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Boundless Bio Presents Preclinical Data on the Discovery of its Second ecDNA-Directed Therapeutic Candidate, BBI-825, at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

On October 13, 2023 Boundless Bio, a clinical stage, next-generation precision oncology company interrogating extrachromosomal DNA (ecDNA) biology to deliver transformative therapies to patients with previously intractable oncogene amplified cancers, reported that it will present preclinical data on its second ecDNA-directed therapy (ecDTx), BBI-825, as well as present additional research on the intrinsic genomic plasticity of cancer cells enabled by ecDNA at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Boundless Bio, OCT 13, 2023, View Source [SID1234635960]).

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BBI-825 is a novel, orally available, selective inhibitor of ribonucleotide reductase (RNR), which is a rate-limiting enzyme in the cellular production of deoxynucleotide triphosphates (dNTPs), essential building blocks for ecDNA assembly and repair in cancer cells. BBI-825 has demonstrated RNR inhibition in a host of tumor cell lines and tumor regressions in ecDNA-enabled preclinical cancer models and is currently being evaluated in Investigational New Drug (IND)-enabling studies. BBI-825 was discovered using Boundless Bio’s proprietary Spyglass platform, a drug discovery engine to identify and preclinically validate targets that are essential for cancer cells’ reliance on ecDNA for growth, treatment resistance, and survival.

"We are excited to unveil our second ecDTx program, BBI-825, which has demonstrated promising preclinical proof of concept in multiple tumor types and across different oncogene amplifications, particularly in resistance associated with targeted therapy treatment of MAPK pathway activated cancers," said Chris Hassig, Ph.D., Chief Scientific Officer of Boundless Bio. "In addition to single agent anti-tumor activity, BBI-825 also has shown synergistic activity when combined with specific targeted therapies in ecDNA-enabled in vivo tumor models, and in particular, cancer models that develop resistance amplifications on ecDNA in response to KRASG12C inhibitors in KRASG12C mutated CRC. We believe a selective, oral RNR inhibitor has broad potential for patients with ecDNA-enabled and oncogene amplified cancers and that the discovery and preclinical validation of BBI-825 underscores the power of our Spyglass platform."

The second poster presentation extends the field’s understanding of ecDNA and its key role in enabling resistance to cancer therapy. Unique properties of ecDNA drive genomic plasticity and tumor heterogeneity, enabling rapid acquired resistance to targeted therapies and resulting in poor patient outcomes; however, the potential adaptive and resistance properties in the chromosomal state are not well characterized. The findings from this study provide a model for how cancer cells with ecDNA-derived, chromosomally reintegrated homogeneous staining regions (HSR) retain the capacity to amplify ecDNA, thus further enabling rapid adaptation to therapeutic pressure and highlighting the urgent need for ecDNA-directed therapies for patients with oncogene amplified cancers.

Details of today’s presentations are as follows:

Title: A novel, potent and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, blocks extrachromosomal DNA (ecDNA) amplification-mediated resistance to KRASG12C inhibitor in colorectal cancer (CRC)
Abstract Number: B082
Session: Poster Session B
Date/Time: Friday, October 13 | 12:30 – 4:00 pm ET

Title: Intrinsic genomic plasticity of extrachromosomal DNA (ecDNA) enables oncogene amplified tumor cells to develop rapid acquired resistance to targeted therapy
Abstract Number: B092
Session: Poster Session B
Date/Time: Friday, October 13 | 12:30 – 4:00 pm ET

About BBI-825

BBI-825 is a novel, orally available, selective inhibitor of ribonucleotide reductase (RNR), a rate-limiting enzyme responsible for cellular production of deoxyribonucleotide triphosphates (dNTPs), the building blocks of DNA, and essential to the assembly and repair of ecDNA. In preclinical studies, BBI-825 starved ecDNA-reliant cancer cells of dNTPs, depleted ecDNA, and was synthetic lethal in ecDNA-bearing cancer cells. BBI-825 has demonstrated preclinical in vivo proof of concept in multiple tumor types and across different oncogene amplifications, including both driver oncogene and resistance settings, particularly in MAPK pathway activated cancers. RNR was identified and preclinically validated as an ecDNA essential target via Boundless Bio’s proprietary Spyglass platform and led to the development of BBI-825, which is currently being evaluated in IND-enabling studies.

GENESEEQ RECEIVES CHINESE NMPA APPROVAL FOR LUNG CANCER TUMOR MUTATIONAL BURDEN NGS TEST KIT

On October 13, 2023 Geneseeq Technology Inc. reported that Geneseeq’s Non-Small Cell Lung Cancer Tumor Mutational Burden Test Kit (Reversible terminator sequencing method) (NSCLC TMB Kit) has gained approval from the Chinese National Medical Products Administration (NMPA) on October 12, 2023 as a Breakthrough Medical Device (Press release, Geneseeq, OCT 13, 2023, View Source [SID1234635959]).

This NSCLC TMB kit entered the NMPA special examination and approval procedures for Breakthrough Medical Devices in January 2020. With the NMPA approval, this kit is used for in vitro qualitative detection of TMB in FFPE tissue samples from patients with EGFR/ALK-negative non-squamous NSCLC. This is the first next-generation sequencing (NGS)-based TMB test kit approved in China with a large gene panel covering 425 cancer-associated genes (GENESEEQPRIME). TMB is a predictive biomarker for the efficacy of immune checkpoint inhibitor therapy.

Prior to this, Geneseeq already had one NGS-based CDx kit for NSCLC, ESSENCARE (EGFR/ALK/ROS1/BRAF/KRAS/HER2 mutation testing kit), approved by the NMPA through the Breakthrough Medical Devices pathway. GENESEEQPRIME was also CE-IVD marked by the European Medicines Agency in August 2023 for detecting single nucleotide variants, gene amplifications/deletions, translocations, TMB, and microsatellite instability in patients with solid tumors.

"This approval will significantly benefit the clinical implementation of immunotherapy in China with a standardized TMB assessment assay," Dr. Yang Shao, founder and CEO of Geneseeq Group, said in a statement.

Sapience Therapeutics Presents ST101 Clinical Data and ST316 Preclinical Data at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

On October 13, 2023 Sapience Therapeutics, Inc., a clinical-stage biotechnology company focused on the discovery and development of peptide therapeutics to address oncogenic and immune dysregulation that drive cancer, reported the presentation of two posters at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place October 11-15, 2023, in Boston, MA (Press release, Sapience Therapeutics, OCT 13, 2023, View Source [SID1234635958]).

Poster Presentation Details:

Title: "Clinical and Biological Activity of ST101, a Peptide Antagonist of C/EBPβ, in Recurrent Glioblastoma (rGBM) Patients. Results From the rGBM Cohort of a Multi-Cohort Phase 2 Study"
Poster Number: B038
Session Title: Poster Session B
Date/Time: Friday, October 13, 2023, 12:30 pm-4:00 pm
Session location: Level 2, Exhibit Hall D

ST101 is a first-in-class antagonist of C/EBPβ that has demonstrated clinical proof-of-concept in advanced solid tumors. ST101 is currently being evaluated in the Phase 2 portion of an ongoing Phase 1-2 clinical study in patients with advanced unresectable and metastatic solid tumors (NCT04478279).
The poster summarized clinical data from ST101’s recurrent Glioblastoma (rGBM) Phase 2 expansion cohort of 30 patients. The GBM cohort showed ≥ 1 response in the first 15 patients, triggering the criteria to expand to a total of 33 patients enrolled; 30 were evaluable for efficacy in this cohort.
Key Conclusions:
ST101 demonstrates the ability to pass through the blood-brain-barrier and engage C/EBPβ.
Single agent ST101 demonstrated clinical activity and tissue treatment effect.
This data snapshot also demonstrated that patients receiving ST101 monotherapy exhibited encouraging response and survival outcomes.
Results from the ST101-101 study warrant further assessment of ST101 as part of a combination treatment approach for patients with rGBM.
Title: "Anti-tumor and Immunostimulatory Properties of ST316, a Peptide Antagonist of β-Catenin for Treatment of Cancers with Aberrant Wnt Pathway Activity"
Poster Number: B149
Session Title: Poster Session B
Date/Time: Friday, October 13, 2023, 12:30 pm-4:00 pm
Session location: Level 2, Exhibit Hall D

ST316, a first-in-class antagonist of β-catenin, is designed to selectively target oncogenic activation of the Wnt/β-catenin signaling pathway without impacting its activity in normal cells. ST316 is currently being evaluated in the Phase 1 portion of a Phase 1-2 study, ST316-101 (NCT05848739), which is a limited solid tumor basket study for tumors likely to harbor abnormalities in the Wnt pathway, such as colorectal cancers.
The poster summarized preclinical data demonstrating the anti-tumor and immunostimulatory properties of ST316 in multiple cancer models.
Key Conclusions:
ST316 effectively inhibits the transcriptional activity of oncogenic β-catenin, resulting in reduction of Wnt target genes involved in carcinogenesis, cell division, cell migration and immunoinhibitory processes.
ST316 treatment results in reduced cell viability and tumor growth inhibition, marked by the reduced expression of Wnt target genes within tumor tissue.
ST316 induces polarization of hPBMC-derived M2 macrophages toward the M1 phenotype and enhances CD8+ T cell activation in mixed cultures of macrophages and T cells. Furthermore, subpharmacologic ST316 augments the efficacy of anti-PD-1 antibody in an orthotopic 4T1 TNBC tumor model.
These findings underscore ST316’s potential as a therapeutic agent for targeting cancers characterized by aberrantly activated Wnt signaling pathways, showcasing its antitumor and immunostimulatory effects.
More information can be found on the AACR (Free AACR Whitepaper)-NCI-EORTC website.

About ST101

ST101, a first-in-class antagonist of C/EBPβ, is currently being evaluated in the Phase 2 portion of an ongoing Phase 1-2 clinical study in patients with advanced unresectable and metastatic solid tumors (NCT04478279). ST101-101 is an open-label, Phase 1-2 dose-finding study designed to determine the safety, tolerability, PK, PD, and proof-of-concept efficacy of ST101 in patients with advanced solid tumors. The study consists of two phases: Phase 1 dose escalation/regimen exploration and Phase 2 dose expansion. In the ongoing Phase 2 dose expansion part of the study, ST101 has demonstrated clinical proof-of-concept with a mRANO-confirmed partial response in a patient with recurrent GBM and evidence of long-lasting stable disease in several additional patients.

ST101 has been granted Fast Track designation for recurrent GBM and advanced cutaneous melanoma in patients who have disease progression on or after anti-PD-1/anti-PD-L1 therapy, as well as orphan designations from the FDA for Stage IIb-IV melanoma, glioma and AML, and from the European Commission for the treatment of glioma.

About ST316

ST316 is a first-in-class peptide antagonist of the interaction between β-catenin and its co-activator, BCL9, a complex that drives oncogene expression in multiple cancers where aberrant Wnt/β-catenin pathway signaling is observed. ST316 exposure in cancer cells prevents BCL9-driven nuclear localization of β-catenin and inhibits formation of the Wnt enhanceosome protein complex. Disruption of this interaction selectively suppresses the transcription of oncogenic Wnt target genes that regulate proliferation, migration, invasion and the metastatic potential of tumor cells, as well as genes that regulate the immunosuppression of the tumor microenvironment. ST316 creates a pro-immune tumor microenvironment and in preclinical models has shown to be synergistic with checkpoint inhibition. Due to its selectivity and downstream modulation of the Wnt/β-catenin pathway, ST316 presents an opportunity to safely and effectively target Wnt/β-catenin driven cancers without the toxicities previously seen with other Wnt pathway agents.

ST316-101 (NCT05848739) is a first-in-human, open-label, Phase 1-2 dose-escalation and expansion study designed to determine the safety, tolerability, PK, PD and early efficacy of ST316. The Phase 1 dose-escalation portion of the Phase 1-2 study has begun enrolling and dosing patients with select advanced solid tumors that are known to harbor abnormalities of the Wnt/β-catenin signaling pathway. With its first patient dosed on June 5, 2023, the Company expects to complete the Phase 1 portion of the study in the second half of 2024. Following completion of the study’s Phase 1 portion, the recommended dose will advance to the Phase 2 dose expansion portion of the study.

Flare Therapeutics Presents Novel, AI-Based Method Identifying Luminal Subtype of Urothelial Cancer Supporting Lead Asset FX-909 at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

On October 13, 2023 Flare Therapeutics, a biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, reported a new study describing a robust artificial intelligence (AI)-based model in partnership with PathAI that accurately predicts luminal muscle invasive urothelial cancer (MIUC), characterized by high peroxisome proliferator-activated receptor gamma (PPARG) expression using H&E-stained slides (Press release, Flare Therapeutics, OCT 13, 2023, View Source [SID1234635957]). This approach supports the clinical development of the Company’s first-in-class clinical candidate, FX-909, for the treatment of patients with advanced Urothelial Carcinoma (UC). These findings were shared at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) being held in Boston, Mass. from October 11-15, 2023.

"The digitization of pathology has ushered in a new era of AI and machine learning that can inform patient diagnosis and guide clinical decision-making. We are excited to be at the forefront of applying these innovative biomarker approaches to identify patients with advanced urothelial cancer that may potentially respond to PPARG inhibition," said Michaela Bowden, Chief Development Officer at Flare Therapeutics. "High PPARG expression is a defining feature of luminal MIUC, accounting for approximately 65% of cases in the advanced and metastatic setting. The ability to further stratify patient subsets could offer a powerful tool to inform the path forward for therapy that could include Flare Therapeutics’ lead investigational compound, FX-909."

The poster presentation, titled "AI Analysis of Histological Images Accurately Identifies Luminal Subtype Urothelial Carcinomas Characterized by High PPARG Expression," analyzed H&E-stained slides from 367 unique primary MIUC cases obtained from the TCGA BLCA dataset and 42 MIUC cases from an independent dataset. An end-to-end additive multiple-instance learning model was deployed, resulting in excellent performance typified by AUROC values ³95%, correctly classifying advanced urothelial cancer of luminal subtype, across the test, validation and independent data sets.

"We conducted machine-learning driven analyses of digital images from H&E-stained tissues to identify patients with luminal MIUC," said Michael Montalto, Chief Scientific Officer at PathAI. "We are highly encouraged by the initial results relative to current molecular approaches and look forward to collaborating with the Flare Therapeutics team to evaluate the performance of this novel algorithm in support of the FX-909 program. The model could have tremendous utility in helping to improve MIUC patient outcomes. It was a pleasure to work closely with the Flare Therapeutics team and apply our model to a real-world application."

FX-909 is a first-in-class novel, highly potent and selective small molecule that inhibits PPARG to treat patients with the luminal subtype of advanced UC. The Company recently initiated clinical trials for FX-909.

Anixa Biosciences Completes Treatment of First Patient Cohort in Ovarian Cancer CAR-T Clinical Trial

On October 13, 2023 Anixa Biosciences, Inc. ("Anixa" or the "Company") (NASDAQ: ANIX), a biotechnology company focused on the treatment and prevention of cancer, reported that, in partnership with Moffitt Cancer Center, it has completed treatment of the first patient cohort in the ongoing clinical trial of Anixa’s novel chimeric antigen receptor T-cell (CAR-T) therapy for ovarian cancer (Press release, Anixa Biosciences, OCT 13, 2023, https://www.prnewswire.com/news-releases/anixa-biosciences-completes-treatment-of-first-patient-cohort-in-ovarian-cancer-car-t-clinical-trial-301955685.html [SID1234635956]).

All three patients in the first cohort received the same dose of engineered T-cells, with no dose-limiting toxicities observed. Following the requisite wait time after the last patient was dosed, a comprehensive review of the safety data from this cohort, and confirmation that it is safe to escalate, the trial will begin enrolling patients in the second dose cohort immediately. Patients enrolled in this second cohort will receive three times the cell dose compared to the first cohort.

Dr. Amit Kumar, Chairman and CEO of Anixa Biosciences, stated, "We are pleased with the positive safety data from the first cohort and look forward to advancing to the next higher dose cohort. We hope to continue observing good safety results as we continue to increase dosage, and eventually objective efficacy data."

The study (NCT05316129), which is being conducted at Moffitt Cancer Center, is a dose-escalation Phase 1 trial to evaluate the therapy’s safety; determine the maximum tolerated dose of T-cells targeting the follicle stimulating hormone receptor (FSHR); and preliminarily assess clinical activity. All patients being enrolled in the trial have disease that is progressing and have failed at least two, but often more, therapeutic interventions.

Dr. Robert Wenham, the Principal Investigator of the trial, and the Head of Gynecological Oncology at Moffitt stated, "We are very pleased with the results to date. The first three patients were dosed through a peritoneal catheter and no patient has had a dose-limiting toxicity. Since most lesions in ovarian cancer are within the peritoneum, we hope the delivered CAR-T cells remain localized and active in the vicinity of the tumors. It’s possible that we may see very limited side effects due to this local, as opposed to systemic, delivery. The very selective target also gives us reason to hope that on-target, off-tumor effects will not be prevalent as in other solid tumor studies. Perhaps this delivery approach may enhance efficacy as well. However, we will also test this therapy by intravenous administration, in patients for whom peritoneal administration is not possible."

The CAR-T approach used for Anixa’s therapy is known as chimeric endocrine receptor T-cell (CER-T) since the target of the engineered T-cells is an endocrine receptor. While CAR-T therapy has shown efficacy in some hematological tumors, reproducing the same results with solid tumors, such as ovarian cancer, has proven challenging. One of the reasons for this difficulty is that effective CAR-T therapy needs to attack a specific antigen present only on targeted cells to avoid negatively affecting healthy cells. The cell therapy being evaluated in Anixa’s Phase 1 study differs from traditional CAR-T therapy in that it targets the FSHR, which research indicates is exclusively expressed on ovarian cells in healthy adult females.