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MEI Pharma Announces FDA Clearance of Investigational New Drug Application for CDK Inhibitor Voruciclib

On January 8, 2018 MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug Application (IND) for voruciclib, an orally available Cyclin Dependent Kinase 9 (CDK9) inhibitor, for patients with relapsed/refractory B-cell malignancies (Press release, MEI Pharma, JAN 8, 2018, View Source [SID1234523013]). Under this IND, MEI Pharma plans to initiate a Phase 1 study designed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of voruciclib in patients with B-cell malignancies.

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"Inhibiting the function of certain CDK family members has shown significant clinical activity in breast cancer. Voruciclib inhibits CDK9 which controls expression of MCL-1, a known mechanism of resistance to apoptosis. Therefore, voruciclib alone or in combination with a BCL-2 inhibitor such as venetoclax offers a potential novel approach for treatment of B-cell malignancies," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "With the FDA clearance of our IND, we look forward to advancing voruciclib through the clinic in the second quarter of 2018 to demonstrate its clinical and commercial value."

About Voruciclib

Voruciclib (formerly P1446A; ME-522) has been tested in more than 70 patients in multiple solid tumor Phase 1 studies and has been associated with side effects consistent with other drugs in its class, including nausea, vomiting and diarrhea. In pre-clinical studies, voruciclib alone induces cell death in multiple patient-derived chronic lymphocytic leukemia (CLL) samples1. In additional pre-clinical studies, voruciclib shows dose-dependent suppression of MCL-1 at concentrations achievable with doses that appeared to be generally well tolerated in the Phase 1 studies2. Studies have shown that MCL-1 is an established resistance mechanism to the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (marketed as Venclexta)3.

Mateon Announces New Preclinical Data Demonstrating Enhanced Tumor Immune Responses when CA4P is Given in Combination with Checkpoint Inhibitors

On January 8, 2018 Mateon Therapeutics, Inc. (OTCQX:MATN), a biopharmaceutical company developing investigational drugs for the treatment of orphan oncology indications, reported new preclinical data further characterizing the improved anti-tumor immune response observed when animals are treated with CA4P in combination with anti-CTLA-4 antibodies (Press release, Mateon Therapeutics, JAN 8, 2018, View Source [SID1234523012]).

The new findings show that treatment with the combination of CA4P and an anti-CTLA-4 antibody nearly doubles the amount of tumor necrosis (mean = 63.9%) compared to treatment with an anti-CTLA-4 antibody alone (32.8%), CA4P alone (37.3%) or vehicle control (25.8%) in a preclinical CT-26 mouse colon cancer model using immunohistochemistry analyses. Results from these analyses confirmed previously announced findings showing that treatment with CA4P and an anti-CTLA-4 antibody resulted in increased overall median numbers of tumor infiltrating CD8+ T lymphocytes. The new preclinical data also showed that the distribution of these beneficial CD8+T lymphocyte cells was observed throughout the tumor – in both the tumor rim and tumor core.

"These new data further show the promise of CA4P to stimulate the immune system and enhance the efficacy of checkpoint inhibitors," said William D. Schwieterman, M.D., President and Chief Executive Officer of Mateon Therapeutics. "We are excited that CA4P, when combined with a checkpoint inhibitor, shows dramatic increases in tumor necrosis which are clearly correlated with an increased immunologic response, more tumor regressions and increased overall survival. Given these new findings, the large clinical safety database for CA4P, and the need for new therapies for the many patients who have not responded to checkpoint inhibitor therapy, we believe CA4P has great promise for use with these immuno-oncology agents."

About Checkpoint Inhibitors

Anti-CTLA-4 antibodies stimulate a patient’s immune system by blocking immunosuppression and include the approved anti-cancer drug Yervoy. Mateon’s investigational drug CA4P stimulates a patient’s immune system in a different but complementary manner – by inducing immediate, rapid and extensive tumor cell necrosis. Utilizing these two different but complementary immune-stimulating approaches simultaneously has the potential to improve patient outcomes for the majority of cancer patients that do not respond adequately to therapy with checkpoint inhibitors alone.

About CA4P With Checkpoint Inhibitors

Mateon previously reported data from a CT-26 colon cancer animal model showing that combination treatment with CA4P and an anti-CTLA-4 antibody causes large reductions in tumor volume and statistically significant improvements in survival when compared to anti-CTLA-4 alone, CA4P alone, or vehicle control. Similar anti-tumor effects were observed when this combination was studied in an EMT-6 mammary tumor animal model. The CT-26 model was repeated for the studies reported today, again showing large reductions in tumor volume with combination therapy and also indicating a heightened immunologic response to the tumor in the presence of the two-drug combination. Importantly, treatment with both CA4P and an anti-CTLA-4 antibody generally maintains an elevated tumor-associated median effector T cell/regulatory T cell ratio, which also indicates a heightened immune response. Work to further characterize the immune response seen with the combination is ongoing.

Inovio Receives Milestone Payment from MedImmune as MEDI0457 and Checkpoint Inhibitor Combination Trial in Head and Neck Squamous Cell Cancer Advances to Phase 2

On January 8, 2018 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported it has received a milestone payment from MedImmune as MEDI0457 (formerly called INO-3112 which MedImmune in-licensed from Inovio) in combination with durvalumab (MEDI4736) satisfactorily completed the phase 1 safety review portion of the study and has advanced to the phase 2 efficacy stage of the trial (Press release, Inovio, JAN 8, 2018, View Source [SID1234523010]). As part of a $700 million 2015 license and collaboration agreement, MedImmune, the global biologics research and development arm of AstraZeneca, is evaluating MEDI0457 in combination with durvalumab, its PD-L1 checkpoint inhibitor, in patients with recurrent/metastatic HPV-associated head and neck squamous cancer (HNSCC) in a clinical trial with an estimated enrollment of 50 patients.

Under the 2015 agreement, MedImmune acquired exclusive rights to Inovio’s MEDI0457 immunotherapy. MEDI0457 targets cancers caused by human papillomavirus (HPV) types 16 and 18 which are responsible for more than 70 percent of cervical pre-cancers and cancers and are involved in the development of other tumors as well such as HNSCC. Within the broader license and collaboration agreement, MedImmune and Inovio will develop two additional DNA-based cancer therapy products not included in Inovio’s current product pipeline, which MedImmune has exclusive rights to develop and commercialize. Inovio will receive development, regulatory and commercialization milestone payments and will be eligible to receive royalties on worldwide net sales for these additional cancer vaccine products.

Dr. Ildiko Csiki, MD, PhD, Inovio Vice President, Clinical Development said, "We are pleased to see this combination study advance to the efficacy portion of the trial. Published preclinical studies suggest that treatment with HPV targeted immunotherapeutic approach in combination with PD-1/PD-L1 inhibition may be synergistic, and potentially increase efficacy of checkpoint inhibitors."

Dr. J. Joseph Kim, Inovio’s President and Chief Executive Officer, said, "Inovio’s primary goal is to become the global leader in HPV-related disease treatment. Along with MEDI’s development of MEDI0457 for HPV-related cancer, Inovio’s VGX-3100, is currently being tested in global phase 3 pivotal trials for cervical pre-cancer as well as a treatment for vulvar and anal pre-cancers caused by HPV. Overall, these products could be well-positioned to comprehensively treat HPV-related diseases across the continuum of HPV infections from pre-cancerous conditions to cancer in both women and men."

In a phase 1 study of MEDI0457 in 22 HPV-positive patients with HNSCC, Inovio has previously demonstrated that MEDI0457 generated robust antigen-specific CD8+ killer T cell responses in both tumor tissue and peripheral blood. One patient in that trial who initially displayed a slight increase in T cell immune responses developed progressive disease at 11 months into the study and subsequently received a PD-1 checkpoint inhibitor. The patient had a sustained complete response after only four doses of a checkpoint inhibitor, and continues on anti PD-1 therapy with no evidence of disease 18 months after initiation of the checkpoint inhibitor.

About MEDI0457 and VGX-3100

MEDI0457 (formerly called INO-3112 (VGX-3100, plus IL-12) which MedImmune in-licensed from Inovio) is under evaluation by MedImmune to treat HPV-associated cancers. Inovio is investigating VGX-3100, a DNA-based immunotherapy for the treatment of HPV-16 and HPV-18 infection and pre-cancerous lesions of the cervix (phase 3) and vulva (phase 2). VGX-3100 has the potential to be the first approved treatment for HPV infection of the cervix and the first non-surgical treatment for pre-cancerous cervical lesions. VGX-3100 works by stimulating a specific immune response to HPV-16 and HPV-18, which targets the infection and causes destruction of pre-cancerous cells. In a randomized, double-blind, placebo-controlled phase 2b study in 167 adult women with histologically documented HPV-16/18 cervical HSIL (CIN2/3), treatment with VGX-3100 resulted in a statistically significantly greater decrease in cervical HSIL and clearance of HPV infection vs. placebo. The most common side effect was injection site pain, and no serious adverse events were reported. VGX-3100 utilizes the patient’s own immune system to clear HPV-16 and HPV-18 infection and pre-cancerous lesions without the increased risks associated with surgery, such as loss of reproductive health and negative psychosocial impacts.

Exelixis and StemSynergy Enter into Exclusive Licensing Agreement for the Discovery and Development of Novel Anticancer Therapies

On January 8, 2018 Exelixis, Inc. (NASDAQ: EXEL) reported that it has entered into an exclusive collaboration and license agreement with StemSynergy Therapeutics, Inc., (StemSynergy) for the discovery and development of novel oncology compounds targeting Casein Kinase 1 alpha (CK1α), a component of the Wnt signaling pathway implicated in key oncogenic processes (Press release, Exelixis, JAN 8, 2018, View Source;p=RssLanding&cat=news&id=2325370 [SID1234523005]). The agreement is part of Exelixis’ ongoing strategy to build an innovative pipeline beyond its two internally-discovered, commercially available compounds, cabozantinib and cobimetinib.

Under the terms of the agreement, Exelixis will partner with StemSynergy to conduct preclinical and clinical studies with compounds from StemSynergy’s CK1α Activator Program. Exelixis will pay StemSynergy an upfront payment of $3M and up to $3.5M in initial research and development funding. StemSynergy will be eligible for a variety of milestones for the first product to emerge from the collaboration, including preclinical and clinical development and regulatory milestone payments, commercial milestones, as well as single-digit royalties on worldwide sales. Exelixis will be solely responsible for the commercialization of products that arise from the collaboration.

"Supported by revenues from its commercial products and collaborations, Exelixis is on a growth trajectory and now actively focused on augmenting our pipeline both through targeted business development and internal drug discovery activities," said Peter Lamb, Ph.D., Executive Vice President, Discovery Research and Chief Scientific Officer of Exelixis. "CK1α activation is an underexplored and intriguing mechanism for addressing the Wnt/β-catenin axis, a major pathway deregulated in multiple cancers. We look forward to working with StemSynergy to advance this compelling program as we build the next generation of Exelixis medicines."

The CK1α Activator Program is representative of StemSynergy’s focus on treating cancer by targeting developmental processes that are reactivated in cancer cells. The Wnt signaling pathway is a prominent example of this process: the pathway plays an important role in embryonic development, but can support oncogenic processes when deregulated in adult tissues. Activation of β-catenin, a key downstream component of the pathway, is increased in multiple tumors, including a majority of colorectal cancers, where mutations in the APC gene that result in beta-catenin stabilization are prevalent. CK1α Activator Program compounds have been shown to induce degradation of β-catenin and pygopus, another member of the pathway, in preclinical CRC models, and to inhibit the growth of tumors. Importantly, their GI-sparing qualities may help overcome limitations of other approaches targeting the Wnt pathway.

"StemSynergy is developing compounds that can specifically address developmental pathways reactivated in cancer cells to potentially deliver greater benefit to patients," said Anthony J. Capobianco, Ph.D., President and Co-Founder of StemSynergy. "Our CK1α Activator Program has been supported in part by the National Cancer Institute through the SBIR program. With deep drug discovery and development expertise and a proven track record of successfully bringing medicines to market, Exelixis is a natural partner for our CK1α Activator Program as it advances. We look forward to collaborating with the experienced Exelixis team to move the program forward."

BeiGene and Mirati Therapeutics Announce Exclusive License Agreement for Sitravatinib in the Asia Pacific Region

On January 8, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, and Mirati Therapeutics (NASDAQ:MRTX), a clinical-stage targeted oncology company, reported an exclusive license agreement for the development, manufacturing and commercialization of Mirati’s sitravatinib in Asia (excluding Japan), Australia, and New Zealand (Press release, BeiGene, JAN 8, 2018, View Source;p=RssLanding&cat=news&id=2325285 [SID1234523004]). Mirati will retain exclusive rights for the development, manufacturing and commercialization of sitravatinib for the rest of world.

Sitravatinib is an investigational tyrosine kinase inhibitor that has demonstrated potent inhibition of receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, MER), split family receptors (VEGFR2, KIT) and RET. It is being evaluated by Mirati as a single agent in a Phase 1b expansion trial in patients whose tumors harbor specific genetic alterations in non-small cell lung cancer (NSCLC) and other tumors types. Sitravatinib has shown encouraging interim results in an ongoing Phase 2 trial in combination with nivolumab in NSCLC patients who have progressed after prior treatment with a checkpoint inhibitor.

"We are delighted to enter into this exclusive clinical development and commercialization agreement for sitravantinib and look forward to working with the experienced team at Mirati. Sitravatinib is an exciting compound that has demonstrated a unique tyrosine kinase inhibition profile and promising clinical activity both as a single agent and in combination with a checkpoint inhibitor in non-small cell lung cancer. This collaboration complements our portfolio and will allow us to investigate sitravatinib in combination with tislelizumab, our investigational anti-PD-1 antibody, in China and the rest of the licensed territory," commented John V. Oyler, Founder, Chief Executive Officer, and Chairman of BeiGene.

"We are excited to begin a partnership with BeiGene, which has built a world-class global development organization with a strong presence in Asia-Pacific, as well as an established commercial organization in China. They have demonstrated an ability to enroll patients quickly in a variety of indications which will augment our development capabilities and expand the evaluation of sitravatinib to additional tumor types for patients who are checkpoint inhibitor naïve or who have been previously treated with a checkpoint inhibitor," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer of Mirati Therapeutics.

Under the agreement Mirati will receive an upfront cash payment of $10 million from BeiGene. Additionally, Mirati is eligible to receive up to $123 million of additional payments based upon the achievement of certain development, regulatory and sales milestones as well as significant royalties on future sales of sitravatinib in the licensed territory.

About Sitravatinib

Sitravatinib (MGCD-0516) is a spectrum-selective kinase inhibitor which potently inhibits receptor tyrosine kinases (RTKs) including RET, TAM family receptors (TYRO3, Axl, MER), and split family receptors (VEGFR2, KIT). Sitravatinib is being evaluated as a single agent in a Phase 1b expansion trial enrolling patients that harbor RET, CHR4Q12, and CBL genetic alterations in NSCLC and other tumors.

As an immuno-oncology agent, sitravatinib is being tested in combination with anti PD-1 checkpoint inhibitor nivolumab in NSCLC patients who have progressed after prior treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family receptors may help overcome resistance to checkpoint inhibitor therapy through enhancement of dendric cell-dependent antigen presentation, targeted depletion of immunosuppressive T regulatory cells and myeloid-derived suppressor cells, and conversion of tumor associated macrophages to an immune-enhancing Type I composition, in the tumor microenvironment.

About Tislelizumab (BGB-A317)

Tislelizumab is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. Tislelizumab has demonstrated high affinity and specificity for PD-1. It is differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for tislelizumab for solid tumors outside of Asia (except Japan).