On April 12, 2021 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC) reported preclinical data highlighting pelareorep’s ability to synergize with multiple classes of anti-cancer agents (Press release, Oncolytics Biotech, APR 12, 2021, View Source [SID1234577920]). The data are featured in two electronic poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021.

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Experiments presented in the posters evaluate the mechanisms of therapeutic synergy between pelareorep and anti-cancer agents identified via a non-biased high throughput screening assay. The top results identified in the screen were the poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor talazoparib and the Cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib, which are both FDA approved for the treatment of breast cancer.

"Preclinical data presented at AACR (Free AACR Whitepaper) compel the use of pelareorep to broaden the therapeutic applicability of approved anti-cancer agents," said Thomas Heineman, M.D., Ph.D., Global Head of Clinical Development and Operations at Oncolytics. "Notably, the synergistic interactions between pelareorep and both talazoparib and palbociclib were mediated through immunological effects rather than through the molecular pathways typically associated with PARP-1 and CDK 4/6 inhibition. These findings suggest that pelareorep may expand the mechanisms by which PARP-1 and CDK 4/6 inhibitors exert anti-tumor effects, which may enhance their therapeutic potential."

Key findings from the first poster titled, "Talazoparib interacts with oncolytic reovirus to enhance death-inducing signaling complex (DISC)-mediated apoptosis and immune response" include:

Pelareorep and talazoparib synergistically increase cancer cell apoptosis in vitro and in vivo
Pelareorep and talazoparib mechanistically synergize through enhancement of IFN-β signaling pathways
Combining pelareorep with talazoparib led to enhanced anti-tumor efficacy and inhibition of recurrent tumor growth in murine tumor models
The synergistic anti-cancer effects of pelareorep-talazoparib therapy correlated with an increased immune response
Key findings from the second poster titled, "Mechanisms of therapeutic synergy between pattern recognition response agonists and cdk4 inhibitors" include:
Combining pelareorep with palbociclib increased cancer cell death in vitro and reduced in vivo tumor burden compared to pelareorep or palbociclib monotherapy
Pelareorep and palbociclib mechanistically synergize through enhancement of endoplasmic reticulum (ER) stress signaling
Pelareorep-palbociclib enhanced ER stress signaling promoted cancer cell apoptosis by increasing innate immune activation and effector function
Andrew de Guttadauro, President of Oncolytics Biotech U.S. and Global Head of Business Development, commented, "Our most recent clinical and preclinical findings support pelareorep’s potential to boost the effectiveness of various immunotherapies beyond merely checkpoint inhibitors. Moreover, these findings codify pelareorep’s position as a simple and effective enabling technology to enhance the clinical effectiveness of a wide range of immunotherapeutic agents."

The electronic posters are available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 e-poster website and on the Posters & Publications page of Oncolytics’ website (LINK).

About Pelareorep

Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.

On April 12, 2021 Antengene Corporation Limited ("Antengene", SEHK: 6996.HK), a leading innovative biopharmaceutical company dedicated to discovering, developing, and commercializing global first-in-class and/or best-in-class therapeutics in hematology and oncology, reported preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, which demonstrated the synergistic effect of the combination of ATG-010 (selinexor, XPO1 inhibitor) and ATG-008 (onatasertib, mTORC1/2 inhibitor) for the treatment of triple-hit diffuse large B-cell lymphoma (DLBCL) (Press release, Antengene, APR 12, 2021, View Source [SID1234577937]).

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#1380: Synergistic effect of the combination of XPO1 and mTORC1/2 inhibition for the treatment of triple-hit DLBCL
Results from this study demonstrated potent in vitro and in vivo anti-tumor efficacy and synergy with the combination of ATG-010 and ATG-008, including strong synergistic activities in the triple-hit DLBCL cell line. Meanwhile, in the DLBCL circulating tumor cell-derived explants (CDX) model, the combination of ATG-010 and ATG-008 also showed enhanced tumor growth inhibition and synergism.

The single agent oral XPO1 inhibitor, ATG-010, is a first-in-class and only-in-class selective inhibitor of nuclear export (SINE) compound, approved by the US Food and Drug Administration (FDA) for the treatment of patients with DLBCL after at least two prior therapies. ATG-008 is a dual mTORC1/2 kinase inhibitor, which has shown preclinical and clinical activity in treating DLBCL. Antengene is currently developing a clinical study to investigate the combination of ATG-010 and ATG-008 in relapsed or refractory DLBCL (the MATCH trial).

The preclinical data showed:

ATG-008 and ATG-010 both inhibit the growth of the DLBCL cell line in vitro.
ATG-008 combined with ATG-010 enhanced the growth inhibition of triple-hit DLBCL cells.
ATG-008 combined with ATG-010 showed in vitro synergism in triple-hit DLBCL cells.
ATG-008 combined with ATG-010 showed in vivo synergism in CDX of the triple-hit DLBCL cell line.
Dr. Jay Mei, Founder, Chairman and CEO of Antengene, commented: "ATG-010 has been approved for the treatment of relapsed or refractory DLBCL, whilst ATG-008 has shown early clinical activity in the same disease. Using in vitro and in vivo DLBCL models, we found that ATG-010 combined with ATG-008 at certain concentrations could achieve amplified anti-tumor activity in triple-hit DLBCL. The strong synergism of the ATG-010 plus ATG-008 combination suggests a promising therapeutic strategy for the treatment of patients with DLBCL, including triple-hit disease where significant unmet medical needs exist, that we are looking forward to exploring in the MATCH trial."

On April 12, 2021 Lonza reported an expansion to its popular PyroTec PRO Automated Robotic Solution for endotoxin testing (Press release, Lifescience Newswire, APR 12, 2021, View Source [SID1234577978]). The new PyroWave Reader add-on has been designed specifically for use with the sustainable PyroGene Recombinant Factor C (rFC) Assay. This brings a third test type option to the platform, allowing QC microbiologists to choose the endotoxin test method best suited for their testing needs. The PyroTec PRO Solution, now compatible with Lonza’s PYROGENT-5000 Turbidimetric LAL (Limulus Amebocyte Lysate) Assay, Kinetic-QCL Chromogenic LAL Assay and the PyroGene rFC Assay, expands the options available for streamlined, automated endotoxin testing.

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The PyroWave Reader add-on is built upon the original release of the PyroTec PRO Automated System that includes two absorbance readers for traditional LAL-based assays. Able to easily accommodate different assay types in the same run and powered by the world-class WinKQCL Endotoxin Analysis Software, this complete system further increases the efficiencies and data integrity gained from automated endotoxin testing.

The PyroGene rFC Assay is an animal-free method for endotoxin detection that works through a single enzymatic step. It has been shown to be equivalent to other photometric endotoxin methods that use LAL to detect endotoxins according to the parameters listed in the USP chapter <1225> "Validation of Compendial Procedures". These parameters include linearity, specificity, precision, accuracy, and limit of detection.

The need for accurate and dependable endotoxin testing technology continues to grow, especially with the pharmaceutical industry increasingly focusing on the development of innovative biotherapeutics that carry a higher risk of endotoxin contamination. Through process optimization and automation of routine manual tasks, the PyroTec PRO Automated Robotic Solution enables users to streamline and improve the performance of the QC laboratory, increasing lab efficiency and productivity. Automated endotoxin testing can also substantially reduce the potential for human error, enhancing the accuracy, reliability, and traceability of results.

On April 12, 2021 C4X Discovery Holdings plc (AIM: C4XD), a pioneering Drug Discovery company, reported that its subsidiary, C4X Discovery Limited ("C4XD", "C4X Discovery" or the "Company"), has signed an exclusive worldwide licensing agreement with Sanofi (NASD: SNY, PAR: SAN – "Sanofi "), worth up to €414 million, for C4XD’s oral pre-clinical IL-17A inhibitor programme (Press release, C4X Discovery, APR 12, 2021, View Source [SID1234577886]). Under the terms of the agreement, C4XD will receive an upfront payment of €7 million and could receive up to a further €407 million in potential development, regulatory and commercialisation milestones, of which €11 million is in pre-clinical milestones, in addition to single digit royalties.

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Under the license, Sanofi will develop and commercialise an oral therapy for the treatment of inflammatory diseases, a multi-billion dollar market. The IL-17 family of cytokines are strong inducers of inflammation and are implicated in a variety of autoimmune diseases including psoriasis, psoriatic arthritis and ankylosing spondylitis. Current treatments targeting IL-17 are monoclonal antibodies administered via an injection. There is an urgent need for safe and efficacious oral small molecule therapies to increase the number of patients able to access IL-17 targeted drugs and expand availability into new inflammatory disease indications. C4XD’s small molecule IL-17A inhibitor programme can selectively block IL-17 activity in vivo whilst maintaining molecular size of the molecule in the traditional "drug-like" range suitable for oral administration. Sanofi will continue to work with the C4XD team to access its unique and proprietary 4D Conformetrix technology, as the programme advances towards clinical studies.

Clive Dix, CEO of C4X Discovery, said: "We are proud to be working with Sanofi to create much needed oral therapies in the underserved inflammatory disease space. While antibody therapies have demonstrated the potential of IL-17 inhibition in the generation of highly effective treatments, the injectable route means many patients currently do not have access to the medicines that can change their lives. We believe that our small molecule programme has the potential to create high value, efficacious and convenient oral IL-17 therapeutics for this large market. The Psoriasis market alone is estimated to be worth c.$24 billion per annum by 20271, and when combined with Sanofi’s development expertise our programme has the potential to address a number of indications.

"This is the second significant agreement for a C4XD programme and marks a major milestone for the Company, not only validating the strength of our Drug Discovery expertise, but also our strategy to drive shareholder value through early-stage revenue generating deals. With Indivior progressing our molecule for opioid addiction through a Phase I clinical trial and now our partnership with Sanofi driving potential next generation oral IL-17 therapies, we look forward with confidence to further develop our portfolio and deliver additional novel small molecule drug candidates tackling significant patient needs."

On April 12, 2021 Replimune Group, Inc. (Nasdaq: REPL), a biotechnology company developing oncolytic immuno-gene therapies derived from its Immulytic platform, reported additional data supporting the multiple mechanisms of action for its lead programs, RP1 and RP2, during two presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually April 10-15, 2021 and May 17-21, 2021 (Press release, Replimune, APR 12, 2021, View Source [SID1234577905]).

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"We developed Replimune’s Immulytic platform with the intention of developing therapies with both enhanced tumor killing potency and with an enhanced ability to initiate a systemic anti-tumor immune response. This pre-clinical and clinical biomarker data provides further evidence that these objectives are being achieved, and that RP1 and RP2 are able to initiate a potent systemic immune response against a patient’s cancer," said Robert Coffin, PhD, President and Chief Research and Development Officer, Replimune.

Details of the presentations are as follows:

Abstract Title: Clinical biomarker studies with two fusion-enhanced versions of oncolytic HSV (RP1 and RP2) alone and in combination with nivolumab in cancer patients indicate potent immune activation – Abstract #: LB180

In patients dosed with RP1 in combination with nivolumab or single agent RP2 alone and in combination with nivolumab, immunohistochemistry for CD8 and PD-L1 from paired tumor biopsies demonstrated robust and increased infiltration of CD8+ T cells and PD-L1 expression across different tumor types, including reversal of T cell exclusion following prior combined treatment with ipilimumab and nivolumab in melanoma.
A significant increase in the expression levels of genes associated with innate and adaptive immune activation and genes previously reported to be associated with responsiveness to anti-PD1 therapy was demonstrated.
In patients dosed with RP2 monotherapy, an increase in CD8+ T cell infiltration as well as robust changes in expression of key tumor and immune cell signalling pathway genes was observed.
Peripheral blood T cell receptor (TCR) sequencing indicated the expansion of existing T cell clones and generation of new T cell clones.
Increased CD8+ T cell infiltration and PD-L1 expression, coupled with changes in TCR clonal expansion in PBMC samples, suggest systemic immune activation.
This presentation is now available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 website linked here and also posted to the presentations section of the Replimune website and linked here.

RP1 is Replimune’s lead Immulytic product candidate and is based on a proprietary new strain of herpes simplex virus (HSV) engineered to maximize tumor killing potency, the immunogenicity of tumor cell death and the activation of a systemic anti-tumor immune response through the expression of a GALV-GP R- fusogenic protein and GM-CSF. RP2 is a derivative of RP1 that expresses an anti-CTLA-4 antibody-like molecule intended to provide targeted and potent delivery to the sites of immune response initiation in the tumor and draining lymph nodes, with the goal of focusing systemic immune-based efficacy on tumors and limiting off-target toxicity.

Abstract Title: Immunomodulatory effects of a novel, enhanced potency gibbon ape leukemia virus (GALV) fusogenic membrane glycoprotein-expressing herpes simplex virus platform with increased efficacy combined with anti PD-1 therapy – Abstract #1917

This poster presentation is a collaboration between Replimune and The Institute of Cancer Research, London, UK.

In a histological examination of tumors injected with RP1 or RP2, large areas of necrosis in syngeneic mouse tumours were observed, even in a model where GALV-GP R- is not functional. In models where GALV-GP R- is functional, including in human xenograft tumors in nude mice (which have no adaptive immune system, but retain innate, e.g. NK cell mediated, immune function), GALV-GP R- was observed to give anti-tumor activity in both injected and in uninjected tumors, whereas a virus without GALV-GP R- only exhibited anti-tumor activity in injected tumors. These effects in uninjected tumors were presumed to result from enhanced innate immune activation mediated by GALV-GP R-.
RP1 increased PD-L1 expression, particularly on neutrophils, and increased CD3 T cell infiltration in injected and contralateral tumors.
Profound effects on the gene expression profile were also seen in both injected and contralateral tumors which are consistent with potent and broad immune activation. These were significantly greater than that seen with single agent anti-PD1, and were further enhanced when RP1 was combined with anti-PD1.
This presentation is now available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 website linked here and also posted to the presentations section of the Replimune website and linked here.

"RP1 and RP2 represent attractive potential treatment modalities with the ability to self-amplify, kill through multiple mechanisms and promote anti-tumour immune responses," said Professor Kevin Harrington, PhD, Professor in Biological Cancer Therapies at The Institute of Cancer Research, London, and Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust ​in the UK. "These data show that RP1 increases PD-L1 expression, increases CD3 T cell infiltration in injected and contralateral tumors, and has profound effects on the gene expression profile in both injected and non-injected tumors which are consistent with potent and broad immune activation. These benefits are then further enhanced by treatment with anti-PD1 creating the potential for an attractive treatment option for patients with difficult to treat tumor types who are currently underserved."

Opdivo is a registered trademark of Bristol Myers Squibb.