On October 19, 2015 Pfizer Inc. reported that investigational antibody-drug conjugate (ADC) inotuzumab ozogamicin received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for acute lymphoblastic leukemia (ALL) (Press release, Pfizer, OCT 19, 2015, View Source [SID:1234507735]).

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The Breakthrough Therapy designation was based on the results of the Phase 3 INO-VATE ALL trial, which enrolled 326 adult patients with relapsed or refractory CD22-positive ALL and compared inotuzumab ozogamicin to standard of care chemotherapy. Topline results from the trial were announced in April 2015 and also presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper).

"Inotuzumab ozogamicin is the third Pfizer oncology medicine to be granted Breakthrough Therapy designation by the FDA, underscoring our commitment to innovative research and development that addresses significant unmet needs. Breakthrough Therapy designation will allow us to work more closely with the FDA to bring this important therapy to patients as rapidly as possible," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "Advancing therapies for patients with adult acute lymphoblastic leukemia is crucial as only 10 percent of adults with ALL who relapse after first-line therapy survive five years or more with current treatment options."1

Enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA), Breakthrough Therapy designation is intended to expedite the development and review of a potential new medicine if it is "intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies."2 The Breakthrough Therapy designation is distinct from the FDA’s other mechanisms to expedite drug development and review.3

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with high unmet need and a poor prognosis in adults.4The current standard treatment is intensive, long-term chemotherapy.5 In 2015, it is estimated that 6,250 cases of ALL will be diagnosed in the United States6, with about 1 in 3 cases in adults. Only approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.7 For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.8

About Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22,9 a cell surface antigen expressed on approximately 90 percent of B-cell malignancies,10 linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.11

Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development and commercialization activities for this molecule.

On October 19, 2015 OXiGENE, Inc. (Nasdaq:OXGN), a biopharmaceutical company developing novel cancer therapeutics, reported the presentation of interim phase 2 data for the company’s lead investigational drug, CA4P (also known as fosbretabulin) (Press release, OXiGENE, OCT 19, 2015, View Source [SID:1234507734]). The data were presented in a poster session on October 16 at the North American Neuroendocrine Tumor Society (NANETS) Annual Symposium in Austin, Texas.

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Interim data from the first nine subjects in the study suggested that CA4P monotherapy may improve biomarkers and quality of life (QOL) measures. Additionally, CA4P appears to be relatively well tolerated by subjects. The poster also notes that results are preliminary, due to the small number of subjects analyzed at this point.

"The encouraging interim results seen in this Phase 2 study add to the body of evidence showing that CA4P has a positive effect in the treatment of solid tumors," said William D. Schwieterman, MD, OXiGENE’s President and CEO. "We look forward to full results from this trial anticipated in the second half of 2016, as we simultaneously move to advance CA4P in later-stage trials in our core programs for ovarian cancer and glioblastoma multiforme, which will evaluate CA4P in combination with complementary, approved anti-angiogenic agents."

The poster presentation, entitled "Phase 2 study (OX4218s) of fosbretabulin tromethamine (CA4P) for the treatment of well-differentiated, low-to-intermediate-grade unresectable, recurrent or metastatic pancreatic or gastrointestinal neuroendocrine tumors/carcinoid (PNETs or GI-NETs) with elevated biomarkers," was authored by Steven K. Libutti, MD1, Lowell Anthony, MD2, Julie Ann Sosa, MD3, Pamela Kunz, MD4, James Thomas, MD, PhD5, Susan A. Cruikshank6, Alice Varga6, David J. Chaplin, PhD6, James Burke, MD6, and Edward M. Wolin, MD2. A copy has been posted to the company’s website under "Presentations."

About CA4P

CA4P (also known as fosbretabulin), is a vascular disrupting agent (VDA) and is OXiGENE’s lead investigational drug. CA4P exerts its anti-tumor effects by targeting an established tumor’s immature endothelial cells within the tumor’s blood vessels, compromising the tumor vasculature and leading to widespread ischemia and necrosis of the cells within the central core of the tumor. OXiGENE plans to advance CA4P in clinical development in combination with approved anti-angiogenic agents which prevent the growth of new tumor blood vessels. Following an extensive clinical review, OXiGENE recently announced its plans to focus on initiation of two late-stage clinical programs for CA4P in 2016. These planned programs would combine CA4P with standard-of-care in platinum-resistant ovarian cancer and in glioblastoma multiforme. CA4P is also being evaluated in ongoing studies in neuroendocrine tumors and in recurrent ovarian cancer.

On October 19, 2015 Galectin Therapeutics, Inc. (Nasdaq: GALT), the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, reported that Providence Cancer Center has filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to study GR-MD-02 in combination with Keytruda (pembrolizumab), an immune checkpoint inhibitor, in a Phase 1b study of patients with advanced refractory metastatic melanoma (Filing, 8-K, Galectin Therapeutics, OCT 19, 2015, View Source [SID:1234507733]). GR-MD-02 binds to and inhibits galectin proteins, predominantly galectin-3 (Gal-3). Galectin will provide GR-MD-02 to the investigators, who are funding the costs of this study.

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The IND filing was prompted by findings from preclinical studies led by tumor immunology expert William L. Redmond, Ph.D. of the Providence Cancer Center’s Earle A. Chiles Research Institute. That study found that GR-MD-02 increased tumor shrinkage and enhanced survival in immune competent mice with multiple types of cancers when combined with one of the immune checkpoint inhibitors, anti-CTLA-4 or anti-PD-1. Pembrolizumab (anti-PD-1) was approved by the FDA in September 2014 to treat patients whose melanoma had progressed after treatment with Yervoy (ipilimumab) or targeted therapy in melanomas that have a BRAF mutation. GR-MD-02 is also the subject of an ongoing Phase 1b study in combination with Yervoy in patients with malignant melanoma, also by Providence Cancer Center. Details of the study design can be found at clinicaltrials.gov: here

"This proposed study will be the second involving a checkpoint inhibitor in combination with GR-MD-02, and we are very pleased to reach this milestone with the investigators at the Portland Cancer Center," said Peter G. Traber, M.D., president, chief executive officer and chief medical officer of Galectin Therapeutics. "Preclinical data show that GR-MD-02 holds potential to increase the effectiveness of other therapies and represents a promising approach to enhance cancer immunotherapy."

Pending FDA review of the IND, the Phase 1b study will be conducted by the Providence Cancer Center under principal investigator Brendan D. Curti, M.D., director of the Providence Biotherapy Program. Providence Cancer Center researchers have been leaders in immunotherapy research and translational clinical trials in melanoma and other cancers.

"Clinical research has shown that therapeutic combinations involving checkpoint inhibitors have improved outcomes in patient survival. The Phase 1b study will determine if GR-MD-02 enhances the probability of melanoma response with pembrolizumab by inducing proliferation, activation and memory function of CD8+ T cells," said Dr. Curti. "The combination of GR-MD-02 and pembrolizumab has a strong scientific rationale based on Dr. Redmond’s laboratory work. This study represents a novel approach for patients with metastatic melanoma and complements our similar study of GR-MD-02 in combination with Yervoy."

Study Design
The proposed Phase 1b study is expected to enroll 16 to 22 patients with advanced melanoma whose disease has progressed after treatment with ipilimumab and/or BRAF-targeted therapy in melanomas with a BRAF mutation, and is designed to determine a safe dose of GR-MD-02 in combination with the approved dose of pembrolizumab (2 mg/kg). The study will employ a 3+3 Phase 1 design with dose escalation of GR-MD-02 beginning with 2 mg/kg in the first cohort and increasing to 8 mg/kg, depending on toxicity. In addition to monitoring for toxicity and clinical response, blood samples will be obtained to assess immunologic measures relevant to galectin biology and pembrolizumab T-cell checkpoint inhibition. Galectin Therapeutics will supply researchers with supporting analysis of the pharmacokinetics of GR-MD-02 and the right to reference the Company’s open IND on GR-MD-02.
Yervoy is a registered trademark of Bristol-Myers Squibb. Keytruda is a registered trademark of Merck.

About Metastatic Melanoma
Melanoma, the most dangerous form of skin cancer, is one of the most widespread cancers among young adults. Metastatic melanoma occurs when the cancer cells spread (or metastasize) through the lymph nodes to other parts of the body. The liver, lungs, bones and brain are most often affected by these metastases. The American Cancer Society estimates that there were more than 76,000 new diagnoses and 9,100 deaths from melanoma in the United States in 2012.

On October 19, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that yesterday it presented positive preclinical data demonstrating the promising potential of its lead product candidate VAL-083 (dianhydrogalactitol) as a treatment for ovarian cancer (Press release, DelMar Pharmaceuticals, OCT 19, 2015, View Source [SID:1234507732]).

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The Company presented data from its collaboration with researchers at MD Anderson Cancer Center in a poster entitled, "A Comparison of the Mechanisms and Cytotoxic Activity of Dianhydrogalactitol (VAL-083) to Cisplatin in Ovarian Tumor Models Harboring Wild-type and Mutant p53," at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Advances in Ovarian Cancer Research: Exploiting Vulnerabilities Conference.

The data demonstrate the effectiveness of VAL-083 against cisplatin-resistant ovarian cancers and raise the potential for VAL-083 as a treatment for ovarian cancers as a single-agent against platinum-resistant tumors or in combination with platinum-based chemotherapeutic regimens.

VAL-083 is a bi-functional alkylating agent, whose cytotoxic activity is due to the formation of DNA cross links at the N7 position of guanine. Unlike platinum-based chemotherapies such as cisplatin, carboplatin and oxaliplatin, which predominantly form intrastrand DNA cross-links, VAL-083 is believed to derive its anti-cancer activity via interstrand DNA cross-links, which leads to a distinct downstream of biological events within the tumor leading to apoptosis and cancer cell death. In prior NCI-sponsored clinical studies, VAL-083 demonstrated clinical activity against a range of tumor types, including ovarian cancer.

"These data represent another success in our strategy to leverage VAL-083’s historical clinical data with contemporary biological research to address significant unmet medical needs in the modern treatment of cancer," stated Jeffrey Bacha, president & CEO of DelMar Pharmaceuticals.

"Onset of drug resistance is a major factor limiting the clinical utility of platinum-based therapeutic regimens. Such regimens form the basis of ovarian cancer treatment and produce an initial 70% response rate. Unfortunately, many patients experience relapse as their cancer becomes resistant to currently available chemotherapy. The average duration of survival after recurrence of ovarian cancer is about 12 to 18 months with fewer than one in ten patients surviving beyond five years following standard salvage chemotherapy treatment," added Mr. Bacha. "We believe that these data, coupled with evidence of historical clinical activity against ovarian cancer, represent the promise of VAL-083 to address a major modern unmet medical need by providing a potential new treatment option for ovarian cancer patients whose tumors exhibit resistance to platinum-based therapy."

Platinum drug resistance is normally ascribed to several mechanisms. The current study investigated the activity of VAL-083 in multiple ovarian cancer models including both cisplatin-sensitive (A2780); and cisplatin-resistant (2780CP-16, OVCAR-10, Hey and OVCA-433) phenotypes in vitro. The data support the potential of VAL-083 to circumvent drug-resistance in the treatment of ovarian cancer.

DelMar previously reported that the combination of VAL-083 and cisplatin demonstrated significant super-additivity (p<0.05) in animal models of non-small cell lung cancer (NSCLC) and synergy (CI < 1) in vitro.

Mr. Bacha continued, "We have a growing body of evidence indicating that, in comparison to platinum-based chemotherapy, the anti-cancer mechanism of VAL-083 is less dependent on, or independent of, wild-type p53. The current ovarian study provides additional proof that there is a lack of cross-resistance between cisplatin and VAL-083 further suggesting distinct modes of action for the two drugs. Importantly, the non-overlapping mechanisms of action support the potential of VAL-083 in the treatment of platinum-resistant cancers as well as the potential for therapeutic benefit in combining VAL-083 with platinum-based chemotherapy regimens."

HIGHLIGHTS OF DELMAR’S PRESENTATION

VAL-083 demonstrated cytotoxic activity in all tested ovarian cancer cell lines, including cisplatin-resistant cell lines, in vitro;
VAL-083 is significantly less dependent on wild-type p53 for its activity than both cisplatin and oxaliplatin, and appears to have a distinct mode of action;
VAL-083 exhibits significantly different cytotoxic-related cell-signaling patterns against resistant tumor phenotypes in comparison to platinum-based chemotherapy, in vitro;
VAL-083 displays significant synergy with cisplatin in vitro; and
Taken together, these results support VAL-083 as a viable treatment option for ovarian cancer patients failing platinum-based therapy, and suggests a potential benefit of a VAL-083 + platinum combination therapy.

SUMMARY

VAL-083 activity in five wild-type p53 ovarian cancer cell lines
The activity of VAL-083 was examined in five ovarian cancer cell lines: including one cisplatin-sensitive (A2780), and four cisplatin-resistant (2780CP-16, OVCAR-10, Hey and OVCA-433) tumors in vitro. The relative tumor-killing effect (IC50) was compared in cisplatin-sensitive versus cisplatin-resistant cell-lines. VAL-083 maintained significantly greater cytotoxic activity in comparison to cisplatin. These results demonstrate a lack of significant cross-resistance between cisplatin and VAL-083, further suggesting distinct modes of action for VAL-083.

Limited dependence of VAL-083 on p53 status
The dependence on p53 status was investigated in isogenic models with (HCT-116p53-/-) or without (HCT-116p53+/+) p53 knockout. Loss of p53 increased resistance to cisplatin and oxaliplatin by 3- and 6-fold, respectively, whereas the increase in resistance to VAL-083 was <2-fold. These data suggest that the cytotoxic a mechanism of VAL-083 that is much less dependent on, or independent of, p53.

VAL-083 signaling is distinct from platinum-based chemotherapy in drug-resistant ovarian tumors
Resistance to platinum-based chemotherapy can also arise in tumors bearing wild-type (non-mutant) p53 due to other factors effecting p53 function, such failure to induce downstream regulation of checkpoint proteins or activation via phosphorylation of p53 itself. VAL-083 and cisplatin demonstrate similar effects on p53 induction and activation via phosphorylation and CHK2-related p21 induction in p53 wild-type cisplatin-sensitive (A2780) ovarian cancer cells. However, in cisplatin-resistant (2780CP-16) ovarian cancer cells, only VAL-083 caused significant activation of p53 and p21, and induced greater Ser-15 and Ser-20 phosphorylation of p53, all of which are hallmarks of cytotoxic DNA damage. This further supports the conclusion of distinct modes of action for VAL-083 versus platinum-based chemotherapy and activity against platinum-resistant cancer phenotypes.

Combination of VAL-083 with platinum-based chemotherapy in p53 mutant H1975 NSCLC
The combination of VAL-083 with either cisplatin or oxaliplatin in the human H1975 model demonstrated significant super-additivity (p<0.05) and synergy (CI<1). These results suggest non-overlapping mechanism of action between the platinum drugs and VAL-083, and support the potential for synergistic benefit for a combination of VAL-083 and platinum-based therapies in the treatment of cisplatin resistant cancers.

The Company’s poster presentation from AACR (Free AACR Whitepaper) Advances in Ovarian Cancer Research and other VAL-083 posters and scientific publications may be found on DelMar’s website under View Source

On October 19, 2015 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, reported the expansion of its pipeline with the addition of two programs, the first of which is an oral, small molecule immune checkpoint antagonist targeting programmed death ligand-1 (PD-L1) and V-domain Ig suppressor of T cell activation (VISTA), and the second is focused on inhibitors of Interleukin-1 receptor-associated kinase 4 (IRAK4) (Press release, Curis, OCT 19, 2015, View Source [SID:1234507731]).

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The additions to the pipeline come through the Company’s exercise of its options under a collaboration agreement with Aurigene announced earlier this year. In the area of immuno-oncology, Curis exercised its option to exclusively license a first-in-class oral, small molecule antagonist designated as CA-170 that targets PD-L1 and VISTA, which function as negative checkpoint regulators of immune activation. CA-170 was selected from the broad PD-L1 antagonist program that the companies have been engaged in since the collaboration was established in January 2015.

Curis also exercised its option to exclusively license a program of orally available small molecule inhibitors of IRAK4 kinase. IRAK4 is a serine/ threonine kinase involved in the regulation of innate immune responses and also plays an important role in certain hematologic cancers. IRAK4 is inappropriately activated, and drives pro-survival and cytokine mediated pathways in cancers such as activated B cell-diffuse large B cell lymphoma (ABC-DLBCL), an aggressive form of lymphoma with poor prognosis. Targeting IRAK4 has potential therapeutic implications in both cancer and cytokine-driven inflammatory and autoimmune diseases.

The exercise of options for the PD-L1/VISTA and IRAK4 programs resulted in an aggregate one-time payment of $6 million by Curis to Aurigene in exchange for an exclusive, royalty-bearing license to develop, manufacture and commercialize compounds from the programs, including the development candidate, CA-170 and products containing such compounds, anywhere in the world with the exception of India and Russia, where Aurigene will hold an exclusive, royalty-free, fully paid license to commercialize such compounds.

Additionally, Curis has selected a second preclinical program within the immuno-oncology collaboration with Aurigene that is focused on evaluating small molecule antagonists with dual PD-L1 and T-cell immunoglobulin and mucin domain containing protein-3 (TIM-3) targeting properties. TIM-3 is an inhibitory checkpoint molecule that plays an important role in immune suppression and is co-expressed with programmed cell death-1 (PD-1) receptors on highly exhausted cytotoxic T cells in tumor tissues as well as expressed on certain regulatory T cells.

Curis expects that Aurigene scientists will present data from the PD-L1/VISTA immuno-oncology and the IRAK4 programs at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), which will take place Nov. 5-9 in Boston.

"We are pleased with the progress in our collaboration with Aurigene and the small molecule candidates emerging from the PD-L1 antagonist program," said Ali Fattaey, Ph.D., Curis’ President and CEO. "Based on its preclinical profile in multiple in vitro and in vivo activity and safety models, we have selected CA-170 as our clinical candidate. By targeting both PD-L1 and VISTA with CA-170, we potentially have the opportunity to address exhausted T cells as well as other inhibitory immune cells such as myeloid derived suppressor cells or MDSCs, in the tumor microenvironment with one drug candidate. We believe that this property of targeting two unique checkpoint regulators provides CA-170 with the potential to not only address, but potentially expand beyond tumors with PD-L1 overexpression or those that may have relapsed after PD-1/ PD-L1 targeting therapies. Development of CA-170 is a priority for Curis, and we and Aurigene are working diligently to complete the required IND-enabling studies in the coming months. We expect to file an IND and initiate Phase 1 clinical testing of CA-170 during the first half of 2016. We also expect to file an IND for development of the IRAK4 inhibitor within the first half of 2016."

Dr. Fattaey continued, "We are also encouraged with the progress in our second immuno-oncology program that is generating small molecules targeting PD-L1 and TIM3, which may provide for additional opportunities to relieve the inhibitory effects of multiple immune checkpoints on exhausted T cells using our small molecule antagonist approach."

The development of the Company’s immuno-oncology programs will be led by David Tuck, M.D., the Company’s Vice President, Clinical and Translational Sciences. Dr. Tuck joined Curis from EMD Serono in May 2015, where he served as Senior Medical Director in the Oncology Translational Innovation program. Prior to that, Dr. Tuck was employed by Bristol-Myers Squibb Global Oncology Research in the role of Translational Physician for ipilimumab, with a primary focus on external development of immune checkpoint inhibitors in solid tumors and hematological malignancies. Dr. Tuck was previously an Associate Professor at Yale University and Associate Director of the Yale Cancer Center. Dr. Tuck earned his Medical Degree at the University of Vermont School of Medicine and is board certified in internal medicine, medical oncology and hematology.

Dr. Tuck said, "I am excited to lead the development of our immuno-oncology drug candidates and believe that oral, small molecule checkpoint inhibitors may provide a favorable drug profile to better address immune-related adverse events and the potential for combination with other therapies in a convenient manner for patients."