On October 9, 2024 BridGene Biosciences, a leader in the discovery of small molecule drugs for traditionally "hard-to-drug" targets, reported it will present three groundbreaking posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2024 Annual Meeting in Barcelona, on October 25, 2024 (Press release, Bridgene Biosciences, OCT 9, 2024, View Source [SID1234647116]). The posters will showcase the company’s latest advancements in the development of covalent inhibitors for key oncogenic targets, including cMyc, ADAR1, and PAX8, each representing promising new treatment avenues for various cancers.

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"These three presentations represent significant strides in our mission to develop novel therapeutics for cancer patients," said Ping Cao, Ph.D., Co-Founder and CEO of BridGene Biosciences. "By focusing on these high-value, historically hard-to-drug targets, we aim to create first-in-class therapies that address critical gaps in cancer treatment. Our platform continues to unlock new possibilities in drug discovery, and we are excited to share these advancements with the scientific community at AACR (Free AACR Whitepaper)."

BridGene’s work on cMyc, titled "Discovery of a Covalent Inhibitor Targeting the Undruggable Oncogene cMyc," focuses on overcoming the challenges posed by its intrinsically disordered structure, which has historically rendered the protein hard-to-drug. Through its proprietary Isobaric Mass Tagged Affinity Characterization (IMTAC) platform, BridGene identified two hit compounds, which effectively inhibit cMyc signaling. These inhibitors showed potent activity in reducing transcriptional function and offering a potential therapeutic strategy for cancers driven by cMyc amplification, which accounts for nearly one-third of all tumors.

In addition to its work on cMyc, BridGene will present research titled "Discovery of a Novel Covalent ADAR1 Inhibitor," focusing on a novel covalent inhibitor targeting ADAR1, an enzyme that plays a critical role in RNA editing and immune suppression in cancer. By inhibiting ADAR1, BridGene’s compounds, could be expected to enhance the efficacy of immune checkpoint blockade therapies. This research highlights the potential for ADAR1 inhibitors to reshape the tumor microenvironment, paving the way for more effective immunotherapies.

BridGene’s third poster presentation, "Discovery of a Novel Covalent PAX8 Inhibitor," will unveil a covalent inhibitor of PAX8, a transcription factor linked to poor prognosis in renal cell carcinoma and ovarian cancer. Utilizing its IMTAC platform, BridGene discovered a compound that disrupts the DNA binding activity of PAX8. This discovery opens the door to new therapeutic strategies for cancers with elevated PAX8 expression, which have traditionally been difficult to target.

On October 9, 2024 Nanjing Leads Biolabs Co., Ltd. ("Leads Biolabs") reported that Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation to LBL-024, an anti-PD-L1/4-1BB bispecific antibody independently developed by Leads Biolabs with global intellectual property rights, for the treatment of the patients with advanced extrapulmonary neuroendocrine carcinoma (EP-NEC) who have progressed after receiving two or more lines of chemotherapy (Press release, Nanjing Leads Biolabs, OCT 9, 2024, View Source [SID1234647115]). The Breakthrough Therapy Designation awarded to LBL-024 stems from its remarkable clinical efficacy and safety profile in patients with advanced EP-NEC who failed in second-line and above chemotherapy. The current clinical data demonstrate that LBL-024 monotherapy has more than doubled both the Objective Response Rate (ORR) and Overall Survival (OS) compared to existing treatments for this disease.

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Breakthrough Therapy refers to innovative or improved drugs that treat life-threatening conditions or significantly impact quality of life, where no effective treatment exist, or there is sufficient evidence that the therapy offers clear advantages over existing treatment options. In July 2012, the U.S. Food and Drug Administration (FDA) pioneered the "Breakthrough Therapy" review process, complementing fast track, accelerated approval, and priority review mechanisms. By accelerating the approval process and fostering closer collaboration, Breakthrough Therapy Designation facilitates faster development and market access for drugs with significant clinical potential. Historically, FDA data suggests that Breakthrough Therapy Designation can reduce time-to-market by approximately 2.5 years on average.

In July 2020, CDE officially introduced the Breakthrough Therapy Designation concept in China. Products granted Breakthrough Therapy Designation status will receive closer guidance and various forms of support to ensure that patients are provided with new treatment options as soon as possible.

Dr. Charles Cai, Chief Medical Officer of Leads Biolabs, said "According to historical data from the China Drug Review Annual Report, only a few products are eligible for Breakthrough Therapy Designation, and even fewer have been approved. The designation for LBL-024 is another proof of the robust R&D capabilities of Leads Biolabs, and it is also a major victory for Leads Biolabs’ insistence on focusing on the first-in-class product R&D strategy for the global market. Leads Biolabs will vigorously pursue the global clinical development of LBL-024, with the anticipation of offering more effective treatment options for patients with EP-NEC at the earliest opportunity."

Dr. Xiaoqiang Kang, founder, chairman and CEO of Leads Biolabs, said "The Breakthrough Therapy granted by the CDE prioritizes candidates that demonstrate exceptional clinical data, differentiated targets, and therapies with a high degree of efficacy certainty. This Designation represents the highest threshold and most prestigious qualification within China’s pharmaceutical regulatory system, functioning as a crucial benchmark for uncovering valuable new drug projects. Leads Biolabs has consistently embraced differentiated innovation, and we eagerly anticipate the timely market introduction of LBL-024 as a novel immunotherapy, following the groundbreaking successes of anti-PD-1/PD-L1, CTLA-4, and LAG-3."

About LBL-024

LBL-024 is a tetravalent bispecific antibody that simultaneously targets PD-L1 and 4-1BB, serving dual functions: blocking the immunosuppressive PD-1/PD-L1 pathway, and selectively co-stimulating 4-1BB in the tumor microenvironment to enhance immune responses. The dual functions of LBL-024—lifting PD-1/PD-L1 immune inhibition and intensifying 4-1BB modulated T cell activation—synergistically enhance the anti-tumor immune response.

About EP-NEC

Neuroendocrine carcinoma (NEC) is a class of poorly differentiated, high-grade neuroendocrine neoplasms (NENs), which originate in the diffuse neuroendocrine cell system and can occur in many different sites. NEC can be categorized into pulmonary NEC and EP-NEC. EP-NEC exhibits similar highly aggressive and metastatic characteristics to small cell lung cancer (SCLC). Most patients are diagnosed at a later stage or already have distant metastases, resulting in rapid disease progression and a poor prognosis.

Currently, the primary first-line treatment for advanced EP-NEC involves platinum-based chemotherapy, achieving an overall response rate (ORR) of approximately 30% to 50%, with a median overall survival (mOS) of only approximately one year. Treatment options for advanced EP-NEC are limited, and there are no standard treatment strategies for patients who progress beyond second-line chemotherapy. These underscore the urgency to develop novel therapeutic approaches.

On October 9, 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 it will present four posters with clinical and preclinical data from RVU120 (CDK8/19 inhibitor), RVU305 (MTA-cooperative PRMT5 inhibitor), WRN and novel synthetic lethality programs at the 2024 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (ENA), October 23-25, Barcelona, Spain (Press release, Ryvu Therapeutics, OCT 9, 2024, View Source [SID1234647114]).

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"We are thrilled to showcase our latest advancements on RVU120, RVU305, and other synthetic lethality projects at the 2024 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium this year. The strong preclinical data from our PRMT5 synthetic lethality program is highly encouraging as we target IND/CTA filing and continue to advance our project toward clinical studies." – said Krzysztof Brzózka, Ph.D., Chief Scientific Officer.

Poster highlights:

Abstract Title: Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers
Abstract Number: ENA24-0205
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. Structure-based optimization has resulted in a compound exerting selective efficacy in MTAP-deleted cell lines and a DMPK profile suitable for oral administration. RVU305 exhibits robust antiproliferative activity in MTAP-null cancer models, with a favorable safety margin in MTAP wild-type cells. Comparative studies against other clinical-stage PRMT5 inhibitors confirmed RVU305’s favorable antitumor activity in vitro and in vivo. Overall, the findings highlight the potential of RVU305 as a promising therapeutic option for patients with MTAP-deleted cancers.

Abstract Title: Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors
Number: ENA24-0364
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). These compounds show nanomolar potency in viability assays in MSI-H cell lines, with excellent selectivity over microsatellite-stable (MSS) cells. In in vivo studies, RVU305 strongly suppressed tumor growth in an MSI-H model (SW48) while not impacting the MSS model (SW620). Additionally, the compounds exhibit favorable pharmacokinetics, achieving optimal exposure and target engagement, further enhancing their therapeutic potential in MSI-H cancers.

Abstract Title: Exploring synthetic lethality and novel drug combinations in patient-derived cells
Poster Number: ENA24-0395
Session date and time: Wednesday, October 23 (12:00-19:00 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. By integrating CRISPR/Cas9 technology and machine learning, Ryvu generated isogenic cancer models, performed high-throughput screenings, and validated the findings through transcriptomic profiling of clinically relevant samples. This approach enabled the identification of essential and tumor suppressor genes critical for CRC and other cancers, focusing on SL targets specific to transformed cells.

Abstract Title: Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors
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. Stable disease (SD) was achieved in multiple patients, with tumor size reductions in three patients with adenoid cystic carcinoma (AdCC). The recommended phase 2 dose (RP2D) for the QOD schedule was identified as 250 mg, with dose escalation continuing for the QD schedule. These promising safety and preliminary efficacy results support further clinical investigation of RVU120.

Investor Event:
Ryvu Therapeutics will host a webinar to discuss new data from our latest poster presentations. The date and time of the webinar will be announced soon.

On October 9, 2024 Arbele, a leading innovator in biopharmaceutical & biotechnology focused on targeting cadherin-17 (CDH17), reported strategic collaborations in precision oncology using artificial intelligence (AI) to advance targeted immunotherapeutics of bispecific T-cell engagers (TCEs) and antibody-drug conjugates (ADCs) (Press release, ARBELE, OCT 9, 2024, View Source [SID1234647113]). These partnerships, aimed at advancing the quantification and prognostic prediction of CDH17 expression in tumor tissue and the surrounding tumor immune microenvironment, are expected to accelerate the development of precise companion diagnostics and effective clinical trials for the treatment of advanced cancer patients.

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Collaboration with BioAI: Development of IHC-Based Quantification Algorithm

Arbele enters a strategic alliance with BioAI Health to develop a prototype of an immunohistochemistry (IHC)-based quantification algorithm. Leveraging the PredictX platform to develop AI-based models using Arbele’s clinical trial data on colorectal cancer (CRC) biomarker screening, we join force to establish a gold standard companion diagnostic test for anti-CDH17 therapies for patient selection and prediction of clinical outcomes.

"By partnering with Arbele, we are excited to apply our novel AI platform and expertise to accelerate the development of innovative treatment options for gastrointestinal cancers," said Thomas Colarusso, CEO of BioAI. "This partnership underscores our commitment to revolutionizing personalized medicine through cutting-edge machine learning."

"BioAI’s machine learning capabilities offer a transformative approach to biomarker identification and patient stratification through predicting CDH17 expression and its spatial interaction with immune cells in tumor microenvironment," said Dr John Luk, CEO of Arbele. "This collaboration is a critical step in guiding us the uses of the right treatment modalities and/or therapeutic regimens, thereby improving outcomes for patients with high mortality cancers."

Collaboration with Chime Biologics: Accelerated CMC Process Development of novel ADC and TCE

Arbele has entered a strategic alliance with Chime Biologics to accelerate chemistry, manufacturing and control (CMC) process development of the novel designs of ADCs and TCEs. The partnership supports multiple pipelines of about 10 first-in-class and best-in-class immunotherapeutics, including monoclonal, bispecific/biparatopic and TriAx antibodies within the coming 3 years. The collaboration will ensure Arbele continues to have at least 1-2 new molecular entities (NMEs) successfully filing for investigational new drug (IND) application and entering clinical studies in the next 5 years without any technical and supply-chain interruptions. The first deliverable will be anti-CDH17 ADC (ARB102A), for IND submission in early 2025.

"Chime Biologics has partnered Arbele for several years, with our advanced biologics development supporting key milestones such as previous IND filings for multinational clinical trials," said Dr. Jimmy Wei, President of Chime Biologics. "We adopt the Quality-by-Design (QbD) strategy for process development to yield optimal outcomes cost-effectively, delivering innovative immunotherapeutics to enhance the global accessibility of these treatments."

On October 9, 2024 Harbour BioMed (the "Company"; HKEX: 02142), a global biopharmaceutical company committed to the discovery, development, and commercialization of novel antibody therapeutics focusing on oncology and immunology, reported the online publication of the results from its phase I clinical trial of porustobart (HBM4003), the Company’s first-in-class fully human heavy chain antibody targeting CTLA-4 (Press release, Harbour BioMed, OCT 9, 2024, View Source [SID1234647111]). The trial evaluated porustobart in combination with the anti-PD-1 antibody toripalimab for the treatment of advanced solid tumors, with a particular focus on melanoma. These results were published in the Journal for ImmunoTherapy of Cancer (IF=10.3, 2023).

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This multicenter, open-label phase I trial was led by Dr. Jun Guo, Chief Physician of the Department of Melanoma and Soft Tissue Sarcoma at Beijing Cancer Hospital. The data demonstrated that the combination of porustobart and toripalimab had a manageable safety profile with no new safety signals in the treatment of solid tumors. Initial results also indicated promising antitumor activity, particularly in PD-1 treatment-naïve mucosal melanoma.

Dual immunotherapy combining anti-CTLA-4 and anti-PD-1 antibodies is currently approved as a frontline treatment for several solid tumors, including melanoma, renal cell carcinoma, and non-small cell lung cancer. However, the high toxicity associated with anti-CTLA-4 antibodies has limited their broader use. Porustobart, a next-generation fully human anti-CTLA-4 antibody developed using the HCAb Harbour Mice platform, is the first of its kind to enter clinical development globally. Its unique properties offer the potential to overcome the efficacy and toxicity challenges of conventional anti-CTLA-4 therapies, making it a promising candidate in the field of cancer immunotherapy.

The phase I trial was conducted in two stages: a dose-escalation phase (Part 1) and a dose-expansion phase (Part 2). A total of 40 patients received treatment aimed at evaluating the safety, pharmacokinetics, immunogenicity, and preliminary efficacy of the combination therapy for the treatment of solid tumors, with a particular focus on melanoma.

Safety Results

Among the 40 patients who received study treatment, 10 (25.0%) patients reported grade ≥3 treatment-related adverse events (TRAEs). The commonly reported TRAEs were rash (30.0%), abnormal liver function (30.0%), leukopenia (25.0%), and fever (20.0%). Additionally, 5 (12.5%) patients experienced immune-related adverse events (irAEs) with maximum severity of Grade 3. No Grade 4 or 5 irAEs occurred.

Efficacy Results

Efficacy was evaluated in 32 melanoma patients treated with the recommended phase II dose (RP2D) of porustobart 0.3 mg/kg combined with toripalimab 240 mg every three weeks (Q3W), and who had available post-baseline imaging data. The objective response rate (ORR) was 33.3% in the anti-PD-1/PD-L1 treatment-naïve subgroup. For patients with mucosal melanoma, the ORR in this anti-PD-1/PD-L1 treatment-naïve subgroup was 40.0%. A high baseline Treg/CD4+ ratio in the tumor was identified as an independent predictive factor for immunotherapy efficacy.

In summary, the combination of porustobart 0.3 mg/kg with toripalimab 240 mg Q3W demonstrated promising antitumor activity and manageable safety in patients with advanced melanoma, including the difficult-to-treat mucosal subtypes. Further studies are needed to confirm these findings, particularly in patients with mucosal melanoma.

"We are encouraged by the positive results from our phase I study of porustobart in combination with an anti-PD-1 antibody, which has shown a favorable safety profile and early signs of clinical activity," said Dr. Jingsong Wang, Founder, Chairman and CEO of Harbour BioMed. "Porustobart is the first internally developed molecule generated from our HCAb Harbour Mice platform. We look forward to moving forward with further studies to fully explore the potential of this combination in addressing unmet medical needs and ultimately making a meaningful difference in patients’ lives."

About Porustobart

Porustobart (HBM4003) is a fully human anti-CTLA-4 monoclonal heavy chain only antibody (HCAb) generated from Harbour Mice. It is the first fully human heavy-chain-only monoclonal antibody entered into clinical stage globally. By enhancing antibody-dependent cell cytotoxicity (ADCC) killing activity, porustobart has demonstrated significantly improved depletion specific to high CTLA-4 expressing Treg cells in tumor tissues. The potent anti-tumor efficacy and differentiated pharmacokinetics with durable pharmacodynamic effect present a favorable product profile. This novel and differentiated mechanism of action has the potential to improve efficacy while significantly reducing the toxicity of the drug in monotherapy and combination therapy.