On June 22, 2020 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that preclinical data from the company’s glucocorticoid receptor (GR) antagonist and CD73 inhibitor programs in five poster presentations during the ongoing American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II (Press release, ORIC Pharmaceuticals, JUN 22, 2020, https://investors.oricpharma.com/news-releases/news-release-details/oric-pharmaceuticals-presents-preclinical-data-glucocorticoid-1 [SID1234561301]).

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"We are pleased to be able to present these compelling preclinical data from our ORIC-101 and CD73 programs, which continue to validate our scientific platform focused on overcoming therapeutic resistance in cancer," said Lori Friedman, chief scientific officer. "In particular, we are encouraged to see ORIC-101 reversing GR-mediated resistance in a variety of tumor models, and preliminary evidence of differentiation of ORIC-533 versus competitor compounds in preclinical studies. We look forward to the continued advancements of these programs and our discovery research pipeline as we work to improve patients’ lives."

ORIC-101 (GR Antagonist):
ORIC-101 is a potent and selective small molecule antagonist of GR, which has been linked with resistance to multiple classes of cancer therapeutics across a variety of solid tumors. ORIC-101 is currently being investigated in two separate Phase 1b combination trials, with enzalutamide in prostate cancer and with nab-paclitaxel in solid tumors.

Key findings of the presentations:

A transcriptional signature of GR activity was identified in a panel of 32 cell lines across triple negative breast cancer, non-small cell lung cancer and pancreatic ductal adenocarcinoma, which translated from preclinical models to human tumors
ORIC-101 overcame GR-mediated resistance to chemotherapeutic agents including taxanes, antimetabolites and platinums, in both in vitro and in vivo efficacy studies spanning a variety of solid tumor types
Transcriptional and histological profiling showed that ORIC-101 reversed GR-activated pathways involved in drug resistance, and reversed in vivo markers of epithelial-to-mesenchymal transition, antiapoptosis, and hypoxia
The company is further assessing the GR activation signature and mechanistic findings in an ongoing Phase 1b trial of ORIC-101 in combination with nab-paclitaxel in adults with advanced or metastatic solid tumors
Poster Presentations:

ORIC-101 comprehensively inhibits glucocorticoid pathways to overcome therapeutic resistance in pan-cancer models (Poster #4120)
ORIC-101 overcomes resistance to diverse chemotherapeutics across cancer types (Poster #4121)
ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models (Poster #4123)
ORIC-533 (CD73 Inhibitor):
CD73 is a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy and immunotherapy. ORIC discovered and characterized differentiated orally bioavailable small molecule inhibitors of CD73, including clinical candidate ORIC-533, that revert immunosuppression and promote anti-tumor responses in vivo.

Key findings of the presentations:

ORIC’s CD73 inhibitors demonstrated suppression of adenosine production in vitro across multiple cell types and rescued activation of CD8+ T cells exposed to AMP with greater potency than competitor compounds
ORIC-533 was shown to result in sustained inhibition of adenosine production after drug washout, consistent with its slow off-rate, and differentiating from other CD73 inhibitors
ORIC-533 potency in high AMP environments distinguishes it from other compounds, with activity in AMP concentrations as high as 1 millimolar, which may better reflect certain tumor microenvironments
Daily oral delivery of ORIC’s CD73 inhibitors significantly inhibited tumor growth, with corresponding in vivo reduction of adenosine levels in tumors, and immune modulation consistent with decreased immunosuppression
Poster Presentations:

CD73 inhibition with a novel orally bioavailable small molecule blocks adenosine production and rescues T-cell activation (Poster #1023)
An orally bioavailable inhibitor of CD73 reverts intratumoral immunosuppression and promotes anti-tumor response (Poster #LB-115)

On June 22, 2020 HiFiBiO Therapeutics is presenting its three lead pipeline programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II taking place today (Press release, HiFiBiO Therapeutics, JUN 22, 2020, View Source [SID1234561300]). The company is a pioneer of novel antibody drug discovery and development leveraging single-cell analytics to treat cancer, autoimmune and infectious diseases. HiFiBiO invites members of the scientific and medical communities to listen to these poster presentations online at the AACR (Free AACR Whitepaper) meeting website or, after the AACR (Free AACR Whitepaper) meeting has concluded, at the HiFiBiO Therapeutics website.

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"These presentations demonstrate the rapid progress spearheaded by our scientists at HiFiBiO and the development of our pipeline, and we look forward to soon moving our lead programs to IND," said Liang Schweizer, PhD, President and CEO of HiFiBiO Therapeutics. "Given our depth of experience in immune modulation and cutting-edge single-cell science and technology, we believe that HiFiBiO is realizing the potential of single-cell analysis to develop novel, high-quality antibody targets into life-changing treatment options for patients."

POSTER PRESENTATION DETAILS:

Title: HFB301001, a novel OX40 agonistic antibody with a unique pharmacological profile and innovative biomarker strategy
Presenters: Andreas Raue, PhD, Project Leader, Senior Director, Head of Drug Intelligent Science (DIS) at HiFiBiO Therapeutics and Robert Petit, PhD, Senior Scientific Advisor
E-Poster: #2285
HFB301001 is being developed as a potential novel treatment option for cancer coupled with a patient stratification biomarker in solid tumor indications.

Title: Discovery and characterization of novel TNFR2 antibodies to modulate T cell activities in immunosuppressive environment
Presenters: Francisco Adrian, PhD, Senior Vice President, Head of Research and Shuo Wei, PhD, Project Leader, Principal Scientist, Disease Biology
E-Poster: #2282
HFB200301 is an anti-TNFR2 monoclonal antibody being developed as a potential first-in-class therapeutic for the treatment of biomarker-selected patients with advanced cancer.

Title: HFB9-2, a novel Galectin-9 neutralizing antibody to reverse immune suppression in the tumor microenvironment
Presenters: Roshan Kumar, PhD, Senior Director, Head of Discovery Biology and US External Innovation and Yun-Yueh Lu, PhD, Project Leader, Principal Scientist, Disease Biology
E-Poster: #6532
HFB2009 program focuses on developing anti-Gal-9 neutralizing antibodies as a potential first-in-class treatment for AML and solid tumors, both as a single agent and a combination therapy.

More information about these and other programs in the HiFiBiO Therapeutics pipeline is available at View Source

On June 22, 2020 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, reported a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting which further details data demonstrating the potential of a TIGIT targeting INTASYL compound as an immuno-oncology therapeutic through the suppression of TIGIT in the tumor microenvironment (TME) (Press release, Phio Pharmaceuticals, JUN 22, 2020, View Source [SID1234561299]). The Phio poster presentation will also be available under the "Investors – Events and Presentations" section of the Company’s website (click here).

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"In our poster presentation at the AACR (Free AACR Whitepaper) 2020 Virtual Annual Meeting, we announced detailed data supporting the potential for PH-804, our TIGIT targeting INTASYL compound, as an immuno-oncology therapeutic and a viable alternative to anti-TIGIT antibodies. This data provides insight around the mechanisms of action of the tumor growth suppression with PH-804, as previously announced from a study in a validated animal model, namely through increases in immune cell count and immune cell activation in the tumor micro-environment," said Dr. Simon Fricker, Phio’s VP of Research. "These preclinical results build upon the recent data we announced at the ASCO (Free ASCO Whitepaper) 2020 Annual Meeting that show the ability and safety of INTASYL RNAi technology to reprogram immune cells, such as T cells or NK cells, to improve their efficacy."

In an in vivo study, tumor growth inhibition was determined for both PH-804 and an anti-TIGIT antibody in colorectal carcinoma tumor bearing mice. Results from the study demonstrated that our INTASYL compound was efficiently delivered intratumorally to immune cells, resulting in a dose dependent inhibition of tumor growth, reaching statistical significance levels for PH-804 and anti-TIGIT antibody treatment arms. More detailed data from the study provides evidence of an "on-target" effect of PH-804 as shown by silencing of TIGIT mRNA expression in tumor infiltrating lymphocytes isolated from the treated tumors. In addition, analysis of the TME of the PH-804 treated mice showed a dose dependent increase in cytotoxic effector T cells, and a dose dependent activation of such T cells as shown by the expression of activation makers such as CD25 and CD69.

These data demonstrate the potential of a TIGIT targeting INTASYL compound for the suppression of TIGIT in the TME and support the hypothesis that local TIGIT silencing with INTASYL is a promising therapeutic approach.

On June 22, 2020 Alkermes plc (Nasdaq: ALKS) and Clovis Oncology, Inc. (Nasdaq: CLVS) reported positive preclinical data from a study designed to evaluate the combination potential of ALKS 4230, Alkermes’ investigational engineered interleukin-2 (IL-2) variant immunotherapy, with lucitanib, Clovis’ investigational angiogenesis inhibitor (Press release, Clovis Oncology, JUN 22, 2020, View Source [SID1234561298]). The data will be presented during a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, taking place June 22-24, 2020.

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The study evaluated the antitumor efficacy and mechanism of action of mALKS 4230, a mouse ortholog of ALKS 4230, and lucitanib as monotherapies and in combination in a preclinical syngeneic mouse model of colon cancer. The combination of mALKS 4230 with lucitanib resulted in dose-dependent, durable complete responses (absence of any detectable tumor) and enhanced survival compared with monotherapy treatment with mALKS 4230 and lucitanib.

"Combining treatments with complementary mechanisms may offer synergistic clinical benefit and expand treatment options for a broader set of patient populations," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "These compelling preclinical data provide a foundational rationale to further explore novel combination options, such as an angiogenesis inhibitor, for ALKS 4230, with the goal of bringing improved therapeutic outcomes to patients across multiple tumor types."

Key findings presented in the poster include the following:

In the group that received the higher dose of mALKS 4230 (out of two doses tested) combined with lucitanib, 100 percent of the treated mice exhibited complete tumor regression and protection from new tumor growth upon re-challenge, an indication of the development of immunological memory.
The combination of mALKS 4230 with lucitanib resulted in an increase in intratumoral immune cells, including CD8+ T cells and dendritic cells, compared to monotherapy treatment, changes that are associated with anti-tumor immune responses.
The combination of mALKS 4230 with lucitanib elicited a distinct gene expression profile associated with anti-tumor activity, including increased immune cytolytic gene expression with decreased expression of genes with pro-angiogenic functions.
A virtual poster titled, "The Combination of a Mouse Ortholog of ALKS 4230, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, and the Angiogenesis Inhibitor Lucitanib Enhances Antitumor Activity," along with a pre-recorded audio presentation by Dr. Jared Lopes, Principal Scientist, Alkermes will be available on the AACR (Free AACR Whitepaper) website at View Source

About ALKS 4230

ALKS 4230 is an investigational, novel, engineered fusion protein comprised of modified interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor chain, designed to selectively expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by preferentially binding to the intermediate-affinity IL-2 receptor complex. The selectivity of ALKS 4230 is designed to leverage the proven anti-tumor effects of existing IL-2 therapy while mitigating certain limitations.

About Lucitanib

Lucitanib is an oral, potent inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3), platelet-derived growth factor receptors alpha and beta (PDFGRα/β) and fibroblast growth factor receptors 1 through 3 (FGFR1-3). Emerging clinical data support the combination of angiogenesis inhibitors and immunotherapy to increase effectiveness in multiple cancer indications. Angiogenic factors, such as vascular endothelial growth factor (VEGF), are frequently up-regulated in tumors and create an immunosuppressive tumor microenvironment. Use of antiangiogenic drugs reverses this immunosuppression and can augment response to immunotherapy.

Lucitanib is an unlicensed medical product.

On June 22, 2020 Ascendis Pharma A/S (Nasdaq: ASND), a biopharmaceutical company that utilizes its innovative TransCon technologies to address unmet medical needs, reported the presentation of preclinical data for TransCon IL-2 β/γ, an oncology product candidate designed to provide sustained systemic release of a receptor-biased IL-2 (IL-2 β/γ), at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II from June 22 to June 24, 2020 (Press release, Ascendis Pharma, JUN 22, 2020, View Source [SID1234561294]).

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"Our preclinical results have demonstrated that TransCon IL-2 β/γ selectively binds and activates the IL-2 β/γ receptor and provides sustained and long-lasting exposure. By applying our TransCon technology to this clinically validated cytokine, we have overcome the two most significant limitations of IL-2 therapy, improving both the receptor-binding properties and the pharmacokinetic profile," said Juha Punnonen, M.D., Ph.D., Ascendis Pharma’s Senior Vice President and Head of Oncology. "Based on the promising preclinical results we’ve seen with our TransCon IL-2 β/γ and TransCon TLR7/8 Agonist product candidates, we believe our TransCon technologies – which enable systemic and long-acting intratumoral administration – have the potential to improve treatment outcomes in cancer patients. We look forward to our first Investigational New Drug application, or similar, in oncology later this year for TransCon TLR7/8 Agonist, followed by a planned filing for TransCon IL-2 β/γ in 2021."

TransCon IL-2 β/γ is a novel long-acting prodrug of IL-2 β/γ designed to address limitations of alternative IL-2 treatments, including aldesleukin, which has been available since the 1990’s as a treatment for advanced kidney cancer and advanced melanoma. TransCon IL-2 β/γ is designed with a parent drug that selectively binds and activates the IL-2Rβ/γ. By applying the innovative TransCon technology platform, preclinical data also showed that TransCon IL-2 β/γ demonstrated a long in vivo half-life of approximately 32 hours, expected to support potential dosing of every three weeks in patients. Preclinical results show a single dose of TransCon IL-2 β/γ selectively expanded lymphocyte counts (CD8+ T cells and NK cells) in non-human primates, with minimal signs of systemic inflammation (IL-5 and IL-6 markers) or endothelial cell damage (E-Selectin and VCAM-1 markers) and no dose-limiting toxicities.

Presentation Details

American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II

Title Date/Time
P4507: TransCon IL-2 β/γ: a novel long-acting prodrug of receptor-biased IL-2 designed for improved pharmocokinetics and optimal activation of T cells for the treatment of cancer Monday, June 22, 2020

8:45 a.m. Eastern

The poster is available on the company’s website under Selected Publications in the Pipeline section:

View Source

About TransCon Oncology Programs

Ascendis Pharma is developing potentially best-in-class oncology therapies by applying its TransCon technologies for systemic and intratumoral administration to clinically validated pathways in order to improve efficacy and reduce systemic toxicity. Multiple oncology programs are currently in preclinical evaluation.

About TransCon Technology

TransCon refers to "transient conjugation." The proprietary TransCon platform is an innovative technology to create new therapies that are designed to potentially optimize therapeutic effect, including efficacy, safety and dosing frequency. TransCon molecules have three components: an unmodified parent drug, an inert carrier that protects it, and a linker that temporarily binds the two. When bound, the carrier inactivates and shields the parent drug from clearance. When injected into the body, physiologic conditions (e.g., pH and temperature) initiate the release of the active, unmodified parent drug in a predictable manner. Because the parent drug is unmodified, its original mode of action is expected to be maintained. TransCon technology can be applied broadly to a protein, peptide or small molecule in multiple therapeutic areas, and can be used systemically or locally.