On April 10, 2024 Opna Bio, a clinical-stage biopharmaceutical company focused on the discovery and development of novel cancer therapeutics, reported promising preclinical data in two programs, OPN-6602, a dual EP300/CBP inhibitor in multiple myeloma, and OPN-9840, an oral, non-covalent TEAD inhibitor in malignant mesothelioma and metastatic melanoma (Press release, Opna Bio, APR 10, 2024, View Source [SID1234641997]). Data were shared at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5-10, 2024 in San Diego.

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OPN-6602 Significantly Reduced Tumor Growth in Multiple Myeloma Models

OPN-6602 is an orally active, small molecule dual inhibitor of the E1A binding protein p300 (EP300) and CREB-binding protein (CBP) that demonstrated potent in vitro and in vivo anti-tumor activity in preclinical models of multiple myeloma. Multiple myeloma is an aggressive blood cancer derived from malignant plasma cells in the bone marrow.

Significantly reduced tumor growth as single agent (71% tumor growth inhibition, or TGI) in the OPM-2 multiple myeloma cell xenograft model
Demonstrated increased anti-tumor activity (>100% TGI) and sustained duration of response in combination studies with dexamethasone, pomalidomide and mezigdomide
Displayed synergy with dexamethasone and lenalidomide in growth inhibition of MM1.S cells
Showed downregulation of key drivers of the multiple myeloma signaling pathway including MYC, IRF4 and MYB in OPM-2 xenograft tumors
A first-in-human Phase 1 study of OPN-6602 is planned for mid-2024 in patients with multiple myeloma.

"We are excited to begin our Phase 1 study of OPN-6602 in patients with multiple myeloma this summer. While we will study OPN-6602 initially as monotherapy, preclinical data supports testing the compound as a single agent and in combination with standard of care and next generation myeloma therapies," said Jackie Walling, MBChB, PhD, chief medical officer. "The unique pharmacokinetic profile of the compound, with a high c-max and short half-life, in particular, is anticipated to provide a distinct advantage in the combination setting."

OPN-9840 Demonstrated Single Agent Efficacy in Malignant Mesothelioma

OPN-9840 is an oral, non-covalent, pan transcriptional enhanced associate domain (TEAD) inhibitor that demonstrated dose-dependent and on-target in vitro and in vivo efficacy in preclinical models of malignant mesothelioma. Malignant mesothelioma is a rare and aggressive cancer that primarily affects the lining of the lungs or abdomen. In 40% of malignant mesotheliomas, neurofibromatosis 2 (NF2) gene mutations cause dysregulation of the Hippo pathway and increased TEAD-dependent transcription. This aberrant signaling ultimately leads to increased tumor growth and resistance to therapies.

Significantly inhibited tumor growth (88% to >100%) in an NF2-mutant malignant mesothelioma mouse xenograft model. Tumor regression was observed in the 15 mg/kg (2/8 mice) and 50 mg/kg (4/8 mice) dose groups.
OPN-9652, an analog of OPN-9840, showed increased anti-tumor activity (134% TGI) and synergistic inhibition of downstream target genes in a combination study with trametinib
Showed no in vitro cytotoxicity; is well tolerated in vivo while showing potential for blood brain barrier penetration
Additional studies presented through a collaboration with Dr. Andrew Aplin’s laboratory at Thomas Jefferson University demonstrated that Opna TEAD inhibitors enhance BRAF/MEK inhibition in melanoma models by targeting drug-resistant persister cells. Dr. Aplin is a professor in cancer research and deputy director at Jefferson’s NCI-designated Sidney Kimmel Cancer Center.

OPN-9840 is set to begin IND-enabling studies and Opna is currently seeking partnerships for development.

Abstract Information

Title: OPN-6602, a potent dual EP300/CBP bromodomain inhibitor, targets multiple myeloma through concomitant suppression of IRF4 and c-MYC
Abstract Number: #660
Date and time: April 7, 2024; 1:30-5:30 pm PT
Presenter: Bernice Matusow, MS

Title: OPN-9840, a non-covalent potent pan-TEAD inhibitor, exhibits single agent efficacy in preclinical malignant mesothelioma models
Abstract Number: #7264
Date and time: April 10, 2024; 9 am-12:30 pm PT
Presenter: Pan-Yu Chen, PhD

Title: Targeting TAZ-TEAD in minimal residual disease enhances the duration of targeted therapy in melanoma models
Abstract Number: #7201
Date and time: April 10, 2024; 9 am-12:30 pm PT
Presenter: Connor Ott, PhD candidate, Thomas Jefferson University

On April 10, 2024 Nuvation Bio Inc. (NYSE: NUVB), a late-stage, global biopharmaceutical company tackling some of the greatest unmet needs in oncology by developing differentiated and novel therapeutic candidates, reported the completion of the acquisition of AnHeart Therapeutics Ltd. (AnHeart), a late-stage, global biopharmaceutical company developing novel precision therapies for people with cancer (Press release, Nuvation Bio, APR 10, 2024, View Source [SID1234641996]). With the acquisition’s completion, AnHeart is now a wholly-owned subsidiary of Nuvation Bio.

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"The closing of the acquisition transforms Nuvation Bio into a late-stage, global oncology company that is well-capitalized and positioned to develop our newly expanded pipeline as we move toward becoming a commercial organization," said David Hung, M.D., Founder, President, and Chief Executive Officer of Nuvation Bio. "We welcome the AnHeart team and look forward to leveraging our combined expertise to bring new cancer therapies to patients who need them most."

Nuvation Bio will continue to be led by its current management team, including David Hung, M.D., its Founder, President, and Chief Executive Officer. In addition, Min Cui, Ph.D., Founder and Managing Director of Decheng Capital, an investor in AnHeart, and Junyuan Jerry Wang, Ph.D., Co-Founder and Chief Executive Officer of AnHeart, have joined the Nuvation Bio board of directors.

Following completion of the acquisition, Nuvation Bio issued to the AnHeart security holders, in exchange for all outstanding AnHeart shares, options, and other securities, approximately 43,590,188 shares of Nuvation Bio’s Class A common stock (inclusive of the shares of Class A common stock underlying the AnHeart equity awards assumed by Nuvation Bio), 851,202 shares of Nuvation Bio’s Series A Non-Voting Convertible Preferred Stock (automatically convertible into 85,120,200 shares of Nuvation Bio’s Class A common stock upon the approval of Nuvation Bio’s stockholders), and warrants collectively exercisable for approximately 2,893,731 shares of Nuvation Bio’s Class A common stock at an exercise price of $11.50 per share.

Advisors
Evercore acted as Nuvation Bio’s exclusive financial advisor and Cooley LLP acted as legal counsel, alongside Morrison & Foerster LLP as intellectual property counsel, Haiwen & Partners as Chinese legal counsel, and Conyers as Cayman Islands legal counsel. Davis Polk & Wardwell LLP acted as legal counsel for AnHeart, alongside Fangda Partners as Chinese legal counsel and Walkers (Cayman) LLP as Cayman Islands legal counsel.

On April 10, 2024 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the approval of the CE Mark for the VENTANA HER2 (4B5) Rabbit Monoclonal Primary Antibody RxDx* to identify metastatic breast cancer patients with low HER2 expression for whom ENHERTU (trastuzumab deruxtecan) may be considered as a targeted treatment (Press release, Hoffmann-La Roche, APR 10, 2024, https://www.prnewswire.com/news-releases/roche-obtains-ce-mark-for-first-companion-diagnostic-to-identify-patients-with-her2-low-metastatic-breast-cancer-eligible-for-enhertu-302112437.html [SID1234641995]). The test, which is branded PATHWAY in the United States, received US Food and Drug Administration (FDA) approval in October 2022. ENHERTU is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by Daiichi Sankyo and AstraZeneca.

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HER2 is a receptor protein that helps cancer cells grow quickly. To determine a patient’s HER2 status, pathologists evaluate, or score, the level of HER2 protein expressed in breast cancer tissue samples. If a patient’s tumour expresses high levels of HER2, the patient is identified as HER2-positive and may be considered for HER2-targeted treatment. However, half of all patients with metastatic breast cancer express low levels of HER2 which historically classified them as HER2-negative.

"We are proud to continue our innovation in breast cancer diagnostics through critical tests like this one, which helps identify patients with HER2-low status," said Jill German, Head of Pathology Lab at Roche Diagnostics. "With this expanded approval of our test, we’re pleased that more metastatic breast cancer patients across the world may be correctly identified and potentially eligible for this targeted therapy."

The VENTANA HER2 (4B5) test now includes a scoring algorithm that helps pathologists to identify "low expressors" of HER2, assigning a HER2 low status to this group of patients. With this lower cutoff, the test is able to identify patients who may benefit from ENHERTU as a treatment option.

Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases diagnosed worldwide each year. More than 685,000 people die from breast cancer every year.4,5

The CE Mark of the new HER2-low indication expands on the intended use for Roche’s proven, on-market VENTANA HER2 (4B5) test, delivering timely, clear and confident results. The launch exemplifies Roche’s commitment to continuing to innovate integrated, high medical value solutions that help to advance personalised healthcare.

About VENTANA HER2 (4B5) Rabbit Monoclonal Primary Antibody RxDx
Roche’s pre-diluted VENTANA HER2 (4B5) Rabbit Monoclonal Primary Antibody RxDx, used in combination with the fully automated BenchMark IHC/ISH slide staining instrument, standardises all immunohistochemistry (IHC) processes from baking through staining, and reduces the possibility of human error.5 It also minimises inherent variability resulting from individual reagent dilution and other processes found in manual and semi-automated IHC methods. The Roche HER2 (4B5) clone achieves consistently high proficiency assessment scores compared to other clones6 and demonstrates high concordance with HER2 FISH7,8, empowering laboratories to employ the most widely adopted and reliable HER2-IHC primary antibody.

The VENTANA HER2 (4B5) test was used as part of the DESTINY-Breast04 trial to identify patients whose tumours expressed low levels of HER2 protein (IHC 1+ or IHC 2+/ISH-). The trial reported a 50% reduction in the risk of disease progression or death and an overall survival gain of six months over standard of care in patients treated with ENHERTU whose tumours had low levels of HER2 expression, leading to the approval of ENHERTU in this patient population.

On April 10, 2024 Compugen Ltd. (NASDAQ: CGEN) (TASE: CGEN) a clinical-stage cancer immunotherapy company and a pioneer in computational target discovery, reported the simultaneous online publication of a peer reviewed paper titled ‘Unleashing natural IL-18 activity using an anti-IL-18BP blocker antibody induces potent immune stimulation and anti-tumor effects’ link, in Cancer Immunology Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) with a presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting on April 5-11, 2024, in San Diego, California (Press release, Compugen, APR 10, 2024, View Source [SID1234641994]).

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"There is a growing recognition of the importance of the IL-18 pathway in cancer immunology reflected in the surge in investment and collaboration in this space," said Anat Cohen-Dayag, Ph.D., President, and Chief Executive Officer of Compugen. "Through our computational discovery work at Compugen we identified that IL-18 binding protein (BP), a natural inhibitor of IL-18, is highly expressed in patients as a potential immune resistant mechanism. Taking advantage of the high levels of endogenous IL-18BP bound-IL-18 in the tumor microenvironment, we, along with our partner Gilead Sciences are developing COM503, a differentiated antibody approach to harness cytokine biology for cancer therapeutics."

Eran Ophir, Ph.D., Chief Scientific Officer at Compugen added, "Our paper published online yesterday in Cancer Immunology Research describes how COM503, a potential first-in-class high affinity monoclonal antibody, blocks the interaction between IL-18 and IL-18BP, unleashing the activity of endogenous IL-18 in the tumor. By relying on endogenous production of IL-18, we found that COM503’s activity is localized to the tumor microenvironment with the additional advantage of a wider therapeutic window than systemic IL-18 delivery."

Dr. Cohen-Dayag continued, "Combining the cutting-edge capabilities and expertise of both Compugen and Gilead, our goal is to expedite the development of COM503. This year, we are progressing towards COM503 IND filing and are planning initiation of a Phase 1 study evaluating safety and tolerability of COM503."

On April 10, 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 preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24) at the 2024 AACR (Free AACR Whitepaper) Annual Meeting, April 5-10 in San Diego, California (Press release, Ryvu Therapeutics, APR 10, 2024, View Source [SID1234641993]).

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"We are excited to present our latest advancements in oncology therapeutics at the AACR (Free AACR Whitepaper) Annual Meeting this year. Strong preclinical data from our two lead synthetic lethality programs – PRMT5 and WRN – are encouraging as we make progress toward the identification of competitive clinical candidates," said Krzysztof Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics.

Dr. Brzózka added, "We are also proud of our ONCO Prime target discovery platform, which recently received a significant grant from the Polish Agency for Enterprise Development, giving validation and financial support to our innovative drug discovery efforts. At AACR (Free AACR Whitepaper), we present promising data in KRAS-mutant patient-derived colorectal cancer cells, where the ONCO Prime platform has identified promising novel drug targets. With these initial data, we continue to expand the platform’s potential to discover novel anticancer targets across various tumor types."

The ONCO Prime target discovery platform aims to identify novel drug targets based on patient-derived primary cell cultures, omics characterization, and functional assays. It already supports preclinical development of Ryvu programs, including PRMT5 and WRN. In March 2024, the Polish Agency for Enterprise Development (PARP) recommended awarding a PLN 26 million (approx. USD 6.6 million) grant to Ryvu to cover five years of ONCO Prime research activities retroactive to May 2023. The ONCO Prime platform covers a broad spectrum of tumor types, and data from colorectal cancer are presented in AACR (Free AACR Whitepaper) Poster No. 4684, ‘A comprehensive platform for identification of KRAS-specific synthetic lethal targets using patient-derived cells.’

AACR 2024 Poster highlights:

Abstract Title: ‘Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers.’
Session Name: HDAC and Methyltransferase Inhibitors
Session date and time: Tuesday, April 9, 9:00 AM – 12:30 PM PST
Poster Number: 4598

Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors showing favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding.
Ryvu PRMT5 inhibitor has a robust antiproliferative effect on MTAP-deleted cell lines and provides a good safety window for MTAP WT cells, as shown in a wide cell line panel.
Novel Ryvu compounds are characterized by significantly improved PK profile that allow for oral administration.
In vitro safety evaluations did not reveal any significant liabilities of the tested compounds.
The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies in MTAP-deleted tumor models.
Abstract Title: ‘Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors.’
Session Name: Novel Antitumor Agents 4
Session date and time: Tuesday, April 9, 1:30 PM – 05:00 PM PST
Poster Number: 5942

Structure-based optimization performed at Ryvu facilitated the rapid expansion and delivery of a compound library with novel intellectual property (IP), demonstrating target engagement in cells and selective potency over other RecQ family members.
The pharmacokinetic properties of these compounds were favorable, allowing progress to in vivo studies, which confirmed the efficacy of Ryvu’s WRN inhibitors in xenograft MSI-H cancer models.
Data on Ryvu’s WRN inhibitors provide pharmacological proof-of-concept with synthetic lethal effect and support WRN inhibition as a new, targeted oncological therapy in MSI-high tumors.
Abstract Title: ‘A comprehensive platform for identification of KRAS-specific synthetic lethal targets using patient-derived cells.’
Session Name: New Targets, Technologies, and Drug Delivery Systems
Session date and time: Tuesday, April 9, 9:00 AM – 12:30 PM PST
Poster Number: 4684

Ryvu’s cutting-edge drug discovery platform uniquely combines high throughput capabilities with the precision and translational impact traditionally associated with later, lower throughput stages.
By leveraging human stem cell-derived model cells (PDC), patient-derived xenografts (PDXs) and clinical samples, we have created a groundbreaking approach to identifying synthetic lethal (SL) targets specific to oncogenic pathways.
In conjunction with our novel ranking algorithm, these models have successfully identified potential drug targets in KRAS-mutant cells—targets that remained undetected in immortalized CRC cell lines, likely due to genetic and epigenetic alterations accumulated over years of cell culture.
Chemical compound screening has produced promising results that have been further validated through comparison with a varied collection of patient-derived CRC cultures, ensuring the findings’ reliability and clinical relevance.
These data position Ryvu’s primary model platform as an invaluable resource for target discovery research with broad applicability across a variety of tumors.
Abstract Title: ‘Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms.’
Session Name: Targeted, Combination, and Differentiation Therapies
Session date and time: Wednesday, April 10, 9:00 AM – 12:30 PM PST
Poster Number: 7225

RVU120, a highly selective and potent CDK8/19 inhibitor, shows potential efficacy as both monotherapy and in combination with ruxolitinib (RUX), a JAK1/2 inhibitor, for the treatment of myeloproliferative neoplasms (MPN) and polycythemia vera (PV).
In vivo treatment with RVU120/RUX+RVU120 significantly reduced disease manifestation (splenomegaly, WBC, fibrosis scoring, hematopoiesis) compared to VEH/RUX.
These data suggest that inhibition of JAK1/2 and CDK8/19 could be a novel therapeutic strategy in MPNs.
Abstract Title: ‘MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib.’
Session Name: Novel Antitumor Agents 2
Session date and time: Sunday, April 7, 01:30 AM – 05:00 PM PST
Poster Number: 665

MEN1703 (SEL24) demonstrates efficacy both as a monotherapy and in combination with the JAK inhibitor ruxolitinib (RUX) in preclinical models of myelofibrosis (MF).
MEN1703 demonstrated anti-tumoral efficacy in MF preclinical models, exhibiting in vitro activity at clinically relevant concentrations. Notably, the combination of MEN1703 with the standard of care, RUX, exhibited synergistic effects and molecular analyses confirmed the inhibition of downstream targets of PIM.
The results support the therapeutic potential and relevance of MEN1703 in treating myelofibrosis.
Posters are available on View Source