On April 17, 2023 Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, reported preclinical proof-of-concept data and highlighting a clinical case study in Claudin 18.2-expressing cancers for the company’s lead candidate, EO-3021 (Press release, Elevation Oncology, APR 17, 2023, View Source;utm_medium=rss&utm_campaign=elevation-oncology-presents-eo-3021-preclinical-proof-of-concept-data-and-highlights-a-clinical-case-study-in-claudin-18-2-expressing-cancers-at-aacr-2023 [SID1234630150]). The data are being featured in an oral presentation as part of the New Drugs on the Horizon special session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, being held April 14-19, 2023, in Orlando, Florida.

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EO-3021 is a potential best-in-class antibody-drug conjugate (ADC) that has been designed to selectively deliver a cytotoxic payload directly to Claudin 18.2-expressing cancer cells to minimize toxicities and maximize anti-tumor activity. EO-3021 is a fully human monoclonal antibody (mAb) that targets Claudin 18.2 and is site-specifically conjugated to the cytotoxic agent monomethyl auristatin E (MMAE), via a cleavable linker with a drug-to-antibody ratio (DAR) of 2.

"This is the first time that preclinical data are being presented for EO-3021, supporting its potential to effectively target cancer cells expressing Claudin 18.2," said David Dornan, Ph.D., Chief Scientific Officer of Elevation Oncology. "We are also very encouraged by the results of the clinical case study involving a patient with metastatic gastric cancer who achieved a confirmed partial response on treatment with EO-3021 in an ongoing Phase 1 clinical trial being conducted in China by our partner, CSPC Pharmaceutical Group Limited. We look forward to initiating a Phase 1 clinical trial of EO-3021 in the US in the second half of 2023."

Key Findings

EO-3021 is an ADC comprised of a fully human immunoglobulin G1 (IgG1) mAb that targets Claudin 18.2 and is site-specifically conjugated to the MMAE payload via a cleavable linker with a DAR of 2.
EO-3021 retains antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).
EO-3021 reduction in cell viability requires Claudin 18.2 expression in vitro with no effects seen on Claudin 18.2-negative cells.
EO-3021 demonstrated anti-tumor activity in preclinical xenograft models of pancreatic and gastric cancers expressing varying levels of Claudin 18.2.
A single dose of EO-3021 demonstrated tumor regression across low, medium, and high Claudin 18.2-expressing models, with a lower minimal efficacious dose in models with medium and high levels of Claudin 18.2 relative to models with low levels of Claudin 18.2.
EO-3021 outperformed standard of care chemotherapy in gastric and pancreatic cancer preclinical xenograft models.
A patient with metastatic gastric cancer in an ongoing Phase 1 clinical trial of SYSA1801 (EO-3021) in China (NCT05009966) conducted by CSPC Pharmaceutical Group Limited (HKEX: 01093) was also highlighted.
Patient was treated with dose level 2, or 1.0 mg/kg EO-3021, intravenously, every three weeks for 12 cycles (treatment ongoing).
The best overall response, as evaluated per RECIST v1.1, was a confirmed partial response (66.7% maximal tumor reduction).
Duration of response was approximately 11 months and ongoing.
The full presentation can be accessed under the resources and publications page of the Elevation Oncology website following the completion of the live presentation at AACR (Free AACR Whitepaper).

About EO-3021

EO-3021 (also known as SYSA1801) is a differentiated, clinical-stage antibody drug conjugate (ADC) comprised of an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets Claudin 18.2 and is site-specifically conjugated to the monomethyl auristatin E (MMAE) payload via a cleavable linker with a drug-to-antibody ratio (DAR) of 2. Claudin 18.2 is a specific isoform of Claudin 18 that is only expressed in gastric epithelial cells. During malignant transformation in many solid tumors, the tight junctions may become disrupted, exposing Claudin 18.2 and allowing them to be accessible by Claudin 18.2 targeting agents. An Investigational New Drug application for EO-3021 has been cleared by the U.S. Food and Drug Administration.

On April 17, 2023 Dyve Biosciences, Inc. ("Dyve"), a clinical-stage platform biotechnology company with assets in immunology and oncology, reported that preliminary data from the ongoing pre-clinical partnership with the H. Lee Moffitt Cancer Center & Research Institute will be presented at a poster presentation at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, taking place April 14-19, 2023, in Orlando, Florida (Press release, Dyve Biosciences, APR 17, 2023, View Source [SID1234630149]).

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Dyve will present pre-clinical data from its lead oncology drug candidate, DYV800, a pH modulating agent that targets tumor microenvironment (TME) acidity in solid tumors. DYV800, delivered topically to bypass gastrointestinal absorption challenges, neutralizes the TME acidity that plays a strong role in tumor progression (invasion, metastasis, angiogenesis), immune escape, and treatment resistance (radiation, chemotherapy, and immunotherapy).

"Dyve continues to advance research in areas where we believe our pH modulation program can achieve the biggest impact for patients and we look forward to sharing new pre-clinical data on our DYV800 program at this year’s AACR (Free AACR Whitepaper). We believe we have a unique delivery approach that can unlock the powerful effects of neutralizing TME acidity, and this dataset is further validation of that," said Ryan Beal, M.D., Chief Executive Officer, Dyve.

Poster Presentation Details:

Abstract Title: Transdermal alkalinization treatment induces pH changes in a murine melanoma model as measured with MRI-CEST pH imaging
Session Category: Tumor Biology
Session Title: Photoacoustic Ultrasound, and Fluorescence Imaging
Session Date and Time: Monday, April 17, 2023, 1:30 PM – 5:00 PM
Presenter: Dr. Pietro Irrera, H. Lee Moffitt Cancer Center & Research Institute
Location: Convention Center, Section 2, Poster Board 13
Abstract Presentation Number: 2391

On April 17, 2023 CymaBay Therapeutics, Inc. (NASDAQ: CBAY), a clinical-stage biopharmaceutical company focused on developing therapies for liver and other chronic diseases with high unmet need, reported that management will participate in the H.C. Wainwright BioConnect Investor Conference at NASDAQ (Press release, CymaBay Therapeutics, APR 17, 2023, View Source [SID1234630148]).

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H.C. Wainwright BioConnect Investor Conference at NASDAQ
Date: Tuesday, May 2
Time: 9:00 am Eastern Time
Format: Presentation
Webcast: View Source

On April 17, 2023 Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, reported new data for CPI-818, the Company’s ITK inhibitor, demonstrating its potential to treat a variety of solid and hematological cancers based on a novel immunotherapy mechanism of action (Press release, Corvus Pharmaceuticals, APR 17, 2023, View Source [SID1234630147]). The data will be presented today in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is taking place April 14-19, 2023 in Orlando, FL.

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"The preclinical and laboratory data presented at AACR (Free AACR Whitepaper) demonstrates the potential of targeting ITK with CPI-818 to modulate T cell differentiation and enhance the immune system’s ability to kill both solid and hematological cancers," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "CPI-818 inhibited tumor growth in five different tumor models including colon, renal and melanoma cancers, and in both T and B cell lymphomas. This work builds upon the immunologic properties and anti-tumor activity already seen in our ongoing Phase 1/1b clinical trial in T cell lymphoma, and we now believe we can extend this approach to a wide range of solid tumors. Our data presented at AACR (Free AACR Whitepaper) shows that CPI-818’s novel mechanism of action involves multiple synergistic features including Th1 skewing, increases in T cell cytolytic capacity and reduction in T cell exhaustion. These properties are a result of the myriad of functions that ITK plays in T cell biology. Together, we believe these characteristics position CPI-818 to potentially lead the next generation of tumor immunotherapy if approved."

Dr. Miller added, "We are excited by the long-term potential of CPI-818 across a broad range of cancer indications, but in the near-term our main focus is continuing enrollment in our T cell lymphoma (TCL) Phase 1/1b clinical trial and meeting with the FDA to discuss a potential registration randomized Phase 3 clinical trial."

CPI-818 Preclinical Data Presented at AACR (Free AACR Whitepaper)
The CPI-818 preclinical data was presented by Lih-Yun Hsu, Ph.D., Director of Immunology, Corvus Pharmaceuticals, in a poster session (abstract #1813) today at the AACR (Free AACR Whitepaper) Annual Meeting. The key highlights from the poster, which is also available on the Publications and Presentations page of the Corvus website, include:

CPI-818 monotherapy (7 days oral administration) provided statistically significant inhibition of growth in established tumors in the following cancer models: CT26 colon cancer, RENCA kidney cancer, B16 melanoma, EL4 TCL and A20 B cell lymphoma.

Mechanism studies revealed that CD8 T cells were primarily involved in inhibiting growth in the CT26 colon cancer model and that CD8, CD4 T cells and NK cells were primarily involved in inhibiting growth in the EL4 TCL model.
Studies also showed that CPI-818 increased the cytolytic capacity of tumor infiltrating lymphocytes. These cells produce interferon gamma, tumor necrosis factor (TNF) and perforin, which are cytokines and effector molecules produced by killer T cells.

The preclinical data demonstrated that CPI-818 enhances the anti-tumor efficacy of anti-PD1 and anti-CTLA4 therapy in animal models, including at suboptimal doses of these therapies. The triplet combination led to complete tumor elimination in 19 of 20 animals with established CT26 colon cancer tumors.

The preclinical data also demonstrated that CPI-818 reduced the expression of T cell exhaustion markers in animals treated with anti-PD1 and anti-CTLA4 therapy. T cell exhaustion is a phenomenon seen in tumors and chronic infections where prolonged exposure to antigens results in exhausted or ineffective T cell function and inability to eliminate tumors or infections. The down-regulation of these T cell exhaustion markers suggests that the inhibition of ITK by CPI-818 potentially produces favorable changes in the tumor microenvironment that could enhance anti-tumor immune system activity.

In vitro studies with normal human naïve CD4+ T cells demonstrated that CPI-818 suppressed T cell differentiation into Th2 cells and their production of Th2 derived cytokines IL4, IL5, IL9, IL10 and IL17, however it did not affect differentiation into Th1 cells or their production of the cytokine interferon gamma (IFNg). These findings were the result of Th1 skewing.

CPI-818 is currently being studied in a Phase 1/1b clinical trial as a single agent therapy in patients with relapsed TCL. The Company recently incorporated a minimum absolute lymphocyte count (ACL) as an eligibility criterion for enrollment in the clinical trial and anticipates presenting updated data from this trial at a medical meeting in the second quarter 2023. Based on the current enrollment rate of this clinical trial, the Company believes that the number of patients treated in this clinical trial would provide adequate safety and preliminary efficacy data to inform the design of a potential registration Phase 3 randomized clinical trial. As recommended by the FDA, the Company plans to meet with the FDA to discuss such a clinical trial; it is anticipated that this meeting will take place later this year.

On April 17, 2023 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported updated preclinical data from the Company’s pipeline programs, including its novel EGFR-sparing brain-penetrant ErbB2 inhibitor and its next-generation selective fibroblast growth factor receptor 2 (FGFR2) program (Press release, Cogent Biosciences, APR 17, 2023, View Source [SID1234630146]). The data are being presented today in poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting. Cogent also announced the initiation of Part 2 of the Company’s ongoing APEX trial with bezuclastinib in Advanced Systemic Mastocytosis (AdvSM).

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"We are pleased to share our progress highlighting the Cogent Research Team in their ongoing effort to discover and advance potential best-in-class novel therapies for rare disease populations with high unmet medical need," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "Separately, based on bezuclastinib’s impressive and consistent clinical activity, safety and tolerability, we are also excited to announce the initiation of Part 2 of the APEX trial in AdvSM at a once-daily dose of 150 mg. We remain on track to provide clinical updates in the second half of 2023 from both APEX and SUMMIT, our trial of bezuclastinib in NonAdvSM patients, as well as updated clinical results from the PEAK lead-in trial in GIST patients this quarter."

AACR Poster Details

Title: Identification of a novel EGFR sparing brain penetrant ErbB2 inhibitor with activity against oncogenic ErbB2 mutations
Session Category: Molecular/Cellular Biology and Genetics
Session Title: Cell Cycle Progression, Checkpoint, and Telomeres
Session Date and Time: Monday Apr 17, 2023 9:00 AM – 12:30 PM ET
Location: Poster Section 10
Poster Board Number: 21
Published Abstract Number: 1440

Cogent is developing a potential best-in-class EGFR-sparing, brain-penetrant ErbB2 inhibitor that includes coverage of key mutations (YVMA, S310F, V842I, L755S) inadequately addressed by currently approved therapies. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification. The poster presented today describes a series of novel compounds which potently inhibit several key ErbB2 mutations, including YVMA insertions, while sparing inhibition of EGFR. An exemplar compound from these series demonstrates advantages versus tucatinib, an approved benchmark compound, on tumor growth inhibition in a peripheral ErbB2 L755S driven mutant model, as well as in an ErbB2 driven intracranial model. Recent program advances with a novel chemotype have further improved ErbB2 mutational potency and selectivity, increased estimated brain penetrance to 40% and improved human whole blood stability to nearly 24 hours, suggesting a favorable profile for optimal clinical efficacy.

Title: In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations
Session Category: Molecular/Cellular Biology and Genetics
Session Title: Cell Cycle Progression, Checkpoint, and Telomeres
Session Date and Time: Monday Apr 17, 2023, 9:00 AM – 12:30 PM ET
Location: Poster Section 10
Poster Board Number: 20
Published Abstract Number: 1439

FGFR inhibitors are well-established oncogenic drivers in multiple diseases, but approved medicines fail to capture the full landscape of FGFR altered tumor types, with FGFR1-mediated hyperphosphatemia serving as the most common dose-limiting toxicity for pan-FGFR inhibitors. The poster presented today provides the first published evidence of a reversible, selective FGFR2 inhibitor with coverage of activating and emerging resistance mutations that spares inhibition of FGFR1. Preclinical data demonstrate a profile that delivers equipotent coverage across both key gatekeeper and molecular brake mutations (V564X, N549X) in FGFR2, while avoiding any evidence of FGFR1-linked hyperphosphatemia at efficacious plasma concentrations. In addition, as a reversible inhibitor, the Cogent program retains enzymatic potency against potential cysteine 491 mutations which are known to emerge as key resistance mutations in patients treated with covalent inhibitors.

APEX Part 2 Design Highlights

APEX is an ongoing Phase 2 trial evaluating bezuclastinib in patients with AdvSM. Part 2 will enroll approximately 65 patients treated at a once-daily 150 mg optimized dose and if successful, is designed to support regulatory submission. Enrollment is expected to be complete by the end of 2024. Several additional patient cohorts are anticipated during Part 2 of the APEX trial designed to demonstrate the breadth of AdvSM patients who may benefit from bezuclastinib, including:

Up to 20 patients with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) treated concomitantly with bezuclastinib and AHN directed therapies, including azacitidine.
Up to 15 patients with inevaluable mIWG disease without C-findings.
Approximately 10 patients at a dose of 300 mg once-daily to explore the effect of exceeding IC90 KIT D816V engagement in AdvSM patients.
The predicted clinical exposure of the optimized 150 mg formulation of bezuclastinib is expected to surpass that of the previous formulation of bezuclastinib dosed at 100 mg twice-daily in APEX Part 1. Clinical data from approximately 30 patients from APEX Part 1 will be included in a presentation at a scientific meeting in the second half of 2023. Currently, clinical activity, safety and tolerability of patients dosed in APEX Part 1 remains consistent with results presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in December 2022.