On April 11, 2022 Vivace Therapeutics, Inc., a small molecule discovery and development company developing first-in-class therapies targeting the Hippo pathway, reported that new preclinical data on the company’s transcriptional enhanced associate domain (TEAD) autopalmitoylation inhibitor, VT3989, were reported at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Vivace Therapeurtics, APR 11, 2022, View Source [SID1234612016]). Presented findings demonstrated that the combination of VT3989 and osimertinib (Tagrisso), an epidermal growth factor receptor (EGFR) inhibitor, possessed enhanced anti-tumor activity and delayed tumor growth as compared to osimertinib alone in preclinical EGFR mutant tumor models. The AACR (Free AACR Whitepaper) conference is being held April 8-13, 2022, in New Orleans, Louisiana.

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Data reported in the poster presentation demonstrated that VT3989 exhibits strong synergistic activity with osimertinib. This was highlighted by the ability of the combination to enhance the blocking of tumor growth in EGFR mutant, non-small cell lung cancer (NSCLC) cell-line derived xenograft models, including the HCC827 model that is already known to be particularly sensitive to osimertinib. Furthermore, the combination of VT3989 and osimertinib significantly increased the life span of mice in an NCI-H1975 NSCLC CDX model as compared to osimertinib monotherapy.

Additionally, researchers showed similar synergistic activity in blocking tumor regrowth in human patient-derived xenograft models of EGFR mutant NSCLC. Of note, data demonstrated that TEAD inhibition achieved with VT3989 significantly delayed the re-emergence of tumor mass after osimertinib treatment resulted in non-palpable tumors. This finding offers evidence that EGFR mutant NSCLC relies upon dysfunction in the Hippo pathway to survive treatment with osimertinib, and can thus be targeted with TEAD inhibition.

"The exciting new data presented at AACR (Free AACR Whitepaper) not only support previous research highlighting the potency and selectivity of VT3989 as a TEAD inhibitor and its single agent anti-tumor activity in mesothelioma models, the findings also begin to build a compelling strategy around a synergistic combination treatment approach featuring VT3989 and EGFR inhibitors such as osimertinib," said Tracy Tang, Ph.D., vice president of biology at Vivace Therapeutics and lead author on the AACR (Free AACR Whitepaper) poster presentation. "We are eager to continue our pioneering research into the Hippo pathway and how addressing dysfunction in that pathway may pave the way for first-in-class cancer therapies capable of addressing the unmet needs of patients."

Vivace’s proprietary compounds inhibit palmitoylation of members of the TEAD protein family, including both covalent and non-covalent inhibitors. The company’s clinical candidate, VT3989, is currently in Phase 1 clinical trials. Pre-clinical research and development activities have demonstrated that the clinical candidate is active as a monotherapy against tumors that rely upon dysfunction of the Hippo pathway, and in combination with other anti-cancer therapies in additional tumor types.

The poster presented is available at the company’s website www.vivacetherapeutics.com.

On April 11, 2022 Glenmark Pharmaceuticals Limited, an innovation-driven, global pharmaceutical company, reported that its subsidiary Glenmark Specialty S.A. (Glenmark) received approval from the Indian drug regulator, Drug Controller General of India (DCGI), to conduct a Phase 1 clinical trial of its novel small-molecule, GRC 54276, a hematopoietic progenitor kinase 1 (HPK1) inhibitor (Press release, Glenmark, APR 11, 2022, View Source [SID1234612015]). GRC 54276 is one of the many novel molecules from Glenmark’s resident, Innovative Medicines Group, headed by Dr. Nikhil Amin, Chief Scientific Officer, specializing in the development of novel molecular entities for critical unmet medical needs. HPK1 is a key regulator of T cell, B cell and dendritic cell-mediated immune responses, which improves antitumor immunity by activating and priming T cells. GRC 54276 has shown tumor cell killing ability in preclinical studies as a single agent and as well in combination with checkpoint inhibitors, making it a high-priority target in immuno-oncology.

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The study will evaluate the safety and tolerability of GRC 54276 as a monotherapy, and also in combination with checkpoint inhibitors in patients with advanced solid tumors and Hodgkin’s lymphoma. Glenmark will initiate Phase 1 clinical trial in India by June 2022, and also plans to file an IND in the US and Clinical Trial Applications in Europe to kick-off a fully global clinical study program.

"Glenmark’s endeavor has been to provide innovative treatment solutions in its core therapeutic areas. We are delighted that our first novel molecule from the newly formed ‘Innovative Medicines Group’ within Glenmark has received approval from India’s drug regulator to initiate a Phase 1 clinical trial. This reinforces Glenmark’s growing capabilities of innovative clinical research and is a step closer in providing holistic solutions for cancer treatment," said Glenn Saldanha, Chairman & Managing Director, Glenmark Pharmaceuticals Limited.

On April 11, 2022 Obsidian Therapeutics, Inc., a biotechnology company pioneering engineered cell and gene therapies, reported it will present preclinical data highlighting its cytoTIL15 program during a poster session at the upcoming AACR (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Obsidian Therapeutics, APR 11, 2022, View Source [SID1234612014]). The abstract title has been posted to the AACR (Free AACR Whitepaper) Online Itinerary Planner, will be published in the online Proceedings of the AACR (Free AACR Whitepaper), and is detailed below.

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The data to be presented demonstrate significantly greater anti-tumor activity of cytoTIL15 therapy in vivo compared to conventional TIL + IL2 therapy in a human leukocyte antigen (HLA)-matched, allogeneic patient-derived xenograft (PDX) melanoma model, including greater persistence of cytoTIL15 cells in blood and lymphoid organs, superior tumor growth inhibition including complete responses, and increased infiltration of tumors with cytoTIL15 cells.

"We look forward to presenting these new data at AACR (Free AACR Whitepaper), which continue to validate the exciting potential of our cytoTIL15 therapy to improve the treatment of patients with solid tumors," said Jan ter Meulen, M.D., Ph.D., Chief Scientific Officer at Obsidian Therapeutics. "We are encouraged by the data demonstrating superior anti-tumor activity of cytoTIL15 cells in the absence of IL2 in a novel PDX tumor model. These data deliver preclinical proof of concept for the potential of cytoTIL15 therapy as a treatment for metastatic melanoma and will support the planned filing of an IND for our lead program, OBX-115, later this year."

Details of the poster presentation are as follows:

Abstract Number: 7994
Title: Allogeneic, IL-2-independent tumor-infiltrating lymphocytes expressing membrane-bound IL-15 (cytoTIL15) eradicate tumors in a melanoma PDX model through recognition of shared tumor antigens
Presenter: Dr. Jeremy Tchaicha, Director, Head of In Vivo Pharmacology, Obsidian Therapeutics
Date and Time: Section 18, April 13, 2022, 9:00 a.m.-12:30 p.m. CT
Abstract Summary: Current TIL therapy requires systemic administration of IL2 to promote TIL survival, and IL2-associated toxicities greatly limit patient eligibility and reduce the long-term clinical benefit of TIL therapy. Obsidian designed genetically engineered IL2-free TILs (cytoTIL15) to express a regulated form of membrane-bound IL15 for tunable long-term persistence, leading to enhanced persistence and efficacy in vitro and in PDX tumor models. Obsidian previously demonstrated cytoTIL15 exhibited enhanced potency and persistence over conventional TILs in vitro, and persisted without IL2 at greater frequencies compared to conventional TILs + IL2 in a 10-day antigen-independent in vitro assay. Additionally, cytoTIL15 adoptively transferred into naïve NSG mice demonstrated long-term persistence without antigen or exogenous IL-2.

About OBX-115
OBX-115 is Obsidian’s lead cytoTIL15 program, currently in preclinical development for the treatment of patients with metastatic melanoma and other solid tumors. OBX-115 is a novel engineered tumor infiltrating lymphocyte therapy armed with regulated membrane-bound IL15 that is designed to remove the need for concomitant IL2 therapy, a toxic and costly requirement for conventional TILs. The Company expects to submit an IND for OBX-115 in 2022.

On April 11, 2022 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported presentations from its most advanced oncology program RVU120 and MTA-cooperative PRMT5 inhibitor program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 8-13 in New Orleans, U.S (Press release, Ryvu Therapeutics, APR 11, 2022, View Source [SID1234612012]).

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Poster presentation details:

Title: RVU120, a selective CDK8/CDK19 inhibitor, demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo
Session Title: Novel Targets and Pathways
Abstract Number: 2647
Date and Time: Tuesday, Apr 12, 2022, 9:00 AM – 12:30 PM
Location: Poster Section 24

Title: Discovery of novel MTA-cooperative PRMT5 inhibitors as a targeted therapeutic for MTAP deleted cancers
Session Title: Drug Targets
Abstract Number: 1117
Date and Time: Monday, Apr 11, 2022, 1:30 PM – 5:00 PM
Location: Poster Section 23

Title: Trials in Progress – RVU120 SOL-021: An open-label, single agent, Phase I/II trial of RVU120 (SEL120) in patients with relapsed/refractory metastatic or advanced solid tumors
Session Title: Phase II Trials in Progress
Abstract Number: 8023
Date and Time: Monday Apr 11, 2022 9:00 PM – 12:30 PM
Location: Poster Section 34

About RVU120 (SEL120)

RVU120 (also known as SEL120) is a clinical stage, highly specific and orally bioavailable dual inhibitor of CDK8/CDK19 kinases, which has demonstrated efficacy in a number of solid tumor in vitro and in vivo models as well as in hematologic malignancies.

At present, Ryvu is conducting two clinical studies with RVU120: (i) Phase Ib in patients with AML/HR-MDS (NCT04021368) and (ii) Phase I/II in relapsed/refractory metastatic or advanced solid tumors (NCT05052255). Additionally, multiple translational research activities are underway.
On March 25, 2020, the U.S. Food and Drug Administration (FDA) granted an orphan drug designation (ODD) to RVU120, for the treatment of patients with AML.

RVU120 has been internally discovered by Ryvu and has received support from the Leukemia & Lymphoma Society Therapy Acceleration Program (TAP), a strategic initiative to partner directly with innovative biotechnology companies and leading research institutions to accelerate the development of promising new therapies for blood cancers.

About PRMT5

Deletion of the metabolic gene MTAP occurs in 10 to 15% of all human tumors. Targeting PRMT5 in MTAP-deleted tumors in a synthetic lethal approach represents a promising antitumor strategy across many tumor types. Ryvu has identified a series of MTA-cooperative PRMT5 inhibitors which have good drug-like physicochemical properties and block methyltransferase activity of PRMT5 with nanomolar IC50 values. Ryvu’s compounds selectively inhibit growth of MTAP deleted cancer cells in prolonged 3D culture, which strongly correlates with inhibition of PRMT5-dependent protein symmetric demethylation in those cells.

On April 11, 2022 Phosplatin Therapeutics Inc., a clinical stage pharmaceutical company focused on small molecule immunogenic therapies in oncology, reported new non-clinical data on its lead candidate, PT-112, at the American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Phosplatin, APR 11, 2022, View Source [SID1234612011]). The poster presentation, titled, "PT-112 induces potent mitochondrial stress and immunogenic cell death in human prostate cancer cell lines," is available for viewing in person at AACR (Free AACR Whitepaper), which is taking place through April 13 in New Orleans, Louisiana and online in Proceedings of the AACR (Free AACR Whitepaper) through the meeting website.

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"The study results indicate that PT-112 causes growth inhibition of prostate cancer cells without affecting healthy cells, including effects seen on organelles such as mitochondria, that are consistent with immunogenic cell death (ICD)," said Alberto Anel, PhD, Scientific Researcher at University of Zaragoza/Aragón Health Research Institute, who led the study. "We found that PT-112 selectively induced mitochondrial reactive oxygen species, as well as the release of damage-associated molecular patterns, or DAMPs, which suggests this activity on cellular organelles may be an important component of PT-112’s immunogenic cell death mechanism."

"We are encouraged by the activity seen in this research, which was conducted in parallel with our ongoing Phase 2 clinical trial of PT-112 in patients with metastatic castration resistant prostate cancer," said Phosplatin Executive Vice President and Chief Operating Officer, Matthew Price. "The result of this study provides a better understanding of PT-112’s mechanism of action, in a manner that is linked to its established immunogenic cell death effects. We view this as very supportive of our ongoing clinical efforts in treating metastatic castration resistant prostate cancer patients, a disease state that is heterogenous and that requires an immune priming approach such as ICD."

The non-clinical study of PT-112 (available Monday, April 11, 2022 from 9:00am – 12:30pm CST as poster presentation number 5) assessed differential sensitivity, cell death mechanism, induction of mitochondrial stress and release of DAMPs. Sensitivity to PT-112 was assessed in human prostate cancer cell lines and the non-tumorigenic prostate cell line RWPE-1. Key findings of the study included the following:

PT-112 caused growth inhibition and cancer cell death without affecting healthy RWPE-1 cells.
Caspase inhibition reduced PT-112-induced cell death, with more mild effects seen with necroptosis inhibition, suggesting that cell death is primarily apoptotic.
PT-112-induced cell death was accompanied by a prominent increase of mitochondrial reactive oxygen species (mtROS) and decrease in mitochondrial membrane potential, as well as by DAMP emission.
PT-112 activated markers of autophagy, a process associated with ICD and the cellular stress response
There was a positive relationship between HIF-1alpha expression and the sensitivity to PT-112 in this panel.
PT-112 is a novel small molecule with clinical activity reported across Phase 1 studies in advanced solid tumors including lung, thymoma, castration-resistant prostate cancer, and multiple myeloma. In previous research, PT-112-induced cancer cell death has been shown to be independent of nuclear DNA damage. Additionally, in vitro experiments showed that PT-112 causes mtROS accumulation and DAMP release leading to immunogenic cell death (ICD), a unique form of cancer cell death that elicits an anti-cancer immune response related to the specific way in which a cancer cell dies, and T-cell infiltration.

For more information about Phosplatin’s clinical trials, visit the website at www.Phosplatin.com.

About PT-112

PT-112 is a novel small molecule with a unique, pleiotropic mechanism of action that promotes immunogenic cell death (ICD), through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 may represent the best-in-class inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH (Free ASH Whitepaper) is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and the PD-L1 combination study is ongoing in a dose confirmation cohort of non-small cell lung cancer (NSCLC) patients, and will soon include the Phase 2 proof of concept study in thymic epithelial tumors under the company’s collaboration with the NCI.