On October 1, 2024 Silexion Therapeutics Corp. (NASDAQ: SLXN) ("Silexion" or the "Company"), a clinical-stage biotech developing RNA interference (RNAi) therapies for KRAS-driven cancers, reported new preclinical findings for SIL-204, its second-generation siRNA candidate, following the optimization of its extended-release formulation (Press release, Silexion Therapeutics, OCT 1, 2024, View Source [SID1234646989]). These latest findings demonstrate that the latest SIL-204-microparticle formulation can inhibit the growth and induce necrosis of the human pancreatic cell line that bears the KRAS G12D mutation xenotransplanted into mice. Given that this mutation constitutes the largest segment of pancreatic cancer subtypes, it represents a significant in the development of SIL-204.

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Key new pre-clinical findings include:

Significant Anti-tumor Activity: In recent mouse xenograft studies, SIL-204 demonstrated substantial tumor reduction in the human pancreatic tumor cell lines with the KRAS G12D (Panc -1) mutations using the innovative approach of oncogene silencing with siRNA. Previous studies showed this effect using unformulated siRNA with daily injections. The new studies further show this effect with a single administration of SIL-204 encapsulated in an extended-release formulation. Moreover, histopathological examination of treated tumors showed a very high induction of tumor necrosis.
Improved Formulation In Vivo: The transition from PLGA depot rods to PLGA microparticles (MPs) has resulted in a superior extended-release profile, enhancing the therapeutic potential. We now report in vivo results indicating that our new modified PLGA-microparticle formulation has superior properties over previous extended-release formulations (Loder).
Silexion plans to initiate toxicology studies with SIL-204 within the upcoming months and has plans to advance SIL-204 into Phase 2/3 clinical trials in the first half of 2026, focusing initially on locally advanced pancreatic cancer (LAPC) which has a notoriously high mortality rate. In parallel, the company plans to initiate preclinical studies for SIL-204, in colorectal cancer models.

"These optimizations represent a significant step forward in our development of SIL-204," said Ilan Hadar, Chairman and CEO of Silexion. "The improvements in cellular uptake and the enhanced extended-release formulation further strengthen our confidence in SIL-204’s potential. We look forward to commencing our next set of studies in preparation for our Phase 2/3 clinical trial."

On October 1, 2024 GeneCentric Therapeutics, a company making precision medicine more precise through RNA-based diagnostics, reported that results from the GARNER (Genomic Analysis of high-Risk Non-muscle invasive bladder cancER) study were published in Clinical Cancer Research (Press release, GeneCentric Therapeutics, OCT 1, 2024, View Source [SID1234646988]). The GARNER study, the largest high-risk non-muscle invasive bladder cancer (HR-NMIBC) patient cohort ever assembled with both clinical and genomic detail, investigated fibroblast growth factor receptor (FGFR) DNA alteration (ALT) frequency and activation in HR-NMIBC and the clinical outcomes associated with standard-of-care Bacillus Calmette-Guérin (BCG) treatment. The study was conducted by the Erasmus MC Urothelial Cancer Research Group (EUCRG) at the Erasmus MC Cancer Institute. Janssen Research & Development, LLC, a Johnson & Johnson company, and GeneCentric collaborated to perform genomic testing.

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Although many HR-NMIBC patients respond to BCG treatment, 50-70% have a recurrence, and up to 20% progress to muscle-invasive bladder cancer (MIBC) or locally advanced/metastatic disease. Alternative therapies including FGFR-targeting agents are being investigated. While eligibility for FGFR-targeted therapies has focused on patients who are FGFR ALT (+), DNA alterations may not fully identify all patients who could potentially benefit from FGFR-targeted therapy. In this study, GeneCentric’s novel RNA-based FGFR-PRS identified approximately two-fold more patients with an activated FGFR pathway compared to those who were FGFR ALT (+).

"GeneCentric is intensely focused on developing RNA-based signatures, because DNA alterations and other biomarkers may have limitations in identifying all patients who could potentially benefit from targeted therapies," said Kirk Beebe, PhD, Chief Scientific Officer at GeneCentric. "The GARNER study allowed us to apply the FGFR-PRS to tumors from a high-risk group of patients with bladder cancer to show that the prevalence of FGFR-PRS positive tumors was much higher than the number of tumors identified with FGFR DNA alterations. Beyond HR-NMIBC, we have developed gene signatures for a broad range of targeted therapies, with a vision for this approach eventually becoming the paradigm for patient selection as an adjunct or in place of DNA alteration testing."

Findings related to the FGFR-PRS from the study include:

The FGFR alteration frequency (i.e., FGFR ALT (+)) in HR-NMIBC tumors was 31%.
The frequency of FGFR-activated tumors using the FGFR-PRS was more than twice as high as FGFR ALT+ at 75%.
This enrichment of tumors that may be FGFR-activated identified by the FGFR-PRS compared to FGFR-altered tumors was also observed in more advanced-stage disease (muscle-invasive and metastatic urothelial cancer).
About the GARNER Study

The GARNER study is the largest HR-NMIBC real-world patient cohort ever assembled with both clinical and genomic detail and the first study of the broader GARNER Bladder Cancer Program. The study is comprised of a cohort of almost 1,200 NMIBC patients who underwent surgery and adjuvant BCG treatment. The study was conducted by Tahlita Zuiverloon, MD, PhD, Principal Investigator at the Department of Urology at Erasmus MC Urothelial Cancer Research Group (EUCRG) at the Erasmus MC Cancer Institute. Janssen Research & Development, LLC, a Johnson & Johnson company, and GeneCentric Therapeutics performed retrospective genomic analysis of longitudinal samples collected in this study.

On October 1, 2024 Owkin, the first end-to-end AI-biotech that uses cutting-edge causal AI to unlock precision drug discovery, development and diagnostics, reported a new partnership with AstraZeneca, a global biopharmaceutical company, to develop an AI-powered tool to pre-screen for gBRCA mutations (gBRCAm) in breast cancer directly from digitized pathology slides (Press release, Owkin, OCT 1, 2024, View Source [SID1234646987]). As part of Owkin’s ongoing collaboration with Gustave Roussy and The Centre Léon Bérard through PortrAIt, a French consortium to accelerate precision medicine through AI-enabled digital pathology, this tool aims to significantly accelerate and expand access to gBRCA testing that too many patients may not be considered for.

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Thomas Clozel, MD, CEO of Owkin, said: "We are excited to collaborate with AstraZeneca to bring the benefits of AI to BRCA testing with the gBRCA Pre-Screen solution. During Breast Cancer Awareness Month, it’s especially important to highlight how by streamlining the diagnostic process for determining BRCA mutation status, we can expand access to BRCA testing and identify more gBRCAm patients more rapidly. Our goal is to generate the best possible medical evidence through multiple clinical studies, making genetic testing more accessible and precise, and therefore reduce the inequity of care by allowing more patients to benefit from tailored care."

BRCA testing, which identifies mutations in the BRCA1 and BRCA2 genes, plays a vital role in determining an individual’s risk for developing certain cancers, including breast and ovarian cancers. Knowing the BRCA status of breast cancer patients is important to help identify familial risk and guide treatment options, including responses to targeted therapies. While many professional bodies have released guidelines recommending broader BRCA testing, it is not always consistently offered to eligible individuals, and implementation varies between countries. This is causing an inadvertent exclusion of individuals who may benefit from these tests. If routinely used, this gBRCA pre-screening solution could lead to the identification of thousands more gBRCAm HR-positive early breast cancer patients in France, Germany, Italy, Spain, and the United Kingdom by 2030.

Kristina Rodnikova, Head of Global Commercial Diagnostics, Oncology at AstraZeneca, said: "On average, a woman with a BRCA1 or BRCA2 gene mutation has up to a 7 in 10 chance of being diagnosed with breast cancer by age 80. This collaboration with Owkin underscores our commitment to advancing precision medicine, helping address the unmet need and identifying patients at risk of harboring BRCA mutations to improve their outcomes."

The typical BRCA testing journey for a patient can take several months and involve several healthcare professionals, from initial consultation to results, strongly impacting the patient’s outcomes. The gBRCA pre-screening solution has the potential to significantly enhance the efficiency of BRCA mutation identification. In less than one hour, the solution could identify a patient at high risk of harboring gBRCA mutation by leveraging existing material, including H&E slides. This could greatly streamline the gBRCA testing process, allowing oncologists and genetic counsellors to accelerate the gBRCA genetic testing for high-risk patients and incorporate these genetic test results into the treatment planning process without delays.

The solution is currently in development and undergoing validation.

On October 1, 2024 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 that the first patient has been enrolled in its Phase 2 dose expansion study evaluating ST316, the Company’s first-in-class antagonist of β-catenin (Press release, Sapience Therapeutics, OCT 1, 2024, View Source;catenin-antagonist-in-colorectal-cancer-302263343.html [SID1234646985]). Enrollment of the study’s Phase 1 monotherapy dose escalation portion was completed in July 2024.

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ST316 is designed to selectively shut down the Wnt/β-catenin signaling pathway in tumor cells but not in normal cells, allowing for anti-cancer activity without the toxicity related to broad inhibition of this pathway. The Wnt/β-catenin signaling pathway is one of the most active pathways in several cancers and drives more than 80% of colorectal cancers (CRCs), the first indication to be evaluated in the ST316 Phase 2 expansion. There are more than 1 million people living with CRC in the United States, with another 150,000 expected to be diagnosed this year alone.

Dr. Abi Vainstein-Haras, Sapience’s Chief Medical Officer, stated, "The promising results seen in our Phase 1 study demonstrate ST316’s potential to be an effective therapy for Wnt pathway-driven cancers, including CRC among others. Given ST316’s favorable safety and tolerability profile, together with robust pre-clinical data, Sapience is committed to maximizing the potential of ST316 in various therapeutic combinations across lines of treatment."

"CRC patients who are refractory to current therapies desperately need new options like ST316," said Dr. Barry Kappel, Sapience’s founder and Chief Executive Officer. "With CRC being the second-leading cause of cancer death in the United States, and with alarming increases in incidence among younger Americans, we are dedicated to widening the treatment options for this devastating disease."

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 study tested various dose levels of ST316 in patients with select advanced solid tumors that are known to harbor abnormalities of the Wnt/β-catenin signaling pathway, including CRC. The Phase 1 portion completed enrollment in July 2024. In the Phase 2 dose expansion portion of the study, ST316 is being tested in CRC patients in combination with relevant standards of care and in multiple lines of treatment. Sapience is conducting the Phase 2 study across several sites in the United States.

About ST316

ST316 is a first-in-class peptide antagonist of the interaction between β-catenin and its co-activator, BCL9, a complex responsible for driving 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.

On October 1, 2024 Replimune Group, Inc. (Nasdaq: REPL), a clinical stage biotechnology company pioneering the development of novel oncolytic immunotherapies, reported that members from the Replimune management team will present and host investor meetings at the following two conferences (Press release, Replimune, OCT 1, 2024, View Source [SID1234646982]):

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BMO 2024 Oncology Summit
Date: Tuesday, October 8, 2024

3rd Annual Roth Healthcare Opportunities Conference
Date: Wednesday, October 9, 2024