On March 11, 2021 Nuvation Bio Inc. (NYSE: NUVB), a biopharmaceutical company tackling some of the greatest unmet needs in oncology by developing differentiated and novel therapeutic candidates, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to NUV-422, a cyclin-dependent kinase (CDK) 2/4/6 inhibitor, for the treatment of patients with malignant gliomas (Press release, Nuvation Bio, MAR 11, 2021, View Source [SID1234576551]).

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The FDA’s Office of Orphan Drug Products grants Orphan Drug Designation to support drug candidates in development for underserved patient populations or rare disorders that affect fewer than 200,000 people in the United States. Orphan Drug Designation qualifies a candidate for various development incentives, including tax credits for eligible clinical trials, waiver of application fees and market exclusivity for seven years upon FDA approval.

"We are pleased to receive the FDA’s Orphan Drug Designation, which underscores the potential of NUV-422 to address the significant unmet need of patients with high-grade gliomas," said David Hung, M.D., founder and chief executive officer of Nuvation Bio. "We look forward to continuing the development of NUV-422 through our ongoing Phase 1/2 study."

Patient enrollment and dosing is ongoing in the Phase 1/2 study of NUV-422 in adult patients with recurrent or refractory high-grade gliomas, including glioblastoma multiforme (GBM). The Phase 1 dose escalation part of the study is designed to evaluate safety and tolerability, as well as to determine a recommended Phase 2 dose based on the tolerability profile and pharmacokinetic properties of NUV-422. The Phase 2 dose expansion part of the study is expected to initially focus on patients with high-grade gliomas and is designed to evaluate overall response rate, duration of response and survival. Data from the Phase 1 portion of this study is expected in 2022.

About NUV-422
NUV-422 is a selective small molecule resulting from Nuvation Bio’s cyclin-dependent kinase (CDK) inhibitor program. CDK4/6 inhibitors are known clinical entities with proven efficacy, but cancer cells can evade these treatments by increasing signaling through CDK2. Inhibition of CDK2 in addition to CDK4/6 cuts off the tumor’s natural escape route. NUV-422 is a potent inhibitor of CDK 2, 4 and 6. Preclinical studies have shown that NUV-422 has favorable blood-brain barrier penetration.

About High-Grade Gliomas
Primary tumors of the central nervous system (CNS) remain among the most difficult to treat, with a 5-year overall survival of approximately 35%. Gliomas, which begin in the glial or supportive tissue, represent 75% of malignant primary brain tumors in adults. Glioblastoma multiforme (GBM) accounts for 50% to 70% of all gliomas. More than 10,000 people in the United States each year are diagnosed with this aggressive, difficult-to-treat brain tumor.i No treatment advances have been made in GBM since 2009 when bevacizumab was approved by the FDA. Temozolomide and radiation are considered the current standard of care for newly diagnosed patients with glioblastoma.ii

On March 11, 2021 IDEAYA Biosciences, Inc. (NASDAQ: IDYA), a synthetic lethality-focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported publication of abstracts at the 2021 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Ideaya Biosciences, MAR 11, 2021, View Source [SID1234576550]). IDEAYA will present data for its potential first-in-class synthetic lethality programs IDE397, a Phase 1 methionine adenosyltransferase 2a (MAT2A) inhibitor, poly (ADP-ribose) glycohydrolase (PARG) for which a development candidate is targeted in 2021, and IDE196, a Phase 1/2 protein kinase C (PKC) inhibitor targeting GNAQ/11-mutation cancers.

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The IDEAYA abstracts were posted online by AACR (Free AACR Whitepaper) (View Source) in advance of the 2021 Annual Meeting of AACR (Free AACR Whitepaper), which will be held April 10-15, 2021:

"MAT2A inhibitor, IDE397, displays broad anti-tumor activity across a panel of MTAP-deleted patient-derived xenografts" (Marcus Fischer et al.)
"Genomic and metabolomic analysis of MAT2A inhibition reveals increased RNA splicing, lipid metabolism and cell cycle arrest in MTAP deleted tumor models" (Neil Bhola et al.)
"Synthetic lethality of PARG inhibition in tumors with homologous recombination deficiencies" (Monah Abed et al.)
"Preclinical evaluation of a PKC and MET inhibitor combination in metastatic uveal melanoma" (Marie-Claire Wagle et al.)
IDEAYA is evaluating IDE397, a potential first-in-class small molecule inhibitor targeting MAT2A, in a Phase 1 clinical trial for patients having tumors harboring MTAP deletion. IDEAYA plans to present preclinical data evaluating the efficacy of monotherapy IDE397 in over forty patient-derived xenograft (PDX) models with homozygous MTAP deletions across a range of solid tumor types. IDEAYA will also present preclinical data evaluating the genomic and metabolic effects of pharmacological inhibition of MAT2A in an isogenic cell pair and of proliferation effects in MTAP deleted and MTAP wild type cell lines.

IDEAYA is advancing its wholly-owned PARG synthetic lethality program for patients having tumors with a defined biomarker based on genetic mutations and/or molecular signatures. IDEAYA plans to present preclinical data evaluating the effects of pharmacological inhibition of PARG in a panel of HR-deficient cell lines and cell line derived xenografts (CDX).

"We have established a broad and potential first-in-class clinical stage pipeline in synthetic lethality – an emerging area of precision medicine oncology, and are excited to present our program data at AACR (Free AACR Whitepaper) 2021," said Dr. Michael Dillon, Ph.D., Senior Vice President, Chief Scientific Officer and Head of Research at IDEAYA Biosciences.

IDEAYA is evaluating IDE196, a potential first-in-class PKC inhibitor, in a Phase 1/2 clinical trial for the treatment of metastatic uveal melanoma (MUM) and GNAQ/11-mutation skin melanoma. In MUM, the IDE196 clinical program is focused on clinical combinations, including with binimetinib, a MEK inhibitor, and independently with crizotinib, a cMET inhibitor, pursuant to a clinical trial and supply agreement with Pfizer.

IDEAYA plans to present translational data at AACR (Free AACR Whitepaper) retrospectively evaluating cMET expression in clinical biopsies from MUM patients in an IDE196 Phase 1 clinical trial, as well as preclinical data evaluating synergy between IDE196 and crizotinib in relevant cell models of a liver tumor microenvironment, a site of approximately 90% of uveal melanoma metastases.

"We identified a cMET inhibitor as a potential combination agent through our translational research, and we believe these preclinical data provide a compelling biological rationale for the IDE196 and crizotinib combination to treat patients with metastatic uveal melanoma," said Matthew Maurer, M.D., Vice President, Head of Clinical Oncology and Medical Affairs at IDEAYA Biosciences.

On March 11, 2021 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 that its data from multiple oncology programs will be presented at the upcoming American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting 2021, April 10-15 and May 17-21 (Press release, Ryvu Therapeutics, MAR 11, 2021, View Source [SID1234576549]).

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Data presented will include results from the RVU120 (SEL120), a CDK8/CDK19 inhibitor program, as well as data from small-molecule STING agonists and HPK1 inhibitor projects.

"We are very excited with the possibility to share data from our most advanced fully-owned oncology program – RVU120 (SEL120) – which is currently in Phase 1b clinical development for the treatment of acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (HRMDS). We made a lot of progress in translational research concerning RVU120 and we look forward to sharing it with the scientific community" – said Krzysztof Brzózka, Chief Scientific Officer at Ryvu Therapeutics.

"At the same time, we are pleased to present the most recent data from our two preclinical immuno-oncology projects, which we consider as very promising assets in our pipeline" – added Brzózka.

Details of the e-poster presentations are as follows:

Title: SEL120, a CDK8/CDK19 inhibitor, possesses strong multilineage differentiation potential in AML
Permanent Abstract Number: 1018

Title: New generation of STING agonists – development and characterization of a novel series of systemic immunomodulators with improved potency
Permanent Abstract Number: 1280

Title: Development and characterization of small molecule HPK1 inhibitors
Permanent Abstract Number: 1281

The e-poster website will be launched on Saturday, April 10, which is the first day of the AACR (Free AACR Whitepaper) Virtual Annual Meeting. All e-posters will be made available for browsing on this date through to June 21, 2021.

Additional information is available at on the AACR (Free AACR Whitepaper) conference website View Source

About AACR (Free AACR Whitepaper) Annual Meeting

The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research—from population science and prevention, to cancer biology, translational, and clinical studies; to survivorship and advocacy—and highlights the work of the best minds in research and medicine from institutions all over the world.

On March 11, 2021 Nouscom, a clinical stage immuno-oncology biotech developing next generation viral-vector based immunotherapies, reported it has received approval from the Spanish National Agency of Medicines and Medical Devices (Agencia Española de Medicamentos y Productos Sanitarios (AEMPS)) to start a Phase 1b trial of its personalized cancer immunotherapy, NOUS-PEV (Press release, NousCom, MAR 11, 2021, View Source [SID1234576548]). NOUS-PEV will be investigated in the study as a potential treatment for patients with either locally advanced 1L melanoma or 1L non-small cell lung cancer (NSCLC).

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NOUS-PEV is a personalized vaccine designed for each patient based on selection and prioritization of mutations unique to that patient’s tumor. The strategy is based on Nouscom’s heterologous prime boost platform underpinning its lead off-the-shelf clinical program NOUS-209, composed of a proprietary non-human adenoviral vector (GAd) and Modified Vaccinia Virus (MVA). Each of the two viral vector systems encodes multiple personalized neoantigens selected with a proprietary algorithm (VENUS[1]), which prioritizes up to 60 mutations that represent the most immunogenic neoantigens.

Results from preclinical proof-of-concept studies (published in Nature Communications[2]) demonstrated that a single administration of the GAd vaccine incorporating many neoantigens can eradicate large tumors when combined with checkpoint inhibition such as anti-PD1 or anti-PD-L1 treatment and triples the efficacy of such checkpoint inhibitors. The preclinical results also demonstrated strong and broad CD8+ and CD4+ neoantigen-specific T cell responses following vaccination, which are known to be indicative of a clinical anti-tumor effect.

The new Phase 1b trial will evaluate the safety, feasibility, and preliminary efficacy per RESIST 1.1 criteria of NOUS-PEV in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in 28 patients with either locally advanced 1L melanoma or 1L NSCLC expressing more than 50% PD-L1. This multicenter trial will be conducted in Spain and other European countries.

Patricia Delaite, M.D., Chief Medical Officer of Nouscom, said: "We have generated exciting pre-clinical data, which demonstrated the ability of NOUS-PEV to present multiple cancer neoantigens to the immune system and promote potent and broad immune responses. The enhanced anti-tumor effects seen by combining NOUS-PEV with checkpoint inhibitors suggests these two approaches are highly synergistic and could potentially overcome tumor resistance to anti-PD1 immunotherapies to address a high unmet medical need. We look forward to starting this trial in the coming weeks and to generating results that we hope will confirm these exciting results in patients."

Dr. Marina Udier, Chief Executive Officer of Nouscom, said: "The regulatory approval of this highly sophisticated study to assess our personalized vaccine NOUS-PEV is another critical milestone for the company. Similar to our lead program, NOUS-209, NOUS-PEV leverages the strength and capacity of our platform based on viral vectors, encoding a large number of neoantigens, with proven robust performance in animal models, which we believe has the potential to translate into real clinical benefits for patients."

[1]Vaccine Encoded NeoAg Unrestricted Selection (VENUS)

[2]A.M. D’Alise et al. Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade, Nature Communications 2019

On March 11, 2021 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported that an abstract for a poster presentation at the AACR (Free AACR Whitepaper) (American Association for Cancer Research) Annual Meeting 2021, presenting new preclinical data for the clinical asset mitazalimab, is now released (Press release, Alligator Bioscience, MAR 11, 2021, View Source;alligator-bioscience-presents-new-preclinical-data-at-aacr-301245267.html [SID1234576547]). The AACR (Free AACR Whitepaper) Annual Meeting 2021 will be held in a virtual format over two one-week periods in April and May 2021. Alligator Bioscience’s abstract will be presented in an ePoster session during April 10-15.

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Alligator Bioscience has previously shown that mitazalimab synergizes effectively with immune checkpoint inhibitors and vaccines. The abstract, titled "Mitazalimab, a potent CD40 agonist with potential for combination with chemotherapy", demonstrates that mitazalimab synergizes with chemotherapy, notably FOLFIRINOX, leading to improved long-term survival in a preclinical tumor model.

"The new preclinical data are very encouraging. Together with the clinical data of mitazalimab from a previous Phase I study, where mitazalimab was well tolerated up to 1200 µg/kg, these data support the upcoming clinical Phase II study of mitazalimab in combination with chemotherapy in pancreatic cancer patients," says Per Norlén, CEO of Alligator Bioscience.

Mitazalimab is a human CD40 agonistic antibody developed for immunotherapy of cancer. The chemotherapy cocktail FOLFIRINOX kills tumor cells leading to increased release of tumor antigens. Activation of CD40 leads to improved presentation of tumor antigens, and the consequent T cell priming and initiation of T cell-dependent anti-tumor responses.