On October 23, 2024 BostonGene, a leading provider of AI-driven molecular and immune profiling solutions, reported that it will participate in the 36th edition of the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics (ENA 2024), taking place October 23-25, 2024, at the International Barcelona Convention Center in Barcelona, Spain (Press release, , OCT 23, 2024, View Source [SID1234647358]). The event will bring together academics, scientists and industry leaders from around the world to discuss innovations in drug development, target selection and translational cancer research. ENA 2024 offers a valuable platform for in-depth scientific discussions on preclinical and phase I studies and for sharing insights on advancements in molecular targets and cancer therapeutics, with a focus on the implications of molecular biology discoveries.

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Joe Lennerz, MD, PhD, Chief Scientific Officer at BostonGene, will be a featured speaker during the symposium. Dr. Lennerz will participate in a workshop titled "Innovation and Biomarkers in Cancer Drug Development," where he will deliver a presentation, "FDA’s Oversight of Laboratory Developed Tests: Taming the Wild West in Daily Practice." The presentation is scheduled for October 23, from 16:15 to 16:40 PM, in Room 113+114. Dr. Lennerz will discuss the critical role of regulatory oversight in advancing laboratory-developed tests and their impact on clinical practice, addressing current challenges and exploring solutions to ensure accuracy, reliability and patient safety.

"BostonGene is excited to engage with the international community at ENA 2024," said Dr. Lennerz. "We are eager to share our insights on the regulatory landscape and the importance of biomarkers in shaping the future of cancer therapeutics. The presentation will underscore the need for robust regulatory frameworks to support innovation, speed up drug discovery and ultimately enhance patient outcomes in this rapidly evolving field."

Visit the ENA 2024 website for more information.

On October 23, 2024 Schrödinger (Nasdaq: SDGR) reported new preclinical data on SGR-3515, its investigational Wee1/Myt1 inhibitor, during a poster session at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (ENA 2024) (Press release, Schrodinger, OCT 23, 2024, View Source [SID1234647357]). The data demonstrate that in preclinical models, treatment with SGR-3515 results in synergistic anti-tumor activity that leads to deeper and more durable responses compared to inhibitors that target only Wee1 or Myt1. The preclinical data also show that SGR-3515 has a favorable pharmacological profile and dosing schedule that supports evaluating intermittent dosing in patients.

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Wee1 and Myt1 kinases regulate the cell cycle and DNA damage response, allowing time for DNA repair before cell division takes place. Concurrent loss of function or inhibition of Wee1 and Myt1 confers selective vulnerability in cancer cells, a mechanism referred to as synthetic lethality, which has become an emerging therapeutic strategy for a range of cancers. A Phase 1 dose-escalation study of SGR-3515 in patients with advanced solid tumors is ongoing in the U.S. and Canada, and initial data from the clinical study is expected in the second half of 2025.

Schrödinger will also present preclinical data from its PRMT5-MTA program during a poster session on October 25. Schrödinger scientists have identified a novel series of selective, potent PRMT5-MTA inhibitors and are optimizing lead compounds for use in peripheral and brain tumors.

"We are pleased to share these encouraging preclinical data on SGR-3515, a potential best-in-class treatment for patients with a broad range of solid tumors, including uterine and ovarian cancers, two patient populations with high unmet need," stated Karen Akinsanya, Ph.D., president of R&D therapeutics at Schrödinger. "We also look forward to presenting preclinical data on the discovery of a novel series of compounds for our PRMT5-MTA inhibitor program. These programs highlight how we are deploying our computational platform at scale to discover highly optimized molecules to address diseases with significant medical need, and we believe the future of our therapeutics portfolio is very promising."

SGR-3515 Data at ENA 2024
The presentation (Abstract # 147), "Discovery of SGR-3515, a first-in-class Wee1/Myt1 inhibitor with differentiated pharmacological properties in xenograft tumor models," includes preclinical data demonstrating superior anti-tumor activity of SGR-3515 compared to inhibitors of Wee1 or Myt1 alone due to strong target engagement of both Wee1 and Myt1. The data show that SGR-3515 is a more potent co-inhibitor of both Wee1 and Myt1 than previously disclosed inhibitors of either target. These data are consistent with prior preclinical observations demonstrating that SGR-3515 has a unique and differentiated pharmacological profile that supports evaluating an intermittent dosing schedule of three days on and 11 days off, as well as five days on and nine days off, which maintained anti-tumor activity while allowing recovery from any mechanism-based hematological toxicity in preclinical models.

The preclinical data also demonstrate superior kinase selectivity and in vitro cell potency of SGR-3515 across a broad cell line panel compared to other known Wee1 and Myt1 inhibitors. These new data suggest that SGR-3515 is significantly more selective than existing compounds with low potential for drug-drug interaction.

PRMT5-MTA Data at ENA 2024
Additionally, Schrödinger will present new preclinical data on its PRMT5-MTA inhibitor program at a poster session during the meeting on October 25 from 9:00 a.m. – 3:00 p.m. CEST. The presentation (Abstract # 372), "Discovery of a highly MTA-synergistic series of PRMT5 inhibitors for the treatment of MTAP-deficient tumors by virtual screening technology," will include preclinical data on the discovery of highly selective PRMT5-MTA inhibitors. The poster will describe how Schrödinger’s virtual screening platform facilitated the identification of structurally distinct chemical matter with a high degree of MTA-synergy for compounds within a novel chemical series in vitro and in cellular contexts. Schrödinger has identified a novel series of selective, potent PRMT5-MTA inhibitors that did not show major off-target liabilities such as hERG inhibition in preclinical studies and may be suitable for use in combinations across tumor types.

On October 23, 2024 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported updated data highlighting the benefits of its individualized schedule for the management of anemia in the Phase 1 MYTHIC clinical trial treating patients with the combination of lunresertib, a first-in-class PKMYT1 inhibitor, and camonsertib, a potential best-in-class oral small molecule ATR inhibitor (lunre+camo) (Press release, Repare Therapeutics, OCT 23, 2024, View Source [SID1234647356]).

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Lunre+camo in the MYTHIC clinical trial (NCT04855656) previously demonstrated promising clinical activity in molecularly selected patients across multiple tumor types. In this analysis, Repare followed patients for approximately nine months at the recommended Phase 2 dose (RP2D) to assess the effectiveness of an individualized schedule. The analysis demonstrated a successful approach to mitigating mechanism-based anemia while maintaining clinical benefit. Further, Repare observed no thrombocytopenia of any grade nor serious neutropenia in these patients.

Dr. Martin Højgaard of Rigshospitalet, Denmark presented this data in a poster titled, "Individualized schedule improves rates and severity of anemia in patients treated with lunresertib, a PKMYT1 inhibitor, and camonsertib, an ATR inhibitor, in the Phase I MYTHIC study (NCT04855656)" at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Symposium on Molecular Targets and Cancer Therapeutics, being held October 23-25, 2024 in Barcelona, Spain.

"This individualized schedule in heavily pretreated patients with advanced cancers from our MYTHIC clinical trial met its goal of maintaining antitumor activity while reducing rates of grade 3 anemia," said Maria Koehler, MD, PhD, Executive Vice President and Chief Medical Officer of Repare. "We believe that these data demonstrate a favorable and differentiated tolerability profile versus both current and emerging therapies. We look forward to sharing efficacy data from the gynecological cancer expansion cohort of the MYTHIC clinical trial in December 2024."

Key Clinical Trial Findings:

The individualized schedule mitigated mechanism-based anemia based on entry hemoglobin observed in a minority of patients
Overall clinical benefit was maintained after schedule change with generally maintained radiographic regressions and molecular responses:
– Despite the change in schedule, deepening of target lesion regression was noted in some patients
– After 9 weeks on therapy, there was no observed impact on Progression Free Survival (PFS) in patients who started on or switched to the schedule of 2 weeks on / 1 week off of treatment
Dose optimization meaningfully reduced Grade 3 anemia (22.6% vs. 51.4%, previously) in all patients:
– Baseline marrow function was the key reason for Grade 3 anemia as opposed to exposure to therapy
– Baseline hemoglobin, prior therapies, and treatment intensity (weekly vs. 2 weeks on / 1 week off) predicted Grade 3 anemia frequency with lunre+camo
– Anemia reduction was greatest in patients with baseline hemoglobin less than 11g/dL (Grade 3 anemia at week 12: 34% vs. 68%, previously; overall risk reduction: 58%)
– Red blood cell transfusions (13% vs. 43%, previously), dose interruptions (13% vs. 23%) and dose reductions (6% vs. 17%) were also reduced with the new schedule
– Other Grade 3 events were already uncommon (<5% incidence) and remained consistently low, regardless of schedule

On October 23, 2024 TreeFrog Therapeutics reported a research collaboration with the University of Pittsburgh focused on the potential of tertiary lymphoid structures (TLS) in immuno-oncology, an exciting emerging field in cancer research (Press release, TreeFrog Therapeutics, OCT 23, 2024, View Source [SID1234647355]).

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Harnessing the pioneering research ongoing by Tullia Bruno, Ph.D, Assistant Professor in the Department of Immunology at the University of Pittsburgh and her team at UPMC Hillman Cancer Center, alongside the biotechnology expertise of TreeFrog Therapeutics and its proprietary C-Stem 3D cell encapsulation technology, the collaboration aims to break new ground in 3D immunology.

Tertiary lymphoid structures are ectopic lymphoid structures that develop in chronically infected organs, sites of inflammation, autoimmune diseases, and in transplants subjected to chronic rejection. In recent years, they have been described in solid tumors, where they act as crucial players in the body’s immune response to cancer. By deciphering the intricate mechanisms underlying TLS function and leveraging this knowledge, researchers aim to develop novel treatment approaches that harness the immune system’s inherent capacity to recognize and eliminate cancer cells.

"We are delighted to embark on this collaboration with Professor Bruno to apply our encapsulation technology to further understand and work with TLS, bringing new levels of control over the microenvironment of these amazing 3D immune structures. Research indicates that the presence of TLS in cancer may boost anti-tumor immunity and improve responses and prognosis, so I am excited to work with Professor Bruno and her team to explore synergies and opportunities of our 3D technology in this emerging field" said Maxime Feyeux, Chief Scientific Officer, TreeFrog Therapeutics.

"If we are able to recapitulate TLS using 3D technology, there are so many questions we could ask about their formation and modulation in a controlled manner. With 3D technology being a new frontier, this could help immensely as we work to better understand TLS biology, which could complement our work in patient samples and physiologically relevant murine models," commented Professor Bruno, Assistant Professor, Department of Immunology, University of Pittsburgh.

On October 23, 2024 Akamis Bio, a clinical-stage oncology company using a proprietary Tumor-Specific Immuno-Gene Therapy (T-SIGn) platform to deliver novel immunotherapeutic proteins, biomolecules and transgene combinations to treat solid tumors, reported the publication of data supporting the continued clinical development and intravenous route of administration of NG-350A, its lead program for the treatment of advanced metastatic cancers (Press release, Akamis Bio, OCT 23, 2024, View Source [SID1234647354]).

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NG-350A is a next-generation transgene-armed tumor gene therapy designed to drive intratumoral expression of a CD40 agonist monoclonal antibody resulting from selective replication in both primary and metastatic epithelial-derived solid tumors. Data from the first-in-human dose escalation FORTITUDE study in patients with metastatic/advanced epithelial tumors supports proof-of-mechanism for NG-350A, with strong evidence of tumor-selective delivery, replication and transgene expression. Additionally, this study demonstrates that intravenous delivery of NG-350A results in a superior overall pharmacokinetic and pharmacodynamic profile, with no apparent disadvantages versus intratumoral injection.

Blood sample analysis from patients showed sustained persistence of NG-350A up to seven weeks after intravenous dosing was completed (maximum follow up), particularly at higher dose levels. Further, a dose-dependent pattern was also seen with systemic delivery, resulting in four patients remaining positive for vector DNA in biopsies nearly two months after receiving the treatment. Transgene messenger RNA from replicating NG-350A was detected in nearly half the patients with intravenous treatment but only in one patient that had received intratumoral injection. Sustained increases in inflammatory cytokines were also observed following dosing, particularly with higher intravenous dose levels.

"These findings are highly supportive of our ongoing focus on intravenous administration of NG-350A to safely drive sustained transgene expression within the tumor microenvironment. Systemic delivery offers considerable advantages over current intratumoral approaches, particularly with transgene-containing viral vectors where the cargo needs to reach both the primary tumor and metastases throughout the body – an application for which direct injection or dependence on an abscopal effect is not viable," said Oliver Rosen, M.D., Chief Medical Officer at Akamis.

Dr. Rosen continued: "This study demonstrated that a T-SIGn therapeutic armed with targeted immunostimulatory proteins such as CD-40 agonists can be successfully delivered intravenously, resulting in a superior overall pharmacokinetic and pharmacodynamic profile compared to intratumoral administration. Our preliminary data suggest that the local expression of immunostimulatory therapies following intravenous administration can overcome toxicity that limits non-targeted systemic administration. We look forward to continuing to understand the potential of this treatment in upcoming proof-of-concept studies."

NG-350A will now be studied in combination with chemoradiotherapy in FORTRESS, a multicenter open-label non-randomized Phase 1b trial of patients with locally advanced rectal cancer.

A link to the publication "First-in-human clinical outcomes with NG-350A, an anti-CD40 expressing tumor-selective vector designed to remodel immunosuppressive tumor microenvironments" can be found here.

About T-SIGn

Akamis Bio’s T-SIGn therapeutics are based on a replication competent, chimeric group B adenovirus backbone which has been adapted via directed evolution to home specifically to both primary and metastatic epithelial-derived solid tumor tissue following intravenous delivery. Once at the tumor site, T-SIGn therapeutics can drive the intratumoral expression of multiple transgene payloads, turning solid tumor cells into "drug factories" while leaving healthy tissue unaltered and intact. The intratumoral expression of immunologically active biomolecules and therapeutic proteins can result in the remodeling of the solid tumor microenvironment, triggering robust antitumor immune responses. T-SIGn therapeutics have the potential to be used in the monotherapy setting, as well as in combination with other immuno-oncology agents to target the key mechanisms that tumors use to evade the immune system.