On December 11, 2017 Aura Biosciences, a biotechnology company developing a new class of therapies to target and selectively destroy cancer cells using viral nanoparticle conjugates, reported that Cadmus Rich, M.D., has joined the company’s leadership team as Chief Medical Officer (Press release, Aura Biosciences, DEC 11, 2017, View Source [SID1234522524]). In this role, he will oversee all clinical research and development activities.

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"We welcome Cadmus to our team during a pivotal time at Aura," said Elisabet de los Pinos, Ph.D., founder and CEO of Aura. "As Chief Medical Officer, Cadmus will play an instrumental role as we continue to advance our Phase 1b/2 clinical trial of light-activated AU-011, following release of positive interim safety data last month. We look forward to drawing on his extensive expertise leading product development and commercialization initiatives in ophthalmology."

Dr. Rich joins the company from Inotek Pharmaceuticals, where he was Vice President, Medical Affairs and Clinical Development, responsible for development of therapies to treat glaucoma and other serious eye diseases. Prior to Inotek, Dr. Rich held key leadership roles at Alcon, most recently as a Therapeutic Unit Head leading the intraocular lenses team and prior to this, as Global Head of Pharmaceutical Clinical Trial Management. At Alcon, he managed many development programs and clinical trials; therapeutic and device submissions; and approvals for six drugs and five devices in a number of international markets. Before that, he established a new center of excellence in ophthalmology at Quintiles Transnational (now IQVIA), the world’s largest contract research organization.

Dr. Rich earned a bachelor’s degree in psychology from Case Western Reserve University; a Doctor of Medicine from the University of North Carolina (UNC) School of Medicine, Chapel Hill; and a Master of Business Administration from Regis University. He completed his ophthalmology residency at the UNC Department of Ophthalmology, Chapel Hill and additionally, is a Certified Physician Executive. He serves on the national board of directors of Prevent Blindness, a volunteer eye health and safety organization dedicated to fighting blindness and saving sight.

"I’m pleased to help lead the important work that Aura is advancing in ocular melanoma, which has no FDA-approved, targeted therapies," said Dr. Rich. "In partnership with our global network of ocular oncology experts, we are striving to provide a novel option for early treatment intervention of this rare disease."

Aura also announced today that Alison Lawton has resigned from her role as Chief Operating Officer to pursue other opportunities. She will remain an advisor to Aura.

About ocular melanoma
Ocular melanoma, also known as uveal or choroidal melanoma, is a rare and aggressive eye cancer. Ocular melanoma is the most common primary ocular tumor and develops in the uveal tract of the eye. No targeted therapies are available at present, and current radiotherapy treatments can be associated with severe visual loss and other long-term sequelae such as dry eye, glaucoma, cataracts and radiation retinopathy. The most common current treatment is plaque radiotherapy, which involves surgical placement of a radiation device against the exterior of the eye over the tumor. This technique can control the melanoma but can also lead to radiation-related cataract, retinopathy, optic nerve damage and loss of vision. The alternative is enucleation, or removal of the eye. Ocular melanoma metastasizes to the liver in about 40 percent of cases in the long-term (source: OMF), and only 15 percent of patients whose melanoma has metastasized survive beyond five years after diagnosis (source: ACS).

About light-activated AU-011
AU-011 is a first-in-class targeted therapy in development for the primary treatment of ocular melanoma. The therapy consists of viral nanoparticle conjugates that bind selectively to unique receptors on cancer cells in the eye and is derived from technology originally pioneered by Dr. John Schiller of the Center for Cancer Research at the National Cancer Institute (NCI), recipient of the 2017 Lasker-DeBakey Award. Upon activation with an ophthalmic laser, the drug rapidly and specifically destroys the membranes of tumor cells while sparing key eye structures, which may allow for the potential of preserving patients’ vision and reducing other long term complications of treatment. This therapy can be delivered in the ophthalmologist’s office and does not require a surgical procedure, enabling a less invasive, more convenient therapy for patients and physicians. AU-011 for ocular melanoma has been granted orphan drug and fast track designations by the U.S. Food and Drug Administration and is currently in clinical development.

On December 11, 2017 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data from research led by The University of Texas MD Anderson Cancer Center demonstrating that CG’806, a highly potent pan-FLT3/pan-BTK inhibitor, exerts a profound anti-leukemia effect in human and murine leukemia cell lines harboring FLT-3 ITD mutations, mutations that are usually associated with very poor prognoses in leukemia patients. In addition, CG’806 demonstrates apoptosis, or programmed cell death, in AML patient samples by several mechanisms and is able to overcome resistance that is seen with other FLT3 inhibitors (Press release, Aptose Biosciences, DEC 11, 2017, View Source [SID1234522545]). The data were highlighted in poster presentations on Sunday and Monday, December 10 and 11, 2017 at the American Society of Hematology (ASH) (Free ASH Whitepaper) 59th Annual Meeting & Exposition, being held December 9-12 in Atlanta, GA.

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The poster The Pan-FLT3/BTK Multi-Kinase Inhibitor CG’806 Induces AML Killing in FLT-Mutant and Wild Type Cells, and Exerts Synergistic Pro-Apoptotic Effects with Concomitant Targeting of Anti-Apoptotic Bcl-2 and/or Mcl-1 demonstrated pronounced anti-leukemia activity of CG’806 against a broad array of AML cells, including those with FLT3-wild type, FLT3 with single mutations, or with FLT3 harboring dual ITD plus D835 or ITD plus F691 mutations, and it demonstrated synergistic effects in combination with Bcl-2 or Mcl-1 inhibitors even in FLT3 mutated AML cells. CG’806 elicited its broad spectrum killing of AML cells through its ability to suppress the FLT3 pathway as well the BTK, AURK, AKT and ERK signaling pathways that are differentially operative in different AML cells. Notably, CG’806 maintained cytotoxic activity against AML cells in the presence of FLT3 ligand and bone marrow stromal cells, and CG’806 demonstrated dose-dependent in vivo antitumor activity in a circulating AML murine model.

The poster CG’806, a Novel Pan-FLT3/BTK Multi-Kinase Inhibitor, Induces Cell Cycle Arrest, Apoptosis or Autophagy in AML Cells Depending on FLT3 Mutation Status further elucidated the anti-leukemia effect of CG’806. CG’806 exerted profound suppression of cell proliferation through G1 cell cycle arrest and induction of apoptosis in FLT3-mutant AML cells, which is associated with inhibition of mutant FLT3 signaling and the downstream p-AKT/p-mTOR/cyclin D1/p-Rb signaling axis. In contrast, CG’806 exerted a G2/M arrest in FLT3-wildtype (WT) cells through inhibition of aurora (AURK) and BTK kinases and induction of non-apoptotic cell death (autophagy or polyploidy). CG’806 sensitized AML cells to standard chemotherapeutic agents cytarabine and idarubicin and significantly enhanced pro-apoptotic effects. Taken together, these data support the development of CG’806 for a diverse set of AML patients with FLT3-ITD, FLT3-ITD plus additional TKD/gatekeeper mutations, as well as FLT3-WT.

Data were presented by members of the research team led by Michael Andreeff, M.D., Ph.D., Professor of Medicine, Haas Chair in Genetics, Department of Leukemia, at The University of Texas MD Anderson Cancer Center.

The poster presentations can be accessed on the Events & Presentations section of the Aptose website at the following link.

"As our mechanistic understanding of CG’806 grows, we are beginning to construct a framework of how a single molecule can inhibit specific clusters of kinases and kill a heterogeneous group of AML cells without observed toxicity to normal cells," commented William G. Rice, Ph.D., Chairman and Chief Executive Officer of Aptose. "As a pan-FLT3/pan-BTK multi-kinase inhibitor, CG’806 has the ability to kill a broad range of AML cells through inhibition of multiple oncogenic pathways that are differentially expressed in subgroups of cells. It appears to overcome the limitations of competitive FLT3 inhibitory agents, to enhance the AML cell killing effects of certain other chemotherapies, and to exhibit a robust therapeutic index. We look forward to initiating clinical trials of CG’806 in 2018."

Separately, Aptose and Oregon Health & Science University Knight Cancer Center researchers also announced new data on CG’806 presented at ASH (Free ASH Whitepaper) (see press release here).

In addition to the abstracts that were presented at ASH (Free ASH Whitepaper), two additional abstracts on CG’806 and two abstracts on APTO-253, Aptose’s small molecule c-Myc Inhibitor, have been published on the ASH (Free ASH Whitepaper) abstracts site. All abstracts will become part of the permanent ASH (Free ASH Whitepaper) and Blood abstracts archive.

About CG’806

CG‘806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor. This small molecule demonstrates potent inhibition of all wild type and mutant forms of FLT3 tested (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates AML tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with FLT3-driven AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B cell malignancies, suggesting CG’806 may be developed for CLL and MCL patients that are resistant/refractory/intolerant to covalent BTK inhibitors.

On December 11, 2017 MacroGenics, Inc. (NASDAQ:MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported the presentation of clinical data from its ongoing Phase 1 study of flotetuzumab in an oral session at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, MacroGenics, DEC 11, 2017, View Source [SID1234522556]). John E. Godwin, M.D., Program Leader, Hematologic Malignancies at Earle A. Chiles Research Institute at Providence Cancer Center in Portland, Oregon presented "Preliminary Results of a Phase 1 Study of Flotetuzumab, a CD123 x CD3 Bispecific DART Protein, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome."

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The ongoing Phase 1, first-in-human study of flotetuzumab was designed to determine safety, tolerability, maximum tolerated dose and initial anti-leukemic activity in patients with relapsed or refractory acute myeloid leukemia (AML) or intermediate-2/high risk myelodysplastic syndrome (MDS). To date, a total of 57 patients have been enrolled, including 11 AML patients in the dose expansion cohort.

Consistent with the dose escalation data that was previously presented at ESMO (Free ESMO Whitepaper) Congress 2017 in September, flotetuzumab has continued to demonstrate acceptable tolerability in patients treated to date in the dose expansion cohort. Infusion-related reaction and cytokine release syndrome (CRS) were the most common adverse events observed, with Grade 3 CRS occurring in 9 of 57 patients (15.8%). Implementation of a two-step, lead-in dose as well as early intervention with anti-cytokine therapy has helped to limit the severity and incidence of CRS.

As of the data cut-off date, of the eight evaluable patients in the dose expansion cohort who received a lead-in dose followed by 500 ng/kg/day of flotetuzumab via continuous IV infusion, six patients (75%) have evidence of anti-leukemic activity, with three of these patients experiencing an objective response. This included two patients who experienced CR/CRi and one patient who achieved MLF (morphologic leukemia-free state).

The duration of response for the eight patients who have achieved a MLF, CRi or CR in the dose escalation and dose expansion cohorts ranged from 1.0 to 5.8 months, with five of these responses still ongoing as of the November 30, 2017 data cut-off.

Further, in a translational data poster presentation, MacroGenics also described studies that support a rationale for using checkpoint blockade as an approach to potentially enhance the anti-leukemic activity of flotetuzumab. Among these findings, modulation of the PD-1/PD-L1 pathway was observed in patients treated with flotetuzumab, and the combination of flotetuzumab and PD-1/PD-L1 inhibitors was shown to synergistically enhance T-cell mediated cytotoxicity against AML cell lines in vitro.

"We continue to be encouraged by the tolerability and anti-leukemic activity of flotetuzumab as well as by the early data regarding the durability of responses observed in patients from our ongoing Phase 1 study of flotetuzumab," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "In addition, given the data-supported rationale for combining flotetuzumab with anti-PD-1, we intend to initiate a combination study with the anti-PD-1 mAb, MGA012, in the coming months, while we continue to enroll the AML and MDS dose expansion cohorts. We look forward to sharing additional flotetuzumab clinical data in 2018."

The presentation at the 59th Annual ASH (Free ASH Whitepaper) meeting is available for download from the Events & Presentations page on MacroGenics’ website at View Source

About Flotetuzumab

Flotetuzumab (also known as MGD006 and S80880) is a clinical-stage molecule that recognizes both CD123 and CD3. CD123, the Interleukin-3 receptor alpha chain, has been reported to be over-expressed on cancer cells in a wide range of hematological malignancies, including AML and MDS. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cancer cells.

Flotetuzumab is currently being evaluated at 13 clinical sites in the U.S. and Europe in a Phase 1 study designed to assess the safety, tolerability, maximum tolerated dose and initial anti-leukemic activity of the molecule in patients with relapsed/refractory AML or intermediate-2/high risk MDS. MacroGenics retains full development and commercialization rights to flotetuzumab in the U.S., Canada, Mexico, Japan, South Korea and India. Servier participates in the development of flotetuzumab and has exclusive rights to this molecule in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the treatment of AML.

On December 11, 2017 RXi Pharmaceuticals Corporation (NASDAQ: RXII) reported that it has entered into a research collaboration with Medigene AG (MDG1, Frankfurt, Prime Standard, TecDAX) to explore potential synergies of using RXi’s self-delivering RNAi technology (sd-rxRNA) in combination with Medigene’s recombinant TCRs to develop modified T cells with enhanced efficacy and/or safety (Press release, RXi Pharmaceuticals, DEC 11, 2017, View Source [SID1234522533]). The preclinical research program will examine the applicability of RXi’s sd-rxRNA technology to be integrated into Medigene’s process to produce receptor-modified T cells with the ultimate goal to further improve Medigene’s T cell therapies for the treatment of cancer patients.

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Research teams at Medigene will closely work together with the scientists at RXi to explore potential advantages of transient down regulation of certain genes ("knock down") to prevent negative regulation of T cells expressing a recombinant TCR directed against a predefined tumor antigen. The two complementing technologies could lead to synergistic effects that might further sharpen and improve the therapeutic effects of Medigene’s receptor-modified T cells.

Markus Dangl, Senior Vice President Research and Preclinical Development of Medigene AG, comments: "We are very happy that we found a partner that is fully aligned with our vision to further improve our adoptive T cell therapy approach. We are convinced that this technology can help us to develop the next generation of recombinant T cells that are highly efficacious, also in challenging solid tumor environments. These T cells will contain features that have the potential to further enhance the efficacy and safety of our approach to bring highly beneficial cellular therapies to the market."

Dr. Geert Cauwenbergh, President and CEO of RXi Pharmaceuticals, adds: "We are excited to start this new collaboration. Medigene’s adoptive cell therapy, using their TCR platform, is a very attractive and promising development in immuno-oncology; and we are pleased with their decision to use our sd-rxRNA technology in combination with their TCR approach. The use of our immuno-oncology sd-rxRNA compounds with their receptor-modified T cells could potentially create a next generation of very powerful adoptive cell therapies against serious cancers that currently are difficult to target."

About Medigene’s TCR technology: The TCR technology aims at arming the patient’s own T cells with tumor-specific T-cell receptors. The receptor-modified T cells are then able to detect and efficiently kill tumor cells. This immunotherapy approach attempts to overcome the patient’s tolerance towards cancer cells and tumor-induced immunosuppression by activating and modifying the patient’s T cells outside the body (ex vivo).

TCR therapy is developed to utilize a higher number of potential tumor antigens than other T cell-based immunotherapies, such as chimeric antigen receptor T cell (CAR T) therapy. Medigene is preparing the clinical development of its first TCR candidates and is establishing a pipeline of recombinant T-cell receptors, and has established Good Manufacturing Practice (GMP)-compliant processes for their combination with patient-derived T cells.

Medigene AG (FSE: MDG1, ISIN DE000A1X3W00, Prime Standard, TecDAX) is a publicly listed biotechnology company headquartered in Martinsried near Munich, Germany. The company is developing highly innovative immunotherapies to target various forms and stages of cancer. Medigene concentrates on the development of personalized T cell-based therapies, with associated projects currently in pre-clinical and clinical development.

For more information, please visit View Source

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