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Pharmacokinetics, Safety, and Immunogenicity of a Biosimilar of Nivolumab (LY01015): A Randomized, Double-Blind, Parallel-Controlled Phase I Clinical Trial in Healthy Chinese Male Subjects. Nivolumab(LY01015)生物仿制药的药代动力学、安全性和免疫原性:一项针对中国男性健康受试者的随机、双盲、平行对照 I 期临床试验。
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-24 DOI: 10.1007/s40259-024-00679-w
Wei Wang, Shengnan Zhang, Changlin Dou, Baihui Hu, Hongtao Song, Fan Qi, Yanyan Zhao, Xiaojing Li, Ming Zhou, Jinlian Xie, Kunhong Deng, Qian Wu, Ling Ye, Chang Cui, Li Liu, Jie Huang, Guoping Yang

Background: Nivolumab (Opdivo®) is the first anti-PD-1 antibody approved in the world. LY01015 is a potential biosimilar of nivolumab.

Objectives: This phase I study aimed to establish the pharmacokinetic equivalence between LY01015 and the original investigational nivolumab (Opdivo®) in healthy Chinese male subjects. Additionally, safety and immunogenicity were assessed.

Patients and methods: A randomized, double-blind, parallel-controlled, phase I trial was conducted with 176 healthy male adults receiving a single intravenous infusion of LY01015 or nivolumab at 0.3 mg/kg. Pharmacokinetics, safety, and immunogenicity were evaluated over a 99-day period. The primary pharmacokinetics endpoint was AUC0-∞, and the secondary pharmacokinetic endpoints included AUC0-t and Cmax. Pharmacokinetic bioequivalence was confirmed using standard equivalence margins of 80.00-125.00%.

Results: This study is the first to report on the pharmacokinetics, safety, and immunogenicity of Opdivo® in healthy individuals. The pharmacokinetics profiles of LY01015 and Opdivo® were found to be comparable. The geometric mean ratios (90% confidence intervals) for the AUC0-∞, AUC0-t, and Cmax of LY01015 to Opdivo® were 94.49% (90.29-98.88%), 94.92% (88.73-101.54%), and 96.55% (93.32-99.90%), respectively, falling within the conventional bioequivalence criteria of 80.00-125.00%. The safety and immunogenicity were also comparable between the two groups.

Conclusions: LY01015 demonstrated highly similar pharmacokinetics to nivolumab in healthy Chinese male subjects. Both drugs exhibited comparable safety and immunogenicity profiles.

Trial registration: This trial is registered at the Chinese Clinical Trial Registry website ( https://www.chictr.org.cn/ #ChiCTR2200064771).

背景Nivolumab (Opdivo®) 是全球首个获批的抗 PD-1 抗体。LY01015是Nivolumab的潜在生物类似药:本 I 期研究旨在确定 LY01015 与原研药 nivolumab (Opdivo®) 在中国男性健康受试者中的药代动力学等效性。此外,还评估了安全性和免疫原性:我们对176名健康男性成年人进行了一项随机、双盲、平行对照的I期试验,他们接受了单次静脉输注LY01015或0.3 mg/kg的nivolumab。在 99 天的时间里对药代动力学、安全性和免疫原性进行了评估。主要药代动力学终点是AUC0-∞,次要药代动力学终点包括AUC0-t和Cmax。药代动力学生物等效性采用 80.00-125.00% 的标准等效比值进行确认:该研究首次报告了Opdivo®在健康人体内的药代动力学、安全性和免疫原性。研究发现,LY01015和Opdivo®的药代动力学特征相当。LY01015与Opdivo®的AUC0-∞、AUC0-t和Cmax的几何平均比(90%置信区间)分别为94.49%(90.29-98.88%)、94.92%(88.73-101.54%)和96.55%(93.32-99.90%),符合80.00-125.00%的常规生物等效性标准。两组的安全性和免疫原性也相当:结论:在中国男性健康受试者中,LY01015与nivolumab的药代动力学高度相似。结论:在中国男性健康受试者中,LY01015与nivolumab的药代动力学非常相似,两种药物的安全性和免疫原性也相当:本试验已在中国临床试验注册中心网站注册 ( https://www.chictr.org.cn/ #ChiCTR2200064771)。
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引用次数: 0
Discovery of Therapeutic Antibodies Targeting Complex Multi-Spanning Membrane Proteins. 发现针对复杂多跨膜蛋白的治疗性抗体。
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-11-01 Epub Date: 2024-10-25 DOI: 10.1007/s40259-024-00682-1
Amberley D Stephens, Trevor Wilkinson

Complex integral membrane proteins, which are embedded in the cell surface lipid bilayer by multiple transmembrane spanning polypeptides, encompass families of proteins that are important target classes for drug discovery. These protein families include G protein-coupled receptors, ion channels, transporters, enzymes, and adhesion molecules. The high specificity of monoclonal antibodies and the ability to engineer their properties offers a significant opportunity to selectively bind these target proteins, allowing direct modulation of pharmacology or enabling other mechanisms of action such as cell killing. Isolation of antibodies that bind these types of membrane proteins and exhibit the desired pharmacological function has, however, remained challenging due to technical issues in preparing membrane protein antigens suitable for enabling and driving antibody drug discovery strategies. In this article, we review progress and emerging themes in defining discovery strategies for a generation of antibodies that target these complex membrane protein antigens. We also comment on how this field may develop with the emerging implementation of computational techniques, artificial intelligence, and machine learning.

复杂的整联膜蛋白由多个跨膜多肽嵌入细胞表面脂质双分子层,其中包含的蛋白质家族是药物发现的重要目标类别。这些蛋白质家族包括 G 蛋白偶联受体、离子通道、转运体、酶和粘附分子。单克隆抗体的高度特异性和设计其特性的能力为选择性结合这些靶蛋白提供了重要机会,从而可以直接调节药理学或实现其他作用机制,如杀死细胞。然而,由于制备膜蛋白抗原的技术问题,分离能结合这些类型的膜蛋白并表现出所需药理功能的抗体仍具有挑战性。在这篇文章中,我们回顾了在确定针对这些复杂膜蛋白抗原的一代抗体的发现策略方面所取得的进展和新出现的主题。我们还评论了这一领域如何随着计算技术、人工智能和机器学习的新兴应用而发展。
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引用次数: 0
Introducing the Biosimilar Paradigm to Neurology: The Totality of Evidence for the First Biosimilar Natalizumab. 将生物仿制药范例引入神经病学:首个生物仿制药纳他珠单抗的全部证据。
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1007/s40259-024-00671-4
Krzysztof Selmaj, Karsten Roth, Josef Höfler, Klaus Vitzithum, Rafał Derlacz, Oliver von Richter, Cyrill Hornuss, Johann Poetzl, Barry Singer, Laura Jacobs

A biosimilar medicine is a successor to a reference ('originator'/'original-brand') biologic medicine brought to market once the patent and exclusive marketing rights for the reference have expired. Biosimilar natalizumab (PB006 [biosim-NTZ]; developed by Polpharma Biologics S.A. and marketed globally as Tyruko®; Sandoz) has been developed as a successor to reference natalizumab (Tysabri® [ref-NTZ]; Biogen) and is the first US Food and Drug Administration (FDA)-approved and European Medicines Agency (EMA)-approved biosimilar in neurology. As per the FDA and EMA indications for ref-NTZ, biosim-NTZ is approved to treat relapsing forms of multiple sclerosis (USA, EU) and Crohn's disease (USA only). Approval of biosim-NTZ was based on the 'totality of evidence', a comprehensive body of data collected during the development process, demonstrating similarity to its reference medicine. The foundational step of demonstrating structural and functional similarity between biosim-NTZ and ref-NTZ confirmed identical primary and indistinguishable higher order structures, as well as matching binding affinity to α4β1/α4β7 integrins. Following the confirmation of matching structure and function, pharmacokinetic/pharmacodynamic similarity of biosim-NTZ to ref-NTZ in healthy subjects was demonstrated, with no clinically meaningful differences identified in safety and immunogenicity. A comparative, double-blind, randomized study (Antelope) was also conducted in patients with relapsing-remitting multiple sclerosis and demonstrated matching efficacy, safety, and immunogenicity with no clinically meaningful differences between biosim-NTZ and ref-NTZ. This review presents the totality of evidence that confirmed the biosimilarity of biosimilar natalizumab to its reference medicine, which supported its approval by the FDA and the EMA. [Graphical plain language summary available].

生物仿制药是参照药("原研药"/"原品牌")的后继药,在参照药的专利和独家销售权到期后推向市场。生物仿制药纳他珠单抗(PB006 [biosim-NTZ];由 Polpharma Biologics S.A.开发,以 Tyruko® 在全球销售;Sandoz)是作为纳他珠单抗参照药(Tysabri® [ref-NTZ];Biogen)的后继药物开发的,也是神经病学领域第一个获得美国食品药品管理局(FDA)批准和欧洲药品管理局(EMA)批准的生物仿制药。根据 FDA 和 EMA 对 ref-NTZ 的适应症规定,生物仿制-NTZ 可用于治疗复发性多发性硬化症(美国、欧盟)和克罗恩病(仅限美国)。生物仿制-NTZ 的批准基于 "全面证据",即在开发过程中收集的大量数据,这些数据证明了它与参照药物的相似性。证明生物仿制药-NTZ 和 ref-NTZ 结构和功能相似性的基础步骤是确认两者具有相同的初级结构和无差别的高阶结构,以及与 α4β1/α4β7 整合素匹配的结合亲和力。在确认了结构和功能的匹配性之后,在健康受试者体内,生物 Sim-NTZ 与 ref-NTZ 的药代动力学/药效学相似性也得到了证实,在安全性和免疫原性方面没有发现有临床意义的差异。此外,还在复发缓解型多发性硬化症患者中进行了一项双盲随机对比研究(羚羊),结果表明生物 Sim-NTZ 与 ref-NTZ 的疗效、安全性和免疫原性相匹配,没有发现有临床意义的差异。本综述介绍了证实生物仿制药纳他珠单抗与其参比药物具有生物相似性的全部证据,这些证据为其获得 FDA 和 EMA 批准提供了支持。[提供图形化简明语言摘要]。
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引用次数: 0
Biochemical Amenability in Fabry Patients Under Chaperone Therapy-How and When to Test? 接受伴侣疗法的法布里患者的生化适应性--如何检测、何时检测?
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1007/s40259-024-00678-x
Malte Lenders, Elise Raphaela Menke, Eva Brand

Aim: Current recommendations for Fabry disease include α-galactosidase A (AGAL) activity measurements to assess the biochemical response in migalastat-treated patients. Owing to contradictory data from laboratories, we aimed to analyze why AGAL activity measures from dried blood spots (DBS) often fail to detect migalastat-mediated enzymatic activity increases in treated patients.

Methods: 43 patients with 58 visits under migalastat were consecutively recruited. Enzymatic AGAL activities were measured from DBS and peripheral blood mononuclear cells (PBMCs). Migalastat concentrations in sera were determined using modified serum-mediated inhibition assays to assess Cmax and serum half-life. Results were set in relation to the time of last migalastat intake and blood sampling to assess an optimal timepoint for AGAL activity measures.

Results: DBS-based AGAL activity measurements of 21 (42.0%) amenable patients were below the limit of detection. Serum samples from migalastat-treated patients showed significant AGAL inhibition, depending on the time between migalastat intake and blood sampling (r2 = 0.8140, p < 0.0001). Migalastat concentrations were determined in serum samples confirming a Cmax at 3 h and a serum half-life of 4 h. At 24 h after intake, migalastat clearance was significantly associated with renal function (r2 = 0.3135, p = 0.0102). Enzymatic AGAL activities were higher in samples from DBS and PBMCs 24 h after migalastat intake (both p < 0.05).

Conclusion: The optimal time for enzymatic AGAL activity measurement in migalastat-treated patients appears to be 24 h after the last migalastat intake. Since migalastat is a competitive inhibitor of AGAL, enzymatic AGAL activity measurements should be better performed from PBMCs to reduce migalastat-mediated interferences.

目的:目前针对法布里病的建议包括测量α-半乳糖苷酶A(AGAL)活性,以评估米格司他治疗患者的生化反应。由于实验室提供的数据相互矛盾,我们旨在分析为什么干血斑(DBS)中的 AGAL 活性测量结果常常无法检测出治疗患者中由米格司他介导的酶活性增加。从 DBS 和外周血单核细胞(PBMCs)中测定酶 AGAL 活性。使用改良的血清介导抑制测定法测定血清中的米格司他浓度,以评估Cmax和血清半衰期。结果与最后一次摄入米格司他和采血时间相关,以评估AGAL活性测量的最佳时间点:结果:21名(42.0%)符合条件的患者基于DBS的AGAL活性测量结果低于检测限。米格司他治疗患者的血清样本显示出明显的AGAL抑制作用,这取决于摄入米格司他和采血之间的时间间隔(r2 = 0.8140,p < 0.0001)。血清样本中米格司他浓度的测定结果表明,米格司他的Cmax值为3小时,血清半衰期为4小时。摄入米加司他24小时后,DBS和PBMC样本中的酶AGAL活性较高(P均<0.05):结论:测量米格司他治疗患者酶AGAL活性的最佳时间似乎是最后一次摄入米格司他24小时后。由于米格司他是AGAL的竞争性抑制剂,因此酶促AGAL活性测定最好从PBMCs中进行,以减少米格司他介导的干扰。
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引用次数: 0
Eblasakimab, an Anti-IL‑13Rα1 Antibody, Reduces Atopy-Associated Serum Biomarkers in Moderate‑to‑Severe Atopic Dermatitis. 抗IL-13Rα1抗体Eblasakimab能降低中重度特应性皮炎患者与特应相关的血清生物标志物。
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-11-01 Epub Date: 2024-10-15 DOI: 10.1007/s40259-024-00685-y
Ferda Cevikbas, Alison Ward, Karen A Veverka

Introduction: Eblasakimab, a first-in-class monoclonal antibody with a unique mechanism to target the interleukin (IL)-13 receptor alpha 1 (IL-13Rα1), inhibits IL-4/IL-13 signaling in the pathophysiology of atopic dermatitis (AD). This study investigates the impact of eblasakimab on type 2 inflammatory biomarkers in patients with moderate-to-severe AD.

Methods: A double‑blind, multiple ascending dose, phase Ib study evaluated the effect of eblasakimab (200, 400, 600 mg) or placebo administered subcutaneously once weekly for 8 weeks in patients with moderate‑to‑severe AD. Serum levels of thymus and activation-regulated chemokine (TARC), total immunoglobulin E (IgE), and lactate dehydrogenase (LDH) were assessed.

Results: Eblasakimab suppressed TARC, IgE, and LDH in the 400-mg and 600-mg groups over 8 weeks of treatment. Patients in the 400-mg and 600-mg groups experienced a reduction of 72.8% (p = 0.004) and 62.9% (p = 0.003), respectively, for TARC, 35.1% (p = 0.006) and 20.9% (not significant; NS), respectively, for IgE, and 24.6% (NS) and 23.1% (NS), respectively, for LDH between baseline and Week 8. Reduction in serum TARC in the 400-mg group was significantly greater than placebo as early as Week 1, whereas reductions in total IgE were more gradual. Serum TARC and total IgE remained suppressed in the 400-mg and 600-mg eblasakimab groups for 4-6 weeks following the last administered dose.

Conclusion: The effect of eblasakimab on circulating AD‑associated biomarker levels was accompanied by improvements in signs and symptoms of AD, consistent with the inhibition of IL-13 and IL-4 signaling via the type 2 receptor.

Trial registration number: NCT04090229.

简介依巴沙基单抗是一种首创的单克隆抗体,具有靶向白细胞介素(IL)-13受体α1(IL-13Rα1)的独特机制,可抑制特应性皮炎(AD)病理生理学中的IL-4/IL-13信号传导。本研究探讨了依巴单抗对中重度特应性皮炎患者2型炎症生物标志物的影响:一项双盲、多剂量递增的Ib期研究评估了依巴单抗(200、400、600毫克)或安慰剂对中重度AD患者皮下注射的影响,每周一次,共8周。研究评估了胸腺和活化调节趋化因子(TARC)、总免疫球蛋白E(IgE)和乳酸脱氢酶(LDH)的血清水平:在为期8周的治疗中,易拉西单抗抑制了400毫克组和600毫克组的TARC、IgE和LDH。从基线到第8周,400毫克组和600毫克组患者的TARC分别降低了72.8%(p = 0.004)和62.9%(p = 0.003),IgE分别降低了35.1%(p = 0.006)和20.9%(无显著性;NS),LDH分别降低了24.6%(NS)和23.1%(NS)。早在第 1 周,400 毫克组血清 TARC 的降幅就明显高于安慰剂,而总 IgE 的降幅则较为缓慢。在最后一次给药后的4-6周内,400毫克和600毫克依布拉西单抗组的血清TARC和总IgE仍受到抑制:eblasakimab对循环AD相关生物标志物水平的影响伴随着AD体征和症状的改善,这与通过2型受体抑制IL-13和IL-4信号传导是一致的:NCT04090229.
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引用次数: 0
Adverse Impacts of PEGylated Protein Therapeutics: A Targeted Literature Review. 聚乙二醇化蛋白质疗法的不良影响:有针对性的文献综述。
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-11-01 Epub Date: 2024-10-17 DOI: 10.1007/s40259-024-00684-z
Chae Sung Lee, Yogesh Kulkarni, Vicki Pierre, Manish Maski, Christoph Wanner

The beneficial effects of polyethylene glycol (PEG)-conjugated therapeutics, such as increased half-life, solubility, stability, and decreased immunogenicity, have been well described. There have been concerns, however, about adverse outcomes with their use, but understanding of those adverse outcomes is still relatively limited. The present study aimed to characterize adverse outcomes associated with PEGylation of protein-based therapeutics on immunogenicity, pharmacologic properties, and safety. A targeted review of English language articles published from 1990 to September 29, 2023, was conducted. Of the 29 studies included in this review, 18 reported adverse safety outcomes such as hematologic complications, hepatic toxicity, injection site reactions, arthralgia, nausea, infections, grade 3 or 4 adverse events (AEs), and AE-related discontinuations and dose modifications. Fifteen studies reported immunogenicity-related outcomes, such as the prevalence of pre-existing antibodies to PEG, treatment-emergent antibody response, and hypersensitivity reactions to PEGylated drugs. Seven studies reported pharmacological outcomes such as increased clearance and reduced activity in response to PEGylated drugs. This review aims to contribute to a balanced view of PEGylated therapies by summarizing the adverse outcomes or lack of benefit associated with PEGylated therapeutics reported in the literature. We identified several studies characterizing adverse outcomes, pharmacological effects, and immunogenicity associated with the use of PEGylated therapeutics. Our findings suggest that using PEGylated therapeutics may require careful monitoring for adverse safety outcomes, including screening and monitoring for pre-existing antibodies and those induced in response to PEGylated therapy, as well as monitoring and adjusting the dosing of PEGylated therapeutics.

聚乙二醇(PEG)共轭疗法的有益效果,如增加半衰期、溶解度、稳定性和降低免疫原性等,已得到充分描述。然而,人们对使用这些药物的不良反应一直存在担忧,但对这些不良反应的了解仍然相对有限。本研究旨在描述蛋白质类治疗药物 PEG 化后在免疫原性、药理特性和安全性方面的不良反应。本研究对 1990 年至 2023 年 9 月 29 日期间发表的英文文章进行了有针对性的综述。在纳入本综述的 29 项研究中,有 18 项研究报告了不良安全性结果,如血液学并发症、肝毒性、注射部位反应、关节痛、恶心、感染、3 级或 4 级不良事件 (AE),以及与 AE 相关的停药和剂量调整。15 项研究报告了免疫原性相关结果,如 PEG 原有抗体的发生率、治疗引发的抗体反应以及对 PEG 化药物的超敏反应。七项研究报告了药理学结果,如对 PEG 化药物的清除率增加和活性降低。本综述旨在通过总结文献中报道的与 PEG 化疗法相关的不良结果或缺乏益处的情况,为平衡看待 PEG 化疗法做出贡献。我们确定了几项研究,描述了与使用 PEG 化疗法相关的不良结果、药理作用和免疫原性。我们的研究结果表明,使用 PEG 化治疗药物可能需要仔细监测不良安全结果,包括筛查和监测原有抗体和因 PEG 化治疗而诱发的抗体,以及监测和调整 PEG 化治疗药物的剂量。
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引用次数: 0
Patient Satisfaction and Experience with CT-P17 Following Transition from Reference Adalimumab or Another Adalimumab Biosimilar: Results from the Real-World YU-MATTER Study. 从参考阿达木单抗或另一种阿达木单抗生物类似物过渡到 CT-P17 后的患者满意度和使用体验:真实世界YU-MATTER研究的结果。
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-25 DOI: 10.1007/s40259-024-00681-2
Guillaume Bouguen, Laure Gossec, Vered Abitbol, Eric Senbel, Guillaume Bonnaud, Xavier Roblin, Yoram Bouhnik, Stéphane Nancey, Nicolas Mathieu, Jérôme Filippi, Lucine Vuitton, Stéphane Nahon, Azeddine Dellal, Alice Denis, Lucile Foulley, Caroline Habauzit, Salim Benkhalifa, Hubert Marotte

Background and objectives: Biosimilars are cost-effective alternatives to reference products for patients with inflammatory bowel diseases (IBD) and chronic inflammatory rheumatic diseases (CIRD), but patient beliefs can affect adherence to the transition. This study aimed to explore patient experience and satisfaction after switching to CT-P17, a high-concentration (100 mg/mL), citrate-free adalimumab biosimilar.

Patients and methods: This observational, multicenter, prospective French study included adult patients with IBD or CIRD who switched to CT-P17 from reference adalimumab (R-ADA; 100 mg/mL) or a low-concentration adalimumab biosimilar (ADA-BioS; 50 mg/mL). Patients completed online questionnaires to assess treatment perceptions, satisfaction, and tolerance at study inclusion (under previous treatment) and over 3 months of CT-P17 treatment. The primary criterion was overall patient satisfaction, which was assessed with the question, "What is your global satisfaction with the CT-P17 injection?", using a 7-point Likert scale. Multivariate logistic regression analysis was performed to identify factors associated with increased treatment satisfaction after switching to CT-P17.

Results: The total analysis population included 232 patients (IBD 72.0%, CIRD 28.0%). Median patient age was 57.0 years (interquartile range [IQR] 46.0-63.0), 50.4% were men, and median disease duration was 9 years (IQR 5-16). Approximately half of the cohort (51.2%) switched to CT-P17 from an ADA-BioS (including 19.4% from an ADA-BioS with citrate) and half (48.7%) from R-ADA. The proportion of patients who were satisfied with treatment was stable between baseline (under previous treatment) and 3 months (under CT-P17). More patients reported increased satisfaction after switching to CT-P17 from an ADA-BioS (22.7% vs 8.0% when switching from R-ADA; p = 0.002), or from an ADA-BioS containing citrate (28.9% vs 12.3% when switching from a citrate-free ADA-BioS; p = 0.008). Independent prognostic factors for increased satisfaction were previous treatment with an ADA-BioS (odds ratio [OR] 2.88 [95% confidence interval 1.17-7.08]; p = 0.021) and pain at the injection site under previous treatment (OR 1.26 [1.08-1.47]; p = 0.004). Significantly fewer patients reported pain, redness, itching, and hematoma after 3 months of CT-P17 treatment versus baseline (p < 0.001).

Conclusions: The majority of patients had stable or increased treatment satisfaction after switching from R-ADA or an ADA-BioS to CT-P17. In particular, switching to CT-P17 from a low-concentration ADA-BioS or an ADA-BioS containing citrate was associated with increased patient satisfaction. An improvement in overall tolerance with CT-P17 versus previous adalimumab treatment was also reported.

Trial registration: ClinicalTrials.gov identifier NCT05427942, registered June 22, 2022.

背景和目的:对于炎症性肠病(IBD)和慢性炎症性风湿病(CIRD)患者而言,生物仿制药是具有成本效益的参比产品替代品,但患者的观念可能会影响对过渡治疗的依从性。本研究旨在探讨患者转用CT-P17(一种高浓度(100毫克/毫升)、不含枸橼酸的阿达木单抗生物类似药)后的体验和满意度:这项观察性、多中心、前瞻性法国研究纳入了从参考阿达木单抗(R-ADA;100毫克/毫升)或低浓度阿达木单抗生物类似物(ADA-BioS;50毫克/毫升)转用CT-P17的IBD或CIRD成年患者。患者完成了在线问卷调查,以评估纳入研究时(之前接受过治疗)和接受 CT-P17 治疗 3 个月后的治疗感知、满意度和耐受性。主要标准是患者的总体满意度,采用 7 点李克特量表评估 "您对 CT-P17 注射的总体满意度如何?为确定改用 CT-P17 后治疗满意度提高的相关因素,进行了多变量逻辑回归分析:总分析人群包括 232 名患者(IBD 72.0%,CIRD 28.0%)。患者年龄中位数为 57.0 岁(四分位数间距 [IQR] 46.0-63.0),50.4% 为男性,病程中位数为 9 年(IQR 5-16)。约半数患者(51.2%)从ADA-BioS(包括19.4%从含枸橼酸盐的ADA-BioS)改用CT-P17,半数患者(48.7%)从R-ADA改用CT-P17。对治疗感到满意的患者比例在基线(之前的治疗)和 3 个月(CT-P17 治疗)之间保持稳定。从 ADA-BioS 转用 CT-P17 后(22.7% 对从 R-ADA 转用 CT-P17 时的 8.0%;p = 0.002),或从含有枸橼酸盐的 ADA-BioS 转用 CT-P17 后(28.9% 对从不含枸橼酸盐的 ADA-BioS 转用 CT-P17 时的 12.3%;p = 0.008),更多患者表示满意度提高。满意度提高的独立预后因素是既往接受过 ADA-BioS 治疗(几率比 [OR] 2.88 [95% 置信区间 1.17-7.08];p = 0.021)和既往治疗时注射部位疼痛(OR 1.26 [1.08-1.47];p = 0.004)。与基线相比,CT-P17 治疗 3 个月后报告疼痛、发红、瘙痒和血肿的患者明显减少(p 结论:CT-P17 治疗 3 个月后疼痛、发红、瘙痒和血肿的患者明显减少:从 R-ADA 或 ADA-BioS 改用 CT-P17 后,大多数患者的治疗满意度保持稳定或有所提高。特别是,从低浓度 ADA-BioS 或含有枸橼酸盐的 ADA-BioS 改用 CT-P17 与患者满意度提高有关。与之前的阿达木单抗治疗相比,CT-P17的总体耐受性也有所改善:试验注册:ClinicalTrials.gov标识符NCT05427942,2022年6月22日注册。
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引用次数: 0
Pulmonary Arterial Hypertension and TGF-β Superfamily Signaling: Focus on Sotatercept 肺动脉高压与 TGF-β 超家族信号传导:聚焦 Sotatercept
IF 6.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-18 DOI: 10.1007/s40259-024-00680-3
Benjamin Stump, Aaron B. Waxman

Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.

肺动脉高压(PAH)是一种罕见的渐进性疾病,尽管医学疗法取得了多项进展,但这种疾病的发病率仍然很高。目前仍急需找到新的治疗方法,最好能逆转导致 PAH 发生和发展的病理血管病变。Sotatercept 是一种首创的融合蛋白,据信主要能抑制激活素信号转导,从而减少细胞增殖和分化,但其确切机制仍不确定。在此,我们将回顾目前可用的 PAH 疗法、强调转化生长因子-β(TGF-β)超家族信号在 PAH 发展中重要性的数据,以及已发表和正在进行的评估索特受治疗 PAH 的临床试验。我们还将讨论支持融合蛋白 KER-012 可能用于抑制 TGF-β 超家族异常信号传导以改善 PAH 阻塞性血管病变的临床前数据。
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引用次数: 0
Chikungunya Virus Vaccines: A Review of IXCHIQ and PXVX0317 from Pre-Clinical Evaluation to Licensure 基孔肯雅病毒疫苗:IXCHIQ 和 PXVX0317 从临床前评估到获得许可的回顾
IF 6.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-18 DOI: 10.1007/s40259-024-00677-y
Whitney C. Weber, Daniel N. Streblow, Lark L. Coffey

Chikungunya virus is an emerging mosquito-borne alphavirus that causes febrile illness and arthritic disease. Chikungunya virus is endemic in 110 countries and the World Health Organization estimates that it has caused more than 2 million cases of crippling acute and chronic arthritis globally since it re-emerged in 2005. Chikungunya virus outbreaks have occurred in Africa, Asia, Indian Ocean islands, South Pacific islands, Europe, and the Americas. Until recently, no specific countermeasures to prevent or treat chikungunya disease were available. To address this need, multiple vaccines are in human trials. These vaccines use messenger RNA-lipid nanoparticles, inactivated virus, and viral vector approaches, with a live-attenuated vaccine VLA1553 and a virus-like particle PXVX0317 in phase III testing. In November 2023, the US Food and Drug Administration (FDA) approved the VLA1553 live-attenuated vaccine, which is marketed as IXCHIQ. In June 2024, Health Canada approved IXCHIQ, and in July 2024, IXCHIQ was approved by the European Commission. On August 13, 2024, the US FDA granted priority review for PXVX0317. The European Medicine Agency is considering accelerated assessment review of PXVX0317, with potential for approval by both agencies in 2025. In this review, we summarize published data from pre-clinical and clinical trials for the IXCHIQ and PXVX0317 vaccines. We also discuss unanswered questions including potential impacts of pre-existing chikungunya virus immunity on vaccine safety and immunogenicity, whether long-term immunity can be achieved, safety in children, pregnant, and immunocompromised individuals, and vaccine efficacy in people with previous exposure to other emerging alphaviruses in addition to chikungunya virus.

基孔肯雅病毒是一种新出现的蚊媒α病毒,可引起发热性疾病和关节炎。基孔肯雅病毒在 110 个国家流行,据世界卫生组织估计,自 2005 年再次出现以来,它已在全球造成 200 多万例致残性急性和慢性关节炎病例。基孔肯雅病毒在非洲、亚洲、印度洋岛屿、南太平洋岛屿、欧洲和美洲爆发。直到最近,还没有预防或治疗基孔肯雅病的具体对策。为了满足这一需求,多种疫苗正在进行人体试验。这些疫苗采用信使核糖核酸-脂质纳米颗粒、灭活病毒和病毒载体方法,其中减毒活疫苗 VLA1553 和病毒样颗粒 PXVX0317 正在进行 III 期试验。2023 年 11 月,美国食品和药物管理局(FDA)批准了 VLA1553 减毒活疫苗,并将其命名为 IXCHIQ。2024 年 6 月,加拿大卫生部批准了 IXCHIQ,2024 年 7 月,欧盟委员会批准了 IXCHIQ。2024 年 8 月 13 日,美国 FDA 授予 PXVX0317 优先审查权。欧洲药品管理局正在考虑对 PXVX0317 进行加速评估审查,有可能在 2025 年获得这两个机构的批准。在本综述中,我们总结了 IXCHIQ 和 PXVX0317 疫苗临床前和临床试验的公开数据。我们还讨论了一些悬而未决的问题,包括已有的基孔肯雅病毒免疫力对疫苗安全性和免疫原性的潜在影响,是否能获得长期免疫力,对儿童、孕妇和免疫力低下者的安全性,以及疫苗对除基孔肯雅病毒外还接触过其他新出现的阿尔巴病毒的人的有效性。
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引用次数: 0
Long-Term Efficacy and Safety of Stapokibart in Adults with Moderate-to-Severe Atopic Dermatitis: An Open-Label Extension, Nonrandomized Clinical Trial. 斯达博特对中重度特应性皮炎患者的长期疗效和安全性:一项开放标签延长、非随机临床试验。
IF 5.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-31 DOI: 10.1007/s40259-024-00668-z
Yan Zhao, Jing-Yi Li, Bin Yang, Yang-Feng Ding, Li-Ming Wu, Li-Tao Zhang, Jin-Yan Wang, Qian-Jin Lu, Chun-Lei Zhang, Fu-Ren Zhang, Xiao-Hong Zhu, Yu-Mei Li, Xiao-Hua Tao, Qing-Chun Diao, Lin-Feng Li, Jian-Yun Lu, Xiao-Yong Man, Fu-Qiu Li, Xiu-Juan Xia, Jiao-Ran Song, Ying-Min Jia, Li-Bo Zhang, Bo Chen, Jian-Zhong Zhang

Background: Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials.

Objective: We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis.

Methods: Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300 mg every 2 weeks up to 52 weeks. Efficacy outcomes included the proportions of patients with ≥ 50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale.

Results: In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week 52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥ 2-point reduction was achieved in 39.3% of patients at week 16, increasing to 58.9% at week 52. The proportions of patients with ≥ 3-point and ≥ 4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week 52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events.

Conclusions: Long-term treatment with stapokibart for 52 weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis.

Clinical trial registration: ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021).

背景:Stapokibart/CM310是一种靶向白细胞介素-4受体α链的人源化单克隆抗体,在之前的II期临床试验中显示出对中重度特应性皮炎患者有良好的治疗效果:我们旨在评估 stapokibart 对中重度特应性皮炎成人患者的长期疗效和安全性:入组的患者之前完成了 stapokibart 的母体试验,接受了 600 毫克的皮下注射 stapokibart 负荷剂量,然后每 2 周注射 300 毫克,直至 52 周。疗效结果包括湿疹面积和严重程度指数、研究者总体评估和每周瘙痒峰值数字分级表平均值较母体试验基线改善≥50%/75%/90%的患者比例:共有 127 名患者参加了研究,其中 110 人(86.6%)完成了研究。第52周时,湿疹面积和严重程度指数-50/75/90的应答率分别为96.3%、87.9%和71.0%。第16周时,39.3%的患者达到了研究者总体评估0/1,评分下降≥2分,第52周时,这一比例上升至58.9%。第52周时,瘙痒症日峰值数字评分量表的周平均评分≥3分和≥4分的患者比例分别为80.2%和62.2%。患者生活质量的改善在52周的治疗期内得以持续。88.2%的患者发生了治疗突发不良事件,暴露调整后的事件发生率为299.2起/100患者年。2019年冠状病毒病、上呼吸道感染和结膜炎是最常见的治疗突发不良事件:使用斯普托昔巴特进行52周的长期治疗显示出较高的疗效和良好的安全性,支持将其作为特应性皮炎的长期连续治疗方案:临床试验注册:ClinicalTrials.gov identifier:临床试验注册:ClinicalTrials.gov标识符:NCT04893707(2021年5月15日)。
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