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Approval for Additional Indication for Chemotherapy-Native CCR4-positive ATL of Mogamulizumab

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).

Roche provides update on Phase III MARIANNE study in people with previously untreated advanced HER2-positive breast cancer

On December 19, 2014 Roche reported top-line results of the Phase III MARIANNE study (Press release Hoffmann-La Roche, DEC 19, 2014, View Source [SID:1234501215]). The study evaluated three HER2-targeted regimens – Kadcyla (trastuzumab emtansine) plus Perjeta (pertuzumab), Kadcyla alone, and Herceptin (trastuzumab) plus taxane chemotherapy – in people with previously untreated (first line) advanced HER2-positive breast cancer. The study showed the three regimens helped people live without their disease worsening (PFS) for a similar amount of time, meeting its non-inferiority endpoint as assessed by an Independent Review Committee (IRC). However, neither Kadcyla-containing treatment arm significantly improved PFS compared to Herceptin and chemotherapy. Adverse events observed in the two experimental arms of the study were generally consistent with those seen in previous studies of Kadcyla and/or Perjeta.

In their approved uses for advanced HER2-positive breast cancer, Kadcyla and Perjeta have been shown to extend survival. Kadcyla is approved for people with previously treated disease (second and later lines). Perjeta is approved in combination with Herceptin and chemotherapy for people with previously untreated disease (first line).

“Over the past 30 years, we have made significant progress in treating one of the most aggressive forms of advanced breast cancer with medicines that extend patients’ lives across the course of their disease. In this study, we had hoped to show improvement in progression-free survival without the use of traditional chemotherapy in the first line treatment of patients with advanced HER2-positive breast cancer,” said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. “While MARIANNE didn’t achieve this result, we will continue to study these medicines, as well as investigational treatments for other types of breast cancer, with the goal of improving outcomes for patients.”

Data from the MARIANNE study will be presented at an upcoming medical meeting. Roche will discuss the data with health authorities.

About the MARIANNE Study

The Phase III MARIANNE study (NCT01120184; BO22589) is an international, randomized, multicenter, three-arm study involving 1,095 people with HER2-positive advanced breast cancer – either with inoperable locally advanced disease that had worsened during or returned after previous treatment, or with disease that had spread to other areas of the body.2 People with advanced breast cancer at diagnosis and people whose disease had worsened following either neoadjuvant or adjuvant treatment were eligible.

People enrolled in the study received treatment with either:

A combination of Kadcyla and Perjeta
Kadcyla alone, or
Herceptin and either docetaxel or paclitaxel chemotherapy.

The primary endpoint of the MARIANNE study is PFS as assessed by an Independent Review Committee (IRC). Secondary endpoints include overall survival, response rate, and the incidence of adverse events. Differences in these endpoints were assessed in each of the Kadcyla-containing treatment arms compared to the Herceptin plus chemotherapy arm, and also between the two Kadcyla-containing arms.

Merck Acquires OncoEthix, a Privately Held Oncology Company Developing Novel BET Inhibitors for Hematological and Solid Cancers

On December 18, 2014 Merck, known as MSD outside the United States and Canada, reported that it has acquired, through a subsidiary, OncoEthix, a Swiss-based privately held biotechnology company specializing in oncology drug development (Press release Merck & Co, DEC 18, 2014, View Source [SID:1234501212]). Through the acquisition, Merck has gained an investigational, novel oral BET (bromodomain) inhibitor, OTX015, which is currently in Phase 1b studies for the treatment of hematological malignancies and advanced solid tumors.

“Oncology is a priority area of focus for Merck and the acquisition of OncoEthix supports our strategy to prioritize the development of innovative molecules with the potential to improve the treatment of advanced cancers,” said Dr. Roy Baynes, senior vice president, global clinical development, Merck Research Laboratories. “The potential first-in-class oral BET inhibitor, OTX015, has demonstrated early promising activity in hematological cancers and strategically complements our broad immuno-oncology development program.”

“We are delighted that OTX015 will now be in the hands of Merck, a company with a successful track record of developing cutting-edge therapies,” said Bertrand Damour, chief executive officer, OncoEthix. “The acquisition underlines the promise that OTX015 has shown in the treatment of hematological malignancies, and the potential it has for the treatment of advanced solid tumors. We are confident that our transaction with Merck best positions OTX015 to be developed to its full potential in areas of high unmet medical need.”

BET proteins are considered potential therapeutic targets in cancer, as they play a pivotal role in regulating the transcription of key regulators of cancer cell growth and survival, including c-Myc. Interim data from ongoing Phase I clinical studies of OTX015 have demonstrated meaningful clinical activity in patients with hematological malignancies. Interim data were recently presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2014. An international, open-label Phase 1 study evaluating OTX015 in five different solid tumors was initiated in November 2014.

Financial terms of the acquisition include an upfront payment of up to $110 million to OncoEthix. Additional milestone payments of up to $265 million are contingent upon certain clinical and regulatory events being achieved.

NewGen Therapeutics Targeted Anti-Cancer Drug, NT-113, Demonstrates Compelling Activity in Glioblastoma Xenograft Models

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]).

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.

CRT Pioneer Fund banks £20m investment from BACIT and expands agreement with Chroma Therapeutics to develop cancer immunotherapies

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]).

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."