A Phase 2, Randomized, Double-Blind, Placebo- and Active-Comparator-Controlled Clinical Study of V940 (mRNA-4157) Plus Pembrolizumab Versus Placebo Plus Pembrolizumab in Participants With First-Line Advanced Melanoma (INTerpath-012)

Researchers want to learn if V940 with pembrolizumab can stop advanced melanoma from growing or spreading. Melanoma is a type of skin cancer. Advanced means the cancer has spread to other parts of the body and cannot be removed with surgery. A standard (or usual) treatment for advanced melanoma is immunotherapy. Immunotherapy is a treatment that helps the immune system fight cancer. V940 is a study treatment designed to help a person's immune system attack their specific cancer. Pembrolizumab is an immunotherapy.
The goal of this study is to learn if people who receive V940 with pembrolizumab live longer without the cancer growing or spreading than people who receive placebo with pembrolizumab. A placebo looks like the study treatment but has no study treatment in it. Using a placebo helps researchers better understand the effects of a study treatment.

开始日期2025-06-10

申办/合作机构

Merck Sharp & Dohme LLC

NCT06833073

/ Recruiting临床2期

A Phase 2 Open-label Randomized Study of V940 in Combination With BCG Versus BCG Monotherapy in Participants With High-risk Non-muscle Invasive Bladder Cancer (INTerpath-011)

Researchers are looking for new ways to treat people with high-risk non-muscle invasive bladder cancer (HR NMIBC). NMIBC is cancer in the tissue that lines the inside of the bladder but has not spread to the bladder muscle or outside of the bladder. High-risk means NMIBC may have a high chance of getting worse or coming back after treatment. HR NMIBC can also include carcinoma in situ (CIS). CIS is bladder cancer that appears flat and is only in the inner layer (surface) of the bladder. CIS is not raised and is not growing toward the center of the bladder.
The standard treatment for HR NMIBC is a procedure to remove the tumor called transurethral resection of the bladder tumor (TURBT) followed by Bacillus Calmette-Guerin (BCG). Standard treatment is something that is considered the first line of treatment for a condition. BCG is an immunotherapy, which is a treatment that helps the immune system fight cancer. However, BCG may not work to treat HR NMIBC in some people. Researchers want to learn if adding V940, the study treatment, to standard treatment can help treat HR NMIBC. V940 is designed to help a person's immune system attack their specific cancer.
The goals of this study are to learn:
* If people who receive V940 with BCG live longer without the cancer growing, spreading, or coming back, or dying from any cause, compared to people who receive BCG alone
* If more people who receive V940 with BCG have their cancer go away (complete response), compared to people who receive BCG alone
* How many people who receive V940 without BCG have their cancer go away

开始日期2025-03-11

申办/合作机构

Merck Sharp & Dohme LLC

[+1]

NCT06623422

/ Recruiting临床3期

A Phase 3 Randomized Double-blind Study of Adjuvant Pembrolizumab With or Without V940 in Participants With Resectable Stage II to IIIB (N2) NSCLC Not Achieving pCR After Receiving Neoadjuvant Pembrolizumab With Platinum-based Doublet Chemotherapy (INTerpath-009)

The goal of this study is to learn if people who receive V940 and pembrolizumab after surgery are cancer-free longer than people who receive placebo and pembrolizumab. Researchers want to know if giving V940 and pembrolizumab after surgery can help prevent the cancer from coming back in people with non-small cell lung cancer (NSCLC) whose tumors did not respond completely to treatment before surgery (neoadjuvant treatment).

开始日期2024-10-21

申办/合作机构

Merck Sharp & Dohme LLC

[+1]

100 项与 Intismeran Autogene 相关的临床结果

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100 项与 Intismeran Autogene 相关的专利（医药）

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项与 Intismeran Autogene 相关的文献（医药）

2024-11-01·Cancer Discovery

T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study

Article

作者: Coder, Brandon ; Sun, Jing ; Chen, Xing ; Morrissey, Manju ; Weber, Jeffrey S. ; Gainor, Justin F. ; Hou, Peijie ; Feldman, Igor ; Aanur, Praveen ; Bauman, Julie E. ; Gerbereux, Lauren ; Clarke, Jeffrey M. ; Scott, Aaron J. ; Sehgal, Vasudha ; Daghestani, Hikmat N. ; Meehan, Robert ; Tasneem, Moomal ; Julian, Ricklie ; Kirtane, Kedar ; Srinivasan, Lakshmi ; Porichis, Filippos ; Pollard, Jack Russella ; Gutierrez, Martin ; Zheng, Wei ; Frederick, Joshua P. ; Burris, Howard A. ; Robert-Tissot, Celine ; Brown, Michelle ; Patel, Manish R. ; Geiger, Jessica L. ; Laino, Andressa

Abstract:

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non–small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology.Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors.See related commentary by Berraondo et al., p. 2021

2024-02-01·Lancet (London, England)1区 · 医学

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study

1区 · 医学

Article

作者: Robert-Tissot, Celine ; Hou, Peijie ; Brown, Michelle ; Kim, Kevin B ; Ansstas, George ; Luke, Jason J ; Morrissey, Manju ; Shaheen, Montaser ; Feldman, Igor ; Sullivan, Ryan J ; Weber, Jeffrey S ; Cowey, C Lance ; Faries, Mark ; Carlino, Matteo S ; McKean, Meredith ; Taylor, Matthew H ; Sehgal, Vasudha ; Atkinson, Victoria ; Aanur, Praveen ; Meniawy, Tarek ; Tran, Thuy T ; Medina, Theresa ; Zaks, Tal ; Buchbinder, Elizabeth I ; Khattak, Adnan ; Gibney, Geoffrey T ; Segar, Jennifer ; Healy, Jane A ; Long, Georgina V ; Meehan, Robert S ; Pecora, Andrew ; Huang, Mo ; Zhu, Lili ; Thomas, Sajeve

BACKGROUND:

Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.

METHODS:

We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.

FINDINGS:

From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.

INTERPRETATION:

Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.

FUNDING:

Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

2024-01-01·ONCOLOGY RESEARCH

mRNA vaccines: a new era in vaccine development

Review

作者: WILSON, JENNIFER C. ; GOOD, DAVID ; Good, David ; Wei, Ming Q ; CHANDRA, SHUBHRA ; WEI, MING Q. ; Wilson, Jennifer C ; Chandra, Shubhra

The advent of RNA therapy, particularly through the development of mRNA cancer vaccines, has ushered in a new era in the field of oncology. This article provides a concise overview of the key principles, recent advancements, and potential implications of mRNA cancer vaccines as a groundbreaking modality in cancer treatment. mRNA cancer vaccines represent a revolutionary approach to combatting cancer by leveraging the body's innate immune system. These vaccines are designed to deliver specific mRNA sequences encoding cancer-associated antigens, prompting the immune system to recognize and mount a targeted response against malignant cells. This personalized and adaptive nature of mRNA vaccines holds immense potential for addressing the heterogeneity of cancer and tailoring treatments to individual patients. Recent breakthroughs in the development of mRNA vaccines, exemplified by the success of COVID-19 vaccines, have accelerated their application in oncology. The mRNA platform's versatility allows for the rapid adaptation of vaccine candidates to various cancer types, presenting an agile and promising avenue for therapeutic intervention. Clinical trials of mRNA cancer vaccines have demonstrated encouraging results in terms of safety, immunogenicity, and efficacy. Pioneering candidates, such as BioNTech's BNT111 and Moderna's mRNA-4157, have exhibited promising outcomes in targeting melanoma and solid tumors, respectively. These successes underscore the potential of mRNA vaccines to elicit robust and durable anti-cancer immune responses. While the field holds great promise, challenges such as manufacturing complexities and cost considerations need to be addressed for widespread adoption. The development of scalable and cost-effective manufacturing processes, along with ongoing clinical research, will be pivotal in realizing the full potential of mRNA cancer vaccines. Overall, mRNA cancer vaccines represent a cutting-edge therapeutic approach that holds the promise of transforming cancer treatment. As research progresses, addressing challenges and refining manufacturing processes will be crucial in advancing these vaccines from clinical trials to mainstream oncology practice, offering new hope for patients in the fight against cancer.

413

项与 Intismeran Autogene 相关的新闻（医药）

2025-05-09

·小药说药

未来的黄金宝藏：RNA疗法

1前言在过去的几十年中，人们越来越多地将关注点集中在基于新科学发现的创新治疗策略。人类基因组计划（HGP）揭示了人类基因组的大量信息，而下一代测序技术的进步，使研究人员能够揭示一些遗传因素在许多疾病中的作用，如癌症、类风湿性关节炎、帕金森病和阿尔茨海默病。目前，基于RNA的治疗方法得到快速发展，许多研究的成果已经揭示了编码和非编码RNA（ncRNAs）的重要作用，如miRNA、长ncRNAs（lncRNA）、circRNA和siRNAs。这为通过将核酸引入细胞以永久或瞬时控制改变基因的表达来开发各种疾病的可能治疗方法奠定了基础。此外，通过各种递送系统的开发可以将RNA运送到目标位点，解决了RNA固有的不稳定性带来的问题。因此，许多涉及siRNA、ASO、核酶、mRNA、适配体和CRISPR/Cas的基于RNA的疗法已经开发出来，并正在各种疾病中进行临床试验。基于RNA的药物展现出卓越的应用潜力，属于RNA疗法的时代即将到来。2mRNA以mRNA为基础的治疗代表了一个相对新颖和高效的药物类别。最近发表的几项研究强调了mRNA疫苗在治疗不同类型的恶性肿瘤和传染病方面的潜在疗效，这些疾病中传统的疫苗策略不能引起保护性免疫反应。传染病疫苗是目前mRNA疗法中最领先的应用。Moderma和辉瑞的新冠疫苗已经在数十亿人群中证明了安全性和有效性，展现出未来强大的应用前景。目前，针对肿瘤的mRNA疫苗有2种方式：i）使用体外负载或电穿孔的DC，ii）通过直接注射带有或不带有载体的mRNA。在癌症患者中应用了几项基于DC的mRNA疫苗的临床试验，用编码黑色素瘤相关抗原的mRNA与TriMix联合接种导致晚期黑色素瘤令人印象深刻的肿瘤消退。相比之下，直接注射裸mRNA或复合mRNA被认为是一种快速有效的可行方法。例如，一项I/II期试验在30例转移性肾细胞癌患者皮内反复应用编码6种不同TAA（MUC1、CEA、Her2/neu、telomerase、survivin、MAGE-A1）的mRNA疫苗。10年后的长期结果表明，mRNA疫苗是安全有效的。它延缓了肿瘤生长并提高了生存率，这与检测到的针对TAAs的免疫反应密切相关。CV9202是一种基于RNA的活性疫苗，编码6种NSCLC TAA（NY-ESO-1、MAGE-C1、MAGE-C2、5T4、survivin和MUC-1）。与基线相比，大多数患者的抗原特异性细胞免疫和体液免疫增强。一名接受疫苗、放疗和化疗的患者出现部分缓解（PR），46.2%的患者获得SD。mRNA-4157疫苗是美国Moderna公司研发的一款mRNA疫苗，它是一种针对每位肿瘤患者量身定制的个体化肿瘤疫苗，目前mRNA-4157癌症疫苗能够容纳高达34个编码新抗原的mRNA序列。在mRNA-4157联合Keytruda的I期临床试验中，证明了疫苗的有效性、安全性和耐受性。3miRNAmiRNA是一类短的非编码RNA，其特征是长度为20-22nt，在转录后水平上调节基因表达。它们的作用机制是通过诱导形成RNA沉默复合物，靶向特定mRNA以阻止其翻译和/或诱导其降解。与siRNA和其他非编码RNA不同的是，它们是天然的，能够自然地被加工并发挥作用。根据互补程度，miRNA可以诱导mRNA降解（完全匹配）或翻译抑制（不完全匹配）。此外，它们的活性不只限于单个mRNA，而是通常靶向多个mRNA，这放大了miRNA功能效应。miRNA的治疗潜力基于多种病理生物过程的参与，如心血管疾病、病毒感染、代谢疾病、糖尿病、应激相关疾病和癌症。目前，一些基于miRNA的方法正在进行治疗不同疾病的临床试验。例如，cobomarsen靶向miR-155治疗血癌，remlarsen在瘢痕治疗中模拟miR-29，而MRG110是是用于组织修复的miR-92的拮抗剂。4siRNAsiRNA是由核糖核酸酶Dicer通过内切过程产生的，这是一种属于RNase III家族的内切酶，可以产生21-25核苷酸双链RNA。一旦产生，Dicer将siRNA转移到RNA诱导沉默复合物（RISC），该复合物包含降解靶mRNA分子的Argonaute 2。由于siRNA的这种能力，它们被作为一种可能的治疗方法。SiRNA疗法正在多种癌症治疗中进行测试。siG12D-LODER是一种可生物降解的聚合物基质，含有针对KRASG12D的siRNA，临床研究（NCT01188785）表明，该聚合物能够靶向肿瘤并抑制肿瘤进展。目前，正在进行进一步的研究（NCT01676259），以测试siG12D-LODER与化疗药物（如吉西他滨和nab紫杉醇）联合治疗局部晚期胰腺癌患者的疗效。蛋白激酶N3（PKN3）是磷酸肌醇-3-激酶（PI3K）途径的下游效应器，阻断PKN3可以抑制肿瘤进展和淋巴结转移。Atu027，一种脂质体PKN3 siRNA制剂，在晚期实体瘤患者中安全性良好，在治疗结束时，41%的受试者病情稳定。在随后的研究中，Atu027和吉西他滨联合治疗局部晚期或转移性胰腺癌显示出良好的安全性和耐受性。除了癌症领域，SiRNA在其它疾病领域的应用也在积极开发。Inclisiran，是一种硫代磷酸酯、2′-O-甲基核苷酸和2′-氟核苷酸修饰的siRNA，靶向PCSK9，皮下注射已证明可降低高心血管风险患者的PCSK9水平和LDL胆固醇水平。并且仅半年注射一次，显示出极佳的患者依从性。2020年12月11日，Inclisiran获欧盟批准上市。此外，包括常染色体隐性遗传原发性高草酸尿症（PHs）、乙型肝炎病毒（HBV）和肝脏和特发性肺纤维化中，SiRNA疗法均展现出良好的应用前景。5ASOs反义寡核苷酸（ASO）是一类18-30个碱基对的短单链RNA或DNA寡核苷酸，它们可以由细胞自然产生或人工合成，具有通过碱基互补靶向mRNA的能力。它们可以通过诱导mRNA降解或改变mRNA加工、阻断mRNA翻译、防止核糖体附着来发挥作用。目前，临床试验中有几种ASO正在测试，特别是靶向导致多种疾病的mRNA。Leber先天性黑矇（LCA）由于包括中心体蛋白290（CEP290）在内的各种基因的内含子突变，导致视网膜营养不良，引起青少年失明或严重视力损害。QR-110是一种单链、硫代磷酸化、2′O-甲基修饰的剪接调节RNA寡核苷酸，用于靶向CEP290。临床研究（NCT03140969和NCT03913143）显示，玻璃体内注射QR-110可以重建LCA患者成纤维细胞中的CEP290水平，并具有良好的耐受性和安全性。此外，Eteplirsen结合肌营养不良蛋白前mRNA，通过屏蔽外显子51，恢复肌营养不良转录物的正确阅读框。6IncRNAslncRNAs（长非编码RNA）是长度超过200 nt的非编码RNA。它们的特征是没有开放阅读框，但具有mRNA样结构，经过剪接，具有polyA尾巴与启动子结构，分化过程中有动态的表达与不同的剪接方式。lncRNAs发挥功能主要依靠其二级结构，与蛋白质结合，可引起染色质重构、影响转录因子功能等。另外，还可以在其线性水平与miRNA结合，间接影响mRNA表达，也可以直接与mRNA结合，影响mRNA翻译、剪切、降解过程。基于其多样化的作用，IncRNA被认为是可用于治疗的有效靶点。目前，关于lncRNAs的应用主要是调节其表达，以获得致癌lncRNAs敲低，或肿瘤抑制lncRNA过表达。此外，通过lncRNAs靶向特异性mRNA的一种方法是SINEUPs，SINEUPs是一种新的反义lncRNAs，可以增加特异性mRNA的翻译。这类分子具有两个主要结构域：一个是SINE原件，它是增加翻译活性的效应域；另一个是AS域，其能够通过碱基配对靶向特定mRNA。7circRNA环状RNA（CircRNA）是通过生物发生机制获得的非编码RNA，以反向剪接事件为特征。它们是封闭的单链转录物，由于其环状结构，相对于线性RNA具有更大的稳定性。因此，它们的半衰期可能更长，并且可能用于治疗目的。目前，circRNA的最新应用涉及一种Sars-CoV2疫苗，这种RNA疫苗具有增强的效力和翻译能力，并且在裸的和包封形式下更稳定。这种方法可以诱导有效的体液和细胞免疫，并诱导一定比例的中和抗体，这些抗体相对于N1-甲基假尿嘧啶（1mΨ）修饰的mRNA疫苗具有更持久的抗原产生。8核酶核酶是以催化活性为特征的RNA分子，它们能够切割靶RNA，从而影响基因表达。重要的是，核酶可以在没有细胞蛋白的情况下发挥作用。这类分子具有两个结构域：一个是通过碱基互补识别靶RNA区域的序列，另一个是催化结构域。核酶的治疗潜力在于它们选择性地识别特定RNA并将其切割的能力，使其可作为RNA药物用于治疗。RPI.4610（Angiozyme）是一种化学稳定的抗VEGFR-1核酶，与卡铂和紫杉醇联合用于晚期实体瘤患者，已证明具有良好的安全性、生物利用度和肿瘤定位能力。然而，它未能在转移性乳腺癌患者中证明临床疗效。OZ1是tat-vpr特异性抗HIV核酶，通过自体CD34+细胞递送，在临床试验（NCT00074997）中显示CD4+淋巴细胞显著增加，表明细胞递送的基因转移在维持核酶的安全性和活性方面同样可靠。9CRISPR/CAS9CRISPR- Cas9系统是一种细菌防御机制，利用引导RNA（gRNA）介导DNA内切酶Cas9在靶DNA中引入位点特异性断裂。这种DNA编辑能力使得CRISPR-Cas9通过合成sgRNA在基因组修饰中用作RNA治疗剂，用于生物和治疗应用。许多研究表明CRISPR/Cas9可用于治疗遗传性疾病，如囊性纤维化（CF）、杜氏肌营养不良症（DMD）、血红蛋白病以及HIV和β-地中海贫血。在一项研究中，CRISPR/Cas9能够增加肌管中的utrophin数量并去除重复的DMD外显子18–30，从而在DMD中产生全长dystrophin。此外，CRISPR-Cas9的类似应用也已在艾滋病等免疫疾病中得到证实。然而，尽管这些研究为未来的CRISPR-Cas9临床试验提供了基础，但在CRISPR/Cas9进一步应用于临床试验和随后的治疗之前，仍有一些挑战有待解决。包括向靶细胞递送基因编辑工具可能的靶外效应。此外，在将CRISPR-Cas9转化为治疗应用之前，还需要考虑CRISPR-Cas9的伦理问题和种系应用。10适配体RNA适配体是一类人工结构化序列，可与不同类别的分子特异性结合，可用于治疗，也可作为诊断工具。它们可以影响基因表达，也可以针对特定配体特异性设计适配体，用作RNA抗体。目前，多种适配体已进入各种疾病的临床试验，如黄斑变性、糖尿病性黄斑水肿和慢性炎症性疾病。EYE001是VEGF的聚乙二醇化适配体，在体外模型中显示出完全减少VEGF介导的血管渗漏、抑制视网膜新生血管的能力，从而改善视力。在CNV-AMD患者中进行的EYE001单用或联合光动力疗法的研究中显示出明显的视力稳定或改善。除了VEGF外，补体途径在AMD中也起着重要作用。Zimura，一种聚乙二醇化的单链核酸适配体靶向补体因子C5以及pegcetacoplan靶向C3和C3b，它们的临床研究表明，皮下注射能够减少继发于AMD的地图样萎缩（GA），而不会发生不良事件。此外，ARC1779是一种靶向vWF A1结构域的适配体，在临床试验（NCT00632242）中，ARC1779显示出良好的耐受性以及抑制血栓性血小板减少性紫癜患者vWF依赖性血小板功能的能力。Emapticap-pegol（NOX-E36）是一种靶向CCL2的适配体，在伴有蛋白尿的2型糖尿病患者中，皮下注射Emapticap显示出良好的耐受性和抑制CCL2/CCL2受体轴的能力。小结近年来，以RNA为基础的疗法逐渐成为各种疾病的潜在干预策略。一般来说，RNA疗法根据其作用方式和使用的分子分为不同的类别。许多RNA疗法已被开发用于各种疾病，并且在许多临床前和临床研究中获得非常有希望的结果，尤其是mRNA疫苗成为目前最火热的研究领域之一。目前，基于RNA的疗法依然存在许多障碍，包括递送系统在内的许多方面仍需要得到进一步的研究和开发，然而不可否认，未来十年属于RNA治疗的时代终将到来。参考文献：1.RNA Therapeutics - Researchand Clinical Advancements. Front Mol Biosci. 2021; 8: 710738.2. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat RevDrugDiscov. 2021 Aug 25 : 1–22.3. Clinical and immunological effects of mRNA vaccines inmalignant diseases. Mol Cancer. 2021 Mar 15;20(1):52.4. Next RNA Therapeutics: The Mine of Non-Coding. Int J Mol Sci.2022 Jul; 23(13): 7471.公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。

信使RNA疫苗siRNA临床结果核酸药物

2025-05-02

·生物制品圈

Moderna 联合疫苗遇阻：研发调整与市场考量下的艰难前行

在疫苗研发领域，Moderna 公司一直备受瞩目。然而，近期该公司的流感/新冠联合疫苗 mRNA - 1083 却遭遇诸多挑战，不仅研发优先级被调整，审批进程也出现延迟。这一系列变化背后，反映出公司在成本控制、市场需求以及监管要求之间的艰难权衡。联合疫苗研发计划重大调整Moderna 公司在削减运营成本的大背景下，对流感 / 新冠联合疫苗 mRNA - 1083 的研发策略做出了重大调整。这家总部位于马萨诸塞州的生物技术公司，原本计划在今年为 50 岁及以上成年人申请该疫苗的 FDA 批准，并于 2027 年将适用范围扩大到更年轻的成年人。但在周四公布的第一季度财报中，这两个目标均被取消。Moderna 决定降低针对 18 至 49 岁人群的 mRNA - 1083 研发优先级。这一决策并非偶然。从疫苗接种率数据来看，18 至 49 岁人群对单独的新冠和流感疫苗的接种意愿较低。截至上个月，美国疾病控制与预防中心（CDC）的数据显示，在 2024 - 2025 季节，该年龄段人群中仅 36.2% 接种了流感疫苗，而 50 至 64 岁人群的接种率为 48.9%，老年人的接种率更是高达 72.0% ；新冠疫苗方面，18 至 49 岁人群的接种率约为 14%，65 岁及以上人群则达到 44.2% 。较低的接种率意味着该年龄段市场潜力相对有限，这可能是 Moderna 做出调整的重要原因之一。FDA 审批延迟，上市时间推迟除了研发优先级调整，mRNA - 1083 在审批环节也遇到了阻碍。Moderna 去年向 FDA 提交了 mRNA - 1083 的审批申请，原本期望能顺利获批。但 FDA 要求提供 3 期疗效数据，而不是仅依据免疫原性数据就批准疫苗。这一要求使得疫苗的审批时间大幅推迟，预计要到 2026 年才能获批。此前，Moderna 总裁斯蒂芬・霍格（Stephen Hoge）曾对联合疫苗的前景充满信心，他在 3 月的一次活动中提到，Moderna 的市场研究表明，约三分之二的人可能更倾向于联合疫苗。然而，如今审批的延迟无疑给这款疫苗的推广蒙上了一层阴影。成本削减与研发投入变化Moderna 此次对 mRNA - 1083 的调整，与公司削减运营成本的计划紧密相关。公司在第一季度财报中明确表示，希望到 2027 年将运营成本降低多达 17 亿美元。这一目标的实现，在研发方面体现得尤为明显。第一季度，Moderna 的研发成本下降了 19%，降至 8.56 亿美元。公司表示，这主要是由于呼吸道项目的临床开发成本因试验活动的时间安排和项目收尾而降低。虽然在呼吸道项目上的投入减少，但公司在个性化新抗原疗法 mRNA - 4157 和诺如病毒项目上增加了投资。值得一提的是，FDA 已解除对诺如病毒项目的搁置，此前该项目因一起吉兰 - 巴雷综合征病例而被搁置，3 期试验结果的公布时间将取决于病例的积累情况。Moderna 的流感 / 新冠联合疫苗 mRNA - 1083 所面临的困境，是众多疫苗研发企业可能面临问题的一个缩影。在研发过程中，企业不仅要考虑市场需求和成本控制，还要应对监管部门不断变化的要求。未来，mRNA - 1083 能否成功上市，以及 Moderna 在削减成本的同时如何平衡其他研发项目的推进，都将成为行业关注的焦点。参考来源：https://www.fiercebiotech.com/biotech/modernas-flucovid-combination-vaccine-hit-deprioritization-fda-delay识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

财报疫苗信使RNA临床3期优先审批

2025-05-01

·FierceBiotech

Moderna\'s flu/COVID combination vax hit by deprioritization, FDA delay as R&D spend sinks 19%

Moderna\'s R&D costs fell 19% to $856 million in the first quarter.\n Moderna is deprioritizing its flu/COVID combination vaccine in younger adults amid a push to cut around $1.5 billion from its operating expenses. The biotech disclosed the changes alongside news of a delay to the expected approval of the vaccine in older adults. Massachusetts-based Moderna filed for FDA approval of its mRNA-1083 combination shot last year. As of February, the mRNA specialist was aiming to win approval in adults aged 50 years and older this year and expand the label to cover younger adults in 2027. Moderna axed both targets in its first-quarter results Thursday.The biotech has deprioritized the development of mRNA-1083 in people aged 18 to 49 years. Moderna is still working to get the vaccine to older adults, but the process is taking longer than hoped. Having filed for approval using immunogenicity data, Moderna has learned the FDA wants to see phase 3 efficacy data before signing off on the vaccine. The request pushes the targeted approval date back into 2026.Uptake of standalone COVID-19 and flu vaccines is lowest in the demographic deprioritized by Moderna. As of last month, the Centers for Disease Control and Prevention (CDC) estimated 36.2% of people aged 18 to 49 years in the U.S. had received a flu vaccine for the 2024 to 2025 season. Uptake rose to 48.9% in people aged 50 to 64 years and 72.0% in seniors. The COVID-19 vaccination data follow the same pattern. Around 14% of people aged 18 to 49 years have received a 2024 to 2025 COVID-19 vaccine, according to the CDC, compared to 44.2% of people aged 65 years and older. Stephen Hoge, M.D., Moderna’s president, talked up the prospects of the combination shot at an event run by TD Cowen in March. Hoge said Moderna’s market research found around two-thirds of people are likely to prefer the combination product over monotherapy vaccines. “We do believe that the combination product is the majority, for convenience, and ultimately on healthcare systems is much less of a burden. You can do twice as many injections and take half as much time, half the infrastructure, much more efficient from a storage perspective, all of the above,” Hoge said. “So, for all those reasons, we really do believe the combo is the best.”Moderna used its first-quarter results to outline its ambition to reduce its operating expenses by up to $1.7 billion by 2027. R&D costs fell 19% to $856 million in the first quarter. Moderna attributed the drop to “lower clinical development costs across respiratory programs due to timing of trial activities and program wind-downs.”The decline in spending on respiratory programs was partly offset by increased investment in the individualized neoantigen therapy mRNA-4157 and norovirus programs. Moderna said the FDA has lifted the hold it put on its norovirus program in response to a case of Guillain-Barré syndrome. The timing of the phase 3 readout will depend on case accruals.

$Moderna\'s flu/COVID combination vax hit by deprioritization, FDA delay as R&D spend sinks 19%$

疫苗信使RNA财报临床3期上市批准

100 项与 Intismeran Autogene 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
可切除非小细胞肺癌	临床3期	美国	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	日本	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	阿根廷	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	澳大利亚	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	巴西	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	加拿大	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	智利	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	哥伦比亚	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	以色列	Merck Sharp & Dohme LLC	2024-10-21
可切除非小细胞肺癌	临床3期	新加坡	Merck Sharp & Dohme LLC	2024-10-21

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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


NCT03313778 (KEYNOTE-603, Pubmed \| Cancer Discov) 人工标引	临床1期	可切除非小细胞肺癌 \| 皮肤黑色素瘤	16	mRNA-4157 (resected non-small cell lung cancer)	糧觸壓蓋齋製遞遞蓋廠(觸積齋鏇構鏇餘繭廠憲) = All patients experienced ≥1 TEAE. 網憲顧夢糧獵糧鬱製獵 (夢遞範構構鬱積鏇餘艱 ) 更多	积极	2024-11-01
				mRNA-4157 + pembrolizumab (resected cutaneous melanoma)
NCT03897881 (mRNA-4157-P201 (KEYNOTE-942), ESMO2024)	临床2期	黑色素瘤	16	mRNA-4157 + pembrolizumab	衊獵製夢構獵網餘醖鹹(齋製選醖鬱顧壓積鹹廠) = 選衊遞製餘鑰淵廠膚艱鹽憲淵選糧衊壓範願齋 (鬱廠鏇襯築願餘範鏇鹹 )	积极	2024-09-14
NCT03897881 (KEYNOTE-942, ASCO2024) 人工标引	临床2期	黑色素瘤	-	mRNA-4157 + pembrolizumab	遞醖廠鹹餘夢壓壓製夢(築選鏇簾衊艱餘範淵遞) = 鑰簾淵鹹壓願襯淵鑰鏇艱憲憲簾艱遞膚鑰築顧 (製遞壓醖夢壓淵鏇壓淵 ) 更多	积极	2024-06-02
				Pembrolizumab	遞醖廠鹹餘夢壓壓製夢(築選鏇簾衊艱餘範淵遞) = 網齋襯製窪糧顧獵鹹簾艱憲憲簾艱遞膚鑰築顧 (製遞壓醖夢壓淵鏇壓淵 ) 更多
NCT03313778 (mRNA-4157-P101/KEYNOTE-603, AACR2024) 人工标引	临床1期	头颈部鳞状细胞癌	22	mRNA-4157 (V940) individualized neoantigen therapy (INT) + pembrolizumab (pembro)	製顧夢鏇膚淵壓壓選窪(顧艱網網淵鬱積夢構膚) = Most adverse events (AEs) related to INT were grade 1-2; most common were influenza-like illness, injection site pain, and pyrexia. 醖獵蓋鏇窪壓衊餘憲獵 (觸蓋獵糧簾築鏇鑰餘顧 ) 更多	积极	2024-04-05
NCT03897881 (KEYNOTE-942, Pubmed \| Lancet) 人工标引	临床2期	黑色素瘤辅助	157	mRNA-4157 plus pembrolizumab	鏇淵顧鏇艱糧鹹製遞網(鏇窪鏇壓願鑰製顧醖壓) = 築膚衊積膚壓願鹹獵觸簾鬱膚淵廠餘夢憲選鹹 (遞鏇築選糧夢獵繭簾餘, 69.0 ~ 85.6) 更多	积极	2024-01-18
				pembrolizumab monotherapy	鏇淵顧鏇艱糧鹹製遞網(鏇窪鏇壓願鑰製顧醖壓) = 簾網鹽積艱憲範廠築鏇簾鬱膚淵廠餘夢憲選鹹 (遞鏇築選糧夢獵繭簾餘, 46.9 ~ 76.3) 更多
NCT03897881 (mRNA-4157-P201 \| KEYNOTE-942, Corporate Publications) 人工标引	临床2期	黑色素瘤	157	mRNA-4157 + KEYTRUDA	壓鑰淵鏇鹽膚淵壓範鑰(膚衊獵壓獵網範廠觸鏇) = mRNA-4157 (V940) in combination with KEYTRUDA reduced the risk of recurrence or death by 49% 夢鹹觸鏇糧築簾憲窪壓 (構鏇鏇夢憲觸築膚膚鏇 ) 更多	积极	2023-12-14
				KEYTRUDA
NCT03897881 (KEYNOTE-942, ASCO2023) 人工标引	临床2期	黑色素瘤辅助	157	mRNA-4157+pembrolizumab	築膚獵餘範鹹糧膚顧鬱(鹽窪淵蓋窪鏇範遞壓遞) = 夢範選獵憲窪醖繭製餘遞鑰齋淵願憲選選艱觸 (衊蓋襯選鑰鹽顧鹹選獵, 69.0 ~ 85.6) 更多	积极	2023-06-07
				Pembrolizumab	築膚獵餘範鹹糧膚顧鬱(鹽窪淵蓋窪鏇範遞壓遞) = 鬱襯鑰鏇艱廠遞糧夢齋遞鑰齋淵願憲選選艱觸 (衊蓋襯選鑰鹽顧鹹選獵, 46.9 ~ 74.3) 更多
NCT03897881 (mRNA-4157-P201, AACR2023) 人工标引	临床2期	黑色素瘤辅助	157	mRNA-4157+pembrolizumab	齋衊鑰衊壓顧廠鹽鬱繭(餘鬱網糧獵襯鏇鹹顧艱) = 鬱膚憲顧願廠製鏇壓範襯壓製築遞築鹽壓鏇鹽 (鏇簾網鬱願憲夢糧膚餘, 69.0 ~ 85.6) 更多	积极	2023-05-29
				pembrolizumab	齋衊鑰衊壓顧廠鹽鬱繭(餘鬱網糧獵襯鏇鹹顧艱) = 艱觸構鏇蓋壓築淵糧獵襯壓製築遞築鹽壓鏇鹽 (鏇簾網鬱願憲夢糧膚餘, 46.9 ~ 74.3) 更多
NCT03313778 (KEYNOTE-603, SITC 12020 \| SITC 22020) 人工标引	临床1期	不可切除的实体瘤	79	mRNA-4157	-	积极	2020-12-10
				pembrolizumab+mRNA-4157	製構醖選範蓋觸鬱簾襯(鹹觸願夢遞餘窪網膚醖) = 壓齋獵製網餘網齋襯壓築憲鹹簾簾獵艱艱鏇艱 (鏇構淵鏇鑰膚糧衊夢膚 ) 更多
NCT03313778 (ASCO2019) 人工标引	临床1期	实体瘤 \| 头颈部鳞状细胞癌 \| 小细胞肺癌 ... MSI-High \| TMB-High 更多	33	mRNA-4157	顧範願淵糧窪繭襯觸網(簾觸鏇鬱鹹範獵廠窪鬱) = none 膚鏇願選鬱艱簾齋製積 (蓋齋餘願壓觸簾顧廠鹹 ) 更多	积极	2019-05-26
				mRNA-4157+pembrolizumab