On October 16, 2023 Phanes Therapeutics, Inc. (Phanes), a clinical stage biotech company focused on innovative drug discovery and development in oncology, reported that it has entered into a clinical collaboration agreement with Merck (known as MSD outside the US and Canada) to study PT886, its first-in-class bispecific antibody targeting claudin 18.2 and CD47, in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in patients with claudin 18.2 positive gastric or gastroesophageal junction (GEJ) adenocarcinomas (Press release, Phanes Therapeutics, OCT 16, 2023, View Source [SID1234636033]). PT886 was assembled using Phanes’ proprietary bispecific antibody platforms PACbody and SPECpair and was granted orphan drug designation (ODD) for the treatment of pancreatic cancer by the FDA last year.

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Phanes is currently enrolling patients in a multi-center Phase I clinical trial of PT886 in the U.S. evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with locally advanced or metastatic gastric, GEJ, or pancreatic cancer that have progressed after all available standard therapy or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate (NCT05482893). The next phase of Phanes’ study is investigating the therapeutic potential of PT886 as a combination therapy in gastric, GEJ and pancreatic cancers. The clinical collaboration with Merck will evaluate PT886 in combination with KEYTRUDA (pembrolizumab) in patients with claudin 18.2 positive gastric or GEJ adenocarcinomas with or without chemotherapy.

"Phanes is very excited about partnering with Merck on this novel approach to treat patients with gastric or gastroesophageal cancers," said Dr. Ming Wang, Founder and CEO of Phanes. "Claudin 18.2 is a clinically validated target and is over-expressed in these types of GI tumors. We believe the mechanisms of PT886 and pembrolizumab are complementary and the combination has the potential to improve outcomes for patients. This collaboration marks another milestone for Phanes in fulfilling our vision of developing innovative approaches to treat cancer."

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

ABOUT PT886

PT886 is a first-in-class bispecific antibody targeting claudin 18.2 and CD47. It was constructed using Phanes’ proprietary bispecific antibody platforms PACbody and SPECpair and was granted orphan drug designation (ODD) for the treatment of pancreatic cancer. PT886 is expected to directly kill tumor cells via both the ADCP activity of macrophages and ADCC activity of NK cells, and by targeting both claudin 18.2 and CD47 expressed on the surface of tumor cells, it can broaden the tumor killing spectrum. Additionally, PT886 is expected to induce the presentation of tumor neoantigens by channeling tumor cells into phagocytotic antigen presenting cells (APCs) and stimulate the adaptive immune system by indirectly activating T cell killing of claudin 18.2 expressing tumor cells through recognition of tumor neoantigens. The anti-CD47 arm of PT886 is differentiated and has demonstrated minimum binding to human red blood cells while maintaining strong binding activity to CD47 on tumor cells, thus improving the benefit/risk profile versus other CD47 molecules.

On October 16, 2023 Abbisko Therapeutics Co., Ltd. ("Abbisko" hereafter) reported that the results of the company’s two preclinical studies published at the 35th International Molecular Targets and Cancer Treatment Conference (EORTC) be held in Boston, U.S. (Press release, Abbisko Therapeutics, OCT 16, 2023, https://www.prnewswire.com/news-releases/abbisko-presented-two-preclinical-research-results-at-the-35th-international-molecular-targets-and-cancer-treatment-conference-eortc-nci-aacr-301957292.html [SID1234636032]). These two research results respectively demonstrate the latest preclinical research progress of the next generation of PRMT5*MTA inhibitors and small molecule brain penetrant PD-L1 inhibitors in Abbisko’s pipeline. As the world’s highest-quality research conference focusing on molecular targeting and tumor treatment, the ENA conference collects the most cutting-edge researches on innovative drugs and therapies in the field of tumor treatment.

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Abbisko presented the following posters at the ENA conference:

Title: Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor

Poster number: C130

Session date and time: Saturday, October 14 | 12:30 pm-4:00 pm

Session location: Level 2, Exhibit Hall D

Background: MTAP is homozygous deleted in ~50% in glioblastoma and many other cancers. PRMT5*MTA inhibition has been shown to be synthetic lethal with MTAP deletion. First generation PRMT5 inhibitors could not distinguish between PRMT5*MTA or PRMT5 alone, thus limited by their shallow therapeutic windows in clinical use. Development of selective PRMT5*MTA inhibitors may improve not only safety but also therapeutic efficacy. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a potent and selective MTA-cooperative and brain-penetrable PRMT5 inhibitor ABK-PRMT5-1, which demonstrates strong anti-tumor activity and brain-penetrating activity in various preclinical models.

Conclusion：

ABSK-PRMT5-1 strongly inhibits cell proliferation in MTAP-deleted cancer cell lines, with minimal effects on MTAP wildtype cell lines. Furthermore, it significantly reduces SDMA in MTAP-deleted cancer cell lines. Oral administration of ABSK-PRMT5-1 strongly inhibits tumor growth in MTAP-deleted xenograft tumor models. In addition, ABSK-PRMT5-1 demonstrates strong brain penetration with excellent Kp values in animals. DMPK and safety profiling shows good overall drug-like properties of ABK-PRMT5-1. ABK-PRMT5-1, presented here by Abbisko Therapeutics, is a highly selective MTA-cooperative and brain-penetrable PRMT5 inhibitor. Its superior profile supports fast-track preclinical development.

Title: Discovery and characterization of a novel small molecule brain penetrant PD-L1 inhibitor

Poster number : B151

Session date and time: Friday, October 13 | 12:30 pm-4:00 pm

Session location: Level 2, Exhibit Hall D

Background: Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for treating various cancers. Small molecule PD-L1 inhibitors with brain-penetrating ability may have potential to overcome the limitations of antibodies and bring benefit for patients with intracranial tumors. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have successfully discovered an innovative orally available small molecule PD-L1 inhibitor ABSK044. In preclinical experiments, this compound demonstrates robust T-cell activating ability, strong anti-tumor efficacy, and brain-penetrating activity.

Conclusion：

ABSK044 strongly inhibits PD-1-PD-L1 interaction with an IC50 less than 1nM in vitro and very potently rescues PD-L1-induced suppression of T cell activation signaling in cells. Furthermore, it efficiently rescues cytokine production in CD8+ T cells suppressed by PD-L1, reaching a level comparable to that of PD-L1 antibodies. In in vivo studies, oral administration of ABSK044 strongly inhibits tumor growth to an extent similar to therapeutic anti-PD-L1 antibodies. Notably, ABSK044 demonstrates excellent brain penetration with a Kp value exceeding 0.4. DMPK and safety profiling demonstrate excellent drug-like properties of ABSK044.

ABSK044, presented here by Abbisko Therapeutics, is a highly potent and orally available small molecule PD-L1 antagonist with brain-penetrating activity. Its superior profile supports its fast-track preclinical development.

On October 16, 2023 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the pricing of its previously announced underwritten public offering of 5,357,143 shares of Class A common stock at a price to the public of $56.00 per share (Press release, Nuvalent, OCT 16, 2023, View Source [SID1234636031]). All shares are being offered by Nuvalent. The gross proceeds to Nuvalent from the offering, before deducting underwriting discounts, commissions and other offering expenses, are expected to be approximately $300.0 million. The offering is expected to close on October 19, 2023, subject to the satisfaction of customary closing conditions. In addition, the underwriters have a 30-day option to purchase up to an additional 803,571 shares of Class A common stock at the public offering price less underwriting discounts and commissions.

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J.P. Morgan, TD Cowen, Piper Sandler and BMO Capital Markets are acting as joint book-running managers for the offering. Wedbush Securities is acting as a manager.

The shares are being offered by Nuvalent pursuant to an automatically effective shelf registration statement that was filed with the Securities and Exchange Commission ("SEC") on March 16, 2023. The offering is being made only by means of a prospectus and prospectus supplement that form a part of the registration statement. A preliminary prospectus supplement relating to and describing the terms of the offering has been filed with the SEC and may be obtained for free by visiting the SEC’s website at www.sec.gov. A final prospectus supplement relating to the offering will be filed with the SEC. Copies of the final prospectus supplement and the accompanying prospectus can be obtained, when available, from: J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, by telephone at (866) 803-9204 or by email at [email protected]; Cowen and Company, LLC, 599 Lexington Avenue, New York, NY 10022, by telephone at (833) 297-2926 or by email at [email protected]; Piper Sandler & Co., 800 Nicollet Mall, J12S03, Minneapolis, MN 55402, Attention: Prospectus Department, by telephone at (800) 747-3924, or by email at [email protected]; and BMO Capital Markets Corp., Attn: Equity Syndicate Department, 151 W 42nd Street, 32nd Floor, New York, NY 10036, by telephone at (800) 414-3627 or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On October 16, 2023 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 presentations of preclinical data from the PRMT5 program and synthetic lethality platform, as well as preclinical data on MEN1703 (SEL24) in B-cell lymphomas, at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place in Boston, Massachusetts (Press release, Ryvu Therapeutics, OCT 16, 2023, View Source [SID1234636030]).

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"We are pleased with preclinical data underscoring the promise of our synthetic lethality platform, as highlighted by our leading preclinical program on PRMT5 inhibitors," said Krzysztof Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics. "With the growing evidence of the potential of PRMT5 as a cancer therapeutic target, we are excited to share updated data on our MTA-cooperative PRMT5 inhibitors showing high selectivity and efficacy in animal tumor models. Our potentially best-in-class MTA-cooperative PRMT5 inhibitors exhibit significantly improved pharmacokinetics relative to other PRMT5 inhibitors currently in development. Given their in vivo target engagement and remarkable anti-tumor efficacy, we anticipate further development and progression to IND-enabling studies in 2024. In addition, we presented our comprehensive primary colorectal cancer (CRC) cell models that not only mirror the molecular profile seen in patient-derived specimens but also surpass industry benchmarks in screenings, making them invaluable for future drug discovery."

Ryvu licensee, Menarini Group, and academic collaborators presented preclinical data on MEN1703 (SEL24), a first-in-class, oral, dual type I PIM/FLT3 inhibitor in B-cell lymphomas, where MEN1703 demonstrated promising anti-tumor activity. These data support the Phase II clinical program of MEN1703 in diffuse large B-cell lymphoma (DLBCL).

Details on the poster presentations are as follows:

Abstract Title: "Discovery of Novel MTA-cooperative PRMT5 Inhibitors as Targeted Therapeutics for MTAP-deleted Cancers"

Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors with outstanding drug-like physicochemical properties and the ability to block methyltransferase activity of PRMT5 with nanomolar IC50 values. The novel, optimized inhibitors exhibit a significantly improved PK profile, and in addition, the compounds show antitumor efficacy and target engagement in vivo, providing a strong foundation for further development.

Abstract Title: "A Comprehensive Platform for Unraveling the Molecular Mechanisms and Vulnerabilities of Colorectal Cancer: A Step Forward in Target Discovery"

Ryvu has pioneered an extensive platform that employs primary colorectal cancer (CRC) models, originated from human intestinal stem cells. This innovative approach enables high-throughput phenotypic assays and CRISPR/Cas9 genomic screenings, surpassing conventional industry standards. The robustness of these models has been confirmed through Ryvu’s proprietary ranking algorithm, which identifies potential synthetic lethal drug targets, particularly in KRAS-driven cells.

Abstract Title: "MEN1703/SEL24, A Potent PIM Inhibitor, Demonstrates Promising Anti-Tumor Activity in Activated B Cell Like DLBCL, Mantle Cell Lymphoma and Marginal Zone Lymphoma Cells"

Pharmacological inhibition with MEN1703 (SEL24), a first-in-class, oral, dual type I PIM/FLT3 inhibitor shows anti-proliferative effects in B cell lymphomas of various histotypes. Importantly, MEN1703 was effective in lymphoma cells resistant to other treatments inducing apoptosis in most cell lines. RNA-Seq indicated that the molecule modulates the transcriptome of highly responsive DLBCL cell lines differently from other, poorly responsive cells, providing clues to mechanisms involved in sensitivity to PIM inhibitors and supporting potential in treating B-cell lymphomas.

Posters are available on the Ryvu corporate website.

Webinar on PRMT5 and synthetic lethality pipeline, including WRN project and target discovery efforts

Ryvu will host a webinar today at 9:30 am CEST to discuss the PRMT5 data. To join the webcast, please register here: https://bit.ly/3RL1YWp. A recording from the webinar will be available on the ‘Presentations’ section of the Ryvu website.

On October 16, 2023 IDEAYA Biosciences, Inc. (Nasdaq:IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported initiation of a Phase 2 expansion of the darovasertib and crizotinib combination in GNAQ/11 metastatic cutaneous melanoma (Press release, Ideaya Biosciences, OCT 16, 2023, View Source [SID1234636029]).

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"We are pleased to advance the darovasertib and crizotinib combination into a Phase 2 expansion for GNAQ/11 metastatic cutaneous melanoma, where there are currently no FDA approved therapies in this genetically-defined patient population highlighting the unmet medical need," said Dr. Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences. "As IDEAYA advances the registrational trial for darovasertib in first-line HLA-A2-negative metastatic uveal melanoma, it’s a strategic priority to expand the program’s clinical application in multiple solid tumor settings, including HLA-A2-positive metastatic uveal melanoma, neoadjuvant and adjuvant uveal melanoma, and GNAQ/11 cutaneous melanoma," said Yujiro S. Hata, Chief Executive Officer, IDEAYA Biosciences.

"The clinical efficacy observed in a GNAQ melanoma patient that progressed on immune checkpoint inhibitor therapies and treated in our clinic has been durable and well tolerated. This is a very important finding in this biomarker defined population," said Dr. Marcus Butler, M.D., Medical Oncologist, Tumor Immunotherapy Program, Melanoma/Skin Oncology Site Lead at Princess Margaret Cancer Centre in Toronto, Canada, and Ocular Melanoma Physician Task Force of Canada Co-Lead.

The Phase 2 darovasertib and crizotinib combination expansion is based on preliminary clinical efficacy observed in the GNAQ/11 metastatic cutaneous melanoma setting. The GNAQ/11 prevalence in cutaneous melanoma has been reported at approximately 5% in The Cancer Genome Atlas. The GNAQ/11 cutaneous melanoma estimated annual incidence is approximately 5,000 patients in the US and 8,000 patients in the EU28, and the estimated total prevalence of GNAQ/11 cutaneous melanoma is approximately 70,000 patients in the US and 110,000 patients in the EU28. It has been reported that approximately 12.5% to 15% of cutaneous melanoma patients have been reported to develop metastatic disease, whereas in uveal melanoma, a predominantly GNAQ/11 mediated cancer, the metastatic rate has been reported at approximately 50%. In addition, based on several metastatic cancer patient databases, including Memorial Sloan Kettering Cancer Center (MSKCC) Impact, we project GNAQ/11 metastatic cutaneous melanoma has the potential to double or more the annual addressable metastatic patient population of metastatic uveal melanoma alone. In addition, GNAQ/11 mutation patients are known to have low tumor mutational burden making these patients less likely to benefit from immune checkpoint inhibitor therapies.

Darovasertib (IDE196) is a potent, selective small molecule inhibitor of protein kinase C (PKC). Mutations in GNAQ or GNA11 (GNAQ/11) have been identified in approximately 90% of patients with metastatic uveal melanoma. These mutations are associated with activation of signaling pathways, including oncogenic RAS/RAF/MEK/ERK via PKC activation, driving tumor progression.