On April 18, 2023 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported two preclinical poster presentations at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, ORIC Pharmaceuticals, APR 18, 2023, View Source [SID1234630253]).

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"Our presentations at AACR (Free AACR Whitepaper) reflect the excellent preclinical scientific support of our development pipeline," said Lori Friedman, PhD, chief scientific officer. "Preclinical data provided insights into the comprehensive biomarker strategy for ORIC-944, our PRC2 inhibitor in Phase 1 as a monotherapy for metastatic prostate cancer. We are also pleased with the progress of our PLK4 program, with data showing that the exquisite kinase selectivity is key to synthetic lethality in tumor models with high TRIM37."

Presentation details:

ORIC-944: allosteric inhibitor of PRC2
ORIC-944 is a potent, orally bioavailable, highly selective allosteric small molecule inhibitor of PRC2, the complex which tri-methylates histone H3 lysine 27 (H3K27me3) via targeting the embryonic ectoderm development (EED) subunit, and is in early clinical development as a monotherapy for patients with metastatic prostate cancer.

Poster Presentation:

Biomarker strategy for a phase 1 study of ORIC-944, a potent and selective allosteric PRC2 inhibitor, in patients with metastatic prostate cancer

Key findings of the presentation:

Preclinical pharmacology studies in mice showed that ORIC-944 induces dose- and time-dependent H3K27me3 reduction in the skin epidermis, peripheral blood monocytes, and cell free nucleosomes in plasma, with the latter PD modulation being tumor-specific.
Putative PRC2 target genes were identified via time-dependent transcriptional and epigenetic profiling of xenograft tumor models orally dosed with ORIC-944.
These studies and corresponding assay development support the comprehensive biomarker strategy of target engagement and pharmacodynamic biomarkers implemented in the ongoing Phase 1 trial of ORIC-944 in patients with metastatic prostate cancer.
PLK4 Inhibitor Program
The PLK4 inhibitor program is a small molecule therapeutic program intended to address a mechanism of innate resistance found in a subset of breast cancers, specifically a synthetic lethal interaction of polo-like kinase 4 (PLK4) inhibition in tumors bearing a TRIM37 DNA amplification/elevation. A novel, potent, highly selective, orally bioavailable PLK4 inhibitor was selected as a development candidate in the fourth quarter of 2022.

Poster Presentation:

Selective PLK4 inhibition demonstrates synthetic lethality in TRIM37 amplified neuroblastoma and breast cancer models while less selective inhibitors do not

Key findings of the presentation:

ORIC discovered novel, potent, orally bioavailable small molecule inhibitors of PLK4 that are highly selective, including against the closely related aurora kinases and PLK1-3.
ORIC PLK4 selective inhibitors show greater potency in TRIM37 high cancer cell lines relative to low TRIM37 low cell lines, whereas no differential was observed for non-selective inhibitors.
Apoptotic cell death was observed solely in TRIM37 high cancer cells for ORIC PLK4 selective inhibitors, in contrast to non-selective inhibitors which did not show this synthetic lethality.
Using a genetically engineered PLK4 cell line variant (PLK4 G95L) that prevents compound-mediated inhibition of PLK4, selective PLK4 inhibitors lose activity in TRIM37 high G95L cells, confirming on-target cell activity, compared with non-selective inhibitors whose cell potency is not dependent on PLK4 inhibition.
PLK4 inhibition blocks trans-autophosphorylation and PLK4 protein degradation and correlates with cell viability for selective compounds, and not for non-selective inhibitors.
Together these mechanistic data confirm the potential of highly selective PLK4 inhibition as a synthetic lethal therapy for TRIM37 amplified/elevated cancers.

On April 18, 2023 OncoNano Medicine, Inc. reported three posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, OncoNano Medicine, APR 18, 2023, View Source [SID1234630252]). The posters detail positive nonclinical data for ONM-501, the Company’s dual-activating STING (STimulator of INterferon Genes) agonist and lead therapeutic development candidate, formulated with the company’s OMNI polymer technology as well as positive data for encapsulated bispecific antibody and cytokine using ON-BOARD tumor specific delivery technology.

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"STING plays a critical role in innate immune response against infection and cancer, and we continue to be pleased with the data which support further advancement of the ONM-501 program," said Ruolan Han, Ph.D., Vice President of Nonclinical & Translational Medicine for OncoNano Medicine. "We look forward to bringing ONM-501 to the clinic this year and furthering the development of OMNI as we work toward our goal of delivering critical treatments to patients in need. Previous preclinical studies have shown that ONM-501 works by stabilizing the STING protein and delivering cGAMP intracellularly, where it is shielded from degradation by ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1). Combining these observations and the immune stimulation with limited systemic toxicity observed in the nonclinical species, we believe that ONM-501 has the potential to show an improved clinical profile as compared to earlier experimental STING agonists."

Previously, ONM-501, a dual-activating STING agonist, has demonstrated the ability to produce a burst and sustained activation of STING signaling that leads to a robust adaptive immune response through a unique polymer-STING binding mechanism which differs from earlier cyclic di-nucleotide (CDN) STING agonist programs. This novel mechanism provides potent anti-tumor efficacy as a monotherapy and in combination with anti-PD1 in multiple preclinical mouse models with both "hot" and "cold" tumor microenvironments. In vivo pharmacodynamic (PD) analysis confirmed STING activation, enhanced tumor lymphocyte infiltration, and tumor PD-L1 upregulation by ONM-501 and demonstrated the target-engagement activity of ONM-501 in multiple species. New pharmacokinetics/biodistribution data presented at the conference in tumor-bearing mice revealed that intratumorally injected ONM-501 showed high tumor retention and very low systemic exposure due to the polymeric micelle formulation, maximizing antitumor efficacy while minimizing systemic toxicity. This new data further differentiates ONM- 501 from other small molecule STING agonist programs. Safety studies in multiple species established a wide therapeutic window for ONM-501 making it a promising candidate for clinical evaluation.

Two additional posters were presented earlier in the conference, reporting encapsulation and masked delivery of Interleukin-12 (IL-12) and T cell engager bispecific antibodies using ON- BOARD. The results demonstrate significantly improved tolerability, anti-tumor efficacy in mice and potential for clinical translation.

"Our ON-BOARD pH-sensitive micelle delivery platform continues to demonstrate improvement of therapeutic indices with a variety of therapeutic protein payloads including the highly potent interleukin-12 and T-cell engagers," said Tian Zhao, Ph.D., Vice President of Research and Development for OncoNano Medicine. "We have seen challenges with other IL-12 and T-cell engager programs related to suboptimal therapeutic index, associated with toxicities related to systemic exposure. In contrast, the tumor-specific delivery of ON-BOARD encapsulated molecules demonstrates a much broader therapeutic window. The promising data that we presented at AACR (Free AACR Whitepaper) 2023 suggest our technology may provide a solution to overcome the clinical application limitations of these highly potent protein therapeutics."

Presentation Overview:

TITLE: Improved tolerability and tumor specific delivery of a therapeutic bispecific T cell engager using a pH-sensitive nanoparticle platform
PRESENTER: Qingtai Su, Ph.D.

TITLE: Encapsulation of IL-12 with an ultra pH-sensitive nanoparticle platform improves tolerability and promotes antitumor response in mice
PRESENTER: Tian Zhao, Ph.D.

TITLE: ONM-501, a dual-activating polyvalent STING agonist, enhances tumor retention and demonstrates favorable preclinical safety profile
PRESENTER: Zirong Chen, Ph.D.

On April 18, 2023 Nouscom, a clinical stage immuno-oncology company developing off-the-shelf and personalized viral vector immunotherapies, reported new translational and biomarker data obtained from the ongoing Phase 1b trial evaluating NOUS-PEV in patients with metastatic melanoma (Press release, NousCom, APR 18, 2023, View Source;utm_medium=rss&utm_campaign=nouscom-presents-new-positive-translational-phase-1b-data-of-nous-pev-a-personalized-neoantigen-cancer-immunotherapy-in-a-late-breaking-abstract-at-aacr-2023 [SID1234630250]). The data will be presented today in a Late-Breaking session at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

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Dr. Elisa Scarselli, Chief Scientific Officer and Co-Founder of Nouscom, said: "These translational data presented at AACR (Free AACR Whitepaper) demonstrate NOUS-PEV, in combination with pembrolizumab, induces long-lasting, tumor-infiltrating memory T cells and anti-tumor activity in metastatic melanoma patients, further supporting the mechanism of actions driving clinical efficacy. Our results further validate the immunogenic potency of our viral vector platform targeting shared and personalized neoantigens. We look forward to advancing the clinical development of NOUS-PEV and reporting complete Phase 1 results later this year."

The abstract reports a greater than 90% success in manufacturing feasibility with a median vaccine release of 8 weeks from biopsy. NOUS-PEV was demonstrated to be safe, well tolerated and highly immunogenic, inducing potent neoantigen-specific CD4 and CD8 T cell responses that were detected for greater than six months in all evaluable patients. Biomarker analysis demonstrated neoantigen-specific increased T cell migration and infiltration in tumors in patients with durable clinical responses. Current clinical efficacy data from six melanoma patients with 11 months median follow up demonstrated 4 partial responses, 1 durable stable disease and 1 progressive disease.

Poster Presentation Details:

Title: NOUS-PEV, a Personalized Cancer Immunotherapy targeting neoantigens, induces long lasting, tumor infiltrating memory T cells

On April 18, 2023 Notable Labs, Inc. ("Notable"), a clinical stage therapeutic platform company developing predictive precision medicines for cancer patients, reported clinical data regarding its Predictive Precision Medicine Platform (PPMP) at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held in Orlando, Florida from April 14-19, 2023 (Press release, Notable Labs, APR 18, 2023, View Sourcenbl-validation-aacr-2023/" target="_blank" title="View Sourcenbl-validation-aacr-2023/" rel="nofollow">View Source [SID1234630249]).

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"Together with our collaborators at Washington University, today we are reporting on the fourth successful validation study of our Predictive Precision Medicine Platform (PPMP)," said Thomas Bock, M.D., Chief Executive Officer of Notable. "The study assessed our platform’s accuracy in predicting whether a patient will clinically respond to their induction chemotherapy for acute myeloid leukemia (AML). We are excited about these clinical results as they not only corroborate, but expand upon, those of our three other validation trials. Using a specially designed approach to training our machine learning algorithm, PPMP achieved 100% accuracy in its predictions for response to venetoclax plus decitabine (VenDec). That is, all patients predicted to respond clinically actually did while those patients predicted not to respond, did not. These results add further validation and promise to Notable’s strategy of de-risking precision medicines and developing them selectively in patients predicted to clinically respond."

Abstract title: Predictive precision medicine platform accurately predicts individual patient response to AML treatments to maximize outcomes.

This study assessed the capacity of Notable’s Predictive Precision Medicine Platform to accurately predict newly diagnosed AML patients’ response to treatment with cytarabine plus idarubicin (7+3) or VenDec. Employing two different training methods, the predictive algorithm assessed pre-induction blood samples from 31 patients, 18 of whom received 7+3 and 13 of whom received VenDec. The "original" training approach bases predictions on the number of live blasts remaining after treatment with the induction therapies, while the enhanced PPMP approach employs a novel machine learning method and is explicitly designed to maximize the accuracy of predictions for VenDec. The study assessed the correlations between predictive and actual outcomes using four metrics: positive predictive value (PPV/predictive precision, the proportion of predicted responders who actually responded), the negative predictive value (NPV, the proportion of predicted non-responders who, in fact, did not respond), the area under the curve (AUC) of the Receiver Operating Characteristic (ROC) curve (the probability that the predictor correctly ranks a randomly chosen responder higher than randomly chosen nonresponder), and accuracy (the proportion of correct predictions out of all predictions).

For both 7+3 and VenDec, PPMP trained using the original method achieved a PPV of 100%, i.e., all predicted responders actually responded. A PPV of 100% indicates, for example, that a clinical trial selectively enrolling predicted clinical responders would result in a 100% response rate. The NPV was 67% for 7+3 and 57% for VenDec (i.e., 67% of patients on 7+3 and 57% on VenDec who were predicted not to respond, did not). Trained using the original method AUC was 0.91 for 7+3 and 0.81 for VenDec, and the accuracy of this approach was 94% for 7+3 and 77% for VenDec.

To further increase the accuracy on VenDec, a machine learning algorithm integrated the behavior of malignant and non-malignant cell populations and examined responses to the therapeutics along multiple biological dimensions. This novel enhanced method resulted in 100% PPV, 100% NPV and 100% accuracy on VenDec. These compelling results highlight the platform’s potential as a tool for guiding the identification of, the decision-making regarding, and the clinical development of optimal AML therapies for the individual patient. Additional meeting information can be found on the AACR (Free AACR Whitepaper) website, View Source The poster will be available on the Company’s website at View Source shortly after the event.

On April 18, 2023 Nascent Biotech, Inc. (OTCQB:NBIO) ("Nascent Biotech", "Nascent", or the "Company"), a clinical-stage biotechnology Company whose business is focused in the brain cancer space, reported that the Protocol for the Phase 2 clinical trials was submitted to the FDA for review and approval (Press release, Nascent Biotech, APR 18, 2023, https://www.nascentbiotech.com/nascent-submits-phase-2-clinical-research-protocol-to-fda-for-review-and-approval/ [SID1234630248]). The review is required for approval to commence the next phase in the development of Pritumumab ("PTB"). Data related to Phase 1 Clinical Research evaluating safety and tolerance for PTB as a treatment for Primary and Metastatic Brain Cancers has also been submitted to the FDA. The Company anticipates initial comments from the FDA approximately 30 days from the date of filing.

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PTB is a natural human antibody that binds to Cell surface Vimentin (also referred to as ectodomain vimentin), a protein expressed on the surface of epithelial cancers. PTB is used as a targeted immunotherapy and seek out only cancer cells without damaging healthy cells.