On December 19, 2014 ONO PHARMACEUTICAL and Gilead Sciences reported that the companies have entered into an exclusive license agreement for the development and commercialization of ONO-4059, ONO’s oral Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of B-cell malignancies and other diseases (Press release Gilead Sciences, DEC 19, 2014, View Source [SID:1234501243]). Under the terms of the agreement, Gilead will pay ONO an upfront payment plus additional payments based upon achievement of certain development, regulatory and commercial milestones. The companies will collaborate jointly on global development of ONO-4059. Gilead will have exclusive rights to develop and commercialize ONO-4059 in all countries of the world outside of Japan, South Korea, Taiwan, China and the Association of Southeast Asian Nations (ASEAN) countries, where ONO retains development and commercialization rights.

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ONO-4059 is a selective, once-daily, oral inhibitor of BTK, which has been shown to play a role in the survival and proliferation of malignant B-cells. ONO has presented preliminary Phase 1 data showing clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) at several scientific conferences. ONO and Gilead plan to develop ONO-4059 for the treatment of B-cell malignancies and other diseases as a monotherapy and in combination with approved and investigational agents, including combinations with kinase inhibitors in Gilead’s portfolio.

"We are pleased to partner with Gilead to accelerate worldwide development and commercialization of ONO-4059," said Gyo Sagara, ONO’s President, Representative Director and Chief Executive Officer. "Our goal is to bring better therapeutic options as quickly as possible for the patients with B-cell malignancies or other diseases in the world, and we believe we can fulfill the goal by pursuing the development of ONO-4059 with Gilead."

"With this agreement, Gilead now has compounds targeting four unique signaling pathways associated with B-cell malignancies – PI3K delta, Syk, JAK and BTK," said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. "In addition to evaluating ONO-4059 in combination with standards of care, we believe there is an opportunity to combine this compound with Gilead’s other kinase inhibitors with a goal of achieving more pronounced and more durable response rates. We look forward to working with ONO to move the ONO-4059 development program forward as quickly as possible."

On December 19, 2014 Sorrento Therapeutics and Conkwest, Inc., a privately-held immuno-oncology company developing proprietary Neukoplast (NK-92), a Natural Killer (NK) cell-line based therapy, reported that the companies have entered into a definitive agreement to jointly develop next generation CAR-TNK (pronounced as "Car-Tank") immunotherapies for the treatment of cancer (Press release, Sorrento Therapeutics, DEC 19, 2014, View Source [SID:1234504358]). The CAR-TNK technology platform combines Conkwest’s proprietary Neukoplast cell line with Sorrento’s proprietary G-MAB fully human antibody technology and CAR designs to further enhance the potency and targeting of Neukoplast. Under the terms of the agreement, Sorrento and Conkwest will establish an exclusive global strategic collaboration focused on accelerating the development of CAR-TNKs for the treatment of hematological malignancies as well as solid tumors. Both companies will jointly own and share development costs and revenues from any developed CAR-TNK products. As part of the transaction, Sorrento will make a $9 million strategic equity investment in Conkwest and provide $2 million in research credit payments towards the development of novel CAR-TNK cell lines.

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Adoptive immunotherapy is widely regarded as one of the most impactful and innovative anti-cancer therapy breakthroughs. To date, T-cell based therapies, like CAR-T, have shown the most promise in select hematologic cancers, especially B-cell malignancies such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). They have also demonstrated outstanding therapeutic impact, including a high percentage of complete responses (CRs) in leukemia patients using CD19-CAR-T cells. While the clinical results seen have been promising, CAR-T therapies have been associated with some concerning side effects, especially potentially fatal cytokine-release syndrome that is mediated by interleukin-6 (IL-6) released from the T-cells and characterized by high fevers and sudden drops in blood pressure. Afflicted patients often require aggressive support in an intensive care unit setting. Additionally, most current CAR-T approaches rely upon patient derived T-cells, which require individualized processing, and are thus challenging with regard to commercial scalability, quality control, and consistency. Furthermore, this process relies on the ability to obtain sufficient numbers of the patients’ own immune T-cells to make adequate doses of CAR-T cells.

The "off-the-shelf" CAR-TNK approach will utilize Conkwest’s bioreactor-grown NK-92 cell line, Neukoplast, as the immune effector cells. Among the many features that distinguish Neukoplast from patient derived T-cells are the lack of IL-6 expression (the most common mediator of cytokine release syndrome), an innate capability of destroying a broad range of cancer cells as well as cancer stem cells, and scalability with batch-to-batch consistency. These Neukoplast cells can be re-engineered in a virus-free process to express surface receptors using Sorrento’s G-MAB library to yield a stable line of effector cells that recognize and target specific antigens on tumor cells. The CAR-TNK cells can also be generated and produced in large quantities, thereby obviating the need for expensive, decentralized ‘biologistics’- a critical drawback of current CAR-T and dendritic cell therapies.

"We are extremely pleased with this strategic collaboration with Conkwest", said Dr. Henry Ji, President and CEO of Sorrento. "With Sorrento’s expertise in antibody technology and diverse portfolio of fully human antibodies obtained from the G-MAB library, we believe we will be able to generate an army of stable CAR-TNK cell-lines, including but not limited to CD19-CAR-TNK, PDL1-CAR-TNK, PSMA-CAR-TNK, and CD123-CAR-TNK. It is our goal to rapidly move several of our CAR-TNK cell lines into the clinic to offer patients suffering from hematological malignancies and solid tumors an innovative immunotherapy to fight their cancers."

"Conkwest has made important strides in establishing the safety and anti-cancer activity of Neukoplast in both pre-clinical and clinical phase I trials" said Dr. Barry Simon, President and CEO of Conkwest. "We have also unlocked the potential of CAR-modified Neukoplast cells in preclinical models. By drawing from Sorrento’s treasure trove of CARs derived from their G-MAB library, we believe this partnership will enable us to realize an important part of our vision of designing and commercializing next generation Neukoplast products re-engineered to express one or more proprietary CARs that would matter most to disease outcomes. We are very excited about this opportunity in joining our resources and talent and look forward to working with the Sorrento team on this next generation of cancer immunotherapies."

On December 18, 2014 Kyowa Hakko Kirin Co, Ltd. (Tokyo: 4151, President and CEO: Nobuo Hanai, "Kyowa Hakko Kirin") reported that it has received approval for additional indication for chemotherapy-native CCR4-positive adult T-cell leukemia-lymphoma (ATL) of Mogamulizumab (brand name: POTELIGEO Injection 20 mg) from Japan’s Ministry of Health, Labour and Welfare ("MHLW") (Press release Kyowa Hakko Kirin, DEC 18, 2014, View Source [SID1234501205]).

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Mogamulizumab was launched in Japan with the brand name "POTELIGEO Injection 20 mg" on May 29, 2012 for the treatment of patients with relapsed or refractory CCR4-positive ATL. On March 17, 2014, Kyowa Hakko Kirin has received approval for additional indication for relapsed or refractory CCR4-positive peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).
Mogamulizumab was also granted orphan drug designations for the treatment of CCR4-positive ATL in August 2010 and PTCL/CTCL in March 2013 by the MHLW.

The Kyowa Hakko Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

State of Development of Mogamulizumab for Cancer conducted by Kyowa Hakko Kirin
Indication Status Applicable Locations
Relapsed or refractory CCR4-positive ATL, PTCL and CTCL Launched Japan
Chemotherapy-native CCR4-positive ATL Now approved Japan
Relapsed or refractory ATL Phase 2 trial United States, Europe, Others
Relapsed or refractory CTCL Phase 3 trial United States, Europe, Japan
Relapsed or refractory CCR4-positive PTCL Phase 2 trial Europe

About CC chemokine receptor 4 (CCR4)
CCR4 is one of the chemokine receptors involved in leukocyte migration, selectively expressed in type 2 helper T (Th2) cells and regulatory T (Treg) cells. CCR4 is also shown to be over-expressed in certain hematological malignancies.

About adult T-cell leukemia-lymphoma (ATL)
ATL is a peripheral T-cell malignancy and the retrovirus HTLV-1 is thought to be involved in its onset. Estimates show that around 1,150 new cases occur every year in Japan. In Japan ATL is generally treated with combination chemotherapy, such as mLSG15, but there are currently no therapeutic methods with the potential of providing a cure for ATL, although researchers are actively looking into other methods than transplantation. For relapsed/refractory cases, various chemotherapy regimens based on malignant lymphoma therapies are currently used, but an effective treatment method has yet to be established.

About peripheral T-cell lymphoma (PTCL)
Non-Hodgkin lymphomas account for the majority of malignant lymphoma cases and can be broadly divided into disease of B-cell origin and disease of T/natural killer (NK)-cell origin. Disease of T/NK-cell origin can be classified according to the main lesion site into nodal, extranodal, cutaneous, and leukemic disease. PTCL is a general term describing nodal and extranodal disease of T/NK-cell origin.

About cutaneous T-cell lymphoma (CTCL)
CTCL is a rare, low grade type of non-Hodgkin’s lymphoma. CTCL is one of the most common forms of T-cell lymphoma. The two most common types of CTCL are mycosis fungoides (MF) and Sézary syndrome (SS). MF does not look the same in all patients and may present as skin patches, plaques, and tumors. SS in an advanced form of MF and includes the presence of malignant lymphocytes in the blood.

About orphan drug designation
A drug must meet the following three conditions in order to be granted an orphan drug designation in Japan.
1) The number of patients with severe disease who may use the drug is less than 50,000 in Japan.
2) There are high medical needs for the drug (There is no appropriate alternative drug/treatment, or high efficacy or safety is expected compared with existing products).
3) There is high possibility of development (There should be a theoretical rationale for the use of the drug for the target disease, and the development plan should be appropriate). For designated orphan drugs, measures to support the research and development activities are taken (The orphan drug and orphan medical device research and development promotion program by the MHLW).

On December 18, 2014 Inovio Pharmaceuticals reported that it has initiated a phase I trial of its hTERT DNA immunotherapy (INO-1400) alone or in combination with Inovio’s IL-12 immune activator (INO-9012) in adults with breast, lung, or pancreatic cancer at high risk of relapse after surgery and other cancer treatments (Press release Inovio, DEC 18, 2014, View Source [SID:1234501211]). Because high levels of hTERT (human telomerase reverse transcriptase) expression are found in 85% of human cancers, Inovio’s cancer candidate holds the potential as a broad spectrum cancer therapeutic.

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A previously published study of this product showed that administration in monkeys, whose TERT is 96% similar to human TERT, generated strong and broad TERT-specific immune responses and demonstrated the potential to eliminate tumor cells. Mice immunized with Inovio’s DNA immunotherapy experienced delayed tumor growth, tumor shrinkage, and longer overall survival compared with non-immunized mice.

This human trial is an open label, dose escalation study in subjects with breast, lung, or pancreatic cancer at high risk of relapse after surgery and other treatments including chemotherapy and radiation. Approximately 54 subjects will be enrolled into one of six treatment groups and receive INO-1400 alone or in combination with INO-9012, Inovio’s immune activator. The study will be conducted at the University of Pennsylvania’s Abramson Cancer Center, which will fund all site-specific clinical study costs.

Lung, breast, and pancreatic cancer mortality rates are ranked first, third, and fourth, respectively, among cancer types in the United States, despite improvement in detection and treatment. In each of these three cancer types, significant numbers of patients undergo surgical resection and adjuvant therapy with an attempt at cure, but only a fraction remain in remission. This study will evaluate Inovio’s novel immunotherapy with the ultimate goal of reducing the risk of relapse in these patients.

Robert Vonderheide, MD, DPhil, said, "The next great wave of oncology advancements will be treatments which empower the patient’s own immune system to seek and destroy cancer. In this study we will evaluate a new immunotherapy targeting the hTERT gene found in numerous cancers." Dr. Vonderheide is Professor of Medicine; Hanna Wise Professor in Cancer Research; Associate Director for Translational Research, Abramson Cancer Center; Vice Chief for Research, Hematology-Oncology Division, Department of Medicine.

Dr. J. Joseph Kim, President and CEO, said, "We are enthusiastic about the potential use of INO-1400 cancer immunotherapy in multiple major cancers, given that hTERT is expressed in the vast majority of cancer types yet is rare in normal cells. INO-1400 therapy adds to Inovio’s growing oncology franchise led by our phase III candidate, VGX-3100, for treating HPV-related pre-cancers and cancers."

The primary objective of this study is to evaluate the safety and tolerability of INO-1400 alone or in combination with INO-9012, delivered intramuscularly in subjects with high-risk breast, lung, or pancreatic cancer with no evidence of disease after surgery and adjuvant therapy. The secondary objectives are to evaluate cellular and humoral immune responses, measure time to disease progression, and evaluate immunotherapy-induced changes in subjects.

On December 18, 2014 Seattle Genetics reported the initiation of a phase 1b clinical trial of SGN-CD33A in combination with standard of care chemotherapy, including cytarabine and daunorubicin, for patients with newly diagnosed acute myeloid leukemia (AML) (Press release Seattle Genetics, DEC 18, 2014, View Source;p=RssLanding&cat=news&id=2000668 [SID:1234501213]). The trial will also evaluate SGN-CD33A in the consolidation setting for AML, both in combination with cytarabine and as a single-agent maintenance regimen. SGN-CD33A is a novel antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology. CD33 is expressed on most AML cells regardless of subtype, cytogenetic abnormality or underlying mutational heterogeneity. SGN-CD33A is also under evaluation in an ongoing phase 1 dose escalation trial as a single-agent or in combination with hypomethylating agents for the treatment of patients who have relapsed AML or have declined intensive frontline therapy.

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"There have been few therapeutic advances for the treatment of AML in the past three decades, and there is a significant need to identify more efficacious treatment options that result in durable remissions for patients," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "We are encouraged by the single-agent activity of SGN-CD33A in AML patients from our ongoing phase 1 trial, as well as the preclinical data in AML models supporting combination regimens, both of which were recently presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Based on these data, we are expanding the evaluation of SGN-CD33A to include combination with standard of care chemotherapy in frontline and consolidation AML settings."

The study is a phase 1b, open-label, multi-center, dose-escalation clinical trial designed to evaluate SGN-CD33A administered in combination with frontline standard of care regimens for induction (cytarabine and daunorubicin) and/or consolidation (cytarabine). In addition, the study will evaluate single-agent SGN-CD33A as a maintenance regimen. The primary endpoints are determination of the maximum tolerated dose and safety profile of SGN-CD33A in these settings. In addition, the trial will evaluate anti-leukemic activity, pharmacokinetics, progression-free survival and overall survival. The phase 1b trial will enroll approximately 90 patients at multiple centers in the United States.

Clinical data from an ongoing phase 1 trial of SGN-CD33A in AML were presented in an oral session at the 2014 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #623). In this dose-escalation study, 56 patients had been enrolled. Patients were primarily older (median age 75 years) with relapsed AML, predominantly with intermediate or adverse cytogenetic risk and 55 percent had underlying myelodysplasia. Single-agent SGN-CD33A induced bone marrow blast clearance in 44 percent of evaluable patients treated across all dose levels, including 21 percent with a complete remission or complete remission with incomplete recovery (CR/CRi). A dose-response relationship is evolving, with 77 percent of patients treated at doses greater than or equal to 40 micrograms per kilogram achieving at least 50 percent blast reduction. Adverse events were generally manageable and associated with underlying myelosuppression.

ADCs are monoclonal antibodies that are designed to selectively deliver cell-killing agents to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

SGN-CD33A is comprised of three parts: A cysteine-engineered anti-CD33 antibody enabling uniform site-specific conjugation, a cleavable dipeptide linker that is highly stable in circulation, and a pyrrolobenzodiazepine (PBD) dimer that binds DNA with high intrinsic affinity. PBD dimers are a class of DNA-crosslinking agents significantly more potent than systemic chemotherapeutic drugs. Seattle Genetics has selected and optimized specific PBD molecules for its proprietary use in ADCs. In addition, SGN-CD33A employs a novel linker system and proprietary, site-specific conjugation technology (EC-mAb) that allows uniform drug-loading of the cell-killing PBD dimer to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its cytotoxic agent upon internalization into CD33-expressing cells.

For more information about the trial, including enrolling centers, please visit www.clinicaltrials.gov.