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 16, 2014 NewGen Therapeutics reported the publication of preclinical research strongly supporting NT-113, the company’s novel irreversible pan-erbB inhibitor (EGFR, HER2 and HER4), as a potential new treatment for glioblastoma multiforme (GBM), the most common and most aggressive malignant primary brain tumor in adults (Press release, NewGen Therapeutics, DEC 16, 2014, View Source [SID1234633118]).

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Researchers demonstrated that NT-113 was active against a variety of patient-derived GBM xenografts in which EGFR is amplified, overexpressed and/or expresses the disease-driving EGFRvIII mutation. In studies of intracranial mouse xenografts comparing NT-113 to the approved anticancer therapeutics lapatinib and/or erlotinib, NT-113 was associated with statistically significant improvement in survival. NT-113 both reduced tumor cell proliferation and induced apoptosis (controlled cell death). In previous pharmacokinetic studies, NT-113 demonstrated a long half-life and a high propensity to cross the blood brain barrier.

Researchers concluded that the pan-erbB inhibitory activity of NT-113 and downstream inhibition of Akt provide mechanistic rationale for its heightened anti-tumor activity. Excellent bio-distribution into the brain is also believed to contribute to the anti-GBM xenograft activity of NT-113. NT-113 was active in other GBM xenograft studies including one in which the cells are PTEN deficient, a known resistance mechanism for EGFR inhibitors, and another where cells overexpress both EGFR and HER2. Data support advancing NT-113 into clinical development for the treatment of erbB positive GBM, including patients with the disease driving EGFRvIII mutation.

The findings by NewGen and the company’s collaborators at Northwestern University and The University of California, San Francisco and the Mayo Clinic were published in the December 2014 issue of Molecular Cancer Therapeutics.

Harry D. Pedersen, NewGen Therapeutics President and Chief Executive Officer commented, "EGFR, HER2 and HER4 are part of the erbB family of tyrosine kinase receptors, and 90% of solid tumors have a mutation in at least one erbB receptor family member. By irreversibly inhibiting all family members we hope to shut down the individual receptors and the cooperative signaling between family members associated with resistance."

NT-113 readily penetrates the blood brain barrier resulting in 4-8 times drug concentration in the brain relative to plasma. First-generation EGFR inhibitors like erlotinib and lapatinib are reversible and have very limited penetration of the central nervous system.

"GBM is a molecularly complex disease with significant unmet medical need: over 50% of patients have genetic alterations in EGFR or HER2," Mr. Pedersen said. "These data provide a strong rationale for the clinical investigation of NT-113 in this patient population. We anticipate beginning clinical trials in early 2016."

About NT-113

NT-113 is a potent oral irreversible pan-erbB inhibitor designed specifically to:

Target mutations in both the extracellular domain of EGFR (characteristic of GBM) and the intracellular domain of EGFR (characteristic of other tumours such as NSCLC),
Improve drug delivery into the brain to optimize drug delivery and treatment of patients with primary glioblastoma or brain metastases from an EGFR driven extracellular primary,
Overcome resistance to first generation erbB inhibitors by targeting redundancy in the pathway, and
Improve the efficacy of erbB-targeted therapies by irreversibly inhibiting multiple erbB receptors, and interfering with the cooperation that exists between receptors.

On December 16, 2014 The Cancer Research Technology Pioneer Fund (CPF or the Fund) reported an additional £20m investor commitment from BACIT Limited (BACIT), taking the total fund to £70m (Press release, Cancer Research Technology, DEC 16, 2014, View Source [SID1234523215]).

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The news comes as the fund announces its fifth research investment, expanding its agreement with Chroma Therapeutics Ltd to develop drugs that use immune cells called macrophages – a type of white blood cell – to deliver drugs directly into tumours.

The CPF was established in 2012 by the European Investment Fund and Cancer Research Technology Ltd. It bridges the gap in cancer research between late discovery and Phase II clinical trials. Through its relationship with CRT, the Fund has access to drug discovery and development programmes funded by Cancer Research UK.

Today’s announcement takes the total capital now committed to the Fund to £70m which will allow the CPF to invest in a larger portfolio of cancer research projects and have the potential to develop existing projects further.

Today’s announcement includes an expansion of the license from Chroma to the CPF for all rights in oncology to its Esterase Sensitive Motif (ESM) technology*.

The ESM technology incorporates specific chemical motifs – such as cancer drugs – into active compounds, which are freely transported into cells. Once inside the cell, a specific enzyme found only in certain type of macrophage targeted at tumours, removes the motifs to create a compound that cannot easily exit the cell. Over time, the compound selectively accumulates in the macrophages to significant levels and it becomes active in fighting cancer cells.

Dr Robert James, managing partner of Sixth Element Capital, said: "We’re very excited to welcome BACIT as an additional investor. This enables us to create an even more diversified portfolio of novel world-class cancer therapeutics.

"The expansion of the Chroma agreement enables CPF to develop a portfolio of projects that modulate the immune system. Immunotherapy is an extremely exciting area in cancer research. Developing small molecules which activate the immune system to fight cancer could be of great importance to cancer patients."

Richard Bungay, chief executive of Chroma, said: "It is now widely accepted that modulation of a patients’ own immune system will be an important tool in the fight against cancer. Consequently, we are very pleased to have expanded our collaboration with CPF, which will facilitate further significant investment in our portfolio of novel immunotherapy treatments, and potentially expand the disease targets that the ESM macrophage-targeting technology is applied to."

Dr Piyush Unalkat, Principal – Equity Investments, commented: "I’m extremely pleased to see BACIT formalising its investment to CPF, bringing the fund to £70m. BACIT, CRT and EIF are long-term investors aligned in their mission to catalyse the development of new therapies to fight cancer, of which the ESM technology is a good example. The CPF is a cost efficient model and the additional resources shall allow for more investments than were originally foreseen."

Dr Keith Blundy, CEO of Cancer Research Technology, said: "BACIT’s investment in the CPF is warmly welcomed and will help us further accelerate drug discovery research to bring potential new treatments to patients sooner. Immunotherapy research is looking increasingly promising for the treatment of cancer, so I am delighted to see the progress that the CPF is making in attracting new investment to help bridge the UK’s innovation gap in this important area."

On December 15, 2014 Ignyta reported that it has entered into an amendment to its license agreement with Nerviano Medical Sciences, S.r.l. relating to its entrectinib (formerly RXDX-101) product candidate (Press release Ignyta, DEC 15, 2014, View Source [SID:1234501188]). The amendment modifies the milestones that would trigger the initial three milestone payments specified in the license agreement. Pursuant to the amendment, the initial milestone payment of $10 million will be due and payable to Nerviano by December 31, 2014, and the second and third milestone payments will be triggered by revised clinical and/or regulatory events relating to entrectinib or other licensed products. The amounts of such milestone payments have not changed.

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"The promising clinical data observed with entrectinib have spurred us to develop a more ambitious clinical development plan that enables us to accelerate development while also pursuing multiple opportunities in parallel for this exciting product candidate," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "Under the previous structure, there were future milestone payments that posed potential financial disincentives for Ignyta to accelerate the clinical development program or pursue multiple indications due to potential stacking of milestone payments. By accelerating the first payment, pushing back subsequent payments, and modifying the triggers for milestone payments under our agreement with Nerviano, we have better aligned the companies’ interests. Ignyta may now strategically accelerate the development and potential commercialization of entrectinib for the benefit of cancer patients."