On December 19, 2011 NewGen Therapeutics reported the acquisition of three novel oncology development programs from Kanion USA, Inc. (Hayward, CA) and Kanion Pharmaceutical Co., Ltd. (Lianyungang, China) (Press release NewGen Therapeutics, DEC 19, 2011, View Source [SID:1234501416]). Under an agreement between the companies, NewGen has received exclusive global rights, excluding China, for the development, manufacture and commercialization of three separate small molecule therapeutic programs targeting pan-erbB, EGFR/Her-2, and PARP, respectively. NewGen intends to continue pre-clinical development of the oral lead molecules currently identified within each program, and seek partners for their clinical development and marketing. In return, Kanion Pharmaceutical has taken a minority equity position in privately financed NewGen, and will continue development of the compounds for China markets. The two companies also plan to share data on the compounds’ development. Further financial details were not disclosed.
"Targeted therapeutics should result in higher response rates, more efficient drug development, and an increased likelihood of clinical success," said Harry Pedersen, NewGen Therapeutics President and Chief Executive Officer. "Acquiring the rights to these late pre-clinical programs gives NewGen a strong pipeline and multiple partnering opportunities with molecules that can help advance our mission to make a difference in the treatment of cancer."
The three oncology programs acquired by NewGen Therapeutics include:
Pan-ErbB inhibitor: NewGen’s pan-ErbB inhibitor lead compound (NT-113) is an investigational, orally active, irreversible inhibitor of ErbB1 (EGFR), ErbB2 (Her-2) and the ErbB4 (Her-4). Compounds identified in this program permanently inactivate the ErbB kinases to affect downstream signal transduction events and cell cycle pathways such as cell division, ultimately resulting in decreased cell proliferation.
EGFR/Her-2 Dual Inhibitor: NewGen’s ERFR/Her-2 dual inhibitor lead compound (NT- 004) is an investigational, orally active inhibitor of ErbB1 (EGFR) and ErbB2 (Her-2). The EGFR and Her-2 receptors are both involved in cell proliferation, differentiation and apoptosis (programmed cell death). Their inhibition may play a critical role in the prevention of tumor growth and metasteses. Overexpression of EGFR and Her-2 is associated with poor prognosis and advanced-stage cancers.
PARP Inhibitor: NewGen’s PARP [poly (ADP-ribose) polymerase] inhibitor lead compound (NT-125) is an investigational, orally active inhibitor of PARP, a DNA nicksensor that signals the presence of DNA damage and facilitates DNA repair. PARP has been gaining significant interest as a therapeutic target for cancer, as investigators have reported impressive phase 2 clinical efficacy in BRCA-positive breast and ovarian cancer patients treated with PARP inhibitors. Inhibition of PARP increases the activity of DNA damaging agents including alkylators, platinums, topoisomerase inhibitors and radiation by inhibiting DNA repair. In addition, tumors with DNA repair defects, such as those arising from BRCA and PTEN mutations, appear to be very sensitive to single agent PARP inhibition. Many tumors have defects in DNA repair pathways. Mutations in the BRCA1 and BRCA2 genes have been demonstrated to be synthetic lethal in tumor models and in patients. Tumor cells with BRCA1 or BRCA2 mutations have a deficiency in the repair of DNA double strand breaks (DSBs) by the homologous recombination (HR) pathway.

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Using both Fc mutants and wild type Chinese hamster ovary (CHO) cells as a model, iDD biotech generated anti CD19 antibodies displaying different levels of fucosylation as demonstrated by MALDI-TOF mass spectrometry based glycoprofiling (Poster, 7th Annual European Antibody Congress 2011, November 29–December 1, 2011, Geneva, Switzerland, iDD biotech, NOV 29, 2011, View Source [SID:1234502456]). The downmodulation of the fucose level also led to the construction of antiCD19 MAbs with a strongly enhanced ADCC effector function.

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On November 28, 2011 Exelixis reported that it has entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP) for further evaluation of cabozantinib, Exelixis’ lead compound, in a variety of solid tumors (Press release, Exelixis, NOV 28, 2011, View Source;p=irol-newsArticle&ID=1633691 [SID1234526739]). Cabozantinib is a potent, dual inhibitor of MET and VEGFR2. Exelixis recently announced positive Phase III data in the EXAM trial in medullary thyroid cancer and that the company is initiating pivotal phase 3 trials in castration-resistant prostate cancer.

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The agreement covers up to twenty active clinical trials per year over the lifetime of the CRADA. Under the terms of the CRADA, Exelixis and the National Cancer Institute (NCI) will undertake a series of clinical trials to evaluate the safety and efficacy of cabozantinib in several cancers based upon encouraging anti-tumor activity observed in earlier studies. The trials will be designed to address a number of scientific questions such as how the efficacy of cabozantinib compares with other VEGFR2 inhibitors, the ability of cabozantinib to overcome resistance of tumors to VEGFR2 or EGFR inhibition, and the mechanism of activity of cabozantinib in tumors metastatic to bone.

As data from the CTEP-sponsored studies and other Exelixis-sponsored trials emerge, the NCI and Exelixis will discuss additional trials to complement and support the development of cabozantinib. The NCI may also support non-clinical studies that focus on identifying assays for monitoring the biologic activity of cabozantinib, as well as combination studies of the compound with other targeted agents. Any additional studies will be with mutual agreement and approval of both parties.

"Our CRADA with the NCI’s Division of Cancer Treatment and Diagnosis reinforces our commitment to maximize the broad clinical potential of cabozantinib in a wide variety of tumor indications while focusing our own internal efforts on prostate and thyroid cancer," said Michael M. Morrissey, PhD, Exelixis’ president and chief executive officer. "As we prepare to file our new drug application with the FDA for the medullary thyroid cancer indication, and continue to advance our pivotal trial plans in prostate cancer, we have found an exemplary partner in the NCI to drive clinical research in other key areas. We hope the CTEP collaboration will provide additional clinical data that will highlight cabozantinib’s differentiated clinical profile in multiple different cancer indications."

About Cabozantinib

Cabozantinib is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including:

Extensive apoptosis of malignant cells
Decreased tumor invasiveness and metastasis
Decreased tumor and endothelial cell proliferation
Blockade of metastatic bone lesion progression
Disruption of tumor vasculature

On November 18, 2011, the US Food and Drug Administration (US FDA) reported that breast cancer indication for Avastin (bevacizumab) had been withdrawn after concluding that the drug has not been shown to be safe and effective for the treatment of breast cancer (Press release, US FDA, NOV 18, 2011, View Source,the%20treatment%20of%20breast%20cancer [SID1234634977]). The specific indication that was withdrawn was for the use of bevacizumab in metastatic breast cancer, with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

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The US FDAs decision has been met with emotion and confusion among the public and health professionals. The purpose of this article is to review the regulatory history of bevacizumab for breast cancer and to examine the scientific evidence that led to the approval and subsequent withdrawal of this indication. Bevacizumab also provides the opportunity to illustrate the value of free publicly available US FDA reviews that may contain rigorously reviewed unpublished data and analyses and to contrast the decisions made in the US and Europe about bevacizumab and breast cancer.

On November 11, 2011 Amorfix Life Sciences reported that the Company is collaborating with Helix BioPharma to develop novel therapeutics against cancers associated with misfolded prion protein (Press release, Amorfix Life Sciences, NOV 11, 2011, View Source [SID:1234500907]). These novel therapeutics will specifically target tumour cells and are expected to be more effective and safer than traditional cancer treatments.
Antibodies can be effective as therapeutics by delivering a toxic payload directly to the tumour. As part of this collaboration, Amorfix will provide tumour specific antibodies identified and developed with their proprietary ProMIS discovery technology while Helix BioPharma will utilize their proprietary technology to produce antibody-urease conjugates which are toxic to cells.
"This collaboration represents an important combination of technologies required to produce new therapeutics for the effective treatment of cancer" said Dr. Robert Gundel, Amorfix President and Chief Executive Officer. "We have been very successful in generating high affinity antibodies against disease specific epitopes (DSEs) that show preferred binding to certain tumour cells, but not to normal cells. Our lead misfolded PrP antibody shows selective binding to 5 out of 6 human ovarian cancer cell types but does not bind to normal human ovarian tissue. In addition, this antibody binds selectively to 4 out of 6 human lymphoma cancer cells but not to normal human lymphocytes. Ovarian cancer, in particular, remains an area of very high unmet medical need with a current 5 year survival rate of less than 50%. By attaching Helix’s urease toxin to our antibody, we are providing an effective means for specific delivery directly to the tumours, and not subjecting normal cells to the toxin. We are very pleased to have Helix BioPharma as a partner for this program as their conjugation technology and experience with the urease system is an important component for the overall success of the project."
Details and/or financial terms of the collaboration have not been made public.

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