Core Viewpoint - The article discusses the role of the p53 R172H mutation in pancreatic ductal adenocarcinoma (PDAC), highlighting its contribution to creating an immunosuppressive tumor microenvironment and reducing the efficacy of immune checkpoint inhibitors (ICIs) [4][13][15]. Group 1: Background on PDAC - PDAC is a highly aggressive cancer characterized by KRAS gene activation mutations and TP53 gene alterations, with TP53 mutations leading to the loss of tumor suppressor function [2][6]. - Approximately 90% of PDAC cases have KRAS activation mutations, while around 70% exhibit changes in the TP53 tumor suppressor gene, indicating the critical role of p53 in genomic protection [7]. Group 2: Research Findings - A study published by MIT researchers reveals that the common p53 mutation, p53 R172H, occupies enhancers of immunosuppressive chemokines (e.g., Cxcl1), stimulating their expression and establishing an immunosuppressive tumor microenvironment in PDAC [3][4][11]. - The study indicates that knocking out the p53 R172H mutation enhances the efficacy of immune checkpoint inhibitors [13][15]. - Mechanistically, p53 R172H enhances Cxcl1 expression by occupying its distal enhancer, with NF-κB being a crucial cofactor for this process [12][15]. Group 3: Implications for Treatment - The findings suggest that p53 R172H promotes tumor growth by regulating cancer cell-specific gene expression programs that shape the tumor microenvironment, thereby inhibiting anti-tumor immune responses [15][16]. - In mouse models of PDAC, tumors lacking p53 R172H showed fewer T cells and higher levels of myeloid-derived suppressor cells (MDSCs), indicating a more favorable immune environment for tumor growth [15].

Rezatapopt Clinical Development - PMV Pharma's lead candidate, rezatapopt (PC14586), is a first-in-class p53 Y220C reactivator targeting the previously undruggable p53 Y220C mutation, found in approximately 1% of solid tumors[4,9] - Rezatapopt has shown clinical proof of concept with favorable safety and preliminary efficacy across multiple tumor types[4] - A single-arm, registrational, tumor-agnostic Phase 2 trial was initiated in Q1 2024, with an interim analysis planned for mid-2025 and NDA submission planned for the end of 2026[4] - In the Phase 1 study, tumor shrinkage was observed in 87% of patients with measurable disease at baseline, KRAS wild type, and at least one post-baseline assessment in the efficacious dose range[22] - Confirmed responses at the Recommended Phase 2 Dose (RP2D) of 2000 mg QD showed an Overall Response Rate (ORR) of 38% in TP53 Y220C/KRAS WT patients[24] - The median time to response in the efficacious dose range for TP53 Y220C/KRAS WT patients was 15 months[27] Safety and Tolerability - Rezatapopt demonstrated a favorable safety profile, with most Treatment-Related Adverse Events (TRAEs) being Grade 1 or 2[29] - The most frequent TRAEs were nausea (507%) and vomiting (433%), which improved when rezatapopt was given with food[29] - The rate of drug discontinuation due to a TRAE was low at 3%[29] Financial Position and Future Plans - PMV Pharma had $198 million in cash as of September 30, 2024, providing a cash runway to year-end 2026[4] - The Phase 2 trial includes defined registration paths in ovarian and tumor-agnostic patient populations, with approximately 90% of TP53 Y220C patients being KRAS wild type[39,42]

机构：中金公司 研究员：张琎/刘雅馨/朱言音 APG-115 单药和联合特瑞普利单抗展现出良好的抗肿瘤活性。截至2025年2 月13 日，单药治疗组17 例 疗效可评估患者中，12 例晚期腺样囊性癌（ACC）患者的ORR为16.7%，联合治疗组6 例胆管癌 （BTC）患者的ORR为16.7%，DCR为100%；6 例晚期脂肪肉瘤（LPS）患者的ORR为16.7%，DCR为 66.7%；2 例恶性周围神经鞘瘤（MPNST）患者达到经确认的PR且PFS显著延长。 盈利预测与估值 公司近况 近日，公司在2025 年美国临床肿瘤学会（ASCO）年会上口头报告了Bcl-2抑制剂APG-2575 （lisaftoclax）联合阿扎胞苷针对髓系恶性肿瘤的Ib/II期研究数据i，并更新了MDM2-p53 抑制剂 APG- 115（alrizomadlin）治疗晚期腺样囊性癌（ACC）或其它实体瘤患者的II期临床研究数据ii。 评论 APG-2575 R/R AML数据亮眼，展现出克服维奈克拉耐药的潜力。在APG-2575 的全球多中心Ib/II期研 究中，截至2025 年4 月，在44 例疗效可评估复发难治急性髓系白血病 / ...

PMV Pharmaceuticals (PMVP) 2025 Conference June 05, 2025 03:45 PM ET Speaker0 Hello, everyone. Thank you so much for joining us at the Jefferies Global Healthcare Conference twenty twenty five. We're kind of winding the day down now, but it's my distinct honor and pleasure to be hosting PMV Pharma. We're gonna get a perspective today from the chief development officer, Deepika Jolotta. Deepika, welcome. Speaker1 Thank you so much. It's a pleasure to be here. Speaker0 So maybe we could just get directly into ...

Core Viewpoint - The company has received FDA approval for clinical trials of GenSci128 tablets, a targeted therapy for patients with TP53 Y220C mutation in advanced or metastatic solid tumors [1][2]. Group 1: Drug Information - Product Name: GenSci128 tablets - Application: Clinical trial approval in the US - Acceptance Number: IND 174059 - Applicant: Changchun JinSai Pharmaceutical Co., Ltd. - Approval Conclusion: Permission granted for clinical trials in the US - Indication: Local advanced or metastatic solid tumors with TP53 Y220C mutation [1]. Group 2: Drug Mechanism and Development - GenSci128 is a class 1 new chemical drug designed as a selective reactivator for TP53 Y220C mutation, aiming to restore the normal conformation and function of the mutated protein [2]. - Preclinical data indicates that GenSci128 has good efficacy and safety [2]. - The drug has also been approved for clinical trials in China for the same indication [2]. Group 3: Company Impact - Successful progress in clinical trials could help the company expand its business structure, optimize product offerings, and enhance core competitiveness [3]. - The company will actively promote the research and development of this project and comply with disclosure obligations regarding project progress [4].

Summary of PMV Pharmaceuticals (PMVP) FY Conference Call Company Overview - **Company**: PMV Pharmaceuticals (PMVP) - **Event**: FY Conference Call on May 27, 2025 Key Points Industry and Company Focus - PMV Pharmaceuticals is focused on oncology, specifically targeting p53 mutations in various solid tumors, including ovarian, lung, breast, and endometrial cancers [4][50]. Clinical Trial Updates - The pivotal Phase 2 trial involves 14 patients with p53 mutations and KRAS wild type across five cohorts: ovarian, lung, breast, endometrial, and others [4]. - As of March, approximately 90% of the targeted 60 sites for patient enrollment were open, with plans to complete enrollment by the end of 2025 [5][6]. - The company expects to enroll 50 patients for an interim analysis, with approximately 40% of these being ovarian cancer patients [10][12]. - The trial is designed to provide data on overall response rates (ORR) and durability of response (DOR) across different cohorts [41][43]. Data and Efficacy Expectations - Previous Phase 1 data indicated a median DOR of seven months across various histologies [14][18]. - The company anticipates that the first responses will be observable at the first or second scan, approximately six to twelve weeks into the trial [20]. - The target ORR for the study is set at 30%, which is considered clinically meaningful for ovarian cancer [58][62]. Regulatory and Commercialization Strategy - PMV Pharmaceuticals is considering filing for regulatory approval (NDA) by the end of 2026, likely focusing on ovarian cancer first due to the higher frequency of p53 mutations in this cohort [52][53]. - The company is engaging with the FDA and has had positive interactions, with no significant changes in the review team noted [74][76]. - There is an ongoing evaluation of commercialization strategies, including potential partnerships, especially for markets outside the US [71][72]. Financial Position - PMV Pharmaceuticals reported a cash position of $166 million, which is expected to sustain operations through 2026, covering the NDA submission process [73]. Additional Insights - The company is actively monitoring patient identification and tolerability issues, noting that p53 mutations are present in all next-generation sequencing (NGS) panels, which aids in patient identification [65]. - PMV Pharmaceuticals is also exploring combination therapies, such as with azacitidine for AML and MDS, with initial patient enrollment underway [81][84]. Future Expectations - An update on the trial data is expected in mid-2025, likely between July and August [8][10]. - The company aims to provide a comprehensive breakdown of data by cohort during the interim analysis [42][43]. This summary encapsulates the critical aspects of PMV Pharmaceuticals' current status, focusing on their clinical trials, regulatory strategies, financial health, and future expectations in the oncology sector.

Enrollment on track in Phase 2 pivotal portion of PYNNACLE clinical trial evaluating rezatapopt as monotherapy in patients with TP53 Y220C and KRAS wild-type advanced solid tumorsInterim analysis from Phase 2 PYNNACLE trial expected mid-2025; PMV plans to provide interim analysis data for approximately 50 patients with at least 18 weeks of follow-upCash, cash equivalents, and marketable securities of $165.8 million as of March 31, 2025, providing expected cash runway to end of 2026 PRINCETON, N.J., May 09, ...

Transaction Values Vesicor at a Pre-money Equity Value of $70 millionBusiness Combination is Expected to be Completed in the Fourth Quarter of 2025 DANVILLE, Calif., April 28, 2025 (GLOBE NEWSWIRE) -- Black Hawk Acquisition Corp. (Nasdaq: BKHAU, BKHA, BKHAR), a special purpose acquisition company, (“Black Hawk”) announced the signing of a Business Combination Agreement (“BCA”) on April 26, 2025, with Vesicor Therapeutics, Inc. (“Vesicor”, “Vesicor Therapeutics” or “the Company”), a California-based early de ...