On April 8, 2022 Orphagen Pharmaceuticals Inc., a biotech company pioneering the screening, discovery, and development of small molecule ligands that modulate orphan or unexplored members of the nuclear receptor family, reported a late-breaking presentation of new preclinical data for OR-449 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 being held April 8-13 both virtually and in-person in New Orleans (Press release, Orphagen, APR 8, 2022, View Source [SID1234611691]). The data presented demonstrate efficacy in a preclinical model of a Leydig cell tumor (LCT) of OR-449, the company’s first-in-class small molecule antagonist to the nuclear receptor steroidogenic factor-1 (SF-1 or NR5A1) and support the continued development of OR-449 as a novel targeted therapy for the treatment of LCTs as well as adrenocortical cancer (ACC), the primary indication for which it is being developed.

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"OR-449 was strategically designed at Orphagen and is the first antagonist to SF-1 to be taken into development – potent and orally bioavailable small molecules of this class have not previously been identified," said Scott Thacher, Ph.D., CEO and Founder of Orphagen. "The data presented at AACR (Free AACR Whitepaper) 2022 demonstrate that OR-449, a potent SF-1 antagonist, has clear potential for clinical efficacy in malignant LCTs as well as ACC. There is an urgent need for new therapies for LCT and ACC, and we are focused on completing IND-enabling studies of OR-449 with the goal of filing an investigational new drug application by the end of the year."

The incidence of ACC in the U.S. is 300 patients per year, and existing therapies are very limited. LCTs represent about 3% of all testicular cancers. Testicular cancer is in turn one of the most frequently diagnosed cancers in American males between the ages of 15 and 35. Malignant LCTs, though rare, are an estimated 10% of all LCTs. They are resistant to chemotherapy and radiation, responding primarily to surgery. Median survival from diagnosis is two years for these patients.

Summary of Results

OR-449 exhibits striking anti-proliferative activity in the rat Leydig tumor cell (LCT) line R2C, inhibiting DNA synthesis by >90% at 1 mM with an estimated IC50 of 68 nM.
In cell lines lacking SF-1 expression, such as HEK293, OR-449 has no anti-proliferative activity up to 20 mM, indicating that the anti-proliferative effect on R2C is SF-1-mediated and is not due to cytotoxicity.
OR-449 inhibits R2C xenograft tumor growth in immunocompromised mice at oral doses of 3, 10, and 30 mg/kg/day, with complete inhibition at a daily dose of 30 mg/kg.
Based on an mRNA response signature first identified in R2C culture, OR-449 appears to directly engage with SF-1 in the R2C tumors.
The in vivo potency and efficacy of OR-449 in the R2C model corresponds to what we previously reported for SJ-ACC3 (Crowe et al, ENDO 2021), a pediatric ACC patient-derived tumor xenograft (PDX) model.
These results highlight that OR-449 antagonism of SF-1 is a novel targeted therapeutic approach with potential utility in the treatment of ACC and malignant LCTs. Orphagen has initiated IND-enabling studies of OR-449 with an anticipated IND-filing date at the end of 2022.

The poster (abstract #LB144) titled, "Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors," will be available on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website for registered attendees to view from Friday, April 8 through Wednesday, July 13. The poster will also be available via the company on request. The poster will be presented in person on Tuesday, April 12 from 9 am to 12:30 pm CT at the New Orleans Convention Center, Exhibit Halls D-H, Poster Section 27, Poster Board Number 17.

The authors acknowledge the support of the following NIH grants: R43 DK 102221, R43 CA 150540, R43 HD 068078, R43 CA 099875, R44 CA 265639.

Reference: Crowe, et al. A Novel Steroidogenic Factor-1 Antagonist, OR-449, as a Targeted Therapy for Adrenocortical Cancer. ENDO 2021: J Endocr Soc, Vol5, Supplement_1, A1010

About OR-449

OR-449 is the lead candidate identified from Orphagen’s proprietary screening technology, which has led to successful discovery of the first drug-like small molecules to several orphan nuclear receptors. OR-449 is a first-in-class, orally bioavailable small molecule antagonist to SF-1, an orphan nuclear receptor that is essential for the embryonic growth and development of adrenal and gonadal tissues. Clinical targets for SF-1 antagonism by OR-449, such as ACC and malignant LCT, are derived from these tissues and express very high levels of this novel drug target.

On April 8, 2022 OncoMyx Therapeutics, a privately-held oncolytic virus immunotherapy company, reported the presentation of new preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 being held April 8-13 (Press release, OncoMyx Therapeutics, APR 8, 2022, View Source [SID1234611689]). The data presented at AACR (Free AACR Whitepaper) 2022 demonstrate that OncoMyx’s myxoma virus multi-armed with IL-12 and decorin infects and kills human multiple myeloma cells in vitro and demonstrates dose responsive efficacy after intravenous (IV) administration in a mouse model of multiple myeloma.

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"These data demonstrate that OncoMyx’s multi-armed myxoma virus works via direct oncolytic activity as well as immunomodulation of both the innate and adaptive immune response, including T cells and natural killer (NK) cells," said Leslie L. Sharp, Ph.D., chief scientific officer of OncoMyx. "As we look toward the clinic, we have generated a substantial amount of data on the safety and efficacy of our multi-armed myxoma virus and look forward to moving into GMP manufacturing and IND-enabling activities."

"OncoMyx’s myxoma virus is the first large, multi-armed oncolytic virus to demonstrate efficacy in preclinical models of multiple myeloma," said Steve Potts, Ph.D., MBA, cofounder and CEO of OncoMyx. "We continue to demonstrate the differentiated efficacy and immunomodulatory properties of OncoMyx’s multi-armed myxoma virus and its potential to be effective across a broad range of cancers, from hematological malignancies to solid tumors."

Substantial published research demonstrates that the myxoma virus naturally and selectively replicates in human tumor cells, infects and kills multiple myeloma cells, and stimulates the immune system. Furthermore, the large size of the myxoma genome allows for the insertion of multiple genes to arm the virus with immune modulators that can orchestrate the cancer-immunity cycle for optimal viral-mediated cancer-killing activity. OncoMyx has multi-armed myxoma virus to carry IL-12, an immune modulator, and decorin, which can affect tumor cell intrinsic signaling and microenvironment modulation.

The poster (abstract #5618) titled, "Multi-armed myxoma virus has therapeutic potential for treatment of multiple myeloma," will be available on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website for registered attendees to view from Friday, April 8 through Wednesday, July 13. The poster will also be available on OncoMyx’s website.

​​About OncoMyx’s Myxoma Immunotherapy Platform

OncoMyx’s multi-armed myxoma virus delivers multiple antitumor immunomodulatory proteins that target critical points in the cancer immunity cycle to modulate the tumor microenvironment and stimulate a robust anti-tumor response. Myxoma is a natural oncolytic virus, selectively infecting and killing a wide range of cancer cell types. It is also inherently highly immuno-interactive, and as a large dsDNA poxvirus, can be engineered to express multiple payloads to treat cancer. Because myxoma is not pathogenic to humans, there is no pre-existing immunity, making it highly amenable to intravenous and repeat dosing.

On April 8, 2022 Primmune Therapeutics, a biotech company harnessing the power of the innate immune system to treat solid tumors in the advanced cancer setting and for the clearance of human papillomavirus and related pre-cancerous cervical lesions, reported the presentation of interim data from a first-in-human, Phase 1 study evaluating PRTX007, a novel, small molecule toll-like receptor 7 (TLR7)-specific agonist, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans (Press release, Primmune Therapeutics, APR 8, 2022, View Source [SID1234611687]). The study is a single-center, prospective, randomized, double-blind, placebo-controlled study with 9 single-ascending dose (SAD) cohorts and 4 multiple-ascending dose (MAD) cohorts where PRTX007 is administered orally to adult healthy volunteers. In addition to assessing the safety, tolerability and pharmacokinetics of PRTX007, the study is designed to evaluate pharmacodynamic responses relevant to dose selection for patients with cancer.

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"These data from our ongoing first-in-human trial indicate that Primmune’s lead candidate, PRTX007, is well-tolerated in healthy volunteers and activates the desired components of innate and downstream adaptive immune responses while avoiding induction of proinflammatory cytokines," said James Appleman, Ph.D., Co-Founder and Chief Scientific Officer at Primmune Therapeutics. "We look forward to the clinical advancement of PRTX007 for the treatment of solid tumors in combination with checkpoint inhibitors and as a monotherapy for the treatment of human papillomavirus-driven pre-cancerous cervical lesions and the underlying infection."

Data show that PRTX007 was well-tolerated and expressed a favorable safety profile in the analyzed patient cohorts, with most adverse events (AEs) considered incidental and no instances of moderate, severe or serious AEs. In addition, every other day (QOD) dosing demonstrated stable systemic immune induction without evidence of counter-regulation. Both the clinical characteristics and unique pattern of immune induction by PRTX007 support its use in combination with immune checkpoint inhibitors.

Presentation Title: PRTX007, an Optimized TLR7 Agonist for Systemic Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)s: Interim Analysis of Phase I Study in Healthy Volunteers Presenting Author: Curtis Scribner, M.D., Chief Medical
Presenting Author: Curtis Scribner, M.D., Chief Medical Officer, Primmune
Abstract Number: 1865
Poster Number: CT189
Poster Board Number: 14
Poster Session: Phase I Clinical Trials 2 Session
Session Date and Time: Tuesday, April 12, 9 a.m. to 12:30 p.m. CT
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 33

Additional highlights from the poster presentation include:

Most AEs were incidental and not dose related. The most common drug-related AE was headache, seen across both treated and placebo groups independent of dose.
At the interim analysis, PRTX007 demonstrated a favorable safety profile when administered orally to all 9 SAD and 3 MAD cohorts tested.
PRTX007 demonstrated induction of interferon-stimulated genes (ISGs) without significant increases in circulating interferons (IFNs). There was no increase in expression or circulating levels of proinflammatory cytokines (e.g., TNFα, IL-6, IL-1β)
About PRTX007

PRTX007, Primmune’s lead clinical development candidate, is designed to provide well-tolerated, controlled, long-term stimulation of the innate immune response while also potentiating long-term effective innate and adaptive immune responses. PRTX007 uniquely activates plasmacytoid dendritic cells (pDCs), leading to a systemic immune poly-IFN response without stimulating production of NF-κB-driven proinflammatory factors like IL-6, TNFα or IL-1β. Furthermore, activated pDCs directly deliver interferons to target cells by paracrine transfer. This is functionally equivalent to administering a cocktail of all Type I/III IFN while avoiding the associated side effects and adverse events. PRTX007 is being rapidly advanced towards clinical trials for solid tumors in the advanced cancer setting and for clearing human papillomavirus-driven pre-cancerous cervical lesions.

On April 8, 2022 Nykode Therapeutics AS (Euronext Growth (Oslo): NYKD), a clinical-stage biopharmaceutical company dedicated to the discovery and development of vaccines and novel immunotherapies, reported preclinical data from its second-generation Vaccibody Antigen-Presenting Cell (APC)-targeting vaccine technology, which incorporates immune-stimulatory cytokines (Press release, Nykode Therapeutics, APR 8, 2022, View Source [SID1234611686]). The data will be presented in a poster session at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on Tuesday, April 12, 2022, from 1:30 p.m. – 5:00 p.m. ET.

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"The preclinical data reported at AACR (Free AACR Whitepaper) highlights that Nykode’s unique vaccines co-expressed with immune-stimulatory proteins can produce a nearly three-fold boost in anti-tumor immune cell response in comparison to the first-generation platform. The research showcases the advantages of Nykode’s APC-targeted delivery of tumor specific antigens and its ability to successfully induce a powerful immune response against tumor cells, overcoming a historical challenge in the development of cancer vaccines. We look forward to continued innovation in our platform as we advance our pipeline of vaccine candidates through the clinic," said Mikkel Pedersen, Chief Scientific Officer of Nykode Therapeutics.

The preclinical results demonstrate that the co-expression of the Vaccibody molecule and immune-stimulatory cytokines enhances anti-tumor immune responses, leads to an expansion of antigen-specific polyfunctional effector T cells and superior tumor control. In addition, the data demonstrate that the second-generation platform enhances APC infiltration, proliferation and differentiation, measured by live CD45+ infiltrated cells and the proportion of DCs in live CD45+ cells, including cDC1.

Details of the poster presentation are as follows:

Abstract #: 2232
Title: A novel and versatile cytokine empowered DNA vaccine platform with superior immune activating potential
Authors: Beraas, et al.
Session Title: Vaccines: Oncolytic and Prophylactic
Session Date and Time: Tuesday, April 12, 2022 | 1:30 p.m. – 5:00 p.m. ET

The poster presentation is available in the AACR (Free AACR Whitepaper) 2022 Annual Meeting program and in the Scientific Papers and Presentations section of the Company’s website.

On April 8, 2022 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported the presentation of new data from its preclinical-stage IL-18 and LAG3-targeted IL-15 cytokine programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Xencor, APR 8, 2022, View Source [SID1234611684]).

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"XmAb cytokines are engineered to be long acting and more drug-like in order to overcome inherent limitations facing cytokine therapeutics. At AACR (Free AACR Whitepaper), we are presenting two additions to our wholly owned cytokine portfolio — a decoy-resistant and potency-reduced IL18-Fc fusion protein, and a LAG-3 targeted IL15/IL15Rα-Fc fusion protein, which is biased toward binding and activating LAG-3-positive lymphocytes that are more likely to be tumor-reactive," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "Later this year we plan to submit an investigational new drug application for XmAb662, our wholly owned, reduced-potency IL12-Fc cytokine, which has demonstrated remarkable preclinical anti-tumor activity and improved therapeutic index in vivo."

The posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

Abstract 2080, "LAG3-targeted IL15/IL15Rα-Fc (LAG3 x IL15) fusion proteins for preferential TIL expansion"

Session: Immunomodulatory Agents and Interventions 1
Date and Time: Monday, April 11, 2022, 1:30 – 5:00 p.m. CDT
Location: Exhibit Halls D-H, Section 38, Board 18
IL-2 and IL-15 are cytokines that cause the activation and proliferation of T cells and NK cells. Their therapeutic potential has been well established in preclinical models and clinical studies; however, when given systemically, these potent cytokines have historically provided a poor therapeutic window, as they are not well tolerated and are quickly cleared from circulation.

Xencor engineered LAG3-targeted IL15/IL15Rα-Fc cytokine/antibody fusion proteins (LAG-3 x IL-15) for selective activation of LAG3-positive immune cells, which may potentially avoid systemic toxicities arising from off-target activation and expansion of peripheral immune cells. An XmAb heterodimeric Fc domain serves as a molecular scaffold, and Xtend technology promotes longer circulating half-life. LAG-3 is an immune checkpoint expressed on tumor-infiltrating lymphocytes (TILs), is frequently co-expressed with PD-1 and has limited expression in normal peripheral immune cells. Recently, anti-LAG3 agents have generated promising results in clinical studies, and LAG-3 x IL-15 agents could be combined with anti-PD1 agents. Xencor’s LAG-3 x IL-15 candidate molecules demonstrated high selectivity for LAG3-positive cell populations in multiple in vitro and in vivo models.

Abstract 3515, "Engineered IL18 heterodimeric Fc-fusions featuring improved stability, reduced potency, and insensitivity to IL18BP"

Session: Immunomodulatory Agents and Interventions 2
Date and Time: Tuesday, April 12, 2022, 1:30 – 5:00 p.m. CDT
Location: Exhibit Halls D-H, Section 37, Board 17
IL-18 is a proinflammatory cytokine that modulates both the innate and adaptive immune responses. IL-18 receptor 1, the primary co-receptor for IL-18, is overexpressed on activated T cells and NK cells, which are critical for anti-tumor responses. Additional preclinical studies of IL-18 have demonstrated its anti-tumor activity, including synergy with immune checkpoint inhibitors and CAR-T therapies. In contrast with other potent cytokines, IL-18 has been well tolerated in clinical trials but demonstrated a lack of efficacy despite heavy dosing. IL-18 participates in a negative feedback loop with a high affinity natural inhibitor, IL18BP, which was observed to be upregulated in early phase clinical studies and may have directly resulted in IL-18’s limited clinical performance.

Xencor engineered stabilized, potency-reduced, monovalent IL-18 cytokines fused to an XmAb heterodimeric Fc domain with Xtend Fc technology for longer half-life. Importantly, these cytokine-Fc fusions were engineered to not bind its inhibitor, IL18BP. In a preclinical mouse model of graft-versus-host disease, an analog of the candidate XmAb143 led to the expansion and proliferation of target immune cells and induced high levels of interferon gamma. Further, it was well tolerated in non-human primates and exhibited favorable pharmacokinetics, such as slow receptor-mediated clearance.