assessment in the EU. ºÚÁÏÍø will continue to file applications seeking regulatory approval for the agent in countries around the world, and the company will market the agent in those countries where approval has been received. Furthermore, ºÚÁÏÍø is conducting a global Phase Ⅲ trial of Lenvima in hepatocellular carcinoma as well as Phase Ⅱ studies of Lenvima in several other tumor types such as renal cell carcinoma and non-small cell lung cancer.

The number of patients newly diagnosed with thyroid cancer in 2012 in the United States was estimated to be approximately 52,000. Although treatment is possible for most types of thyroid cancer, there are few treatment options available once thyroid cancer has progressed, therefore it remains a disease with significant unmet medical needs. In addition to providing Lenvima as a new treatment option for thyroid cancer, ºÚÁÏÍø is committed to exploring the potential clinical benefits of Lenvima in order to further contribute to patients with cancer, and their families.

Lenvima, discovered and developed by ºÚÁÏÍø, is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4)), in addition to other proangiogenic and oncogenic pathway-related RTKs (including fibroblast growth factor (FGF) receptors FGFR1, 2, 3 and 4; the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation. In particular, the agent simultaneously inhibits VEGFR, FGFR and also RET which are especially involved in tumor angiogenesis and proliferation of thyroid cancer. Furthermore, Lenvima has been confirmed through X-ray crystal structural analysis to be the first compound to demonstrate a new binding mode (Type Ⅴ) to VEGFR2, and exhibits rapid and potent inhibition of kinase activity, according to kinetic analysis¹. Lenvima has been approved for the treatment of refractory thyroid cancer in the United States, and is currently undergoing regulatory review for this indication in Japan, the EU, Switzerland, South Korea, Canada, Singapore, Russia, Australia and Brazil. Meanwhile, ºÚÁÏÍø is currently conducting clinical studies of Lenvima in several types of cancer including hepatocellular carcinoma (Phase Ⅲ), renal cell carcinoma (Phase Ⅱ), non-small cell lung cancer (Phase Ⅱ) and endometrial cancer (Phase Ⅱ). Furthermore, Lenvima was granted Orphan Drug Designation in Japan for thyroid cancer, in the United States for treatment of follicular, medullary, anaplastic, and metastatic or locally advanced papillary thyroid cancer and in Europe for follicular and papillary thyroid cancer.

Kinase inhibitors are categorized into several types (Type Ⅰ to Type Ⅴ) depending on the binding site and the conformation of the targeted kinase in complex with them. Most of the currently approved tyrosine kinase inhibitors are either Type Ⅰ or Type Ⅱ, however according to X-ray crystal structural analysis, Lenvima was found to possess a new Type Ⅴ binding mode of kinase inhibition that is distinct from existing compounds. In addition, Lenvima was confirmed via kinetic analysis to exhibit rapid and potent inhibition of kinase activity, and it is suggested that this may be attributed to its novel binding mode.

The SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid) study was a multicenter, randomized, double-blind, placebo-controlled Phase Ⅲ study to compare the progression-free survival (PFS) of patients with radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within the prior 13 months, treated with once-daily, oral Lenvima (24mg) versus placebo. Participants were randomized 2:1 to either Lenvima or placebo therapy. The primary endpoint was PFS assessed by independent radiologic review. The secondary endpoints of the study included response rate (sum of complete and partial responses), overall survival (OS) and safety. The study enrolled 392 patients in over 100 sites in Europe, North and South America and Asia, including Japan, and was conducted by ºÚÁÏÍø in collaboration with SFJ Pharma Ltd.

Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat near the trachea. It is more common in women than in men. The most common types of thyroid cancer, papillary and follicular (including Hürthle cell), are classified as differentiated thyroid cancer and account for approximately 95% of all cases. The remaining cases are classified as either undifferentiated (3-5% of cases) or medullary carcinoma (1-2% of cases). While most differentiated thyroid cancer patients are curable with surgery and radioactive iodine treatment, there are a small percentage of patients for which these types of therapies are not suitable.

The SFJ Pharmaceuticals Group, which includes SFJ Pharma Ltd., is a global drug development company, which provides a unique co-development partnering model for some of the world's top pharmaceutical and biotechnology companies. SFJ uses its financial strength and core team of pharmaceutical development experts to provide highly customized partnering models in which SFJ provides the funding and clinical development supervision, necessary to obtain regulatory approval for some of the most promising drug development programs of pharmaceutical and biotechnology companies.