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OncoSec Presents Significant Advancements in Electroporation Technology for Immunotherapy

On June 28, 2016 OncoSec Medical Incorporated ("OncoSec") (NASDAQ: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, reported recent advancements in electroporation (gene electro-transfer) for immunotherapy in two poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Special Conference on Engineering and Physical Sciences in Oncology in Boston (Press release, OncoSec Medical, JUN 28, 2016, View Source [SID:1234513598])1. New data related to OncoSec’s Tissue-based Real-time Adaptive Controlled Electroporation (TRACE) technology and helical integrated applicator (Helix) showed that these technologies have the potential to reduce procedural frequency as well as enhance usability by physicians. Together, these novel technologies may improve a patient’s experience to gene electro-transfer and improve therapeutic outcomes, which will help broaden the adoption of gene-electro transfer technologies in immunotherapy.

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The TRACE and Helix technologies are central to OncoSec’s next-generation device development and represent a significant advancement in electroporation technology. Existing electroporation systems apply fixed pulses, independent of tissue conditions, that are typically optimized by heuristics. The new TRACE technology brings together OncoSec’s research and engineering efforts to adapt the pulses to tissue conditions in real time and detect when optimal conditions have been achieved to complete electroporation treatment. The new Helix applicator integrates engineering advancements to function synergistically with the TRACE technology. The TRACE and Helix technologies have the potential to improve delivery of new therapeutic agents and access a variety of new tumor types and locations.

"The new TRACE and Helix technologies are a testament to the expertise of OncoSec’s engineering and research teams," said Punit Dhillon, President and CEO. "Electroporation is a powerful gene delivery tool, and we believe that these novel technologies are a breakthrough in the field of electroporation therapy. As we look beyond the proof-of-concept stage for our intratumoral immunotherapy programs, these advancements are a major step forward in being able to consistently deliver more advanced therapeutic agents with the potential to target multiple facets of tumor immune subversion."

TRACE Technology
The poster presentation entitled "Feedback Optimized Gene Electro-Transfer for Immunotherapy" highlights the efficacy of modulating pulse durations in real-time for the intratumoral delivery of plasmid DNA in mouse tumor models. OncoSec’s generator incorporating TRACE technology was used to perform electroporation with electrochemical impedance spectroscopy feedback operating in a closed-loop configuration to optimize each pulse duration in real-time.

Preclinical studies demonstrated electroporation integrating TRACE technology is capable of achieving maximum expression of reporter genes with minimal energy delivered. Based on these findings, it is hypothesized that this technology will minimize collateral cell death and reduce treatment variability observed in patients. These findings represent a significant advancement in gene electro-transfer, because retaining the viability of transfected cells is critical for treatment success.

Helix Technology
The poster presentation entitled "A Novel Applicator for Endoscopic Gene Electro-Transfer" discusses the role of DNA dispersion during intratumoral gene delivery and its impact on gene electro-transfer efficiency. OncoSec researchers developed a single-helical injection needle that anchors the target tissue and delivers plasmid DNA. This achieves delivery of the plasmid to an area three times larger than that of a standard injection needle. Helix combines the helical needle with electroporation electrodes on a single applicator, which may enhance gene delivery by increasing surface area for tissue-DNA-electroporation interaction.

The Helix technology showed enhanced efficacy of IL-12 plasmid electroporation in an aggressive B16.F10 mouse melanoma model, significantly reducing tumor growth rate and increasing survival after a single treatment. The anchoring associated with the helical needle and the close proximity of the electrodes ensures co-localization of the electric field with the injected plasmid DNA as well as repeatable treatment of malleable tumors. In addition, the compact design of the electrodes and helical needle could make the applicator compatible with standard medical devices, including trocars, endoscopes, and other catheter based devices, thus enabling the application of intratumoral gene immunotherapy to a broad range of deep tissue cancers.

The poster presentations are available in the Publications section of OncoSec’s website.

Novartis adds bispecific antibodies to its growing immuno-oncology portfolio through collaboration and licensing agreement with Xencor

On June 28, 2016 Novartis reported that it has entered into a collaboration and licensing agreement with Xencor for the development of bispecific antibodies for treating cancer (Press release, Novartis, JUN 28, 2016, View Source [SID:1234513584]). The agreement is the latest in a series of acquisitions and strategic collaborations between Novartis and biotech companies that have helped bolster its deep and diverse immuno-oncology pipeline.

Traditional monoclonal antibodies target and bind to a single antigen. Bispecific antibodies are engineered to recognize and target two different antigens, which makes them potentially more effective in targeting complex diseases. A T-cell engaging bispecific antibody is able to bind an antigen on a tumor cell with one arm and engage T-cells capable of their destruction with the other.

Novartis receives the right to develop four additional bispecific antibodies and to use other Xencor proprietary antibody engineering technology for up to ten additional biotherapeutic programs across the Novartis R&D portfolio. In addition, The companies will collaborate to co-develop Xencor’s two bispecific T-cell engaging antibodies targeting CD3xCD123 and CD3xCD20 for the treatment of acute myeloid leukemia and B-cell malignancies.

"This collaboration is part of our strategy to join forces with technology innovators who can help us rapidly advance new medicines to the clinic, " said Jay Bradner, President of the Novartis Institutes for BioMedical Research. "We look forward to working with the Xencor team to advance these programs in immuno-oncology and to using their antibody engineering platform to develop biotherapeutics for additional diseases."

The addition of Xencor’s T-cell engaging bispecific antibody programs expands Novartis’ immuno-oncology portfolio that includes novel checkpoint inhibitors, chimeric antigen receptor T-cell (CART) technology, myeloid cell targeting agents, the T-cell stimulating factor IL-15, STING agonists that enhance immune recognition of cancers, and adenosine receptor antagonists and TGF-beta blocking antibodies that overcome immunosuppression in the tumor microenvironment. Currently seven of these programs are in the clinic and five more are expected to enter the clinic individually and as combinations by the end of 2016.

Under the terms of the agreement, Xencor is receiving a $150 million upfront payment from Novartis and the two companies will equally share the cost to jointly develop two Xencor antibodies targeting the CD3 domain. Xencor retains full US commercial rights to these programs, and Novartis has ex-US commercial rights. In addition to these antibodies, Novartis receives worldwide rights to develop and commercialize four additional bispecific programs, with Xencor eligible to "opt in" to one of these programs in the U.S..

GlycoMimetics Doses First Patient in Phase 2 Portion of Clinical Trial of GMI-1271 in Newly Diagnosed Acute Myeloid Leukemia

On June 28, 2016 GlycoMimetics, Inc. (NASDAQ: GLYC) reported dosing of the first patient with newly diagnosed acute myeloid leukemia (AML) in the Phase 2 portion of its ongoing Phase 1/2 study evaluating its novel E-selectin antagonist, GMI-1271, combined with chemotherapy (Press release, GlycoMimetics, JUN 28, 2016, View Source [SID:1234513599]). Earlier this month, the company announced it had received Fast Track designation from the U.S. Food and Drug Administration (FDA) for GMI-1271 for treatment of adult patients with relapsed or refractory AML and elderly patients aged 60 years or older with AML. In addition, GlycoMimetics recently announced that the first patient with relapsed or refractory AML has been dosed in the other arm of the Phase 2 portion of this study.
For the study’s Phase 2 portion, the optimal dose of GMI-1271 has been determined, and in this arm of the study clinical investigators will study the effects on newly diagnosed patients receiving the drug candidate to obtain additional safety and efficacy data. Study enrollment in this arm is limited to patients at least 60 years of age who have been newly diagnosed with AML and are eligible to receive treatment with the chemotherapy agents cytarabine and idarubicin (‘7+3′). All patients must be eligible to receive this intensive chemotherapy regimen, and will be given GMI-1271 in addition to this combination chemotherapy. During the Phase 1 portion of the study, patients received a single cycle of treatment including GMI-1271. During this Phase 2 portion, certain patients will be eligible to receive additional cycles of treatment.

“The data from the first cohorts point to both the safety and potential efficacy of GMI-1271 as a treatment for AML,” said Helen Thackray, M.D., Chief Medical Officer of GlycoMimetics. “We are now enrolling a new group of study participants to evaluate the effects of GMI-1271 on newly diagnosed patients who also are receiving chemotherapy. If the second half of the trial confirms our earlier preclinical and clinical findings, we believe that GMI-1271 could well address the unmet needs of AML patients, beyond what is currently possible with available therapies.”

This clinical trial is a multinational open-label study evaluating endpoints for safety, pharmacokinetics (PK) and efficacy of GMI-1271 in combination with induction chemotherapy in patients with high-risk AML. This trial is being conducted at a number of academic medical institutions in the United States, Ireland, and Australia. While the primary objective is to assess safety, additional endpoints include overall response rate, biomarkers of activity, durability of response and overall survival. This Phase 2 portion of the study in newly diagnosed patients is expected to include approximately 25 participants.

GlycoMimetics announced on June 10, presentation of data in patients with relapsed/refractory acute AML from the Phase 1 portion of this ongoing study. Data were reported at the European Hematology Association (EHA) (Free EHA Whitepaper) 21st Congress in Copenhagen, Denmark in a poster entitled “Results of a Phase 1 study of GMI-1271, a potent E-selectin antagonist in combination with induction chemotherapy in relapsed/refractory AML: a novel, well-tolerated regimen with a high remission rate.”

About GMI-1271

GMI-1271 is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with AML cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. Preclinical research points to the drug’s potential role in moving cancerous cells out of the protective environment of the bone marrow where they hide and escape the effects of chemotherapy. In preclinical studies using animal models of AML, the results of which were presented at meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper), GMI-1271 was also associated with a reduction of chemotherapy-induced neutropenia and chemotherapy-induced mucositis.

GlycoMimetics Doses First Patient in Phase 2 Portion of Clinical Trial of GMI-1271 in Newly Diagnosed Acute Myeloid Leukemia

Earlier this month, the company announced it had received Fast Track designation from the U.S. Food and Drug Administration (FDA) for GMI-1271 for treatment of adult patients with relapsed or refractory AML and elderly patients aged 60 years or older with AML. In addition, GlycoMimetics recently announced that the first patient with relapsed or refractory AML has been dosed in the other arm of the Phase 2 portion of this study.
For the study’s Phase 2 portion, the optimal dose of GMI-1271 has been determined, and in this arm of the study clinical investigators will study the effects on newly diagnosed patients receiving the drug candidate to obtain additional safety and efficacy data. Study enrollment in this arm is limited to patients at least 60 years of age who have been newly diagnosed with AML and are eligible to receive treatment with the chemotherapy agents cytarabine and idarubicin (‘7+3′). All patients must be eligible to receive this intensive chemotherapy regimen, and will be given GMI-1271 in addition to this combination chemotherapy. During the Phase 1 portion of the study, patients received a single cycle of treatment including GMI-1271. During this Phase 2 portion, certain patients will be eligible to receive additional cycles of treatment.

"The data from the first cohorts point to both the safety and potential efficacy of GMI-1271 as a treatment for AML," said Helen Thackray, M.D., Chief Medical Officer of GlycoMimetics. "We are now enrolling a new group of study participants to evaluate the effects of GMI-1271 on newly diagnosed patients who also are receiving chemotherapy. If the second half of the trial confirms our earlier preclinical and clinical findings, we believe that GMI-1271 could well address the unmet needs of AML patients, beyond what is currently possible with available therapies."

This clinical trial is a multinational open-label study evaluating endpoints for safety, pharmacokinetics (PK) and efficacy of GMI-1271 in combination with induction chemotherapy in patients with high-risk AML. This trial is being conducted at a number of academic medical institutions in the United States, Ireland, and Australia. While the primary objective is to assess safety, additional endpoints include overall response rate, biomarkers of activity, durability of response and overall survival. This Phase 2 portion of the study in newly diagnosed patients is expected to include approximately 25 participants.

GlycoMimetics announced on June 10, presentation of data in patients with relapsed/refractory acute AML from the Phase 1 portion of this ongoing study. Data were reported at the European Hematology Association (EHA) (Free EHA Whitepaper) 21st Congress in Copenhagen, Denmark in a poster entitled "Results of a Phase 1 study of GMI-1271, a potent E-selectin antagonist in combination with induction chemotherapy in relapsed/refractory AML: a novel, well-tolerated regimen with a high remission rate."

About GMI-1271

GMI-1271 is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with AML cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. Preclinical research points to the drug’s potential role in moving cancerous cells out of the protective environment of the bone marrow where they hide and escape the effects of chemotherapy. In preclinical studies using animal models of AML, the results of which were presented at meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper), GMI-1271 was also associated with a reduction of chemotherapy-induced neutropenia and chemotherapy-induced mucositis.

Bayer’s Regorafenib Significantly Improves Overall Survival in Patients with Unresectable Liver Cancer (for specialized target groups only)

On June 28, 2016 Bayer reported results from the Phase III RESORCE trial investigating its oncology compound regorafenib in patients with unresectable hepatocellular carcinoma (HCC) who progressed during treatment with sorafenib (Nexavar) tablets (Press release, Bayer, JUN 28, 2016, View Source [SID:1234513591]). In this trial, treatment with regorafenib plus best supportive care significantly improved overall survival (OS) compared to the control group receiving placebo plus best supportive care.

The results showed that the Hazard Ratio (HR) for OS in patients who received regorafenib compared with the control group was 0.62 (95% CI 0.50-0.78; p<0.001), which translates to a 38% reduction in the risk of death over the trial period. Median overall survival was 10.6 months for those who received regorafenib versus 7.8 months for those in the control group. The safety and tolerability were generally consistent with the known profile of regorafenib. These data will be presented at the ESMO (Free ESMO Whitepaper) 18th World Congress on Gastrointestinal Cancer (WCGC) in an oral abstract session on June 30 at 5.40pm CEST. The congress is taking place on June 29-July 2 in Barcelona, Spain. "The incidence of liver cancer continues to increase globally. There is only one approved systemic treatment option for patients with this disease, and there are currently no proven or approved second-line treatment options for patients with advanced HCC," said Dr. Jordi Bruix, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Spain. Dr. Bruix is the Principal Investigator of the RESORCE study as well as the Phase III study SHARP which investigated sorafenib in HCC. "The regorafenib data seen in RESORCE may translate into additional hope for patients by providing doctors, nurses and other healthcare providers with a much needed second proven option for the treatment of liver cancer. The appropriate and timely start of systemic therapy may be important in improving patients’ treatment outcomes by potentially providing patients with the opportunity of receiving both proven systemic treatment options," Dr. Bruix continued. In addition to the primary endpoint of the study, all secondary endpoints, which were assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST 1.1 criteria, were also met. Median progression-free survival was 3.1 versus 1.5 months, respectively (HR= 0.46 (95% CI 0.37‒0.56; p<0.001). Median time to progression was 3.2 vs. 1.5 months (HR 0.44; 95% CI 0.36–0.55; p<0.001). Disease control rate (composed of complete and partial responses and stable disease) was 65.2% vs 36.1% (p<0.001). Overall response rate (complete and partial responses) was 10.6% vs 4.1% (p=0.005), respectively. All numerical values of the secondary endpoints are based on mRECIST. The safety and tolerability were generally consistent with the known profile of regorafenib. The most common adverse events (grade 3 or higher) were hypertension (15.2% in the regorafenib group vs. 4.7% in the placebo group), hand-foot skin reaction (12.6% vs. 0.5%), fatigue (9.1% vs. 4.7%), and diarrhea (3.2% vs. 0%). Bayer plans to submit data from the RESORCE study as the basis for marketing authorization of regorafenib in the treatment of unresectable HCC in 2016. About the RESORCE trial The Phase III data being presented at WCGC are from the RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma] clinical trial, which enrolled 573 patients who were randomized in a 2:1 ratio to receive either regorafenib plus best supportive care (BSC) or placebo plus BSC. Patients received 160 mg regorafenib once daily or placebo, for 3 weeks on/1week off, with 28 days constituting one full treatment cycle. The primary endpoint of the study was overall survival, and secondary endpoints were time to progression, progression-free survival, objective tumor response rate and disease control rate. Safety and tolerability were also continuously monitored. About Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the most common form of liver cancer and represents approximately 70-85 percent of liver cancer worldwide. Liver cancer is the sixth most common cancer in the world and the second leading cause of cancer-related deaths globally. More than 780,000 cases of liver cancer are diagnosed worldwide each year (more than 395,000 in China, 52,000 in the European Union, and 30,000 in the United States) and the incidence rate is increasing. In 2012, approximately 746,000 people died of liver cancer including approximately 383,000 in China, 48,000 in the European Union, and 24,000 in the United States. About Regorafenib (Stivarga) Regorafenib is an oral multi-kinase inhibitor that blocks various kinases within the mechanisms involved in tumor growth and progression – angiogenesis, oncogenesis and the tumor microenvironment. In preclinical studies, regorafenib has been shown to inhibit several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis (the growth of new blood vessels). In addition to VEGFR 1-3, it also inhibits various oncogenic and tumor microenvironment kinases including TIE-2, RAF-1, BRAF, BRAFV600, KIT, RET, PDGFR, and FGFR, which individually and collectively control tumor growth, formation of a stromal microenvironment and disease progression. Regorafenib is approved under the brand name Stivarga in 90 countries worldwide, including the U.S., countries of the EU and Japan for the treatment of metastatic colorectal cancer. The product is also approved in over 70 countries, including the U.S., countries of the EU and Japan, for the treatment of metastatic gastrointestinal stromal tumors (GIST). In the EU, Stivarga is indicated for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, as well as for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib. Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.