Phase II Clinical Trial of Mezigdomide/Carfilzomib/Dexamethasone (MeziKD) in Patients With Relapsed or Refractory Multiple Myeloma (MM) With Extramedullary Disease (EMD)

This phase II trial studies how well mezigdomide/carfilzomib/dexamethasone (MeziKD) works in treating patients with multiple myeloma (MM) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory) and have tumors from myeloma cells outside the bone marrow in the soft tissues or organs of the body (extramedullary disease [EMD]). Mezigdomide blocks important processes in myeloma cells and may lead to modulation of the immune system, including activation of T-lymphocytes, and downregulation of the activity of other proteins, some of which play key roles in the proliferation of certain cancer cell types. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Dexamethasone is a type of corticosteroid and is used to kill myeloma cells. It is used with other drugs to treat multiple myeloma. Giving MeziKD may kill more cancer cells in patients with relapsed/refractory multiple myeloma (RRMM) with EMD.

开始日期2025-02-01

申办/合作机构

Roswell Park Comprehensive Cancer Center

NCT06645678 / Not yet recruiting临床1/2期IIT

Phase I/II Study of Mezigdomide and Elranatamab for Relapsed/refractory Multiple Myeloma Patients

The goal of this clinical trial is to find out how well a combination of two medicines (mezigdomide and elranatamab) works in treating patients with refractory/relapsed multiple myeloma.

开始日期2024-11-11

申办/合作机构

Seoul National University Hospital

NCT06048250 / Recruiting临床1期IIT

A Phase 1 Study of Mezigdomide (CC-92480) and Dexamethasone Post Idecabtagene Vicleucel in Relapsed Multiple Myeloma

This phase I trial studies the safety, side effects, best dose and effectiveness of mezigdomide (CC-92480) when given after idecabtagene vicleucel (Abecma chimeric antigen receptor [CAR] T-cell therapy) in patients with multiple myeloma that has come back after a period of improvement (relapsed). CC-92480 works by binding to a protein called CRBN that triggers the breakdown of proteins: Ikaros and Aiolos, leading to cell death in multiple myeloma cells. Giving mezigdomide after Abecma CAR T cell therapy may extending the amount of time that the CAR T cells persist in the body in patients with relapsed multiple myeloma.

开始日期2024-04-09

申办/合作机构

City of Hope National Medical Center

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100 项与美齐格米特相关的临床结果

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100 项与美齐格米特相关的转化医学

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100 项与美齐格米特相关的专利（医药）

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项与美齐格米特相关的文献（医药）

2024-11-01·Clinical Lymphoma Myeloma & Leukemia

Cereblon E3 Ligase Modulators Mezigdomide and Iberdomide in Multiple Myeloma

Review

作者: van Rhee, Frits ; Patel, Tanvi H ; Al Hadidi, Samer

Multiple Myeloma (MM) remains a challenging hematological malignancy despite significant advancements made during the past 2 decades. Outcomes have improved by incorporating immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies into treatment algorithms that include high dose chemotherapy and autologous hematopoietic stem cell transplantation. However, many patients may eventually relapse despite these innovations. Newer therapies targeting B-Cell Maturation Antigen (BCMA) offer promise for patients with relapsed or refractory disease. BCMA-targeted therapies carry notable side effects, necessitating vigilant monitoring and proactive infection prevention measures. They can also induce considerable immunosuppression, attributed to lower levels of immunoglobulins and increased susceptibility to infections. There is still a need for alternative treatment options with different mechanisms of action that can be easily administered and have a better safety profile. In addition, pomalidomide only overcomes lenalidomide refractoriness in a subset of patients. This review aims to explore 2 next-generation cereblon E3 ligase modulators (CELMoDs), Mezigdomide (CC92480), and Iberdomide (CC-220). We will discuss the biological aspects of these agents, including their mechanisms of action, efficacy, and toxicity profile, and provide a comprehensive review of current literature. Special attention will be paid to ongoing and future clinical trials that provide insights into the potential of these novel therapies in the management of MM.

2024-04-11·Blood

Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML

Article

作者: Perry, Jennifer A. ; Apazidis, Athina A. ; Wenge, Daniela V. ; Bourgeois, Wallace ; Wen, Yanhe ; Pikman, Yana ; Crompton, Brian D. ; Olsen, Sarah Naomi ; Kirmani, Nadia ; Cutler, Jevon A. ; Ebert, Benjamin L. ; Armstrong, Scott A. ; Sperling, Adam S. ; Nowak, Radosław P. ; Klega, Kelly ; Hatton, Charlie ; Martucci, Cynthia ; McGeehan, Gerard M. ; Aubrey, Brandon J. ; Fischer, Eric S. ; Boileau, Meaghan ; Donovan, Katherine A. ; Pollard, Jessica A. ; Perner, Florian ; Henrich, Jill A.

Abstract:

Small molecules that target the menin-KMT2A protein-protein interaction (menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A or MLL1)–rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study, we show that mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to lenalidomide and iberdomide. Further, we demonstrate that mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with menin inhibitors, including in MEN1 mutant models. We show that the superior activity of mezigdomide compared with lenalidomide or iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent mezigdomide was efficacious in 5 patient-derived xenograft models of KMT2A-r and 1 NPM1c AML. The combination of mezigdomide with the menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single agent or in combination with menin inhibitors.

2024-04-01·Hematology/oncology clinics of North America

Cereblon-Targeting Ligase Degraders in Myeloma

Review

作者: Bahlis, Nizar J ; Lee, Holly ; Neri, Paola

Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and mezigdomide, have demonstrated significant anti-myeloma effects. These drugs play a crucial role in diverse therapeutic approaches for multiple myeloma (MM), emphasizing their therapeutic importance across various disease stages. Despite their evident efficacy, approximately 5% to 10% of MM patients exhibit primary resistance to lenalidomide, and resistance commonly develops over time. Understanding the intricate mechanisms of action and resistance to this drug class becomes imperative for refining and advancing novel therapeutic combinations.

项与美齐格米特相关的新闻（医药）

2024-12-09

·Business Wire

Opna Bio Announces Interim Data from Phase 1 Combination Study of OPN-2853 with Ruxolitinib in Patients with Advanced Myelofibrosis

SAN DIEGO--( BUSINESS WIRE )--Opna Bio, a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics, announced interim data from its lead clinical program, OPN-2853, in patients with advanced myelofibrosis showing encouraging levels of spleen reduction, with minimal toxicities and adverse events. Preclinical data from a second program, OPN-6602, showed significant tumor regression in multiple myeloma models as a single agent and in combination with other therapeutics. The presentations took place this weekend at the American Society of Hematology (ASH) annual meeting, December 7-10, 2024, in San Diego. OPN-2853 Shows Spleen Reduction in Patients with Advanced Myelofibrosis OPN-2853, a small molecule bromodomain and extra-terminal motif (BET) inhibitor, is being evaluated in an ongoing Phase 1 investigator-led study in patients with advanced myelofibrosis who are no longer responding to ruxolitinib alone. Myelofibrosis is a type of blood cancer that causes fibrosis in the bone marrow, anemia and enlarged spleen, amongst other symptoms. The study is testing three dose levels of OPN-2853 (20 mg, 40 mg and 80 mg), given orally once daily, in combination with ruxolitinib. As of February 2024, the cut-off date, 16 patients had been enrolled at different dose levels, across multiple sites in the United Kingdom, coordinated by the Cancer Research UK (CRUK) Clinical Trials Unit at the University of Birmingham. In 12 evaluable patients, the median spleen size was reduced from baseline with spleens no longer palpable in 50% of evaluable patients. The combination dose has been well tolerated, and the majority of patients have completed eight cycles of combination treatment. “We are very encouraged by these data to date, which demonstrate that daily dosing of OPN-2853 in combination with ruxolitinib was well tolerated, and showed spleen reduction in patients with myelofibrosis who have very limited options once they have progressed,” said principal investigator Adam Mead, PhD, MRCP, FRCP, professor of hematology at the University of Oxford and CRUK senior cancer research fellow. “We are enthusiastic about the OPN-2853 and ruxolitinib combination and expect to have a recommended Phase 2 dose in early 2025.” Opna Bio is planning further clinical development with OPN-2853. OPN-6602 Combinations Demonstrate Complete Tumor Regression in Preclinical Multiple Myeloma Models OPN-6602, an oral, small molecule inhibitor of the E1A binding protein (EP300) and CREB-binding protein (CBP), is currently being tested in a Phase 1 trial in patients with multiple myeloma (MM) . MM is a type of blood cancer derived from malignant plasma cells in the bone marrow. In MM mouse xenograft models, OPN-6602 showed 71% tumor suppression as a single agent, and 100% tumor regression when combined with dexamethasone, pomalidomide or mezigdomide with a sustained duration of response. RNA sequencing of treated tumors showed that OPN-6602 downregulated key MM driver and signature genes, and has the potential to overcome resistance mechanisms to standard-of-care regimens. “We are very encouraged by the strength of the OPN-2853 clinical and OPN-6602 preclinical data, which highlights the potential of their unique pharmacokinetic profiles and validates our ‘safety by design’ approach. Both drug candidates have a high Cmax and short half-life, which allows for continuous daily dosing and effective target engagement with rapid clearance to mitigate toxicities,” said Gideon Bollag, PhD, co-founder and chief scientific officer of Opna Bio. “This confers a significant advantage to these drugs when used as single agents and a potentially synergistic effect when used in combination with other therapies.” About Opna Bio Opna Bio is a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics. The company’s broad portfolio targets multiple drivers of cancer, including a novel oncology discovery program focused on the fragile-X multifunctional RNA-binding protein (FMRP) and a diversified pipeline of promising oncology assets. The Opna team has a proven track record of scientific expertise and commercial value creation, having advanced multiple FDA-approved drugs to market. Opna’s lead clinical compounds include OPN-2853, a potentially best-in-class BET bromodomain inhibitor, being evaluated in patients with myelofibrosis in combination with ruxolitinib, and OPN-6602, a dual EP300/CBP inhibitor, currently being studied in a first-in-human Phase 1 clinical trial in multiple myeloma patients. For more information, please visit opnabio.com .

临床1期临床结果ASH会议

2024-12-04

·PRNewswire

Stay Ahead in Hematology: Strategic Competitive Intelligence for Informed Decision-Making | DelveInsight

A case study on how a leading pharma company in hematology turned to DelveInsight for long-term competitive intelligence support. DelveInsight provided an in-depth analysis of competitive activity in key hematological malignancies, helping the company stay ahead of the competition. LAS VEGAS, Dec. 4, 2024 /PRNewswire/ -- DelveInsight, a leader in healthcare competitive intelligence and consulting, released a case study on Competitive Intelligence in the Hematology Domain. A Europe-based client approached DelveInsight to evaluate a long-term partnership for insights supporting their clinical, commercial, and launch strategies for a novel oncology product targeting acute myeloid leukemia (AML), multiple myeloma, and acute lymphoblastic leukemia (ALL). The client sought detailed intelligence on competitive activity, class-wise market trends, launch estimates in countries of interest, and regulatory landscapes to inform their development and commercialization plans. An additional request for the segregation of mutation/protein expression-specific therapies was also taken into consideration. DelveInsight provided timely, in-depth analysis of the competitive landscape, emerging therapies, and regulatory situations across multiple countries. This enabled the client to make informed decisions on clinical development, market positioning, and commercialization, helping them stay ahead of the competition in the hematology space. With hundreds of thousands of new cases diagnosed annually, hematologic cancers, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and multiple myeloma, among others present a serious global health challenge while also opening doors for breakthroughs in targeted and personalized treatments. These cancers affect the blood, bone marrow, and lymphatic system, and often require aggressive therapies due to their rapid progression and complex nature. AML and ALL are particularly aggressive, with AML being one of the most common forms of leukemia in adults and ALL affecting both children and adults. Innovations in precision medicine and immunotherapy are transforming hematology, with CAR-T therapies showing promise for leukemias and CELMODs, like Iberdomide, emerging as potential successors to REVLIMID for multiple myeloma. Bristol Myers Squibb's collaboration with Karyopharm on mezigdomide highlights the growing focus on CELMODs. Additionally, FDA-approved therapies like CARVYKTI and TECVAYLI, along with ongoing advancements in bispecific antibodies and proteasome inhibitors, are reshaping the multiple myeloma treatment landscape, despite safety, cost, and manufacturing challenges. The market is rapidly evolving, with new therapies continually entering the pipeline. Several companies, including Bristol Myers Squibb, Celgene, Arcellx, Novartis, Regeneron Pharmaceuticals, Cartesian Therapeutics, Heidelberg Pharma, BeiGene, CARsgen Therapeutics, C4 Therapeutics, AbbVie (TeneoOne), Roche (Genentech), Pfizer, Agios Pharmaceuticals, Jazz Pharmaceuticals, Astellas Pharma, Novartis Oncology, Daiichi Sankyo, AstraZeneca/Astex Pharmaceuticals, Chimerix, Takeda, Rafael Pharmaceuticals Inc., Delta-Fly Pharma, GlycoMimetics Incorporated, BerGenBio ASA, MacroGenics, Syndax Pharmaceuticals, Arog Pharmaceuticals, Forma Therapeutics, Sellas Life Sciences Group, Autolus Therapeutics, Cellectis, Wugen, Servier, Allogene, and Precision BioSciences, are currently advancing the therapeutic landscape for hematological disorders. As research and innovation progress, there is renewed hope for improving survival rates and enhancing the quality of life for those affected by these challenging diagnoses. DelveInsight's Methodology for Competitive Intelligence in the Hematology Domain helped the client by: Comparative Analyses: Evaluating competitor products to identify strengths, weaknesses, and market positioning, enabling the client to understand where their product stands relative to competitors along with identifying the patient segment with high unmet need KOL Insights: Gathering opinions from Key Opinion Leaders (KOLs) on clinical development strategies, client's product acceptability scenarios, data presentation, probable uptake of their asset,, providing valuable perspectives to refine the client's approach. Current Treatment Paradigms: Analyzing existing treatment approaches to identify market trends, gaps, and unmet needs, helping the client position their product effectively in the market. In-depth Competitive Benchmarking: Assessing competitors' commercial launch preparedness, patient awareness campaigns, and pricing strategies to inform the client's product's market entry and competitive strategy. Market Intelligence: Providing insights into competitors' marketing, sales, and patient engagement approaches, guiding the client's commercialization and go-to-market strategies. Clinical Development Trends: Evaluating clinical trial timelines and strategies, tracking phase shifts in terms of probability of their entry into the higher phase, and analyzing trial data to anticipate future market shifts and inform strategic decision-making. Pricing and Access Strategies: Analyzing competitor pricing models and access strategies, allowing the client to make informed decisions on pricing and reimbursement for their product. Request a proposal to see how DelveInsight's Competitive Intelligence services can support your long-term strategic insights. How DelveInsight's In-Depth Competitive Intelligence in Hematology Helped Clients Stay Ahead in the Market Periodic Competitive Inputs: Provided regular updates on competitor activities, keeping the client informed of market shifts. Enhanced Market Awareness: Delivered ongoing insights into competitor strategies, enabling quick adaptation to market changes. Short-Term Strategies: Developed actionable strategies for immediate response to competitor moves. Counter-Messaging Design: Assisted in crafting counter-messaging strategies to address competitor claims and strengthen brand positioning. Positioning Refinement: Helped refine product positioning to gain a competitive advantage. Promotional Strategy Support: Offered recommendations on promotional tactics to boost market presence and attract key audiences. Why Choose DelveInsight? DelveInsight offers tailored, comprehensive competitive intelligence to keep your hematology product developmental and commercial strategy a step ahead. With expertise in AML, Multiple Myeloma, ALL, and other hematology domains, we support your clinical, commercial, and launch strategies with insights that matter. What Sets Us Apart: Timely Intelligence: Consistent, real-time updates on competitor activities, clinical shifts, and regulatory changes, ensuring you're never caught off-guard. Expert Analysis: From comparative assessments to pricing benchmarks, we provide actionable data that sharpens your positioning. Strategic Edge: We don't just offer data—we deliver strategic recommendations for counter-messaging, promotional tactics, and market adaptation. Choosing DelveInsight means partnering with a team dedicated to turning competitive intelligence into growth and success for your business. Transform your business with our case study. Schedule a call with our DelveInsight Business Development expert today! Conference Coverage Services : DelveInsight's Conference Coverage Services offer a thorough analysis of outcomes from major events like ASH, EHA, AACR, ESMO, ASCO, and others. This detailed examination provides businesses with essential insights for competitive intelligence and market trend forecasting, supporting the formulation of future strategies. Competitive Intelligence Services: DelveInsight's competitive intelligence services provide real-time, accurate insights across the pharmaceutical, life sciences, and medical diagnostics sectors, helping clients stay ahead in a dynamic market. With over 100 years of combined experience, our experts deliver actionable strategic insights, backed by robust research methodologies, to support critical business decisions and create a competitive advantage for our clients. Hematology Pipeline Assessment: Our hematology pipeline evaluation offers a comprehensive overview of cancer treatment options, clinical trials, and key areas within the hematological disorders field, all summarized in an accessible report format. The hematology-focused reports, available in our Report Store, provide in-depth insights into treatment strategies, mechanisms of action (MoAs), drug components, and launch plans for therapies in the late stages of development. This assessment enhances understanding of their launch timelines and strategic initiatives. R&D Analysis: Our skilled research and development analyst specializes in the complexities of hematology, offering essential insights and advice to clients aiming to advance in hematological research and development. They utilize a methodical assessment approach, aligned with industry norms, to track the progress of each hematology drug in both pre-clinical and clinical stages. DelveInsight's comprehensive hematological reports are crafted to reduce uncertainties and highlight overlooked areas, providing organizations with timely and strategic intelligence. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法ASH会议

2024-11-18

·医药魔方

Nature：蛋白降解剂迈向下一程

近年来，靶向蛋白质降解剂（TPD）逐渐走进人们的视野，以PROTAC、分子胶为代表的靶向蛋白降解技术已发展为小分子药物的重要模式。从2019年首个PROTAC分子（ARV-110）进入临床开始，层出不穷的蛋白降解剂相继进入临床研究阶段。受益于独特的作用机制，蛋白降解剂不仅能靶向以往难成药的靶点，还为耐药患者提供了可选治疗方案。图1. 蛋白降解剂发展时间线[1] 根据医药魔方NextPharma®数据库，蛋白降解剂早期研发主要围绕AR、ER、BTK等靶点。如今，蛋白降解领域迎来了新的发展阶段，研究人员正将目光投向更多新颖的靶标领域。越来越多的蛋白降解剂管线显示，传统上难以成药的靶标（如IKZF1/3、GSPT1、VAV1、WIZ、BCL6等）正变得越来越容易实现（表1）。这一转变标志着靶向蛋白质降解技术的应用范围正在不断扩大，为药物研发带来了新的机遇和挑战。表1. 靶向蛋白降解领域的靶点[2] 分子胶的新发现科学家通过对来那度胺（FDA批准的多发性骨髓瘤药物）及其相关免疫调节药物（IMiDs）的作用机制进行深入研究，发现了这些药物能够结合并重塑E3泛素连接酶CRBN，进而促进转录因子IKZF1和IKZF3（IKAROS家族锌指转录因子1/3）的泛素化。研究人员进一步认识到，其他分子胶可能也具备重塑CRBN的潜力，从而能够靶向更多蛋白质。尽管如此，早期进入临床的项目仍然集中在来那度胺所降解的靶点上。例如，Celgene（2019年被BMS收购）基于来那度胺类似物发现了CC-92480（又名mezigdomide），并对其进行优化，以降解IKZF1和IKZF3。目前，该药物正处于多发性骨髓瘤的III期临床开发阶段。此外，激酶CK1α作为来那度胺的另一个降解靶点，也成为了早期开发的重点。 GSPT1（G1 to S phase transition 1）是一种翻译终止因子，通过与eRF1结合识别终止密码子，迫使蛋白质在翻译后与核糖体分离。GSPT1的下调可导致多种肿瘤细胞中关键蛋白的异常表达，抑制肿瘤细胞增殖或诱导其凋亡。BMS在2016年首次将GSPT1降解剂CC-90009推进到临床阶段，但后来由于未公开的原因终止了该项目。 GSPT1的降解可能会关闭整体蛋白质翻译，并可能引发许多不良事件。为了提高GSPT1降解的有效性和耐受性，BMS转向了抗体-分子胶偶联物策略。BMS-986497分子将GSPT1降解分子胶和CD33靶向抗体结合，这样能更有效地将降解剂递送到癌细胞。今年7月，诺华在Science杂志发表论文，他们发现了一种基于CRBN的、能够靶向转录因子WIZ的分子胶降解剂。该分子胶可以提高小鼠和灵长类动物体内的胎儿血红蛋白（fetal hemoglobin，HbF）水平。这一发现表明，分子胶有望为开发治疗镰状细胞病（SCD）的新药铺平道路。新靶点，新征程 Monte Rosa是开发靶向GSPT1分子胶的先驱之一，他们研发的MRT-2359临床表现出色，在MYC驱动的实体瘤患者中具有良好的治疗指数和可耐受的安全性。随着其降解平台的建立，Monte Rosa发现了更多的靶点，VAV1就是其中之一。Monte Rosa首席执行官Markus Warmuth表示：“我确信，在过去10-20年里，大型制药公司的每个免疫学团队都曾关注过VAV1这一靶点。” VAV1是一种鸟嘌呤核苷酸交换因子（GEF），与B细胞和T细胞的信号传导密切相关。Monte Rosa研发的VAV1降解剂MRT-6160在自身免疫性疾病动物模型中显示出临床前疗效，效果与标准治疗（JAK抑制剂和S1P调节剂）相当。目前，这种降解剂已进入临床I期试验，并将在自身免疫性疾病中进一步的试验。此外，转录因子IKZF1和IKZF3是经典的CRBN的新底物。研究人员指出，数百种转录因子含有G-loop的C2H2锌指结构（包括IKZF2和WIZ），这为分子胶降解剂提供了更多潜在靶点。然而，像GSPT1和CK1α这样的非转录因子蛋白中的CRBN新底物，也携带G-loop降解结构域，使它们也处于IMiDs的作用范围内。目前，大多数分子胶是偶然发现的。人体内有600多种E3连接酶，但目前的分子胶大多是基于CRBN，所以开发可招募除CRBN外的其他E3连接酶的分子胶，成为理性设计的重要策略。 SEED Therapeutics正在研发一种利用DCAF15连接酶降解剪接因子RBM39（一种调节mRNA前体剪接的蛋白质）的分子胶降解剂，该公司的ST-00937分子能够通过重塑DCAF15来泛素化RBM39，目前处于临床前阶段，预计明年进入临床阶段。除ST-00937外，SEED Therapeutics还有近10款在研药物，它们都不依赖于常用的CRBN和VHL（另一种常用的E3泛素连接酶）。 PROTAC的探索之路异双功能降解剂（heterobifunctional）是一种“哑铃状”分子，具有独特的结构：一端结合目标蛋白（POI），另一端则与E3泛素连接酶相互作用。首批进入临床的蛋白降解剂主要集中在已有上市药物的靶点。然而，Kymera Therapeutics采取了不同的策略，专注于开发哪些尚未有上市药物的靶点。Kymera Therapeutics的首个进入临床的PROTAC项目靶向IRAK4，这是一个在调节IL-1受体和Toll样受体（TLR）信号通路方面具有重要的作用的蛋白。由于IRAK4的活性既包括酶活性，也包括作为骨架蛋白的功能，因此蛋白降解剂可能比酶活性抑制剂具有更好的效果。Kymera Therapeutics的潜在first-in-class蛋白降解剂KT-474目前处于IIb期试验中，它是首个进入非肿瘤学适应症领域中，进入临床开发阶段的PROTAC分子。 Kymera Therapeutics的下一个临床候选药物KT-621是一种靶向STAT6的PROTAC分子，能够用于特应性皮炎（AD）、哮喘以及慢性阻塞性肺病等疾病。今年10月，Kymera宣布其KT-621的IND已获FDA批准，预计将在不久后在健康志愿者中开展I期试验。 BCL6是一种转录抑制因子，它通过BCL6的BTB结构域招募辅助抑制因子，调节B淋巴细胞的分化，并在生发中心（GCs）的形成中发挥作用。由于BCL6在转录抑制因子复合体中的不受调控的表达和支架作用，使其成为一个理想的PROTAC靶点。 Arvinas公司研发的ARV-393是一种靶向BCL6蛋白的PROTAC药物，目前正在进行临床I期研究。初步研究显示，ARV-393在体内外均能显著降解BCL6，并在多种肿瘤异种移植模型中表现出良好的肿瘤生长抑制（TGI）效果。BMS-986458是由BMS研发的一种BCL6降解剂，目前也处于临床I期，用于治疗非霍奇金淋巴瘤。结语从最初偶然发现的沙利度胺，到如今几百条蛋白降解剂管线；从开发已有上市药物的成熟靶点，到探索新一代靶点；从肿瘤领域，到神经退行性疾病、自身免疫性疾病、炎症性疾病等领域……蛋白降解的应用正被不断拓宽，随着更多新靶点的探索和新药物的开发，蛋白降解技术有望在未来实现更多的突破和创新。参考资料： [1]Brandon Dale et al. Advancing targeted protein degradation for cancer therapy. Nature Reviews Cancer（2021） https://www.nature.com/articles/s41568-021-00365-x [2]Asher Mullard. Protein degraders push into novel target space. Nature Reviews Drug Discovery（2024） https://www.nature.com/articles/d41573-024-00170-9 Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

蛋白降解靶向嵌合体临床3期并购临床结果

100 项与美齐格米特相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
多发性骨髓瘤	临床3期	比利时	Bristol Myers Squibb Co.	2022-09-20
多发性骨髓瘤	临床3期	捷克	Bristol Myers Squibb Co.	2022-09-20
多发性骨髓瘤	临床3期	芬兰	Bristol Myers Squibb Co.	2022-09-20
多发性骨髓瘤	临床3期	法国	Bristol Myers Squibb Co.	2022-09-20
多发性骨髓瘤	临床3期	爱尔兰	Bristol Myers Squibb Co.	2022-09-20
多发性骨髓瘤	临床3期	波兰	Bristol Myers Squibb Co.	2022-09-20
多发性骨髓瘤	临床3期	葡萄牙	Bristol Myers Squibb Co.	2022-09-20
多发性骨髓瘤	临床3期	土耳其	Bristol Myers Squibb Co.	2022-09-20
难治性多发性骨髓瘤	临床3期	比利时	Celgene Corp.	2022-09-20
难治性多发性骨髓瘤	临床3期	智利	Celgene Corp.	2022-09-20

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASH2024	N/A	难治性多发性骨髓瘤	-	MeziVd	範鬱艱蓋獵鏇鏇膚窪觸(蓋廠糧鑰鬱壓鹹艱衊蓋) = The most common grade 3/4 TEAEs were neutropenia (35.7%), thrombocytopenia (21.4%), and infections (17.9%) with MeziVd; and neutropenia (44.4%) and infections (33.3%) with MeziKd 簾壓餘築窪淵蓋鏇鏇觸 (遞選遞願鹽積鹽糧築觸 ) 更多	-	2024-12-09
				MeziKd
SOHO2024	N/A	多发性骨髓瘤	-	Mezigdomide (MEZI) + Dexamethasone (DEX) + Bortezomib (BORT)	糧淵夢鹽壓觸鏇醖膚簾(憲憲衊網繭顧獵觸製夢) = 網鬱襯壓製遞餘衊願齋願齋願構餘顧憲鹹簾糧 (蓋襯網壓鑰鏇選鑰淵簾 ) 更多	-	2024-09-04
				Mezigdomide (MEZI) + Dexamethasone (DEX) + Carfilzomib (CFZ)	糧淵夢鹽壓觸鏇醖膚簾(憲憲衊網繭顧獵觸製夢) = 蓋艱夢鑰鑰鏇廠夢構遞願齋願構餘顧憲鹹簾糧 (蓋襯網壓鑰鏇選鑰淵簾 ) 更多
NCT03374085 (CC-92480-MM-001, ASCO2024) 人工标引	临床1/2期	复发性多发性骨髓瘤 \| 肾功能不全 \| 难治性多发性骨髓瘤	101	mezigdomide + dexamethasone	襯廠網構蓋選夢艱窪願(鏇醖觸夢醖艱獵簾醖繭) = 襯獵壓遞鹽膚壓顧觸鬱範齋選範餘觸廠鹹繭獵 (鏇網夢鏇選膚鏇範範顧 ) 更多	积极	2024-05-24
				mezigdomide + dexamethasone (No RI)	襯廠網構蓋選夢艱窪願(鏇醖觸夢醖艱獵簾醖繭) = 壓願鹽夢襯範簾鏇願網範齋選範餘觸廠鹹繭獵 (鏇網夢鏇選膚鏇範範顧 ) 更多
NCT05372354 (CA057-003, EHA2024) 人工标引	临床1/2期	多发性骨髓瘤 PRC2 Loss of Function Mutation \| EZH2 Overexpression	10	MEZI+TAZ+DEX 0.3mg	範壓糧鏇鑰鹽繭築糧鹹(製範選築糧鹹鹹顧製襯) = 繭顧壓夢鏇鏇衊願製醖築鏇餘網餘繭繭衊鏇願 (選憲鬱簾鏇製願繭廠鹽 ) 更多	积极	2024-05-14
ASH2023	N/A	-	-	Mezigdomide	鬱膚簾積積襯築淵壓艱(顧選窪淵醖製範獵憲鬱) = 98% reduction 窪顧觸範襯蓋繭齋簾醖 (築鑰壓遞築糧餘餘築糧 ) 更多	-	2023-12-09
				DMSO controls
NCT03803644 \| NCT04211545 (Pubmed \| CPT Pharmacometrics Syst Pharmacol)	临床1期	-	64	Mezigdomide	願觸窪齋積壓糧夢壓衊(齋艱襯糧範膚鑰餘壓鬱) = 壓網選艱淵願蓋艱觸醖鑰膚鹹蓋繭鹹構構窪憲 (鑰獵構齋構選遞築淵鑰 ) 更多	积极	2023-10-01
IMS2023	N/A	难治性多发性骨髓瘤	17	Mezigdomide (MEZI)	構繭鏇構構鏇鬱壓選範(糧選積衊觸獵簾願顧築) = 襯製遞齋艱餘觸積鑰願窪鏇積顧簾衊艱艱選積 (鏇襯鬱網顧製膚齋淵醖 )	-	2023-09-26
NCT03989414 (CC-92480-MM-002, IMS2023)	临床1/2期	复发性多发性骨髓瘤	-	MeziVd	襯顧選鑰願網網淵衊積(製築醖觸製顧襯鹽衊網) = 鹽積膚觸遞獵廠淵餘鏇鹹簾網艱淵鹹廠簾鏇壓 (築糧製觸醖選範窪選蓋 ) 更多	-	2023-09-26
				MeziVd-1.0mg	襯顧選鑰願網網淵衊積(製築醖觸製顧襯鹽衊網) = 構夢淵網餘淵構獵鹹膚鹹簾網艱淵鹹廠簾鏇壓 (築糧製觸醖選範窪選蓋 ) 更多
NCT03374085 (CC-92480-MM-001, Pubmed)	临床1/2期	多发性骨髓瘤	101	Mezigdomide plus Dexamethasone	窪製積願襯壓鹹積鏇襯(願網糧鏇觸艱顧範鬱網) = 醖蓋觸蓋製觸繭蓋網廠鏇鏇鹹願艱餘簾蓋艱餘 (鏇壓廠願鑰網窪簾選衊, 31 ~ 51) 更多	积极	2023-09-14
SOHO2023	N/A	多发性骨髓瘤	-	MEZI 1 mg + DEX 40 mg	鑰觸範醖夢觸築觸衊獵(艱糧憲構築鏇構願範蓋) = Ninety-two (91.1%) patients experienced grade 3–4 treatment-emergent adverse events (TEAEs). Most frequent hematologic grade 3–4 TEAEs were neutropenia (75.2%), anemia (35.6%), and thrombocytopenia (27.7%). Grade 3–4 infections occurred in 34.7% of patients; other grade 3–4 non-hematologic TEAEs were low. Due to TEAEs, 76 (75.2%) and 29 (28.7%) patients had MEZI dose interruptions and reductions, respectively. 夢窪願鏇憲廠淵繭遞鬱 (鏇網憲鬱齋遞願鏇襯窪 )	-	2023-09-01