更新于：2024-07-24

Nipocalimab

尼卡利单抗

更新于：2024-07-24

概要

概要

基本信息

药物类型

单克隆抗体

别名

anti-FcRn monoclonal antibody(Momenta Pharmaceuticals)、Immunoglobulin g1, anti-(human neonatal fc receptor) (human monoclonal m281 .gamma.-1 chain), disulfide with human monoclonal m281 .lambda.-chain, dimer、Nipocalimab (USAN)

+ [4]

靶点

FcRn

作用机制

FcRn拮抗剂(IgG受体FcRn大亚基p51拮抗剂)、免疫调节剂

治疗领域

肿瘤免疫系统疾病神经系统疾病+ [7]

在研适应症

胎儿/新生儿同种免疫性血小板减少症新生儿同种免疫性血小板减少症胎儿成红细胞增多症+ [9]

非在研适应症-

原研机构

Momenta Pharmaceuticals, Inc.

在研机构

强生（中国）投资有限公司Janssen Research & Development LLC

非在研机构

Momenta Pharmaceuticals, Inc.

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)临床3期

特殊审评突破性疗法 (美国)、快速通道 (美国)、孤儿药 (美国)、罕见儿科疾病 (美国)、孤儿药 (欧盟)、突破性疗法 (中国)、孤儿药 (日本)

序列信息

Sequence Code 19395495L

来源: *****

Sequence Code 19395504H

来源: *****

关联

项与尼卡利单抗相关的临床试验

NCT04883619 / Not yet recruiting临床2期

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Nipocalimab in Adult Participants With Active Lupus Nephritis

The purpose of this study is to evaluate the efficacy of nipocalimab versus placebo in participants with active Lupus Nephritis (LN).

开始日期2026-01-15

申办/合作机构

Janssen Research & Development LLC

NCT06449651 / Recruiting临床3期

Double-blind, Randomized, Placebo-controlled Study Evaluating the Safety and Efficacy of Nipocalimab in Reducing the Risk of Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) in At-risk Pregnancies

The purpose of this study is to evaluate the effectiveness of nipocalimab compared with placebo in reducing the risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT).

开始日期2024-07-22

申办/合作机构

Janssen Research & Development LLC

NCT05912517 / Recruiting临床3期

A Phase 3 Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Nipocalimab in Pregnancies at Risk for Severe Hemolytic Disease of the Fetus and Newborn (HDFN)

The purpose of this study is to assess the effectiveness of nipocalimab when compared to placebo in decreasing the risk of fetal anemia (a condition in which a baby's red blood cell volume falls below normal levels while the baby is developing in the womb) with live neonates in pregnant participants at risk for severe hemolytic disease of the fetus and newborn.

开始日期2023-12-20

申办/合作机构

Janssen Research & Development LLC

100 项与尼卡利单抗相关的临床结果

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100 项与尼卡利单抗相关的转化医学

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100 项与尼卡利单抗相关的专利（医药）

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项与尼卡利单抗相关的文献（医药）

2024-12-31·mAbs

Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro

Article

作者: Craggs, Graham ; Rapecki, Stephen ; Qureshi, Omar S ; Sutton, Emma J ; Humphreys, David P ; Cutler, Rona M ; Shock, Anthony ; McCluskey, Gillian ; Maroof, Asher ; West, Shauna M ; Smith, Bryan J ; Barnes, Nicholas M ; Bithell, Rosemary F

Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly "silent" in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from in vitro experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of in vitro assays performed in the absence of competing IgG.

2024-02-01·CNS drugs

The Efficacy and Safety of Different Targeted Drugs for the Treatment of Generalized Myasthenia Gravis: A Systematic Review and Bayesian Network Meta-analysis

Review

作者: Nie, Xiangtao ; Ma, Yongbo ; Zhu, Geke ; Guo, Xiuming ; Hao, Lei ; Qi, Wenjing

BACKGROUND:

The treatment of generalized myasthenia gravis (gMG) has been transformed by the development and approval of new targeted therapies. This analysis aimed to rank and compare the new therapies for gMG using efficacy and safety data from randomized controlled trials (RCTs).

METHODS:

We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (up to November 2022) for RCTs of targeted drugs for gMG. We used a Bayesian random-effects network meta-analysis (NMA) model and a Markov chain Monte Carlo (MCMC) model for statistical analysis. The primary outcome was the change in quantitative myasthenia gravis score (QMGS) from baseline, while the secondary outcome was the risk ratio (RR) of adverse events (AEs) during treatment. The surface under the cumulative ranking curve (SUCRA) was used to rank these targeted drugs, with higher SUCRA values indicating better efficacy or lower likelihood of AEs.

RESULTS:

In total, 13 studies (872 subjects) were included in this analysis evaluating 10 targeted drugs (batoclimab, belimumab, CFZ533, eculizumab, efgartigimod, nipocalimab, rituximab, ravulizumab, rozanolixizumab, and zilucoplan). With regards to the primary outcome, batoclimab [standardized mean difference (SMD), - 1.61; 95% credible interval (CrI), - 2.78, - 0.43] significantly reduced QMGS in patients with gMG when compared with placebo and was ranked as the most efficacious drug. Ranked second and third were eculizumab (SMD, - 0.67; 95% CrI, 1.43, 0.01) and zilucoplan (SMD, - 0.54; 95% CrI, - 1.56, 0.46), respectively. Nipoclimab (SMD, - 0.02; 95% CrI, - 1.04, 1.00) had the worst efficacy and ranked last among all targeted drugs. In our study, except for batoclimab, there was no statistically significant difference in the reduction of patient QMGS for the remaining targeted agents compared with placebo. With regards to the secondary outcomes, only batoclimab (RR, 0.19; 95% CrI, 0, 0.97) led to a significant reduction in the incidence of AEs when compared with the placebo. Belimumab (RR, 0.85; 95% CrI, 0.57, 1.19), CFZ533 (RR, 0.95; 95% CrI, 0.72, 1.25), eculizumab (RR, 0.99; 95% CrI, 0.85, 1.21), and efgartigimod (RR, 0.93; 95% CrI, 0.76, 1.15) also led to a lower incidence of AEs, although these effects were not significantly different from the placebo.

CONCLUSIONS:

Batoclimab had the best efficacy and safety for the treatment of gMG and was ranked first out of the 10 targeted drugs included in this study. Eculizumab was ranked second, and nipocalimab had the worst efficacy. With the exception of batoclimab, the incidence of AEs for the remaining drugs was not statistically significantly different from placebo. We note, however, that wide CrIs reflect the uncertainty in this analysis owing to the small number of available studies and low numbers of study participants; moreover, batoclimab had the widest CrI of all drugs in this analysis. More well-designed studies with long-term follow-up are needed to further evaluate and compare the efficacy and safety of these drugs in the future.

2024-01-23·Neurology

Safety and Efficacy of Nipocalimab in Patients With Generalized Myasthenia Gravis

Article

作者: Arroyo, Santiago ; Sun, Hong ; Ramchandren, Sindhu ; Meuth, Sven G ; Gamez, Josep ; Zhu, Yaowei ; Quan, Dianna ; Sevilla, Teresa ; Nowak, Richard J ; Jouvin, Marie-Helene ; Jin, Jim ; Guptill, Jeffrey ; Antozzi, Carlo ; Karcher, Keith ; Ling, Leona ; Bril, Vera

BACKGROUND AND OBJECTIVES:

To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG).

METHODS:

Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups.

RESULTS:

Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend).

DISCUSSION:

Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG.

TRIAL REGISTRATION INFORMATION:

Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019.

CLASSIFICATION OF EVIDENCE:

This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.

146

项与尼卡利单抗相关的新闻（医药）

2024-07-18

·空之客

【医苑观畴】2024年二季度海外药企进展更新：强生JNJ

1 整体表现 JNJ在持续两年多不温不火的业绩之后，医药部分的季度收入首次有了比较可观的增长、到了145亿，但市值依然回不到4,000亿大关，与GLP-1双雄LLY和NOVO的距离仍在越拉越大。扣除新冠影响的收入增长为7.2%，经调整的EPS增长为10.2%，在MNC里面应该属于中规中矩的表现。 2 已上市产品自免板块稍稍止住了前两个季度的颓势：Ustekinumab单季度再创新高，LTM累计已达到$11b，不过随着生物类似药马上进入欧洲、明年进入美国，这个巨大专利悬崖仍无法回避；Guselkumab也维持在高位水平，LTM累计$3.5b，后续公司也很明显投入了相当多的资源来尝试拿它填补Ustekinumab身后的空位；Infliximab和Golimumab两个则确实彻底失去增长动力了。肿瘤板块仍然在高歌猛进：Daratumumab上市已近十年，甚至还能维持着二阶导增速，LTM累计已达到$10.6b；Apalutamide也仍在持续爬坡中，LTM累计也超过$2.7b；Cilta-cel在此前连续三个季度近乎完全滞涨之后，终于有了环比增长、单季度达到$186m，看来产能瓶颈应开始缓解；Teclistamab双抗的爬坡也并不理想，单季度环比也已停滞；Ibrutinib则持续被AZ和百济侵蚀。心血管板块里，Rivaroxaban在达峰后的衰退通道中略有反弹，但Macitentan和Selexipag两个PAH产品爬坡势头略有迟缓，单季度迟迟突破不了$1b大关，似乎想要配得上当初$30b收购Actelion的价格仍有很大距离。传染病板块已接近归零的新冠疫苗突然又有了一些销量，Darunavir和Rilpivirine则已疲态尽显。精神板块虽然Paliperidone早已失去增长，但Esketamine爬坡还是相当有盼头、LTM累计已接近$900m。 3 在研管线在自免板块大哥IL12p40单抗Ustekinumab面临专利悬崖压力的当口，公司果断将IL23p19单抗Guselkumab推到前线顶住压力，除了主打注射和皮下双剂型以外，近期连续公布针对CD维持治疗的三期临床GALAXI 2&3研究结果在内镜终点上与Ustekinumab相比展现出显著优势、针对UC维持治疗的三期临床QUASAR研究结果也都达到各临床终点，此外已向美欧监管部门提交治疗CD的上市申请。自免板块另一个被公司寄予厚望的便是FcRn单抗Nipocalimab，在被argenx的FIC药物Efgartigimod压制了至少三年多之后，近期公布了Nipocalimab在治疗重症肌无力的三期临床Vivacity-MG3研究中达到长期有效性终点，并且公司在这款药物上寄托着$5b以上的期望值。大概也是感到仅靠手头这几杆枪仍旧撑不住自免的危局，这个季度连续出手收购基于成熟靶点的双抗资产，包括从Numab以$1.25b收购将进入二期的IL4Rα/IL31双抗NM26，以及以$850m收购Proteologix获得将进入一期的IL13/TSLP双抗PX128和尚在临床前的IL13/IL22双抗PX130。肿瘤板块比较有趣的进展是膀胱内给药系统，TAR-200（吉西他滨）针对85例BCG不响应的高风险NMIBC患者达到82.8%的CR且DOR超过一年比例为74.6%，TAR-210（厄达替尼）针对21例BCG不响应的高风险NMIBC患者一年无复发生存率达到90%、针对31例中风险NMIBC患者达到90%的CR。当然近期最有想象空间的大事件，就属传奇生物的收购传闻，潜在收购方（也应该是最顺理成章的人选）便是JNJ本尊。除此以外，值得关注的进展还包括：Carvykti获得欧盟批准治疗2-4L MM，EGFR/cMET双抗Amivantamab获得欧盟批准治疗1L EGFR exon20突变NSCLC，两款CD3双抗Teclistamab和Talquetamab分别公布了治疗末线MM的长期有效性数据，OX2R拮抗剂Seltorexant公布了伴随失眠症状的重度抑郁症的三期临床MDD3001研究结果。 4 番外：中国市场在业绩电话会上，有提问者突然问到对于中国市场的看法（当然主要是针对器械业务），公司对集采和医疗反腐给出了积极的态度，表示要顶着价格和地缘政治压力继续深耕中国市场，可以说是MNC中不算常见的明确表态。 JNJ凭借肿瘤和自免两大板块多年来的强势表现，一直是MNC中业绩成长较为稳定的一家。从近几个季度来看，自免板块正处在新老支柱品种的交接棒环节、公司也大手笔引入早期双抗品种来稳住阵脚，肿瘤板块在MM适应症的霸主地位仍能维持、特别是Cilta-cel在产能缓解后重拾爬坡增速且传奇也有了被收购传闻，这两个板块依然将是未来多年公司价值的基石。

并购临床3期疫苗生物类似药临床结果

2024-07-18

·FiercePharma

Argenx posts J&J-rivaling Sjögren's data, massively upscales Vyvgart patient population at R&D day

Vyvgart—which won its original nod in generalized myasthenia gravis (gMG) in late 2021 and another in chronic inflammatory demyelinating polyneuropathy (CIDP) this summer—still has an outsized role to play in argenx's burgeoning success story. Even as argenx begins to chart a course toward a future beyond Vyvgart, the company’s flagship FcRn inhibitor still has plenty of tricks in store for the remainder of the decade. By 2030, argenx is aiming to have five new preclinical assets in phase 3 development, 10 approved indications across Vyvgart and other near-term prospective launches, and 50,000 patients on therapy across current and future argenx products, the company said at an R&D day Tuesday. The plan has been dubbed “Vision 2030: Taking Breakthrough Science to 50,000 Patients.” While up-and-coming candidates like the C2 scavenger antibody empasiprubart and ARGX-121 are certainly expected to contribute to argenx’s growth in the coming years, Vyvgart—which won its original nod in generalized myasthenia gravis (gMG) in late 2021 and another in chronic inflammatory demyelinating polyneuropathy (CIDP) this summer—still has an outsized role to play in the company’s burgeoning success story. For one, argenx has drastically overhauled its projection for the total addressable gMG market. The company now figures the market opportunity for Vyvgart has swelled to 42,000 patients, up from an original estimate of 17,000, analysts at Citi wrote in a note to clients. Argenx credits that market growth to the expansion of biologics share in gMG, plus the increasing use of Vyvgart in earlier lines of therapy. What’s more, argenx figures it could snare another 11,000 seronegative and 7,000 ocular gMG patients through potential label expansions to bring its total addressable population up to roughly 60,000. Argenx is currently marketing Vyvgart for gMG in the U.S., Canada and multiple European countries, as well as China and Japan. The company also has Vyvgart distribution deals in places like the Middle East and Eastern Europe. As for Vyvgart’s CIDP launch, the drug has so far reached two patients, according to a note from analysts at William Blair. One of those patients was commercial, while the other’s medication was reimbursed by Medicare. According to the William Blair team, argenx is actively working through formulary placements with payers and expects prior authorization and coverage denial headwinds to improve as these are finalized. Despite some initial hurdles with the rollout, the William Blair team said that “early underlying demand appears strong” in CIDP. To hear analysts at Citi tell it, meanwhile, over 25% of key CIDP physician targets were reached within the first two weeks of Vyvgart’s launch. Argenx said it’s seeing early adoption and noted that doctors have written prescriptions for multiple CIDP patients. At the same time, roughly 20% of those doctors are first-time Vyvgart prescribers, suggesting an “early expansion of the Vyvgart prescriber base,” according to the Citi team. In argenx’s final Vyvgart trick of the day, the company also posted positive phase 2 data in Sjögren's disease (SjD), where Johnson & Johnson recently found midstage success with its own phase 2 candidate nipocalimab. Argenx’s data provide “encouraging validation for the FcRn mechanism in Sjogren’s,” the team of Citi analysts said, adding that argenx plans to kick off a phase 3 trial of Vyvgart in SjD by year-end. Analysts at Leerink Partners, for their part, said argenx’s SjD data were “encouraging” and “appear competitive” versus J&J’s. Argenx first telegraphed plans for the new Vision 2030 program in mid-June. “[A]rgenx today is better positioned than ever before to deliver on our commitment to transform the autoimmunity treatment landscape for patients,” CEO Tim Van Hauwermeiren said in a statement at the time. “We have grown from our R&D roots over the last five years into a true global innovator, pioneering novel targets into a robust pipeline and delivering safe and effective first-in-class medicines to more than 10,000 patients around the world.”

临床3期临床2期临床结果上市批准

2024-07-16

·CPHI制药在线

重症肌无力抗体类药物治疗的研究进展

关注并星标CPHI制药在线重症肌无力是一种由神经肌肉连接处特异性的自身抗体引起的慢性自身免疫病，虽然静脉注射免疫球蛋白、血浆置换等传统治疗方法具有一定的临床效果，但因传统治疗方法对重症肌无力的选择性问题而存在一系列不良反应。随着对该疾病机理研究的深入及单克隆抗体（单抗）研发技术的发展，近年来用于重症肌无力治疗的抗体类药物也有了新的突破，如新生儿Fc受体（neonatal Fc receptor, FcRn）靶点抗体类药物、抗补体5单抗药物等。 FcRn靶点抗体类药物 FcRn与免疫球蛋白G（immunoglobulin G,IgG）的结合在IgG分布、运输和持久性中起重要作用。研究表明，IgG 回收率比 IgG 产生率高42%，表明IgG的回收是维持人体高IgG血清浓度的主要机制，其高血清浓度和长半衰期很大程度上依赖FcRn介导的再捕获和再循环。因此，抑制FcRn与IgG 的结合可以缩短IgG半衰期，特异性地减少其在体内的滞留时间，进而产生类似于血浆置换的致病性 IgG 清除效果。在酸性和中性环境下，FcRn抑制剂与 FcRn的亲和力均高于IgG，可通过竞争作用阻断致病性IgG与FcRn的结合，进而清除致病性IgG。 1、Efgartigimod α Efgartigimod α 是由荷兰Argenx公司开发的一款人IgG1型抗体Fc片段，经过基因工程技术改造后在生理pH和酸性pH下与FcRn的亲和力增强，通过竞争性阻断致病性IgG抗体再循环，促进靶向降解。Efgartigimod α 作为首款 FcRn抗体类药物于2021年12月被美国食品药品监督管理局（FDA）获批，它也是目前唯一在美国、欧洲的国家和日本获批用于成人全身型重症肌无力治疗的 FcRn拮抗剂。2022年7月，再鼎医药有限公司作为Efgartigimod α注射液的申请人在中国申报上市，申报的适应症为成人全身型重症肌无力。 2、Rozanolixizumab Rozanolixizumab是一种可皮下注射的人源化FcRn抗体，在pH=6.0和pH=7.4条件下对 FcRn具有高亲和力。Rozanolixizumab的Ⅰ期临床试验结果表明，Rozanolixizumab 组患者血清IgG水平降低50%，并于用药后第8周逐渐恢复至基线水平，所有血清IgG亚类均出现剂量依赖性降低，IgG3下降最明显。Rozanolixizumab 皮下注射7mg/kg 的单剂量比静脉注射4mg/kg 的单剂量具有更高的安全性。随后的Ⅱ期临床研究表明，血清IgG和乙酰胆碱受体（acetylcholine receptor, AChR）抗体水平均降低，但主要终点重症肌无力定量评分（QMGS）差异不具有统计学意义。研究期间最常发生的不良事件是头痛，头痛发生率高于安慰剂组。Ⅲ期临床研究结果表明，7mg/kg和 10mg/kg的Rozanolixizumab 在全身性重症肌无力患者中具有一致的、有临床意义的疗效。研究期间，最常发生的不良事件依然也是头痛，大多数头痛为轻度至中度。 3、Batoclimab Batoclimab是由中国和铂医药研发的一款完全人源化的抗FcRn的IgG1型单抗，可用于皮下或静脉注射，其Fc段可减少抗体依赖性细胞介导的细胞毒性作用。Batoclimab 的Ⅱ期临床研究结果显示，研究第7天时，Batoclimab组患者血清IgG水平迅速降低，剂量为340 mg和680 mg 组的血清IgG水平分别降低了23%和44%，而安慰剂组的血清 IgG 水平仅降低了1%。研究第43天时，血清IgG水平降至最低，340 mg和680 mg组分别降低了57%和 74%，安慰剂组则降低了2%。研究前6周，340 mg 组及 680 mg 组的 MG-ADL 较安慰剂组显著降低，MGC 评分、QMGS 和重症肌无力患者生活质量评价量表（myasthenia gravis quality oflife 15-item scale revised, MG-QoL15r）评分也同样降低。另外，研究中 Batoclimab 组中白蛋白含量呈剂量依赖性下降，可在停药后6周恢复到基线水平。研究期间，Batoclimab 组最常见的不良事件是高胆固醇血症，Batoclimab 组的头痛发生率低于其他 FcRn 抑制剂报道的发生率。 4、Nipocalimab Nipocalimab是美国强生公司开发的一款完全人源化、去糖基化的IgG1型抗FcRn单抗，在细胞内和细胞外pH条件下均与FcRn有极高的亲和力，可极大限度地降低脱靶效应。临床Ⅰ期研究结果显示，当Nipocalimab剂量≥3 mg/kg时，用药2h后受体结合率大于90%（流式细胞术测量），SAD 研究中，所有剂量组均可观察到总 IgG 血清水平呈剂量依赖性的降低，60mg/kg组在2周内血清IgG较基线水平降低约80%；MAD研究中，Nipocalimab组IgG水平降低约85%，并持续24d保持较基线水平降低≥75%。研究中SAD 60 mg/kg 组及 MAD 15、30 mg/kg 组可观察到无症状、短暂的总蛋白和白蛋白含量下降。Nipocalimab的Ⅱ期临床研究结果表明，Nipocalimab组中52%的患者MG-ADL评分出现快速、显著且持久的降低，并且在M281组中观察到IgG减少与临床症状改善之间存在显著相关性。该研究中，Nipocalimab显示出良好的安全性，未发生严重不良事件。人源化 FcRn 抑制剂在治疗重症肌无力方面有很多优势。例如，可在细胞表面以高亲和力结合FcRn，在酸性条件下对FcRn的亲和力高于IgG；可增加IgG的清除而不影响IgG的产生；不影响免疫球蛋白A、免疫球蛋白D、免疫球蛋白E 和免疫球蛋白M的血清水平，降低感染风险。这些优势表明 FcRn 抑制剂比传统的免疫治疗更有效且安全。尽管如此，FcRn 抑制剂长期治疗的效果需要继续观察，Batoclimab和Nipocalimab 研究中，检测到与药物相关的白蛋白水平下降，尽管这种改变可逆，且没有症状，仍需要进一步研究来解释这些不良反应的机制及其影响。除了上述进展较快的品种外，还有一些 FcRn 靶点抗体类药物也在临床试验进程中，如英国阿斯利康制药有限公司的Orilanolimab（SYNT001）、美国Immunovant公司的imimvt-1402、中国领诺（上海）医药科技有限公司的LIN-2007、美国Syntonix制药公司的SYN1436等。FcRn 靶点抗体类药物开发的适应症除了全身型MG，还包括慢性炎症性脱髓鞘性多发性神经病、免疫性血小板减少症、肌炎、新生儿溶血性疾病、膜性肾病、甲状腺相关性眼病等自身免疫病。抗补体5单抗药物重症肌无力患者体内抗AChR抗体结合抗原后可以激活补体活化通路，活化级联反应中形成补体5（complement 5，C5）转化酶，它将C5分裂成C5a和C5b。C5b与C6-C9因子结合形成膜攻击复合物（membrane attack complex，MAC），导致细胞损伤和裂解。动物模型和临床实践研究结果显示，降低补体水平可降低重症肌无力的发病率，减轻疾病的严重程度。基于这一证据，开发抑制共同补体途径的抗C5转化酶抗体成为用于重症肌无力治疗的另一药物研发方向。 1、Eculizumab Eculizumab是一种人源化IgG2/4型单抗，能够特异性结合补体蛋白C5并阻止C5裂解为C5a和C5b，从而抑制MAC的生成。它是第一种针对补体系统的药物，最初于2007年被FDA批准用于治疗阵发性睡眠性血红蛋白尿。Eculizumab 的Ⅲ期多中心试验结果显示，Eculizumab组的MG-ADL评分、QMGS和MGQoL15r 评分、MGC 评分均降低，研究中出现的不良事件包括头痛、呼吸道感染等均表现轻微，严重导致停药的不良事件为陷窝菌菌血症及肠穿孔，但不能证明与药物相关。Eculizumab 的安全性良好，最常见不良事件是头痛和鼻咽炎，15% 的患者出现重症肌无力恶化，3%的患者出现肌无力危象。2017年 FDA批准Eculizumab用于治疗抗AChR抗体阳性的全身型重症肌无力。 2、Ravulizumab Ravulizumab是由美国Alexion制药公司开发的一款人源化的抗C5单抗，相较于Eculizumab，它对C5具有更高的亲和力，且其Fc段经氨基酸改造后延长了抗体的半衰期。2022年4月，FDA批准Ravulizumab用于治疗抗AChR抗体阳性的全身型重症肌无力患者，成为首个获批用于该患者群体的长效C5补体抑制剂。Ravulizumab Ⅲ期临床结果表明，与安慰剂相比，从基线到26周，Ravulizumab在MG-ADL得分和Q重症肌无力总分中平均变化幅度显著增加。2项指标的改善均发生在 Ravulizumab开始给药后1周内，并持续到第26周。与接受安慰剂的患者相比，Ravulizumab治疗患者的Q重症肌无力总分提高了5分或更多。研究至第60周，Ravulizumab 组所有疗效终点变化均有统计学意义。研究期间，Ravulizumab总体耐受性良好，最常见的不良事件是头痛和腹泻，并且大多数不良反应的严重程度为轻度，但Ravulizumab 组患者腹痛、头晕和上呼吸道感染事件发生率高于安慰剂组。 3、Zilucoplan Zilucoplan可抑制补体C5裂解，且可结合预先形成的C5b，阻断其与C6补体的相互作用，其优点是患者可自行、快速皮下注射给药。Zilucoplan 的Ⅱ期临床研究结果表明，较安慰剂组，Zilucoplan 剂量为0.3 mg/ （kg·d）组的QMGS 降低具有统计学意义，并可在1周内开始发挥作用。Zilucoplan 的Ⅲ期临床研究表明，研究至第12周时，Zilucoplan 组患者的 MG-ADL评分较基线的改变显著大于安慰剂组。在次要终点分析中，较安慰剂组，Zilucoplan组的QMGS、MGC评分、MG-QoL15r评分从基线到第12周的降低具有临床意义。研究中，Zilucoplan 组中最常报告的不良事件依次为注射部位瘀肿、头痛、腹泻和重症肌无力恶化，安慰剂组中最常报告的不良事件依次为头痛、重症肌无力恶化和注射部位瘀肿，其中注射部位瘀肿、注射部位疼痛、腹泻在 Zilucoplan组更常见，并且Zilucoplan 组的感染发生率高于安慰剂组。补体抑制剂治疗重症肌无力效果显著、安全性良好，研究中出现的不良事件多为轻度至中度，且以头痛多见，可作为重症肌无力治疗的选择。然而目前的研究中，没有单独使用补体抑制剂治疗，通常是联合其他传统免疫治疗，因此单独使用补体抑制剂的疗效及安全性需要更多的研究证明。参考资料 [1]徐刚领,王兰.治疗重症肌无力抗体类药物的研究进展[J].微生物学免疫学进展,2023,51(04):82-86. [2]崔慧慧,徐梓桐,王金萍,等.重症肌无力生物靶向药物治疗研究进展[J].兰州大学学报(医学版),2023,49(12):88-94. 作者简介：小泥沙，食品科技工作者，现就职于国内某大型药物研发公司，从事营养食品及功能性食品的开发与研究。 END 【智药研习社抗体系列直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床3期临床2期申请上市

100 项与尼卡利单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11666	-	-	DB16257

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
胎儿/新生儿同种免疫性血小板减少症	临床3期	比利时	Janssen Research & Development LLC	2024-07-22
胎儿/新生儿同种免疫性血小板减少症	临床3期	意大利	Janssen Research & Development LLC	2024-07-22
胎儿/新生儿同种免疫性血小板减少症	临床3期	挪威	Janssen Research & Development LLC	2024-07-22
胎儿/新生儿同种免疫性血小板减少症	临床3期	斯洛伐克	Janssen Research & Development LLC	2024-07-22
胎儿/新生儿同种免疫性血小板减少症	临床3期	西班牙	Janssen Research & Development LLC	2024-07-22
胎儿/新生儿同种免疫性血小板减少症	临床3期	瑞典	Janssen Research & Development LLC	2024-07-22
新生儿同种免疫性血小板减少症	临床3期	比利时	Janssen Research & Development LLC	2024-07-22
新生儿同种免疫性血小板减少症	临床3期	意大利	Janssen Research & Development LLC	2024-07-22
新生儿同种免疫性血小板减少症	临床3期	挪威	Janssen Research & Development LLC	2024-07-22
新生儿同种免疫性血小板减少症	临床3期	斯洛伐克	Janssen Research & Development LLC	2024-07-22

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临床结果

适应症

分期

评价

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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


NCT04951622 (Vivacity-MG3, GlobeNewswire) 人工标引	临床3期	重症肌无力 anti-AChR+ \| anti-MuSK+ \| anti-LRP4+	153	nipocalimab plus SOC	網艱窪願衊構夢廠鏇廠(蓋壓憲憲鏇獵憲壓壓繭) = 鹽繭憲鏇顧襯廠獵築積窪觸鑰選鬱觸鑰獵襯蓋 (窪醖鬱艱範鹽積觸顧齋 ) 达到更多	积极	2024-06-28
				Placebo plus SOC	網艱窪願衊構夢廠鏇廠(蓋壓憲憲鏇獵憲壓壓繭) = 築鹽鏇壓襯廠膚鏇鬱鹹窪觸鑰選鬱觸鑰獵襯蓋 (窪醖鬱艱範鹽積觸顧齋 ) 达到更多
NCT04968912 (DAHLIAS, EULAR2024) 人工标引	临床2期	干燥综合征	163	NIPOCALIMAB 5 mg/kg	選鬱餘醖壓觸夢壓鏇鹽(艱壓襯遞顧齋鬱構積鹹) = 夢窪壓壓廠願鹹觸構構鑰糧繭窪醖鏇鑰襯夢憲 (築製範鑰廠衊餘築製鏇, -5.10 ~ -3.07) 更多	积极	2024-06-12
				NIPOCALIMAB 15 mg/kg	選鬱餘醖壓觸夢壓鏇鹽(艱壓襯遞顧齋鬱構積鹹) = 鹹餘繭簾衊遞齋齋鬱遞鑰糧繭窪醖鏇鑰襯夢憲 (築製範鑰廠衊餘築製鏇, -7.43 ~ -5.36) 更多
NCT04951622 (VIVACITY, Corporate Publications) 人工标引	临床3期	重症肌无力	-	Nipocalimab	憲齋觸網鑰襯蓋觸範網(遞廠顧鹹範窪餘顧獵鹹) = achieving statistically significant reduction in MG-ADLa score from baseline over weeks 22 to 24 compared with placebo (PBO) 膚簾築醖鹽構遞鑰糧願 (醖艱憲獵積廠窪餘憲窪 ) 达到	积极	2024-02-05
				placebo
NCT04968912 (DAHLIAS , Corporate Publications) 人工标引	临床2期	干燥综合征	-	Nipocalimab	鬱艱憲鑰淵鏇艱鹽鹽製(餘觸壓構餘積衊獵齋廠) = with a statistically significant reduction in clinESSDAIb score from baseline at week 24 compared with placebo (PBO) 齋壓齋製願願製範壓觸 (鬱願糧艱壓選鹹蓋醖範 ) 达到	积极	2024-02-05
				placebo
NCT04991753 (IRIS-RA, ACR2023) 人工标引	临床2期	类风湿关节炎	53	nipocalimab	範顧繭觸淵夢網廠獵顧(鬱觸襯選簾襯繭壓築鏇) = 廠網鬱齋餘觸窪廠齋積構鹹鹽獵醖範製築醖積 (獵齋鬱鑰膚積鹽艱願淵 )	积极	2023-11-14
				placebo	範顧繭觸淵夢網廠獵顧(鬱觸襯選簾襯繭壓築鏇) = 憲淵遞觸齋鏇衊齋憲衊構鹹鹽獵醖範製築醖積 (獵齋鬱鑰膚積鹽艱願淵 )
ACR2023	N/A	类风湿关节炎	-	Nipocalimab 15 mg/kg	選廠網憲夢鬱衊醖鑰襯(艱夢構遞糧願積鹽構糧) = The proportion of patients with treatment-emergent adverse events (TEAEs) were 81.8% vs 60.0% in the nipocalimab vs placebo groups 簾鹽繭壓憲選膚構遞簾 (觸簾蓋糧憲醖製網範選 ) 更多	-	2023-11-12
				Placebo
NCT03896295 (CTgov)	临床2期	重症肌无力	37	Placebo+Nipocalimab (Placebo-Nipocalimab)	襯製製衊鑰衊糧鏇構廠(繭築遞範淵襯襯憲膚製) = 淵遞繭窪鬱構鏇廠顧鹹顧鑰願壓膚襯糧艱壓艱 (淵簾鑰淵廠選餘鑰衊憲, 遞願構餘鹹齋網鹽製製 ~ 積構繭鏇衊網廠衊繭糧) 更多	-	2022-02-16
				Nipocalimab (Nipocalimab-Nipocalimab)	襯製製衊鑰衊糧鏇構廠(繭築遞範淵襯襯憲膚製) = 廠壓鑰繭蓋餘膚網鏇艱顧鑰願壓膚襯糧艱壓艱 (淵簾鑰淵廠選餘鑰衊憲, 夢鏇衊廠繭膚餘鬱鹽膚 ~ 範廠簾艱築淵廠選衊繭) 更多
NCT03772587 (Vivacity-MG, CTgov)	临床2期	重症肌无力	68	placebo+nipocalimab (Placebo)	齋鹽醖製餘願醖糧淵廠(鬱獵壓蓋餘醖觸壓獵選) = 鏇窪鑰鹽簾壓鹹淵衊衊窪範構鹽醖範壓顧範範 (齋網獵願選鹽窪鏇窪夢, 積顧鹽鏇範築膚觸願鏇 ~ 鏇餘膚齋鬱壓蓋壓顧遞) 更多	-	2021-10-27
				placebo+nipocalimab (Nipocalimab 5 Milligrams/Kilogram (mg/kg))	齋鹽醖製餘願醖糧淵廠(鬱獵壓蓋餘醖觸壓獵選) = 衊範醖鹹觸遞繭齋製蓋窪範構鹽醖範壓顧範範 (齋網獵願選鹽窪鏇窪夢, 築壓鹹簾窪膚窪獵繭鑰 ~ 廠鑰蓋糧窪鑰選淵憲膚) 更多
NCT03772587 (Vivacity-MG, GlobeNewswire) 人工标引	临床2期	重症肌无力	68	Nipocalimab	鏇襯鬱製鬱繭獵膚選繭(鑰淵艱鹹餘餘蓋膚獵網) = 構網網簾膚範製鏇鏇製繭襯鬱鹽廠繭觸鏇壓蓋 (鬱鹽積憲簾鹽網製積壓 )	积极	2020-06-15
				Placebo	鏇襯鬱製鬱繭獵膚選繭(鑰淵艱鹹餘餘蓋膚獵網) = 觸艱願鬱齋夢網築製衊繭襯鬱鹽廠繭觸鏇壓蓋 (鬱鹽積憲簾鹽網製積壓 )