On December 5, 2024 EpicentRx reported that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for the oncolytic adenovirus-delivered transforming growth factor beta (TGFβ) inhibitor, AdAPT-001, plus the anti-PD-1, nivolumab, or anti-PD-L1, atezolizumab, to treat recurrent or refractory advanced or metastatic soft tissue sarcoma (STS) with disease progression after at least one prior line of therapy (Press release, EpicentRx, DEC 5, 2024, View Source [SID1234648845]). The purpose of Fast Track designation is to facilitate the development and approval process of drugs like AdAPT-001 that treat a serious condition or meet an unmet need such as STS, a rare tumor type with high heterogeneity, low chemo-, radio- and immunosensitivity, and a poor prognosis.

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The Fast Track designation was based on the promising potential of AdAPT-001 to sensitize STS tumors to checkpoint inhibitors like nivolumab or atezolizumab that they previously received and failed or never previously received because of low levels of both tumor mutation burden (TMB) and T-cell inflamed gene expression profiles (GEP) that predicted for non-response. Supporting evidence for Fast Track designation came from Phase 1 and 2 clinical trials and an ASCO (Free ASCO Whitepaper) podium presentation where the activity, safety, and durability of response (progression free survival of ~8.5 months) in patients with STS and other tumor types either alone or in combination with checkpoint inhibition were on full display.

According to EpicentRx CEO and viro-oncologist, Dr. Tony Reid, MD, PhD, "Checkpoint blockade immunotherapies have revolutionized cancer therapy for many patients and prolonged the lives of millions. But efficacy depends on 1) the presence of an immune infiltrate, which is often absent or immunosuppressive, and 2) low levels of immunosuppressive factors like TGFβ, which are frequently overexpressed. AdAPT-001 is designed both to inflame the tumor microenvironment and to combat immunosuppression by neutralization of TGFβ through the expression of a TGFβ trap. Fast Track designation is a terrific acknowledgement of the potential of AdAPT-001 to make a meaningful difference for STS patients who desperately require new treatment options."

About AdAPT-001
AdAPT-001, EpicentRx’s proprietary 2-in-1 biologic, whose activity was highlighted in a 2024 ASCO (Free ASCO Whitepaper) podium presentation, is designed to express a potent TGFβR inhibitor for local TGFβ neutralization, decreased Treg cell function, and superior therapeutic responses in combination with checkpoint inhibitors for several tumor types including STS, colorectal cancer, breast cancer and hepatocellular carcinoma.

On December 5, 2024 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 new preclinical data demonstrating the combination potential of EO-3021, a Claudin 18.2 antibody-drug conjugate (ADC), with VEGFR2 or PD-1 inhibitors (Press release, Elevation Oncology, DEC 5, 2024, View Source [SID1234648844]). The data will be presented in a poster session at the European Society for Medical Oncology Immuno-Oncology Annual Congress 2024 (ESMO-IO), being held December 11-13, 2024, in Geneva, Switzerland.

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"We are pleased to share preclinical data supporting our planned evaluation of EO-3021 in combination with VEGFR2 or PD-1 inhibitors," said David Dornan, Ph.D., Chief Scientific Officer of Elevation Oncology. "The data demonstrate enhanced anti-tumor activity for both regimens, highlighting the potential benefits of a combination approach. This is particularly encouraging given our previously announced, promising initial clinical data from our Phase 1 clinical trial of single-agent EO-3021, which suggest EO-3021 potentially offers competitive efficacy and differentiated safety profile, including minimal payload-associated toxicity. We look forward to initiating dosing in the combination portion of our ongoing Phase 1 clinical trial of EO-3021 in the fourth quarter and unlocking the full potential of EO-3021 as an active, more combinable Claudin 18.2 ADC."

In a poster titled, "Combination potential of EO-3021, a CLDN18.2 vc-MMAE ADC, with VEGFR2 or PD-1 inhibition in preclinical models of CLDN18.2-expressing cancers," Elevation Oncology will present new in vivo data from preclinical studies evaluating the anti-tumor activity of EO-3021 with a VEGFR2 or PD-1 inhibitor. The data show:

Treatment with EO-3021 and DC101, a surrogate of the VEGFR2 inhibitor ramucirumab, exhibited statistically superior tumor growth inhibition (TGI) compared to treatment with either EO-3021 or DC101 alone (TGI: 88.2% for EO-3021 in combination with DC101, compared to 20.1% for EO-3021 and 59.2% for DC101 alone).
Treatment with EO-3021 and a PD-1 inhibitor exhibited statistically superior TGI compared to treatment with either EO-3021 or a PD-1 inhibitor alone (TGI: 79.9% for EO-3021 in combination with a PD-1 inhibitor, compared to 33.8% for EO-3021 and 25.0% for a PD-1 inhibitor alone). 92% (11/12) of mice treated with the combination of EO-3021 and a PD-1 inhibitor achieved a complete response (CR), compared to 50% (6/12) mice treated with EO-3021 monotherapy and 17% (2/12) mice treated with a PD-1 inhibitor alone.
Elevation Oncology expects to initiate dosing in the combination portion of its ongoing Phase 1 clinical trial of EO-3021 in the fourth quarter of 2024. Following clinical supply agreements with Lilly and GSK, the combination cohorts will evaluate EO-3021 and ramucirumab, a VEGFR2 inhibitor, in patients with gastric/GEJ cancer in the second-line setting, and EO-3021 and dostarlimab, a PD-1 inhibitor, in the front-line setting. Additionally, Elevation Oncology continues to enroll patients in the monotherapy dose expansion portion of its ongoing Phase 1 clinical trial and expects to report additional monotherapy data in the first half of 2025. In August 2024, Elevation Oncology reported initial clinical data from the dose escalation portion of the monotherapy study, demonstrating an objective response rate of 42.8% in patients with Claudin 18.2 in ≥20% of tumor cells at IHC 2+/3+, with differentiated safety profile, including minimal hematological toxicity or hepatotoxicity, and no peripheral neuropathy/hypoesthesia.

The ESMO (Free ESMO Whitepaper)-IO poster presentation will be available in the "Publications" section of Elevation Oncology’s website starting December 12, 2024.

About EO-3021

EO-3021 is a differentiated, clinical-stage, potentially best-in-class ADC comprised of an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets Claudin 18.2 and a monomethyl auristatin E (MMAE) payload with a cleavable linker that is site-specifically conjugated to Glutamine 295 providing a drug-to-antibody ratio (DAR) of 2. Claudin 18.2 is a specific isoform of Claudin 18 that is normally expressed in gastric epithelial cells. During malignant transformation, the tight junctions may become disrupted, exposing Claudin 18.2 and allowing them to be accessible by Claudin 18.2 targeting agents. Elevation Oncology is evaluating EO-3021 in the dose expansion portion of a Phase 1 trial (NCT05980416) in patients with advanced, unresectable or metastatic gastric/GEJ adenocarcinoma that express Claudin 18.2. Following recently signed clinical supply agreements with Lilly and GSK, respectively, Elevation Oncology will evaluate EO-3021 in combination with ramucirumab, a VEGFR2 inhibitor, in the second-line setting and in combination with dostarlimab, a PD-1 inhibitor, in the front-line setting.

In September 2024, EO-3021 was granted Fast Track designation by the FDA for the treatment of patients with advanced or metastatic gastric/GEJ cancer expressing Claudin 18.2 that has progressed on or after prior therapy. EO-3021 was granted orphan drug designation by the FDA for the treatment of gastric cancer (including cancer of gastroesophageal junction) in November 2020 and for the treatment of pancreatic cancer in May 2021.

Elevation Oncology has the exclusive rights to develop and commercialize EO-3021 in all global territories outside Greater China.

On December 5, 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 that the first patient had been dosed in the POTAMI-61 study, a Phase II clinical trial investigating RVU120 in the treatment of patients with myelofibrosis (MF) (Press release, Ryvu Therapeutics, DEC 5, 2024, View Source [SID1234648843]).

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Hendrik Nogai, M.D., Chief Medical Officer of Ryvu Therapeutics, said:

"We are excited to announce the initiation of the RVU120 Phase II study, POTAMI-61, the fourth Phase II clinical trial included in the RVU120 development plan that Ryvu presented last year. Based on RVU120’s effect on bone marrow and hematopoietic cells observed in the RIVER-51 study and translational data generated in myelofibrosis with Prof. Raajit Rampal from Memorial Sloan Kettering Cancer Center in New York, we believe there is a strong rationale for RVU120 in the treatment of patients with myelofibrosis, both as a monotherapy and in combination with JAK inhibitors. The favorable RVU120 safety profile may enable targeting patients with unmet medical needs, e.g., patients who are not eligible for or who show a suboptimal response to JAK inhibitor treatment. Additionally, synergy in translational studies indicates potential for use in the frontline setting."

The POTAMI-61 study is an open-label, multicenter Phase II study of RVU120, a novel small-molecule cyclin-dependent kinase (CDK) 8/19 inhibitor, to treat patients with MF. In the POTAMI-61 study, RVU120 is being explored as a single agent for the treatment of patients with primary or secondary MF previously treated with or ineligible for a JAK inhibitor, e.g. ruxolitnib, or in combination with RUX for patients with suboptimal response to JAK inhibitors. Key endpoints will be spleen volume reduction (SVR), total symptom score (TSS) improvement, and bone marrow fibrosis reduction.

The study is being initiated based on RVU120’s clinical safety and efficacy data, and strong preclinical and mechanistic rationale. In vivo data demonstrate the beneficial effects of CDK8 inhibition on the improvement of symptoms, i.e., splenomegaly, hepatomegaly, anemia, and thrombopenia. Importantly, disease modification properties of RVU120 were shown by the reduction of mutated allele burden. RVU120 has the potential to become a novel therapeutic strategy in myeloproliferative neoplasms, including MF.

In the POTAMI-61 study, patients will receive RVU120 until disease progression, withdrawal of consent or other reasons specified in the study protocol. The POTAMI-61 study consists of two parts. Part A of the study with a planned enrollment of approximately 20 patients will comprise two cohorts: 1) single-agent therapy with RVU120 in patients resistant or refractory to prior JAK inhibitor treatment or ineligible for JAK inhibitor treatment, and 2) RVU120 in combination with RUX in patients who experience a suboptimal response to prior JAK inhibitor treatment. Depending on results from Part A, cohorts 1 and/or 2 could be expanded in Part B which will further assess safety, tolerability, and antitumor activity in a larger cohort, totaling up to approximately 230 patients for both Part A and Part B combined. RVU120 could also be investigated in a frontline setting in cohort 3. Ryvu will initially proceed with the execution of Part A of the study, while the decision on the potential initiation of Part B will be based on the outcomes of Part A.

Initially, Part A of the study will enroll patients at clinical sites in Poland and Italy. If the Ryvu Management Board decides to initiate Part B, the study will expand to include additional sites both in the EU and non-EU countries, totaling approximately 50 clinical sites worldwide.

POTAMI-61 represents the fourth planned RVU120 Phase II clinical study launched in 2024. Ryvu is already treating patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (HR-MDS) in the RIVER-52 and RIVER-81 studies, as a single agent or in combination with venetoclax. RVU120 is also being investigated in the REMARK study for the treatment of patients with lower-risk myelodysplastic syndromes (LR-MDS).

POTAMI-61 is part of RVU120’s Development Plan presented in October 2023 and aligns with the company’s cash runway. Clinical trials conducted in various hematological indications and treatment regimens (monotherapy and combination therapy) will contribute to the global RVU120 safety database, supporting potential future regulatory approvals.

MEDSIR, a leading company dedicated to advancing independent clinical research in oncology on an international level and part of Oncoclínicas & Co, the largest oncology treatment group in Latin America with significant strength in the clinical and outpatient setting, reported it will participate in the prestigious San Antonio Breast Cancer Symposium 2024 (SABCS) with the presentation of five innovative studies, including one of particular significance in advanced breast cancer: the DEMETHER study (Press release, MedSIR, DEC 5, 2024, View Source [SID1234648842]). These landmark studies demonstrate remarkable progress in the development of more personalized and less invasive therapies, offering the potential to enhance patients’ quality of life and redefine the treatment approach for advanced breast cancer.

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The DEMETHER clinical trial explores an innovative treatment strategy for previously untreated HER2-positive advanced breast cancer. The study employs a dual-phase approach, beginning with an induction phase using trastuzumab deruxtecan (T-DXd), followed by a maintenance phase with subcutaneous administration of trastuzumab and pertuzumab. This strategy aims to prolong progression-free survival, improve overall survival rates at three years, and provide enhanced safety and quality of life compared to standard treatments.

By offering an alternative to conventional chemotherapy and prolonged T-DXd administration, DEMETHER aims to redefine therapeutic de-escalation. This strategy seeks to minimize the side effects associated with traditional therapies, thereby significantly improving patients’ quality of life. Furthermore, it underscores a commitment to making advanced breast cancer treatments more accessible, less invasive, and patient centered.

23 active centers in 4 countries and several Highly Cited Researchers 2024

The trial is currently being conducted at 23 active centers across the United States, Spain, Italy and Germany. Additionally, the study benefits from the involvement of leading international researchers renowned for their excellence. Among them are several scientists featured in the Highly Cited Researchers 2024 list by Clarivate, including Dr. Javier Cortés, Dr. Hope Rugo, Dr. Nadia Harbeck, Dr. Sara M. Tolaney, and Dr. Peter Schmid, whose expertise and contributions bring exceptional value to the project.

The DEMETHER study seeks to further advance personalized medicine, exploring less invasive, safer, and potential more effective alternatives to conventional treatments. "This study reflects the collaborative efforts of international experts, leading centers, the pharmaceutical industry and MEDSIR in designing therapeutic strategies that enhance patients’ quality of life through treatment de-escalation." highlights Dr. Javier Cortés, principal investigator of the DEMETHER study.

New therapeutic options for patients with metastatic breast cancer: exploring advances in brain metastases with PHENOMENAL and TUXEDO-4

Both the PHENOMENAL and TUXEDO-4 studies presented at SABCS are particularly relevant as they address a critical and historically underserved population: patients with metastatic breast cancer (MBC) and brain metastases (BMs). BMs occur in up to 25% of patients with MBC 1, significantly impacting prognosis and quality of life.

These studies stand out by exploring innovative therapeutic strategies tailored to overcome the unique challenges of treating brain metastases. The PHENOMENAL study focuses on nanoliposomal irinotecan, Nal-IRI, to enhance drug delivery to brain tumors while reducing systemic toxicity. Meanwhile, the TUXEDO-4 study investigates the use of T-DXd, a novel antibody-drug conjugate targeting HER2-low tumors, with the goal of achieving meaningful intracranial tumor shrinkage.

An innovative therapeutic regimen with the potential to expand treatment options and improve the quality of life for patients with advanced breast cancer

The Phase III ADELA study, in collaboration with the MENARINI Group, explores new perspectives in the treatment of advanced ER+ and HER2-negative breast cancer, specifically in patients with mutations in the ESR1 gene whose cancer has progressed after receiving standard first-line of therapy. This gene produces estrogen receptor proteins that can stimulate the growth of this type of breast cancer.

ADELA has the potential, if successful, to pave the way for regulatory approval of this therapeutic combination, making it accessible to a broader patient population.

In addition to this study, MEDSIR is presenting the PRIMED trial, which evaluates the efficacy of prophylactic administration of granulocyte colony-stimulating factor (G-CSF) and loperamide during the initial treatment cycles of sacituzumab govitecan (SG) therapy to mitigate the incidence of neutropenia and diarrhea, aiming to enhance treatment tolerability and patient safety.

The presentation of these results at an event of SABCS 2024’s magnitude not only positions MEDSIR as a leader in oncology research excellence but also highlights its ability to lead transformative projects addressing unmet needs in breast cancer treatment.

On December 5, 2024 Ono Pharmaceutical Co., Ltd. (Headquarters: Osaka, Japan; President: Toichi Takino; "Ono") reported that it has entered into a drug discovery collaboration agreement with Congruence Therapeutics (Headquarters: Montreal, Quebec, Canada; CEO: Clarissa Desjardins; "Congruence") to generate novel small molecule correctors against multiple protein targets in the oncology area by leveraging Congruence’s proprietary drug discovery platform, Revenir (Press release, Ono, DEC 5, 2024, View Source [SID1234648841]).

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Under the terms of the agreement, Congruence will generate small molecule correctors by leveraging Congruence’s proprietary drug discovery engine called, Revenir. Ono will obtain an exclusive option right to develop, manufacture and commercialize the identified small molecule correctors worldwide. Congruence will be eligible to receive an upfront payment, research expenses, milestone payments based on research and development progress and sales, as well as tiered royalties based on net sales.

"We believe that this collaboration with Congruence may help generating novel small molecule correctors for validated targets in the oncology area by leveraging their own technologies in protein dynamics and computational biology, leading to our development pipeline," said Seishi Katsumata, Corporate Officer / Executive Director, Discovery & Research of Ono. "We will be committed to delivering innovative new drugs to cancer patients as soon as possible."

"Congruence is thrilled to partner with Ono, which has established itself as a global leader in drug development, particularly in the oncology space. We believe that our Revenir platform and capabilities in protein dynamics will accelerate the discovery of novel therapies for compelling targets of interest to both companies," said Sharath Hegde PhD, Chief Scientific Officer of Congruence.

About Revenir Drug Discovery Platform

Revenir, Congruence’s proprietary computational drug discovery platform, captures the dynamic biophysical changes caused by mutations in proteins, offering unique insights into protein defects and their correction. By examining surface features and a spectrum of biophysical descriptors across an ensemble of protein conformers, Revenir predicts small molecule induced correction of the underlying defect.