On September 19, 2014 Children’s Cancer Institute and Abcam reported that they have entered into an exclusive licence, supply and distribution agreement for multidrug resistance protein 4 (MRP4/ABCC4) inhibitors, Ceefourin 1 and Ceefourin 2, for research purposes (Press release Children’s Cancer Institute, SEP 19, 2014, View Source [SID:1234500760]).

The first known selective inhibitors of MRP4, Ceefourin 1 and Ceefourin 2 are potent, chemically distinct compounds and are the first known selective inhibitors of MRP4, and represent important tools for investigating essential cellular processes such as multidrug resistance. The agreement was facilitated by Bio-Link Australia, a life sciences commercialisation company.

MRP4 is a protein that belongs to the ATP-Binding Cassette (ABC) transporter superfamily of membrane pumps that export molecules from the cell. MRP4 effectively effluxes elements that are potentially toxic to the cell, protecting it from deleterious chemical build ups and from xenobiotics, such as environmental toxins.

Previous research on MRP4 and other ABC transporter family members has shown that these proteins are often ‘hijacked’ by cancer cells, which produce them at high levels to pump out chemotherapy drugs, effectively protecting the cancer cells from treatment.

The novel MRP4 inhibitors, Ceefourin 1 and Ceefourin 2, discovered and characterised by Children’s Cancer Institute, are exciting new tools for researchers, allowing the further exploration of MRP4 function and potentially the basis for developing therapeutic drugs to treat cancer.

Lead researcher and Children’s Cancer Institute Deputy Director, Professor Murray Norris, said “High-throughput screening has identified Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of MRP4. Up to this point, researchers have not had access to effective MRP4 inhibitors without substantial confounding off-target effects – so this is quite an advancement for the field. Highly specific research reagents are of course crucial to accurately defining how these proteins work.

“We are delighted to now be able to make these research reagents available to the scientific community worldwide through our partnership with Abcam. These compounds should enable researchers to obtain new insights into MRP4 function and to modulate extracellular drug transport.”

Matthew Roe, Head of Reagents, Abcam said: “We are very pleased to partner with Children’s Cancer Institute, and to manage distribution of these reagents to the research community, helping to increase the impact of their findings and help scientists discover more.”

The Ceefourin MRP4 inhibitors now available from Abcam include:

Ceefourin 1 (ab145144)

Selective MRP4 inhibitor. Benzothiazol compound which potently and selectively inhibits MRP4-mediated substrate efflux. For example, Ceefourin 1 inhibits MRP4-mediated D-luciferin transport (IC50 = 1.5µM) as measured indirectly using a bioluminescence assay in HEK293-MRP4 cells with stable luciferase expression. Ceefourin 1 exhibits no detectable inhibition of other ABC transporters such as Pgp, ABCG2 and MRP1, MRP2, MRP3 and MRP5, and is non-toxic in normal fibroblast and cancer cell lines tested up to 50µM. Ceefourin 1 displays metabolic (>30 min) and acid stability (>24hrs at 37oC, pH 2) in a mouse liver microsomal assay and acid-stability assay, respectively.

Ceefourin 2 (ab145145)

Selective MRP4 inhibitor. Pyrazolopyrimidine compound which potently inhibits MRP4-mediated substrate efflux. For example, Ceefourin 2 inhibits MRP4-mediated D-luciferin transport (IC50 = 7.0µM) as measured indirectly using a bioluminescence assay in HEK293-MRP4 cells with stable luciferase expression. Ceefourin 2 exhibits no detectable inhibition of other ABC transporters, such as Pgp, ABCG2 and MRP1, MRP2, MRP3 and MRP5. Ceefourin 2 displayed limited toxicity in two of eleven cancer cell lines tested up to 50µM, and exhibited no toxicity in two normal fibroblast lines tested to the same concentration. Ceefourin 2 shows metabolic stability (>30 min) in a mouse liver microsomal assay and limited acid-stability (half life < 2 hr at 37oC, pH 2). Ceefourin is a trademark of Children’s Cancer Institute. Ceefourin 1 and Ceefourin 2 are claimed under Australian provisional patent application 2014902472. Reference: High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4). Published in Biochemical Pharmacology.

On September 19, 2014 Gilead Sciences reported that the European Commission has granted marketing authorization for Zydelig (idelalisib), 150 mg tablets, a first-in-class oral treatment for two incurable blood cancers – chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) (Press release Gilead Sciences, SEP 19, 2014, View Source [SID:1234500758]). For the treatment of CLL, Zydelig has been approved for use in combination with rituximab for patients who have received at least one prior therapy; or as first-line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. For the treatment of FL, Zydelig has been approved as a monotherapy in patients who are refractory to two prior lines of treatment. Zydelig inhibits PI3K delta, a protein that is overexpressed in many B-cell malignancies and plays a role in the viability, proliferation and migration of these cancer cells.

CLL and FL are slow-growing incurable blood cancers that can lead to life-threatening complications such as anemia, serious infection and bone marrow failure requiring treatment. The goal of therapy for patients with these cancers is to improve overall survival and quality of life.

“Although chemo-immunotherapy is initially used to treat both CLL and FL, relapse is common and many patients run out of treatment options to treat the disease as it progresses,” said Peter Hillmen, PhD, Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust. “Further, CLL patients with the 17p deletion or TP53 mutation are not suitable for chemo-immunotherapy, requiring alternative first-line treatment options. Thus, Zydelig is a welcomed treatment option that offers a new approach in the management of these cancers.”

A chromosome 17 deletion – del (17p) or a mutation in the TP53 gene in CLL cells have been linked to poor prognosis and a more rapid disease progression. For these patients most conventional chemotherapy treatments are not effective and deliver poor responses of relatively short duration. Treatment options are limited for these patients.

“Zydelig represents an important therapeutic advance for patients living with CLL and FL,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. “Gilead is pleased to be making a difference in the lives of people living with these blood cancers and we are committed to helping ensure timely access to the treatment for patients who may benefit from therapy.”

The approval of Zydelig in CLL is supported primarily by data from a randomized, placebo-controlled Phase 3 trial (Study 116) of Zydelig plus rituximab in 220 patients with relapsed CLL who were not able to tolerate standard chemotherapy. Study 116 was stopped early in October 2013 by an independent Data Monitoring Committee due to a highly statistically significant benefit in progression-free survival (PFS) in the Zydelig plus rituximab arm compared with the rituximab only treatment arm (hazard ratio = 0.18 (95 percent CI: 0.10, 0.32), p<0.0001). Median PFS was not reached in the Zydelig plus rituximab arm (95 percent CI: 10.7 months, NR) and was 5.5 months in the placebo plus rituximab arm (95 percent CI: 3.8, 7.1). The approval in FL, the most common type of indolent non-Hodgkin lymphoma (iNHL), is supported by data from a single-arm Phase 2 study (Study 101-09) of Zydelig monotherapy in 125 iNHL patients refractory to rituximab and alkylating-agent-containing chemotherapy. In the 72 patients with FL in this study, Zydelig achieved an overall response rate of 54 percent and the median duration of response was not reached (range: 0.0, 14.8+ months). Results of Study 116 and Study 101-09 were published in The New England Journal of Medicine in March 2014. Adverse drug reactions (including Grade ≥3) reported in clinical studies in patients with hematological malignancies receiving Zydelig included infections, neutropenia, pneumonitis, diarrhea/colitis, increased transaminase (indicator of liver function), rash and pyrexia. For additional safety information, see the Summary of Product Characteristics at www.ema.europa.eu.

On September 18, 2014 Boehringer Ingelheim and CureVac, leader in mRNA (messenger ribonucleic acid)-based drug development, reported jointly an exclusive global license and development collaboration (Press release, Boehringer Ingelheim, SEP 18, 2014, View Source [SID1234518779]). The new collaboration focuses on CureVac’s CV9202, a novel investigational therapeutic mRNA vaccine, in early clinical development for the treatment of lung cancer. Boehringer Ingelheim will start clinical investigation of CV9202 in at least two different lung cancer settings, in combination with afatinib in patients with advanced or metastatic epidermal growth factor (EGFR) mutated non-small cell lung cancer (NSCLC) and in combination with chemo-radiation therapy in patients with unresectable stage III NSCLC. Upon signature, CureVac receives EUR 35 million. Further, CureVac can achieve milestone payments of up to EUR 430 million and royalties on sales.

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This new agreement is part of Boehringer Ingelheim’s long-term commitment to delivering tomorrow’s cancer therapies through the discovery of novel treatment options with high therapeutic value for patients. The company’s oncology portfolio includes Giotrif (afatinib)*, an irreversible ErbB family blocker, approved in a number of markets, including the EU, the US and Japan for the treatment of distinct types of EGFR mutation-positive NSCLC. Boehringer Ingelheim’s oncology pipeline covers a broad range of solid tumors and haematologic malignancies (blood cancer), including two investigational compounds in Phase III clinical development: nintedanib in distinct types of NSCLC and colorectal cancer, and volasertib in acute myeloid leukemia.

Prof. Dr. Klaus Dugi
Prof. Dr. Klaus Dugi

"At Boehringer Ingelheim we are proud of our commitment to help improve the treatment of cancers with a high medical need. In our collaboration with CureVac, we will investigate combining existing treatments with the approach of sustained activation of the immune system. With this we hope to be able to develop new treatments and further expand our broad pipeline in lung cancer." said Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim.

CureVac’s mRNA-based technology represents a novel approach in cancer treatment. For the first time, mRNA could be optimised to mobilise the patient’s own immune system to fight the tumour with a specific immune response elicited through the RNActive vaccine. Cancer immunotherapy has been chosen as the "Breakthrough of the year 2013" by SCIENCE magazine. CV9202 is a combination of mRNA molecules coding for six antigens overexpressed in lung cancer, designed to induce an immune response against the tumour. CV9202 and the preceding RNActive cancer vaccine CV9201 tested in initial clinical trials by CureVac demonstrated clinical safety and activity in generating immune responses against all anti-tumour antigens.

Ingmar Hoerr, co-founder and CEO of CureVac GmbH commented: "This collaboration is extremely relevant for CureVac because, as a biotech enterprise, we rely on collaboration with strong partners for the clinical development and commercialisation of our compounds. Cancer immunotherapy represents one of the biggest innovations in cancer treatment of recent times and we are delighted to now be working with Boehringer Ingelheim. The out-licensing and clinical development of our promising therapeutic vaccine CV9202 represents the logical next step in developing this novel treatment for cancer patients and the significant commitment from Boehringer Ingelheim underscores the relevance of the mRNA technology."

About CureVac
CureVac, a clinical stage biopharmaceutical company from Tübingen, Germany, is pioneering the field of mRNA-based technology platforms for medical purposes with which mRNA is specifically optimised and formulated. Since 2000 the company develops novel mRNA-based cancer immunotherapies and prophylactic vaccines against infectious diseases – both under the brand RNActive. CureVac has successfully established the first GMP (good manufacturing practice) facility worldwide for the manufacture of RNA and mRNA and has pioneered mRNA-based drugs in clinical studies.

The company has successfully completed Phase I/IIa clinical studies with its RNActive cancer vaccines in prostate cancer and non-small cell lung cancer (NSCLC). Results so far have shown that mRNA-based products showed a favorable safety profile and induced immune responses including humoral and cellular, helper (both Th1 and Th2) and effector and memory responses. CureVac is currently conducting a number of clinical trials with its RNActive vaccines. A large randomised Phase IIb clinical trial in castrate resistant prostate cancer with CV9104 has been fully enrolled in December 2013. In the field of cancer immunotherapy CureVac is already collaborating with the Ludwig Cancer Research Institute to enable clinical testing of novel cancer immunotherapy treatment options.

CureVac’s RNActive technology is also used to develop prophylactic vaccines for infectious diseases. In March 2014, CureVac received the EUR 2 million Vaccine Prize from the European Commission for its RNActive vaccine technology. In particular, the jury acknowledged the fact that the RNActive vaccines represent a novel technology enabling the production of safe, efficacious and cost-effective vaccines that are protected against elevated temperature as well as inadvertent freezing. In the field of prophylactic vaccines CureVac is amongst others collaborating with Sanofi Pasteur, In-Cell-Art, DARPA and Janssen Pharmaceuticals.

For more information please visit www.curevac.com (link is external)

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine. In 2013, Boehringer Ingelheim achieved net sales of about 14.1 billion euros. R&D expenditure corresponds to 19.5% of its net sales.

About Boehringer Ingelheim in Oncology
Boehringer Ingelheim has a long-term commitment to deliver tomorrow’s cancer therapies by discovering and developing novel treatment options that combine ground-breaking science with the intent of high therapeutic value for patients. It runs an extensive and diverse study programme involving investigators and patients from around the world. This is supported by a significant financial investment, with the aim of developing treatments, which will make a difference to the lives of patients and their families.

The current focus of research includes compounds in signal transduction inhibition, angiogenesis inhibition and cell-cycle kinase inhibition. Boehringer Ingelheim’s first oncology compound afatinib, approved as Giotrif/Gilotrif, is available to patients with distinct types of Epidermal Growth Factor Receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Two investigational compounds are in Phase III clinical development: nintedanib in distinct types of NSCLC and colorectal cancer, and volasertib in acute myeloid leukemia. A growing pipeline of early-stage oncology compounds in areas such as growth/survival signaling, immunotherapy and epigenetics adds to the later stage compounds and the CV9202 RNActive vaccine will now be investigated in combination with afatinib and chemo-radiation therapy for the treatment of patients with NSCLC.

More than 400 employees around the world (including 250 highly skilled scientists in Vienna, Austria at the Boehringer Ingelheim cancer research centre) are dedicated to the discovery and development of new cancer treatments. They work with the Research Institute of Molecular Pathology (IMP) in Austria and experts in universities, hospitals and companies around the world.