On December 13, 2016 TTY Biopharm’s (4105:TW) reported that anticancer agent S-1 Capsule received a Taiwan National Health Insurance (NHI) reimbursement for adjuvant chemotherapy of locally-advanced gastric cancer [stage II (excluding T1), IIIA or IIIB in TNM system], after the review from Pharmaceutical Benefit and Reimbursement Scheme Joint committee (PBRS) (Press release, TTY Biopharm, DEC 13, 2016, View Source [SID1234527287]). The validated date was December 1st, 2016. This was the second reimbursement indication after S-1 Capsule had received its first reimbursement for locally advanced un-resectable or metastatic pancreatic cancer patient since June, 2014. S-1 Capsule had been developed by Taiho Pharmaceutical Co., Ltd. of Japan and TTY Biopharm received an exclusive right to develop and market in Taiwan.

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According to Ministry of Health and Welfare’s database, around 3,600 to 3,800 new patients were diagnosed with gastric cancer annually. Gastric cancer was ranked the 7th in cancer incidence and 5th in mortality. For the early stage gastric cancer, the primary treatment was surgery; however, about 40% of patients who were diagnosed with stage II and III gastric cancer after surgery would still relapse and nearly 90% of the relapsed cases happened within 3 years. Unfortunately, for those relapsed patients, the median survival rate was less than 10%. The clinical practice recommended chemotherapy to be an adjuvant therapy. S-1 Capsule, after publication of a large-scale randomized Phase III clinical trial, was approved to be the first agent to decrease the risk of death by 33.1% and risk of relapse by 34.7% for stage II (excluding T1)-III gastric cancer patients. It was also the only oral chemotherapy agent with TFDA and NHI reimbursement label in Stage II-IIIB gastric cancer. Clinical results were first published on the New England Journal of Medicine and the final result was published on Journal of Clinical Oncology.

TTY Biopharm indicated: "Although the number of patients with gastric cancer has slowed down, the overall survival rate is lower than other Asian countries, Japan and South Korea for example. We keep not only reminding citizens to receive regular upper gastrointestinal examinations, but also educating public the benefits of adjuvant chemotherapy for lowering the risk of relapse and increasing chances of being cured." S-1 Capsule is expected to allow patients to maintain original lives. With reimbursement for gastric cancer patients, about 1,200 patients would be benefitted.

On December Moleculin Biotech, Inc., (NASDAQ: MBRX) ("Moleculin" or the "Company"), a preclinical pharmaceutical company focused on the development of anti-cancer drug candidates, many of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center, reported its scientific presentation at the 28th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics (Press release, Moleculin, DEC 13, 2016, View Source [SID1234517062]). Waldemar Priebe, PhD, Moleculin’s Founder, Founding Scientist, and Chair of the Scientific Advisory Board presented the Abstract on November 30th at the Symposium in Munich, Germany.

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Wally Klemp, Chairman and CEO stated, "This presentation shows proof of concept data for our WP1122 portfolio, including data demonstrating increased survival of animals with human brain tumors treated with WP1122, as well as its biodistribution and pharmacokinetics. In non-optimal doses and treatment regimens, our lead inhibitor WP1122 performed equal to or better than the current market leader, cytotoxic drug temozolomide and significantly improved survival in animals treated with WP1122 in combination with temozolomide."

The following is an overview of the presentation, titled "Latentiation of 2-deoxy-D-glucose". No curative therapy exists for patients with high-grade malignant gliomas (GBMs). New approaches to the treatment of this disease are currently being evaluated with mixed results. One approach, that deserves to be therapeutically exploited, is targeting brain tumor metabolism. 2-Deoxy-D-glucose (2-DG), a known effective inhibitor of glycolysis, has been clinically tested but results did not meet expectations due to poor drug-like characteristics and inability to achieve therapeutic concentrations of 2-DG in the brain.

Dr. Waldemar Priebe stated, "We proposed to use latentiation of 2-DG to overcome this problem by chemically modifying biologically active 2-DG to form prodrugs with increased brain uptake that will be able to liberate in vivo the parent compound 2-DG in the brain. In our approach, we synthesized a series of differentially acetylated derivatives of 2-DG. Preliminary in vivo studies in mice of selected diacetates of 2-DG demonstrated >9 fold increased levels of 2-DG in the brain when compared with levels of 2-DG after administration of equimolar amount of 2-DG itself. Ultimately, our studies focused on a single compound 3,6-di-O-acetyl-2-deoxy-D-glucose (WP1122)."

Compound WP1122 was administered in vivo without toxic death up to the highest feasible dose of 3.0 g/kg intravenously and orally up to 6.0 g/kg. Significantly increased survival, comparable to or better than that of temozolomide, was observed for orally administered WP1122 in a U87 orthotopic glioma model at a dose of 1.25 g/kg. These promising results prompted continuation of preclinical toxicology evaluation of WP1122 aimed at the initiation of formal IND enabling studies. In addition, the proof of concept delivered by WP1122 has provided not only an effective approach to develop novel agents able to effectively cross the blood brain barrier but also a method to create a new class of dual function prodrugs by exploring biologically active acids.

Moleculin’s Chairman and CEO, Walter Klemp, concluded, "We are excited to present our results at this prestigious symposium. Clearly, the significantly increased survival data is key, especially as no curative therapy exists for patients with high-grade malignant gliomas today. We look forward to presenting additional data as we progress toward our clinical timeline."
For more information on the Symposium click: View Source

On December 13, 2016 CytomX Therapeutics, Inc. (Nasdaq:CTMX), a biopharmaceutical company developing investigational Probody therapeutics for the treatment of cancer, reported that Bristol-Myers Squibb Company has selected a clinical candidate for its CTLA-4 Probody program under the strategic oncology collaboration established in May 2014. Achieving this milestone results in a $2 million payment to CytomX (Press release, CytomX Therapeutics, DEC 13, 2016, View Source;p=irol-newsArticle&ID=2229234 [SID1234517063]).

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"Selecting a candidate for the CTLA-4 Probody program is a pivotal development in our partnership with CytomX Therapeutics and builds on our I.O. leadership," said Carl Decicco, Ph. D., Head of Discovery at Bristol-Myers Squibb. "We are studying the CTLA-4 Probody for its potential to deliver a next-generation anti-CTLA-4 therapy as we continue to explore transformational immuno-oncology medicines."

CTLA-4, a clinically validated inhibitory immune checkpoint protein, is the most advanced target from the companies’ collaboration, which now also includes three additional, unnamed targets in discovery.

"Advancing our CTLA-4 Probody program to clinical candidate stage with Bristol-Myers Squibb underscores the potential of the Probody platform to transform the field of immuno-oncology by delivering safer, more effective therapies," said Sean McCarthy, D.Phil., President and Chief Executive Officer of CytomX. "This partnership milestone, taken together with CytomX’s recently filed Investigational New Drug application for CX-072, a wholly owned PD-L1-directed Probody therapeutic, highlights the potential of our innovative platform to deliver a new generation of anti-cancer treatments."

About the Collaboration Agreement
Under the terms of the May 2014 agreement, CytomX granted Bristol-Myers Squibb exclusive worldwide rights to discover, develop and commercialize Probody therapeutics for up to four oncology targets. Bristol-Myers Squibb made an upfront payment of $50 million to CytomX in 2014, and is providing research funding over the course of the research term. Upon the selection of the third and fourth targets, Bristol-Myers Squibb paid CytomX selection payments. CytomX is also eligible to receive additional preclinical payments and up to $298 million in development, regulatory and sales milestone payments for each collaboration targe

On December 12, 2016 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, and Synthon Biopharmaceuticals B.V., an international biopharmaceutical company with highly focused development activities for new molecular entities in the therapeutic areas of oncology and autoimmune diseases, reported they have entered a license and collaboration agreement for the development of MGC018, an antibody-drug conjugate (ADC) directed against solid tumors expressing B7-H3 (Press release, MacroGenics, DEC 12, 2016, View Source [SID1234517232]). This molecule is based on a MacroGenics proprietary B7-H3 antibody and Synthon’s proprietary duocarmycin-based, linker-drug technology.

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Under the terms of the agreement, Synthon has licensed rights to its linker-drug technology to MacroGenics to enable future development and commercialization of MGC018. Synthon will also provide manufacturing support and supply ADC to MacroGenics and will be entitled to receive license fees, milestone payments and royalties based on successful development and commercialization of MGC018. Additional details of the transaction were not disclosed.

Based on favorable activity and safety profiles in the non-clinical setting, MacroGenics has selected MGC018 as its lead anti-B7-H3 ADC candidate. MacroGenics has recently initiated IND-enabling studies for this molecule.

"We are encouraged by the data generated with Synthon’s ADC platform and believe that MGC018 will nicely complement our broader portfolio of B7-H3-directed agents," said Scott Koenig, M.D., Ph.D., President and Chief Executive Officer of MacroGenics. "The team at Synthon brings tremendous expertise in linker-drug chemistry and product development that complements our existing capabilities. We look forward to continuing to collaborate with them on this important molecule."

Jacques Lemmens, founder and CEO of Synthon added: "We are very pleased with this commercial licensing agreement with MacroGenics, which enables us to deploy our unique linker-drug technology against a therapeutic target that is complementary to those in our own pipeline. We believe that such collaborations are an important means to accelerate the availability of important therapeutic treatment options to patients who need them."

MacroGenics’ B7-H3 Franchise

MGC018 represents the third molecule in MacroGenics’ franchise of B7-H3-directed molecules. In addition to MGC018, MacroGenics is pursuing two other therapeutic product candidates utilizing different and complementary immune-based mechanisms of action. The leading program, enoblituzumab, is an Fc-optimized monoclonal antibody directed against B7-H3 and is currently in clinical testing as both monotherapy and in combination with either pembrolizumab or ipilimumab. The second program, MGD009, also in clinical testing, is a bispecific DART molecule designed to target tumors expressing B7-H3 by recruiting and expanding T cells at the tumor site. MacroGenics retains worldwide development and commercialization rights to all three of these programs.

Synthon’s Unique Technology Based on Duocarmycin Analogs

Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxicity. Upon internalization of the ADC, the antibody-bound cytotoxins are released intracellularly, leading to programmed tumor cell death.

While the cytotoxins used in the majority of advanced programs in the field prevent tubulin polymerization during cell division, Synthon’s differentiating linker-drug technology − which applies valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA) − is based on synthetic duocarmycin analogs, which bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually leads to tumor cell death.

Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic phase. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in solid tumors.

Although based on natural products, Synthon’s proprietary ADC linker-drug technology uses fully synthetic duocarmycin analogs. The unique design of the selectively cleavable linker connecting the antibody to a duocarmycin prodrug leads to high stability in circulation, and induces efficient release of the cytotoxin in the tumor.

On December 12, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that the results of an interim analysis of a global Phase Ib/II clinical study (Study 218) of its in-house discovered and developed anticancer agent eribulin mesylate (halichondrin class microtubule dynamics inhibitor, product name: Halaven, "eribulin") in combination with the anti-PD-1 antibody pembrolizumab developed by Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the U.S. and Canada), in patients with metastatic triple-negative breast cancer have been presented at the 39th Annual San Antonio Breast Cancer Symposium held from December 6 to 10, 2016 (Press release, Eisai, DEC 12, 2016, View Source [SID1234517039]). Development of this combination regimen is being conducted jointly under the cooperation of both companies.

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Study 218 is a Phase Ib/II clinical study which examined the activity and safety of eribulin in combination with pembrolizumab in 95 patients with metastatic triple-negative breast cancer previously treated with 0 – 2 lines of chemotherapy in the metastatic setting. The primary objective of the Phase Ib part was safety and tolerability, and the primary objective of the Phase II part was objective response rate (ORR).

This presentation reported on the results of an interim analysis of 39 evaluable patients out of the 89 patients enrolled in the study as of July 2016. Eribulin (1.4 mg/m2 intravenously on Day 1 and Day 8) and pembrolizumab (200 mg intravenously on Day 1) were administered to patients over 21 day cycles. From the results of the study, ORR was 33.3% (1 patient experienced a complete response and 12 patients experienced a partial response). In addition, the ORR was similar between PD-L1 positive and negative cohorts.

In this study, the most common treatment-emergent adverse events (incidence greater than or equal to 35%) in patients treated with the combination regimen were fatigue, nausea, peripheral neuropathy, neutropenia and alopecia, with Grade 3 or higher Treatment-Emergent Adverse Events (TEAEs) observed in 66.7% of patients. The most common Grade 3 or higher TEAEs (incidence greater than or equal to 7%) observed were neutropenia (30.8%) and fatigue (7.7%).

Eribulin is a halichondrin class microtubule dynamics inhibitor with a novel mechanism of action. Recent non-clinical studies showed that eribulin is associated with increased vascular perfusion and permeability in tumor cores.1 Eribulin promotes the epithelial state and decreases the capacity of breast cancer cells to migrate and invade.2 It was first approved for use in the treatment of metastatic breast cancer in the United States in November 2010, and is currently approved for use in the treatment of patients with breast cancer in over 60 countries including Japan and countries in Europe, the Americas and Asia.

Eisai positions oncology as a key therapeutic area, and is aiming to discover revolutionary new medicines with the potential to cure cancer. As exemplified by this combination regimen, Eisai remains committed to providing further clinical evidence for eribulin aimed at maximizing value of the drug as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

*Please refer to the following notes for the approved indications in the United States, Japan and Europe

Media Inquiries:
Public Relations Department,
Eisai Co., Ltd.
+81-(0)3-3817-5120

< Notes to editors >

1. About eribulin mesylate (product name: Halaven, "eribulin")
Eribulin is a halichondrin class microtubule dynamics inhibitor with a novel mechanism of action. Structurally, eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, recent non-clinical studies showed that eribulin is associated with increased vascular perfusion and permeability in tumor cores.1 Eribulin promotes the epithelial state and decreases the capacity of breast cancer cells to migrate and invade.2

Eribulin was first approved for use in the treatment of metastatic breast cancer in the United States in November 2010. Eribulin is currently approved for use in the treatment of breast cancer in over 60 countries worldwide, including Japan and countries in Europe, the Americas and Asia.
Furthermore, eribulin was first approved as a treatment for liposarcoma in the United States in January 2016, and is also approved for liposarcoma in countries in Europe and soft tissue sarcoma in Japan.

Specifically, eribulin is approved for the following indications.
In the United States for the treatment of patients with:
Metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.
Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
In Japan for the treatment of patients with:
Inoperable or recurrent breast cancer
Soft tissue sarcoma
In Europe for the treatment of adult patients with:
Locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments.
Unresectable liposarcomas who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease.
2. About the Phase Ib/II Study (Study 218)
Study 218 is a multicenter, single-arm, open-label Phase 1b/II clinical study which examined the activity and safety of eribulin in combination with pembrolizumab in 95 patients (12 patients for the Phase Ib part, 83 patients for the Phase II part) with metastatic triple-negative breast cancer previously treated with 0-2 lines of chemotherapy in the metastatic setting. Eribulin (1.4 mg/m2 intravenously on Day 1 and Day 8) and pembrolizumab (200 mg intravenously on Day 1) were administered to patients over 21 day cycles. The primary objective of the Phase Ib part was safety and tolerability, and the primary objective of the Phase II part was ORR. Progression-free survival was assessed as a secondary objective.

In this interim analysis of 39 patients, 22 patients were previously treated with 1 to 2 lines of chemotherapy in the metastatic setting. The ORR was similar between PD-L1 positive (17 patients, ORR 29.4%) and negative (18 patients, ORR 33.3%) cohorts and it was 50% for PD-L1 unknown cohorts. Pembrolizumab alone demonstrated the tendency to increase the antitumor activity with PD-L1 positive in triple-negative breast cancer patients (KEYNOTE-012 study)3
In this study, eribulin in combination with pembrolizumab is expected to show similar antitumor activity regardless of PD-L1 status.

3. About triple-negative breast cancer
Triple-negative breast cancer is a type of breast cancer where the cancer cells tested negative for expression of estrogen receptors, progesterone receptors and HER-2 receptors. Since the tumor cells lack the necessary receptors, common treatments like hormone therapy and drugs that target HER-2 are ineffective. This remains a disease with significant unmet medical need. Therefore, the development of new medicines is necessary to advance the treatment of triple-negative breast cancer.

4. About non-clinical research related to the mechanism of action for eribulin in combination with pembrolizumab
Eribulin contributes to maintaining or increasing the activity of cytotoxic T lymphocytes (CTLs), which play a leading role in attacking cancer cells, via reduction of immune suppressive Treg cells and M2 tumor macrophages4. The anti-PD-1 antibody pembrolizumab maintains or activates CTLs via its immune-checkpoint blockade. Eribulin in combination with pembrolizumab is expected to work synergistically in cancer immunotherapy.