Forimtamig

正文共：2434字 1图 预计阅读时间： 6分钟 在2024年第三季度，跨国药企对其新药管线进行了一系列的增加和删除调整，以适应不断变化的市场需求和科研进展。以下是对这些调整的详细总结。 Novartis（诺华） 2023年，诺华成功剥离山德士之后，完成了向“纯药企”定位的转型。诺华明确聚焦心血管-肾脏-代谢、免疫、神经科学和肿瘤业务四大核心治疗领域。 诺华在第三季度的管线调整中，增加了几个新药项目，包括FXX489和177Lu-NNS309 Radioligand therapy用于实体瘤治疗，GIZ943针对FOLR1的放射性配体疗法，ITU512作为HbF诱导剂（WIZ降解剂）用于镰状细胞病，以及VHB937作为TREM2稳定剂和激活剂（单克隆抗体）用于肌萎缩侧索硬化症治疗。 同时，诺华也从管线中删除了QGE031（ligelizumab），一种IgE抑制剂，用于食物过敏；PHE885（durcabtagene autoleucel），BCMA细胞疗法，用于4线多发性骨髓瘤；以及CMK389，IL-18抑制剂，用于肺结节病。 BMS（百时美施贵宝） 百时美施贵宝在第三季度增加了BMS-986460针对去势抵抗前列腺癌的治疗，BMS-986484针对实体瘤，以及RYZ801，GPC3-225Ac。 公司删除了MAGEA4/8 TCER (IMA401)，IMA401原研为Immatics，今年9月份Immatics在ESMO会议刚公布IMA401的初步临床验证数据，便遭退货。此外，还有一款TIGIT双特异性抗体以及抗IL8抗体BMS-986253均遭删除。 Roche（罗氏） 罗氏在第三季度的管线调整中增加了RG6434针对神经退行性疾病，LTBR激动剂针对实体瘤，以及CDK4/2i (RGT419B)针对HR+乳腺癌。 与此同时，罗氏从管线中删除了多个项目，包括tobemstomig PD1/LAG3双抗针对实体瘤，forimtamig GPRC5D/CD3双抗用于多发性骨髓瘤，RG6341 TRPA1拮抗剂用于慢性咳嗽，bepranemab抗Tau单抗用于阿尔茨海默病，ruzotolimod TLR7激动剂用于乙型肝炎病毒（HBV），xalnesiran RNAi用于HBV，PDL1 LNA用于HBV，以及HBsAg Mab用于慢性乙型肝炎。 Pfizer（辉瑞） 辉瑞在第三季度，宣布自愿从目前所有获批的市场中撤回所有批次的镰状细胞病（SCD）治疗药物Oxbryta，并停止所有正在进行的临床试验和全球扩展访问计划。 同时，公司还从管线中剔除了一种早期阶段的RSV和流感的组合疫苗PF-07941314；目前处在临床二期的CDK2抑制剂Tagtociclib ；下一代CDK4抑制剂PF-07220060联合内分泌治疗。 GSK（葛兰素史克） 葛兰素史克在第三季度将GSK4527363，一种B细胞调节剂，用于系统性红斑狼疮，新加入到I期临床研究。 公司从管线中删除了GSK5101956（肺炎球菌24价疫苗）用于成人肺炎球菌病；淋病疫苗GSK4348413，其疫苗类型显示为膜抗原（GMMA）；首款单纯疱疹病毒（HSV）疫苗GSK3943104；以及GSK3858279（抗CCL17单抗）用于骨关节炎疼痛。 Sanofi（赛诺菲） 赛诺菲在第三季度移除了三项研究，包括losmapimod（p38α/β MAPK抑制剂）用于治疗面肩肱型肌营养不良（FSHD）的III期临床研究，以及oditrasertib（RIPK1抑制剂）用于多发性硬化症（MS）的II期研究。 Merck（默沙东） 默克在第三季度从管线中删除了MK-8189，一种PDE10A抑制剂，用于精神分裂症，以及MK-7264（gefapixant），一种P2X3受体拮抗剂，用于咳嗽（美国）。 J&J（强生） 强生在第三季度管线中删除了一款IL-17抑制剂JNJ-1459，以及三款神经科学领域的临床研究项目：包括：seltorexant治疗阿尔兹海默病的II期临床研究、P2X7拮抗剂治疗双相障碍（Bipolar Depression）的II期临床研究，以及另一项JNJ-0376治疗帕金森病的I期临床研究。 其中，seltorexant是强生在研的OX2R拮抗剂，其在重度抑郁症和失眠症领域的开发已进入III期临床阶段。 Eli Lilly（礼来） 礼来在第三季度从管线中删除了APOC3 siRNA，用于心血管疾病的I期研究，DC-806，一种用于银屑病的IL-17A/IL-17F蛋白-蛋白相互作用抑制剂，以及PERESOLIMAB，一种用于类风湿性关节炎的抗PD1单抗。 小结 对于市场而言，管线的剔除多被市场认定为“失败”，多会影响投资界与研发界的判断。 当然，"砍管线”对于企业本身并非坏事，反映了药企在新药研发领域的动态变化，旨在优化管线，集中资源于最有前景的项目，并及时淘汰那些不符合预期的项目。 随着临床试验的进展和市场需求的变化，我们可以预期这些药企将继续调整其管线，以保持竞争力和创新能力。 封面图来源：123rf 欢迎参加进博会自身免疫、炎症和癌症首届创新药研发峰会暨JAK-STAT信号通路发现30周年庆典！ 2024-11-03 转机！FDA高级官员发话，CAR-T有望摘下 “黑框警告” 2024-11-02 复宏汉霖「地舒单抗」上市申请获FDA受理！ 2024-11-01 版权声明/免责声明 本文为原创文章。 本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。 文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。 如有任何问题，请与我们联系。 衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 点击查看更多精彩！

A recent review in the journal Nature Reviews Clinical Oncology has explored new therapeutic approaches for multiple myeloma (MM) targeting cell membrane proteins. Among these are B-cell maturation antigen (BCMA), G-protein-coupled receptor family C group 5 member D (GPRC5D), and Fc receptor-like protein 5 (FcRL5). These are transmembrane proteins expressed on plasma cells and have been identified as prominent immunotherapeutic targets in MM over the past decade. They've shown significant activity in heavily pre-treated patients with relapsed and/or refractory disease. the mechanism of action for a novel immunotherapy targeting a key membrane protein in multiple myelomaIn August 2023, Johnson & Johnson announced that the U.S. FDA had approved TALVEY™ (talquetamab-tgvs) for the treatment of adult patients with relapsed or refractory multiple myeloma. Talquetamab is the first-in-class bispecific antibody that binds to GPRC5D, a protein highly expressed on multiple myeloma cells, and the CD3 molecule on the surface of T cells. This binding facilitates the recognition and attack of myeloma cells by T cells. The engagement activates T cells, leading to their proliferation and cytokine release, which triggers a cytotoxic response against the tumor cells. Mechanism of Action Diagram of the GPRC5D/CD3 Bispecific Antibody Talquetamab (JNJ-64407564) Developed by Johnson & JohnsonGPRC5D (G-protein-coupled receptor family C group 5 member D) is a protein found on the surface of human cells, belonging to the GPCR family, and is classified as an orphan receptor whose natural ligand is yet to be identified. As of 2019, PubMed database searches revealed fewer than 20 publications on GPRC5D before then. How did Johnson & Johnson identify GPRC5D so quickly by 2016 and utilize it in developing the world's first bispecific product? Preliminary Target IdentificationIn 2001, a team led by Danish scientist Hans Bräuner-Osborne published pioneering work on the cloning and identification of GPRC5D. This receptor is predicted to have seven transmembrane segments and is expressed on cell membranes. The target shows 31-42% amino acid sequence homology among the four human receptor subtypes in the C family GPCR's fifth group, but lower homology with the transmembrane domains of metabotropic glutamate receptor subtypes 2 and 3 and other C family members. GPRC5D was found on chromosome 12p13.3, located alongside RAIG1, and is expressed peripherally with unknown function. Tissue DistributionIn 2004, a Japanese team led by Shinichi Inoue studied the unique tissue distribution and expression mechanism of GPRC5D. Their research demonstrated that GPRC5D is expressed in differentiated cells that produce hard keratin, including cortical cells of the hair shaft and keratinized regions of nails. GPRC5D transcripts are present during the mid-to-late anagen and catagen phases of hair growth but not during the telogen and early anagen phases. The differentiation inducer all-trans retinoic acid (ATRA) can induce GPRC5D expression in cultured hair follicle matrix cells. Therefore, GPRC5D's biological function is thought to play a critical role in hard keratinization. ATRA, a derivative of vitamin A, plays important roles in regulating gene expression, promoting cell differentiation, and inhibiting cell proliferation. It has been extensively studied, especially in cancer treatment. RAIG1, an orphan GPCR member related to GPRC5D, was the first to be shown to be induced by ATRA in head and neck squamous cell carcinoma (HNSCC). Subsequently, related family members GPRC5B and GPRC5C have also been shown to have increased mRNA levels induced by ATRA treatment. The figure below provides evidence of GPRC5D expression induced by ATRA in cultured hair follicle matrix cells. ATRA-induced upregulation of GPRC5D expression. (a) Northern blot analysis of GPRC5D, Ha1, 2, 3, and 4. (b) Time series of mRNA expression determined by reverse transcription and real-time quantitative PCR after adding ATRA (+/–) to cultured hair bulb cells (HBC)Genetic EvidenceEarly genome-wide RNA interference (RNAi) screening experiments conducted in the breast tumor cell line MCF7 revealed a significant correlation between the knockdown of GPRC5D and resistance to the estrogen receptor modulator Tamoxifen in breast cancer cells. This correlation involved multiple tumor-related genes. Clinical Relevance StudiesIn 2012, a team led by Alexander Gaiger at the Medical University of Vienna in Austria analyzed GPRC5D mRNA expression levels in the bone marrow of 48 patients with multiple myeloma. Their findings indicated that GPRC5D expression is low in normal tissues but elevated in multiple myeloma. Furthermore, high GPRC5D expression was positively correlated with high plasma cell counts, elevated β2-microglobulin levels in the bone marrow, and various high-risk cytogenetic features. This suggests that GPRC5D may serve as a novel cancer antigen and therapeutic target.  The expression of GPRC5D could help distinguish high-risk from low-risk multiple myeloma patients, implying a role for GPRC5D in the pathogenesis of multiple myeloma and its potential clinical applications. Targeting GPRC5D could guide clinical treatment decisions and the development of anti-tumor drugs. Concurrently, Israeli scientist Yossi Cohen and his team conducted clinical studies on multiple myeloma, demonstrating high levels of GPRC5D gene expression in bone marrow samples from 10 MM cases, while expression was low in 8 other hematological malignancies. This strong selective expression makes the GPRC5D gene and its encoded surface protein a reliable marker for monitoring tumor burden.  Further research observed that GPRC5D expression levels significantly decreased following anti-myeloma treatment. This decrease suggests that GPRC5D expression could serve as an indicator for evaluating treatment efficacy, and developing clinical therapeutic drugs targeting GPRC5D may provide novel treatment options for patients with high expression of this receptor. Differential Expression CharacteristicsThe differential expression profile of GPRC5D in healthy tissues, MM patients, and various tumor cells is illustrated in Figure 4 . Comprehensive genetic, biological, and clinical evidence suggests that developing therapeutic drugs targeting GPRC5D may offer new opportunities for the treatment of MM patients. Expression characteristics of GPRC5D. (A) mRNA expression levels of GPRC5D in various healthy tissues; (B) Comparison of mRNA expression levels of GPRC5D in multiple myeloma with a range of hematological and solid tumor malignanciesEarly focus of biological functionsThough the endogenous ligand for GPRC5D is unknown, and limited research has been conducted on its upstream and downstream biological functions, potential insights into its biological functions can be drawn from various dimensions before Johnson & Johnson selected GPRC5D for drug development in 2019.  Dimension 1 - Cancer: GPRC5A, a member of the GPCR subfamily to which GPRC5D belongs, has been studied in detail. Extensive research on GPRC5A suggests that the protein may play diverse roles in various cancer models. For instance, in non-small cell lung cancer (NSCLC) models, loss of GPRC5A activates NF-κB in mice, promoting lung inflammation and tumor formation, and enhances the transformed phenotype of normal and malignant lung epithelial cells through the STAT3 signaling pathway. In oral squamous cell carcinoma (OSCC) models, GPRC5A is highly expressed in normal oral tissues, particularly in differentiated areas. In vitro experiments demonstrate that overexpression of GPRC5A in OSCC CAL27 cells inhibits anchorage-independent growth, implying a tumor suppressor role for GPRC5A in oral tissues. The role of GPRC5D in MM tumor cells warrants further investigation. Dimension 2 - Skin Health: Oral collagen peptides (CP) are generally considered beneficial for the skin. In vivo studies in mice have shown that oral collagen peptides increase the expression of proteins such as GPRC5D, keratin-associated protein (Krtap), and keratin (Krt) in mouse skin. These proteins play key roles in various aspects of skin health, including barrier function, hair structural integrity, and overall skin health. The relationship between GPRC5D and skin health merits further study. Preclinical Model ValidationBetween 2016 and 2018, companies such as Johnson & Johnson, Daiichi Sankyo, Roche, Chugai, and Juno Therapeutics submitted patents for GPRC5D antibody development or chimeric antigen receptors for oncology research. Preclinical model studies validated the therapeutic potential of targeting GPRC5D. For example, in 2016, Johnson & Johnson submitted a priority patent for bispecific antibodies targeting GPRC5D and CD3 (WO2018017786A2). These multispecific antibodies or antigen-binding fragments may be useful in treating GPRC5D-expressing cancers, particularly B-cell malignancies like multiple myeloma (MM).  Given the difficulty in preparing GPRC5D antigens, Johnson & Johnson opted to use HEK293 cells expressing GPRC5D as the antigen. They utilized their proprietary human Fab library for phage display screening, which included classical cell selection and FACS screening, and identified target antibody sequences using NGS sequencing. After developing the bispecific antibody, they conducted in vitro T-cell-dependent cytotoxicity assessments and in vivo efficacy evaluations. In 2020, Johnson & Johnson published an article in the journal Blood detailing the development process of the bispecific antibody JNJ-64407564 and its preclinical study data in MM models. As demonstrated by the results, the bispecific antibody JNJ-64407564 effectively promoted T-cell-mediated cytotoxicity in various GPRC5D+ cells (MM.1R, OPM-2, H929 cell lines), while there was no effect on the control group, which consisted of GPRC5D- cell lines. JNJ-64407564 kills GPRC5D+ target cells (A), accompanied by T cell activation (B), and stimulates the expression of various cytokines (C)Regarding the GPRC5D x CD3-related antibody discovery, the Johnson & Johnson team has had 8 related patent applications approved and is conducting several clinical studies focused on MM and RRMM. During the same period, Chugai released preclinical data on its bispecific T-cell redirecting antibody targeting GPRC5D/CD3, developed for the treatment of multiple myeloma.  Researchers established xenograft tumor models in NOD-SCID mice using the GPRC5D-expressing NCI-H929 (a human multiple myeloma cell line isolated by the NCI) and KMS-26 (a multiple myeloma cell line derived from a Japanese patient), and inoculated these mice with human T cells. The results showed that a single intravenous dose of 10 mg/kg of the GPRC5D/CD3 bispecific antibody significantly reduced the tumor volume of NCI-H929 and KMS-26 compared to a control antibody at the same dosage.  Researchers extracted total RNA from the tumors to analyze the expression of approximately 594 immune-related genes. Most genes upregulated by the GPRC5D/CD3 bispecific antibody were related to immune activation, such as IFNγ, IFNγ-induced chemokines CXCL9 and CXCL10, and IL2RA expressed on activated T cells. Collectively, these findings suggest that in mouse models, the GPRC5D/CD3 bispecific antibody exhibits potent antitumor activity against GPRC5D-expressing multiple myeloma by activating T cells. Teams, including those at Novartis and Juno Therapeutics, pioneered the CAR (chimeric antigen receptor) strategy to develop cancer therapies targeting GPRC5D. In 2019, the Juno team reported in Science Translational Medicine on the world's first CAR-T cell therapy targeting GPRC5D. Using reporter cell lines capable of providing specific readouts of CAR signaling, researchers identified optimized CAR designs for linker length and reduced antigen-independent signaling, offering preclinical evidence that the CAR-T cell therapy candidate targeting GPRC5D is safe and effective. Owing to this CAR-T product's leading position, Celgene acquired Juno for $9 billion in January 2018. The following year, Bristol-Myers Squibb completed its acquisition of Celgene for $74 billion, making Celgene a wholly-owned subsidiary of BMS. This acquisition strengthened BMS's standing in cancer treatment, particularly in immunotherapy and cell therapy. Through this merger, BMS gained multiple pipeline assets, including Juno Therapeutics, as well as the world's leading GPRC5D CAR-T pipeline. Clinical Safety and Efficacy StudiesIn December 2022, Johnson & Johnson published results in the New England Journal of Medicine from a Phase 1 clinical trial on the safety and efficacy of the T-cell redirecting GPRC5D bispecific antibody Talquetamab for multiple myeloma treatment. Results indicated that 232 patients received Talquetamab (102 intravenously, 130 subcutaneously). With median follow-up periods of 11.7 months for the 405 μg dose group and 4.2 months for the 800 μg dose group, patient response rates were 70% and 64%, respectively. The median response duration was 10.2 months and 7.8 months. In terms of safety, the common adverse events for both subcutaneous dosing regimens (405 μg/kg weekly and 800 μg/kg biweekly) included cytokine release syndrome (noted in 77% and 80% of patients), skin-related events (67% and 70%), and oral ulcers (63% and 57%); apart from one instance of severe cytokine release syndrome, others were grades 1 or 2.  Based on subsequent submission materials to the FDA, Johnson & Johnson's Phase 2 MonumenTAL-1 study included patients who had received at least four prior therapies and were naive to T-cell redirecting therapies (187 patients), showing a significant overall response rate (ORR). At a 0.8 mg/kg SC biweekly dose, 73.6% of patients achieved ORR. After nearly 6 months of follow-up (range: 0 to 9.5 months), 58% achieved very good partial response (VGPR) or better, with 33% achieving complete response (CR) or better. The most common grade 3/4 adverse events were hematological: anemia, neutropenia, lymphopenia, and thrombocytopenia, mostly during the initial treatment cycles. Common non-hematological adverse events included cytokine release syndrome, skin-related events, nail-related events, and taste disorders, with most dermatological adverse events being grades 1/2.  Subsequently, Roche developed the GPRC5D/CD3 bispecific antibody Forimtamig, which has demonstrated similar safety and efficacy profiles. In terms of efficacy, phase 1 clinical results for Forimtamig showed an objective response rate (ORR) of 71% in the intravenous (IV) cohort, with 59% of patients achieving very good partial response (VGPR) or better. The subcutaneous (SC) cohort reported an ORR of 64%, with 53% of patients reaching VGPR or better. The median time to the first response was 1.4 months and 1.6 months in the two cohorts. Regarding safety, dose reduction due to adverse events (AEs) occurred in 6 (12%) and 2 (4%) patients in the IV and SC cohorts, respectively; 3 (6%) and 5 (9%) patients discontinued the drug due to AEs. Cytokine release syndrome (CRS) was a common adverse event, usually low grade and confined to the first cycle, with a median onset time of 5 hours in the IV group and 24 hours in the SC group; most CRS events were resolved (98%). Hematologic adverse events were frequent in both groups. AEs related to non-myeloma cell GPRC5D expression were mostly grade 1/2, including skin-related events, mucosal events, and changes in hair and nails. Compared with bispecific antibody products, several CAR-T products have shown better efficacy, albeit in a limited number of patients. For example, Juno's CAR-T product MCARH109 had a 71% ORR in the overall population (n=17); OriCell’s OriCAR-017 achieved a 100% ORR in the overall population (n=10); BMS's BMS-986393 reported a 100% ORR in its overall efficacy population (N=19). Market Competition Landscape As a representative GPCR target in recent years, GPRC5D is increasingly favored in the treatment of multiple myeloma (MM). To date, various bispecific (BCMA/GPRC5D, CD3/GPRC5D, CD38/GPRC5D) or trispecific products (BCMA/CD3/GPRC5D, BCMA/NKG2D/GPRC5D, BCMA/CD30/GPRC5D), as well as new modalities like CAR-T, CAR-NK, and ADC, have emerged rapidly, supported by advancing technologies. Technological innovation continues to spur advancements in anti-cancer drug development across the industry. With the progress of cancer immunology, GPRC5D has become an important target in cancer immunotherapy due to its advantageous expression profile (low natural expression and high expression in MM tumors). While the potential clinical indications for GPRC5D are currently mainly limited to multiple myeloma, the long-standing unmet clinical needs in the MM space have become a crucial foundation for this target's rising popularity. Talquetamab from Johnson & Johnson, the first and only approved drug in this area, is expected to face competition from multiple entrants over the next 2-5 years, bringing real benefits to patients. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!