On October 23, 2024 General Proximity reported the company has been selected as one of the 24 awardees of the highly competitive Advanced Research Projects Agency for Health (ARPA-H) Sprint for Women’s Health (Press release, General Proximity, OCT 23, 2024, View Source [SID1234649816]).

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Chosen from over 1,700 applicants representing 34 countries, this recognition underscores the transformative potential of our technology in addressing unmet needs in women’s health. This $3M award will support our team as we advance next-gen proximity therapeutics for high value undruggable targets in the women’s cancer space toward the clinic.

We are honored by ARPA-H’s support on this groundbreaking program and remain committed to advancing solutions that redefine possibilities in women’s healthcare.

On October 23, 2024 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported the addition of a potent and selective KRAS inhibitor to its pipeline (Press release, Cogent Biosciences, OCT 23, 2024, View Source [SID1234647335]). Preclinical data from this program as well as its newly announced H1047R mutant-selective PI3Kα clinical candidate will be presented in two poster presentations at the 2024 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) International Symposium on Molecular Targets and Cancer Therapeutics taking place in Barcelona, Spain October 23-25, 2024.

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"Our Research team continues to make amazing progress, and we are excited to announce our third clinical candidate and fourth preclinical program today," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "Building upon earlier data presentations and recent advancements in the field, our first poster describes the properties of CGT6297, which we believe has the potential to emerge as a best-in-class H1047R mutant-selective PI3Kα inhibitor. Separately, for the first time, we outline our progress toward developing a potential best-in-class KRAS(ON) inhibitor, which in addition to its mechanistic attributes, has pharmacological properties differentiated from existing compounds in the class. Each of these programs align with our long-term strategy of creating and developing best-in-class molecules with the potential to have a broad impact on patients with genetically defined diseases."

Poster Details
The posters can be accessed in the ‘Posters and Publications’ page of Cogent’s website.

Title: Identification of a Pan KRAS(On) Inhibitor with Selectivity Over KRAS over H/NRAS and pM Activity Across Prevalent KRAS Mutations
Session Date and Time: Wednesday, October 23, 2024 – 12.00 – 19.00 CEST
Location: Exhibition Hall, Centre de convencions internacional Barcelona (CCIB), Barcelona, Spain
Poster Number: PB108
Abstract Number: 120

Mutations in KRAS are among the most prevalent mutations found in cancer, occurring most often in colorectal cancer, non-small cell lung cancer and pancreatic cancer. The poster presented today describes Cogent’s internally-developed pan KRAS(ON) inhibitor with selectivity over HRAS and NRAS and picomolar (pM) activity across KRAS mutations without the potential liabilities of molecules in the class. Following oral administration, CGT6737 demonstrated robust PK/PD and tumor growth inhibition with 90% PD inhibition in mouse xenograft models. Lead optimization of CGT6737 is ongoing.

Title: Preclinical Characterization of a Novel PI3Kα H1047R Mutant Selective Inhibitor
Session Date and Time: Wednesday, October 23, 2024 – 12.00 – 19.00 CEST
Location: Exhibition Hall, Centre de convencions internacional Barcelona (CCIB) Barcelona, Spain
Poster Number: PB133
Abstract Number: 145

Cogent is also developing a potential best-in-class, wild-type-sparing, PI3Kα inhibitor that provides coverage for the H1047R mutation, which affects >55,000 cancer patients each year. The phosphoinositide 3-kinase (PI3K) pathway is a key cell cycle regulating pathway that has an established role in tumor growth and development. The approved agents for these patients often lead to dose limitations, resulting from activity against wild-type PI3Kα.

The poster presented today highlights Cogent’s clinical candidate CGT6297, a potent allosteric inhibitor of PI3K, with 25-fold selectivity over PI3Kα WT. CGT6297 has high oral bioavailability and low clearance across species, providing robust inhibition of downstream signaling and efficacy in animal models. Importantly, when compared to a clinically relevant dose of a currently approved therapy in a mouse tumor model, CGT6297 demonstrated superior efficacy with no increase in insulin. IND-enabling studies are expected to be initiated in 2025.

Upcoming Investor Conference
Cogent will participate in the following upcoming investor conference:

Guggenheim Healthcare Innovation Conference – November 12, 2024 at 10:30 a.m. ET.

A live webcast of the fireside discussion will be available in the Investors & Media section of Cogent’s website at investors.cogentbio.com/events. A replay of the event will be archived on Cogent’s website for up to 30 days.

On October 23, 2024 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 four posters with clinical and preclinical data from RVU305 (MTA-cooperative PRMT5 inhibitor), WRN program, ONCO Prime, and RVU120 at the 2024 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (ENA), October 23-25, Barcelona, Spain (Press release, Ryvu Therapeutics, OCT 23, 2024, View Source [SID1234647351]).

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"It is an exciting time for Ryvu’s pipeline as we advance a potentially best-in-class PRMT5 inhibitor, RVU305, through IND-enabling studies. We are pleased to highlight data from this program, with expected initiation of clinical development in Q4 2025, and other Ryvu projects at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium this year. We are especially proud of our ONCO Prime target discovery platform, which demonstrates the progress of our scientific efforts on novel synthetic lethal (SL) inhibitors targeting key oncogenic drivers such as KRAS and other mutations." – said Krzysztof Brzózka, Ph.D., Chief Scientific Officer.

Upcoming Events

R&D Update at ENA 2024: webinar on Friday, October 25 at 11:00 AM CET to discuss the data presented at the ENA Symposium. To join the webcast, please register here: View Source
RVU120 Program Progress and Data Update: webinar on Thursday, December 12, 10:00 AM CET to discuss the ongoing RVU120 Phase II studies.
Poster highlights:
Poster Title: Discovery of novel MTA-cooperative PRMT5 preclinical candidate as targeted therapeutics for MTAP-deleted cancers
Poster Number: 32
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

Ryvu has developed a potentially best-in-class MTA-cooperative PRMT5 inhibitor, RVU305, demonstrating favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding.

RVU305 exhibits robust antiproliferative activity in MTAP-null cancer models, including over 100% tumor growth inhibition (TGI) at several dose levels and multiple complete remissions (CRs) at several dose levels in a DoHH2 MTAP-deleted model.
Tolerability and selectivity towards MTAP-deleted cells was also demonstrated in in vitro and in vivo preclinical models.
Overall, the findings highlight the potential of RVU305 preclinical candidate as a promising therapeutic option for patients with MTAP-deleted cancers.
Poster Title: Exploring synthetic lethality and novel drug combinations in patient-derived cells
Poster Number: 417
Session date and time: Friday, October 25 (09:00-15:00 CEST)

Ryvu has developed a proprietary platform, ONCO Prime, to discover novel synthetic lethal (SL) inhibitors targeting key oncogenic drivers such as KRAS and other mutations.

Initial data are presented in colorectal cancer (CRC), but the platform has the potential to discover novel SL targets across all tumor types. ONCO Prime uses human intestinal stem cell (hISC)-derived cancer model cells, patient-derived xenografts (PDXs), and clinical samples to conduct genomic and functional analyses.
Ryvu generated isogenic cancer models and validated them through transcriptomic profiling of patient-derived xenografts (PDXs) and patient-derived cell cultures to ensure clinical relevance.
The data presented in this poster highlights the outcomes of chemical compound and CRISPR/Cas9 screenings, confirming the reliability and relevance of our model for identifying new therapeutic targets in oncology.
Poster Title: Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors
Poster number: 107
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

Ryvu is developing a series of potent and selective WRN helicase inhibitors that demonstrate pronounced efficacy in tumors with high microsatellite instability (MSI-H).

Ryvu WRN inhibitors show nanomolar potency in viability assays in MSI-H cell lines, with excellent selectivity over microsatellite-stable (MSS) cells.
In in vivo studies, Ryvu inhibitor strongly suppressed tumor growth in an MSI-H model (SW48) while not impacting the MSS model (SW620).
The compounds exhibit favorable pharmacokinetics, achieving optimal exposure and target engagement, further enhancing their therapeutic potential in MSI-H cancers.
Poster Title: Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors
Poster Number: 34
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

RVU120 is being tested in patients with solid tumors in an ongoing Phase I/II clinical trial, AMNYS-51. RVU120 has demonstrated a manageable safety profile across multiple dose levels and dosing schedules in patients with advanced or metastatic solid tumors.

No dose-limiting toxicities (DLTs) were observed, and most treatment-emergent adverse events (TEAEs) were mild to moderate, with nausea and vomiting being the most common.
6/8 patients with adenoid cystic carcinoma achieve a longer duration of treatment on RVU120 compared with their most recent prior line of therapy. A reduction of 20% of target lesions was observed in 2 patients with adenoid cystic carcinoma.
The recommended phase 2 dose (RP2D) for the QOD schedule was identified as 250 mg and remains the primary dosing schedule in clinical studies, but a continuous dosing schedule was explored and could offer an alternative to patients: continuous every day administration (QD) of RVU120 at doses of 100 mg and 150 mg is considered safe and may improve tolerability of RVU120 compared with 250 mg every other day.

On October 23, 2024 Interius BioTherapeutics, a clinical-stage company engineering targeted, programmable vectors for the precision delivery of genetic medicines, reported that the first study participant has been dosed in INVISE, its first-in-human Phase 1 clinical trial of INT2104, a first-in-class gene therapy that delivers a CAR transgene to generate effector CAR-T and CAR-NK cells in vivo for the targeting of CD20-positive B cells for the treatment of B-cell malignancies (Press release, Interius BioTherapeutics, OCT 23, 2024, View Source [SID1234647336]).

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"Interius was founded with a sense of urgency to provide patients with a new therapeutic option that does not require preconditioning or long manufacturing and wait times. Interius’s breakthrough technology allows precise targeting of gene therapies to specific cells via intravenous administration," said Interius President and CEO, Phil Johnson, M.D. "This milestone marks the first time that a durable in vivo CAR therapy has been used in the clinic. INT2104 has the potential to overcome ex vivo CAR therapy challenges with a single-dose, off-the-shelf, widely accessible therapy for the treatment of B cell malignancies enabled by Interius’s programmable platform. In our preclinical studies, we achieved successful B cell depletion in small and large animal models without chemotherapy and observed no signs of cytokine release syndrome (CRS) or neurotoxicity. We look forward to sharing interim clinical safety and proof-of-concept data at a scientific meeting next year."

Dr. Michael Dickinson, MBBS, FRACP, Lead of the Aggressive Lymphoma Disease Group at Peter MacCallum Cancer Centre and Royal Melbourne Hospital and INVISE Principal Investigator, added, "The need for new, accessible treatment options for patients with cancer is critical. Innovative approaches, like in vivo CAR gene therapies, have the potential to transform how we treat cancer, offering faster, single-dose solutions that are less burdensome on patients and treatment centres."

About INVISE
INVISE (INjectable Vectors for In Situ Engineering) is a first-in-human Phase 1 clinical trial evaluating the safety of INT2104 intravenous infusion in adults with refractory/relapsing B cell malignancies. The study is a global, two-part, multicenter, open-label, single dose design with a dose escalation portion designed to inform the dose of INT2104 to be used in the dose confirmation part of the trial and future studies. INVISE has been granted Human Research Ethics Committee (HREC) approval and Clinical Trial Notification (CTN) clearance by the Australian Therapeutic Goods Administration (TGA). Additional information and enrollment criteria may be found on clinicaltrials.gov (NCT06539338).

About INT2104
INT2104 is a wholly-owned investigational gene therapy candidate, which specifically targets CD7-positive T and NK cells and delivers a CAR transgene to create effector CAR-T and CAR-NK cells in vivo. The CAR cells target CD20-positive B cells for the treatment of B cell malignancies. Unlike ex vivo CAR-T therapies, INT2104 is an off-the-shelf, single dose treatment, administered systemically through intravenous infusion without the need for lymphodepletion or for any special equipment or training.

On October 23, 2024 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported it will present preclinical data from the Company’s mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential in NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (Press release, HotSpot Therapeutics, OCT 23, 2024, View Source [SID1234647352]).

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MALT1 is a component of the CBM protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies and solid tumors. Leveraging the Company’s proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule signalosome glue designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1’s protease function.

"Our proprietary Smart Allostery platform has enabled the development of a MALT1 signalosome glue designed to selectively inhibit MALT1’s scaffolding function, a distinct activity profile that enables deep inhibition of the NF-kB pathway," said Geraldine Harriman, Ph.D., Chief Scientific Officer of HotSpot Therapeutics. "As the NF-kB signaling pathway is a well-characterized oncogenic driver, these preclinical data lend support for HST-1021’s potential utility for NF-kB-driven tumors, including as a precision oncology approach for solid tumors mediated by this pathway."

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 CBM signalosome glue development candidate:

In contrast to MALT1 protease inhibitors, HST-1021 demonstrated robust inhibition of CBM signalosome activity.
In an NF-kB-driven nasopharyngeal carcinoma patient-derived xenograft model, HST-1021 demonstrated dose-dependent anti-tumor activity, supporting HST-1021’s potential for the treatment of NF-kB-driven solid tumors.