On April 12, 2017 argenx (Euronext Brussels: ARGX), a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported the initiation of a Phase II trial of ARGX-110 as a monotherapy in patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) (Press release, arGEN-X, APR 12, 2017, View Source [SID1234518530]). ARGX-110 is the Company’s SIMPLE Antibody targeting CD70.

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"We have previously observed evidence of biological activity and a promising safety profile in several CD70-positive CTCL patients treated in an ongoing Phase I safety-expansion cohort, resulting in several patients with partial response or stable disease. Based on these preliminary results, we opted to further evaluate ARGX-110 as a monotherapy in an exploratory Phase II study to demonstrate the intrinsic activity of the drug in relapsed/refractory CTCL patients and to broaden our efficacy database," commented Nicolas Leupin, CMO of argenx. "This marks the second Phase 1/2 study of ARGX-110 with the first having launched in December 2016 as a combination therapy with standard of care in AML."

The Phase II clinical trial will enroll up to 10 additional relapsed/refractory CTCL patients, and will be conducted at multiple centers in Europe. The primary endpoints of the trial are safety and efficacy and secondary endpoints include pharmacokinetics and immunogenicity. Interim data are expected by the end of 2017, and we expect to report topline data in the second half of 2018.

ARGX-110 is also being studied as a combination therapy with standard of care azacitidine in newly diagnosed, elderly acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) patients.

About ARGX-110

ARGX-110 is a SIMPLE Antibody targeting CD70, an immune checkpoint target involved in hematological malignancies, several solid tumors and severe autoimmune diseases. ARGX-110 works in three ways: i) blocks growth of tumor cells, ii) kills cancer cells and iii) restores immune surveillance against tumors (Silence K. et al. mAbs 2014; 6 (2):523-532). ARGX-110 is currently being evaluated in a Phase II combination trial in patients with newly diagnosed acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome and a Phase II trial in patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL). Preclinical work on ARGX-110 in AML was done in collaboration with the Tumor Immunology Lab of Prof. A. F. Ochsenbein at the University of Bern, who won together with Prof Manz from the University Hospital of Zürich, the prestigious 2016 Otto Naegeli Prize for his breakthrough research on CD70/CD27 signaling with therapeutic potential for cancer patients.

About CTCL

Lymphoma is the most common type of blood cancer. TCL accounts for 6% of all cases of lymphoma and can be divided into subtypes such as peripheral TCL (PTCL), angioimmunoblastic TCL (AITL), anaplastic large cell lymphoma (ALCL), and CTCL. According to the Cutaneous Lymphoma Foundation, the incidence of CTCL in the United States is approximately 3,000 new cases per year. The two most common types of CTCL are mycosis fungoides, representing approximately 50% of CTCL patients, and a more advanced form known as Sezary syndrome, representing approximately 15% of CTCL patients. In both mycosis fungoides and Sezary syndrome, visible skin lesions offer an ongoing means with which to monitor both the progression of disease and the impact of treatment. Sezary syndrome is distinguished by the presence of malignant lymphocytes in the blood, an extensive rash covering over 80% of the body and tumors visible on the skin.

On April 12, 2017 Kancera reported that PFKFB3-inhibitor KAN0438757 increases the effect of a promising class of drugs for intractable cancer (Press release, Kancera, APR 12, 2017, View Source [SID1234518529]). Kancera has strengthened their development of drugs directed against PFKFB3 and DNA repair through a new recruitment. The European and US patent authorities have announced that a patent will be granted for the PFKFB- inhibitor KAN0438757 and analogues of this substance.

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Kancera, together with the Thomas Helleday group at the Science for Life laboratory, have previously shown that Kancera’s PFKFB3 inhibitor increases the effect of DNA-damaging treatment such as chemotherapy and radiation by antagonizing cell repair functions. This treatment concept has grown strongly with the demonstration that PARP inhibitors, which act by this type of mechanism, have proven successful in the treatment of ovarian cancer, breast cancer and castration-resistant prostate cancer.

PARP-inhibitors, such as Veliparib, are effective against cancers that are defective in their ability to repair DNA (recombination-defective), while cancer that retains this ability resists the same treatment.

Studies now show that cancer cells that are resistant to Veliparib become sensitive to treatment when Veliparib is combined with KAN0438757. This means that Kancera’s PFKFB3 inhibitor in combination with PARP inhibitors can combat more treatment-recalcitrant cancers than PARP inhibitors alone. The reason Kancera PFKFB3 inhibitors increase the effect of Veliparib is that they block cancer cells’ ability to repair DNA.

Since normal, healthy cells are neither recombination-defective nor do they depend on PFKFB3 for their DNA repair function, it is possible that such a combination could be well tolerated with few side effects.

Kancera AB (publ) has employed Nina Gustafsson PhD as expert in the biology of DNA repair. Nina will divide her time between Kancera and Thomas Helleday’s Laboratory at the Karolinska Institute, with main responsibility in the latter as project and team leader. Nina holds a PhD from the Karolinska Institute of Medical Sciences and has received numerous research grants for her work on cancer metabolism and its relationship to DNA repair.

"With the recruitment of Nina Gustafsson we strengthen both Kancera’s expertise in DNA repair and our successful collaboration with the Karolinska Institute on the PFKFB3 project," says Thomas Olin, CEO of Kancera.

Kancera has received advance notice from the patent authorities in the EU and the United States that claimed around PFKFB3 inhibitor KAN0438757 will be granted.

About the PFKFB3 project
The project aims to develop inhibitors of the enzyme PFKFB3 so as to strangle cancer cell energy metabolism and thus render them vulnerable to chemotherapy and radiotherapy. Kancera AB has, together with Professor Thomas Helleday and his research group at Karolinska Institutet, made a surprising discovery that shows how the company inhibitor of PFKFB3 enters the cancer cell’s nucleus and enhances the effects of a newly given dose of radiation.

On April 12, 2017 Transgene (Paris:TNG), a company that designs and develops viral-based immunotherapies, reported that the first patient with soft tissue sarcoma (STS) has been treated in the Phase 2 part of the METROmaJX clinical trial at Institut Bergonié (Bordeaux, France) (Press release, Transgene, APR 12, 2017, View Source [SID1234518528]). METROmaJX is a Phase 1/2 clinical trial evaluating the tolerability and efficacy of the co-administration of Pexa-Vec with metronomic cyclophosphamide (low doses given with high frequency) in patients with advanced solid tumors such as breast cancer and STS (NCT02630368).

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In the Phase 1 part of the trial, the combination of Pexa-Vec and low-dose cyclophosphamide demonstrated a satisfactory tolerability profile, allowing the trial to progress to the Phase 2 part. The results of the Phase 1 part of the study will be presented at upcoming scientific congresses.

The Phase 2 stage of this open-label trial will enroll patients with soft tissue sarcoma (STS) and HER2 negative-breast cancer. It will primarily assess the anti-tumor efficacy of this novel combination regimen. This investigator-initiated trial is supported by INCa (French National Cancer Institute) within the frame of the CLIP² projects.

Pexa-Vec is a GM-CSF expressing vaccinia derived oncolytic virus co-developed by Transgene and SillaJen. Cyclophosphamide is a chemotherapy. Metronomic administration involves giving low doses of the drug at a higher frequency and is known to have an immunomodulating activity.

Pr Antoine Italiano, MD, PhD, from Institut Bergonié, an expert in early phase research and principal investigator of the study, commented: "The METROmaJX trial has confirmed the good tolerability of intravenous administration of the oncolytic virus Pexa-Vec, when associated with low-dose cyclophosphamide. We hope this novel regimen will demonstrate its efficacy in the Phase 2 part of the trial."

The combination of Pexa-Vec and cyclophosphamide aims at targeting two distinct steps in the immune response against cancer cells and has the potential to be significantly more effective than either product alone. Pexa-Vec is an oncolytic virus designed to (i) selectively destroy cancer cells through the direct lysis (breakdown) of cancer cells via viral replication, (ii) reduce the blood supply to tumors through vascular disruption, and (iii) stimulate the body’s immune response against cancer cells. Pexa-Vec’s mechanism of action and its safety profile make it an appropriate candidate for combinations with other immunomodulating therapies to potentially improve its anti-cancer effects.

Maud Brandely, Chief Medical Officer of Transgene, said: "We are grateful to Institut Bergonié and INCa for supporting the METROmaJX trial. We hope that the Phase 2 part of the study will demonstrate that this novel oncolytic virus plus chemotherapy regimen can be synergistic resulting in a high response rate which could translate into improved overall survival. Advanced breast cancer and soft tissue sarcoma are two diseases which clearly require better treatment options for the patients."

April 12, 2017 /CNW/ – Oncolytics Biotech Inc. (TSX:ONC) (OTCQX:ONCYF) reported its initial registration pathway and clinical development plan for REOLYSIN, its proprietary immuno-oncology viral agent. The Company’s clinical development plan has two main objectives. The primary objective is to obtain regulatory approval for REOLYSIN as quickly as possible and is based on the compelling metastatic breast cancer survival data recently presented at the American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, in Washington, D.C. The second objective is to expand REOLYSIN into commercially valuable new treatment areas that include immunotherapy and immunomodulatory (IMiD) agents in collaboration with pharmaceutical partners.

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Registration Path in Metastatic Breast Cancer
At AACR (Free AACR Whitepaper) the Canadian Cancer Trials Group (CCTG) presented positive overall survival (OS) data from an open-label, randomized, phase 2 study assessing the therapeutic combination of intravenously-administered REOLYSIN given in combination with the chemotherapy agent paclitaxel versus paclitaxel alone, in patients with advanced or metastatic breast cancer (IND 213). Based on CCTG’s compelling clinical results in this indication, where the combined treatment demonstrated a statistically significantly increase in median OS, the Company has consulted with key opinion leaders to develop a registration strategy. Management believes that these results are the most compelling data generated by the Company to date and will support a rapid route to market in an important therapeutic area.

The 74-patient study, powered to 90% and designed by the CCTG, reported that in the intention-to-treat patient population there was a statistically significant improvement in median OS from 10.4 months on the control arm to 17.4 months on the test arm (Hazard Ratio 0.65, 80% CI 0.46-0.91, p=0.1). The presentation also indicated that of the 74 patients in the study, 82 percent (61 patients) presented with mutated p53 tumors. The results showed that patients with mutant p53 metastatic breast cancer who were treated with REOLYSIN in combination with paclitaxel (n=30) had a median OS of 20.9 months versus 10.4 months in patients treated only with paclitaxel (n=31) (Hazard Ratio 0.52, 80% CI 0.35-0.76, p = 0.03).

The Company intends to present this data to regulators as part of an End-of-Phase 2 Meeting with a focus on obtaining scientific advice to support a registration pathway. Specific features of any future clinical studies are expected to include: overall survival as a primary endpoint; other exploratory endpoints to identify potential markers of response; and a trial design to ensure a sufficient number of patients are run to reach a statistically significant outcome while balancing the financial resources required.

"We have developed a comprehensive clinical plan for REOLYSIN predicated on its mechanism of action, excellent safety profile with more than one thousand patients treated and the compelling overall survival data recently announced in metastatic breast cancer," said Dr. Matt Coffey, President and CEO of Oncolytics. "The registration path in the near term will look at combinations of REOLYSIN and chemotherapy agents, beginning with metastatic breast cancer. In parallel, we intend to look at other pillars of the platform and our long-range focus for REOLYSIN includes establishing collaborations with large pharma to study both immunotherapy and immunomodulatory drug combinations, such as the recently announced collaboration with Myeloma UK and Celgene using Revlimid and Imnovid in combination with REOLYSIN in myeloma patients."

Mechanism of Action
REOLYSIN is a first-in-class, systemically administered, immuno-oncology viral agent with a robust safety history. During the last few years, in both single-arm and randomized phase 2 clinical studies, REOLYSIN, in combination with various chemotherapeutic agents, has shown a trend to improve OS in certain indications and patient populations, while having a limited impact on objective response rate (ORR) or progression-free survival (PFS). This therapeutic profile is consistent with those observed with approved immunotherapies, where patients receive OS benefit, the gold standard of registrational endpoints, without seeing meaningful improvements in ORR or PFS.

REOLYSIN has multiple components to its mechanism of action (MOA):

· Direct tumor lysis – selective viral replication in permissive cancer cells leading to tumor cell lysis;
· Innate immune response – viral replication resulting in a cascade of chemokines/cytokines causing NK (natural killer) cells to recognize and attack cancer cells; and
· Adaptive immune response – antigen presenting cells (APCs) display tumor-associated antigens (TAA) and viral-associated antigens (VAA) to educate T-cells to recognize and destroy cancer cells.
Clinical Development Plan
Based on Oncolytics’ evolving understanding of REOLYSIN’s mechanism of action, along with survival data generated to date, the Company is dedicated to the metastatic breast cancer program as its primary focus to quickly move the agent towards a commercial path. In parallel, management has identified two additional pathways that will be advanced simultaneously in collaboration with large pharma colleagues to support the second objective of expanding REOLYSIN into commercially valuable new treatment areas:

Combinations with IMiDs
The initial activity supporting the innate immunity component of REOLYSIN’s MOA, is in collaboration with cancer charity Myeloma UK and Celgene. MUK eleven was launched in March of this year: a first of its kind immunotherapy trial that aims to modulate the immune system to target myeloma. The Phase 1b trial will study REOLYSIN in combination with Celgene’s Imnovid (pomalidomide) or Revlimid (lenalidomide) as a rescue treatment in relapsing myeloma patients. The dose escalation trial will look at the safety and tolerability of these combinations, and will investigate whether the addition of REOLYSIN extends disease control in this patient group.

The trial will recruit approximately 44 patients across up to six Myeloma UK Clinical Trial Network centres in the UK. MUK eleven is part of the Myeloma UK Clinical Trial Network, a portfolio of early-stage trials coordinated by the Clinical Trials Research Unit at the University of Leeds, which aims to test and speed up access to promising new treatments for patients.

Oncolytics and Celgene UK & Ireland are providing their respective products for MUK eleven: Oncolytics is providing REOLYSIN and Celgene UK & Ireland is providing Imnovid and Revlimid.

Combinations with Immunotherapy
In support of the adaptive immunity component of the MOA, the Company is currently running its first study in combination with an emerging class of immuno-oncology agents known as checkpoint inhibitors. REO 024 is an open-label phase 1b trial to determine the safety and dose-limiting toxicity of REOLYSIN in combination with pembrolizumab (KEYTRUDA) and chemotherapy in patients with histologically confirmed, advanced or metastatic pancreatic adenocarcinoma who have failed, or did not tolerate, first-line treatment. The goal of this study is to establish the safety profile of the REOLYSIN/KEYTRUDA combination and to determine how a checkpoint inhibitor could improve the immune system’s ability to recognize cancer cells through the stimulation of the adaptive immune response in patients caused by REOLYSIN. The Company expects to report on the safety data from REO 024 in 2017 and looks to expand its clinical collaborations using other checkpoint inhibitor agents and investigating different indications, dose levels and efficacy.

"While our near-term focus will be on chemotherapy combinations, our longer-term goal is to establish REOLYSIN as the backbone of an immuno-oncology regimen in combination with other agents, including checkpoint inhibitors and other immunomodulatory drugs," said Dr. Andres Gutierrez, Chief Medical Officer of Oncolytics. "The combinations with emerging immunotherapies could be transformative when taking into account REOLYSIN’s continuing positive safety profile in ongoing studies."

In summary, in 2017 Oncolytics expects to make progress against a number of milestones including:

· Discussions with regulators focused on obtaining scientific advice on the best registration path in metastatic breast cancer;
· Announcing a detailed registration study in metastatic breast cancer;
· Reporting safety data from the phase 1b REO 024 pancreatic cancer study evaluating REOLYSIN in combination with pembrolizumab (KEYTRUDA); and
· Expanding clinical collaborations with large pharma in an effort to support further development around the innate and adaptive immunity components of REOLYSIN’s MOA.