Investigating the Effects of Th2 Modulation on the Generation and Persistence of Tissue Adaptive Immune Memory in Chronic Rhinosinusitis With Nasal Polyposis

Chronic rhinosinusitis (CRS) is a condition of persistent sinonasal mucosal inflammation which affects 11.9% of the US population. Mepolizumab is newly approved to treat chronic rhinosinusitis with nasal polyps (CRSwNP, the spaces inside nose and head are swollen and inflamed) and acts booking interleukin-5 (IL-5) a protein implicated in the inflammatory process. We aim to use Single-cell RNA sequencing (RNA-Seq, a method of genetically 'barcoding' cells to allow gene expression to be profiled at the level of individual cells) to study the effects of IL-5 blockade on the generation and maintenance of nasal adaptive immune responses, in CRS subjects.

开始日期2024-06-01

申办/合作机构

St. Paul's Hospital

NCT05708300 / RecruitingN/AIIT

Novel Insight in pathologiCal and clinicAl Attributes in Response to mepoLizumab Treatment in Patients With Chronic rhInosinusitis With Nasal pOlyPs With or Without bronchIal Asthma on a Long-term Basis (CALIOPI STUDY)

Mepolizumab is a biologic agent already approved for severe asthma. Recently, there is increasing evidence concerning the benefit of anti-IL5 treatments upon patients with nasal polyposis with or without severe asthma.
The novelty of this project is that no biologic agent has yet been fully investigated to identify any biomarkers of response for patients with nasal polyps with or without asthma including sinonasal tissue remodeling a key element in the resultant histopathological changes of the inflammation. The investigation of airway remodeling of various locations (nose and bronchus) under mepolizumab treatment will be our primary objective on the long-term basis of 156 weeks of treatment.
Endobronchial and nasal biopsies will be performed as routine care for tissue evauation and disease investigation for every patient.
Besides, the united airways will provide better guidance for medical treatment of chronic rhinosinusitis (CRS) patients with nasal polyps (CRSwNP) and asthma.
The initial idea is based on investigating the characteristics that could predict the effectiveness of mepolizumab on patients with nasal polyposis with or without asthma. Patients will receive 39 doses of mepolizumab for 156 weeks. An additional aim of this study is to identify characteristics of non-responders and responders to mepolizumab. Responders will be identified based on airway remodeling status, biomarkers in tissue and secretion samples and on the reduction of the need of surgery through Lund-Kennedy endoscopic score, Lund-Mackay score and patient's clinical status in the 6th, 12th and 36th month after the initiation of treatment.
Regarding the unified airway system, nose and pharyngeal microbiome will be evaluated before and after 52 weeks of mepolizumab treatment in patients with nasal polyps whereas in patients with nasal polyps and asthma bronchus microbiome will also be evaluated. Lung samples will help gain information about the inflammatory profile and local microbiome of CRSwNP patients with asthma through molecular and cellular assays. The human Pharyngeal Microbiome might play a protective role in Respiratory Tract Infections and it has been reported that the microbiome provides critical signals to promote maturation of immune cells and differentiation of the tissue. Thus, we will make an effort to correlate microbiome of various locations with clinical and laboratory characteristics of responders and non-responders to mepolizumab treatment.

开始日期2024-02-23

申办/合作机构

Aristotle University of Thessaloniki

[+4]

NCT06258772 / Not yet recruitingN/AIIT

Effectiveness of Mepolizumab in the Treatment of Patients With Severe Uncontrolled CRSwNP: a Multicentric Real Life Observational Study

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a complex chronic inflammatory disease of the nasosinusal mucosa that has a significant negative impact on patients' quality of life.
In CRSwNP, chronic inflammation is primarily driven by type 2 pro-inflammatory interleukins (ILs )such as IL-5, IL-4, and IL-13 along- side high levels of eosinophils in the surrounding tissue. Mepolizumab is a targeted, humanized anti-IL-5 antibody that prevents IL-5 from binding to its receptor on eosinophils and selectively inhibits eosinophilic inflammation.
So far, randomized clinical trials have assessed efficacy and safety of Mepolizumab in a large number of patients, whereas evidences in real life clinical practice are limited to few monocentric series.
Herewith, we present a multicenter, observational, prospective/retrospective nationwide real-life study with the aim to confirm the effectiveness and the safety of Mepolizumab over the first year of treatment in a real life setting.
The primary objective of this study is to evaluate the reduction of dimension of nasal polyps and the improvement of quality of life in the patient measured through symptomatologic questionnaires.
The secondary objective is to evaluate improvements in terms of smell dysfunction, comorbidities, biomarkers (nasal cytology and blood eosinophilia), need of surgery or systemic steroids.

开始日期2024-02-05

申办/合作机构-

100 项与美泊利珠单抗相关的临床结果

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100 项与美泊利珠单抗相关的转化医学

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100 项与美泊利珠单抗相关的专利（医药）

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1,046

项与美泊利珠单抗相关的文献（医药）

2024-12-01·Annals of medicine

Clinical characteristics of complete responders versus non-complete responders to omalizumab, benralizumab and mepolizumab in patients with severe asthma: a long-term retrospective analysis.

Article

作者: Maria Basagaña ; Carlos Martínez-Rivera ; Clara Padró ; Ignasi Garcia-Olivé ; Mimar Martínez-Colls ; Juan Navarro ; Laura Pardo ; Paula Cruz ; Gloria Cardona Peitx ; Lídia Carabias ; Albert Roger ; Jorge Abad ; Antoni Rosell

BACKGROUND:

Some patients with severe asthma may benefit from treatment with biologics, but evidence has been mostly collected from randomized controlled trials (RCTs), in which patients' characteristics are different from those encountered in asthma patients in the real-world setting. The aim of this study was to describe the clinical features of complete responders versus non-complete responders to long-term treatment with biologics in patients with severe asthma attended in routine daily practice.

METHODS:

Data of a cohort of 90 patients with severe asthma who were treated with biologics (omalizumab, benralizumab, and mepolizumab) for at least 12 months and were followed up to March 2022. Data recorded included clinical characteristics and effectiveness of treatment (exacerbation, Asthma Control Test [ACT] score, lung function, use of maintenance oral corticosteroids [mOCS]), FeNO, and blood eosinophils at baseline, at 12 months, and at the end of follow-up. Complete response is considered if, in addition to not presenting exacerbations or the use of mOCS, the ACT score was >20 and, the FEV₁ >80% predicted.

RESULTS:

An improvement in all asthma control parameters was observed after 12 months of treatment and a mean follow-up of 55 months. After 12 months of treatment 27.2% of patients met the criteria of complete response and this percentage even increased to 35.3% at the end of follow-up. Long-term complete response was associated to better lung function with mepolizumab and omalizumab treatment and to less previous exacerbations in the benralizumab group. The main cause of not achieving a complete response was the persistence of an airflow obstructive pattern.

CONCLUSIONS:

This study shows that omalizumab, benralizumab, and mepolizumab improved the clinical outcomes of patients with severe asthma in a clinic environment with similar effect sizes to RCTs in the long term follow-up. Airflow obstruction, however, was a predictor of a non-complete response to biologics.

2024-02-23·The New England journal of medicine

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

Article

作者: Michael E Wechsler ; Parameswaran Nair ; Benjamin Terrier ; Bastian Walz ; Arnaud Bourdin ; David R W Jayne ; David J Jackson ; Florence Roufosse ; Lena Börjesson Sjö ; Ying Fan ; Maria Jison ; Christopher McCrae ; Sofia Necander ; Anat Shavit ; Claire Walton ; Peter A Merkel ; MANDARA Study Group

BACKGROUND:

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA.

METHODS:

We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety.

RESULTS:

A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively.

CONCLUSIONS:

Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

2024-02-22·American journal of respiratory and critical care medicine

Mepolizumab Induced Changes in Nasal Methylome and Transcriptome to Predict Response in Asthma.

Article

作者: Kamini Rakkar ; Yik L Pang ; Poojitha Rajasekar ; Michael A Portelli ; Robert J Hall ; Rachel L Clifford ; Dominick Shaw ; Ian Sayers

117

项与美泊利珠单抗相关的新闻（医药）

2024-04-01

·医药魔方

2024年3月 | 12款创新药进入III期，5款来自中国药企

根据全球临床试验收录网站clinicaltrials和中国临床试验登记平台chinadrugtrials，3月共12款创新药进入III期阶段，其中5款来自中国药企。这些在研药物覆盖靶点不乏HER2、CLDN18.2、IL-5等热门靶点，也包括apo(a)和C1s这类新颖靶点。本文筛选其中6款重点产品加以介绍。注：1.信息来源于clinicaltrials和chinadrugtrials。2.仅登记创新药，微创新和生物类似药不包括在内。3.同一款药物在同一天启动多项III期临床，适应症合并记录；同一款药物在一个月内启动多项III期临床，以最早登记者准。4.EpCAM：上皮细胞黏附分子；IDH：异柠檬酸脱氢酶。药物：Lepodisiran（礼来）靶点：apo(a)适应症：脂蛋白（a）增高脂蛋白（a）主要由低密度脂蛋白（LDL）样微粒与载脂蛋白（a）（即apo(a)）组成，被认为是心肌梗死、中风和外周动脉疾病等心血管疾病（CVD）的危险因素。虽然尚未有研究确定脂蛋白（a）的危险临界值，但约20%的成人脂蛋白（a）水平超过125nmol/L（或约50mg/dL）。Lepodisiran（LY3819469）原是Dicerna Pharmaceuticals（已于2021年被诺和诺德收购）利用其GalXCTMRNAi技术平台开发的一款RNA干扰（RNAi）疗法，旨在使参与产生脂蛋白（a）的mRNA失活来减少肝脏中脂蛋白（a）的产生。2018年10月，礼来与Dicerna达成合作，以5.5亿美元的总交易额引进包括Lepodisiran在内的7款在研药物。去年11月，礼来在美国心脏协会科学年会（AHA 2023）上公布了Lepodisiran的首个I期研究数据。结果显示，在第337天时，单剂量（608mg）Lepodisiran可将患者的脂蛋白（a）水平降低94%，并持续近一年。基于I期研究的积极结果，礼来已在今年3月启动了该药物的III期临床试验，拟招募12500例脂蛋白（a）水平的有冠状动脉疾病或有首次心血管事件风险的患者。除了礼来以外，安进和诺华布局的针对脂蛋白（a）的小核酸药物也进入了III期阶段。安进开发的Olpasiran同为RNAi疗法，其在II期研究中可将患者的脂蛋白（a）水平降低97.5%，疗效显著。诺华开发的Pelacarsen则是一款反义疗法，其在I期研究中可将患者的脂蛋白（a）水平降低85.3%。药物：M701（石药集团）靶点：CD3/EpCAM适应症：癌性腹水M701是石药集团子公司友芝友生物开发的一款CD3/EpCAM双抗，也是目前唯一一款进入临床阶段的国产CD3/EpCAM双抗。I期研究结果显示，在16例可评估疗效的患者中，癌性腹水情况得到缓解的患者比例为62.5%（10/16），疾病控制率（DCR）为100%，中位总生存期（OS）为152天。癌性腹水是一种常见于晚期肺癌和乳腺癌等癌症患者的并发症，其成因是肿瘤细胞侵袭组织和引起负性因子释放等导致内皮细胞异常和渗出液增多、以及肿瘤细胞堵塞淋巴管导致淋巴液积聚。癌性腹水会导致患者产生胸闷、呼吸困难、胸痛、恶心、呕吐等严重影响生活质量的症状，同时也会影响医生对当前全身治疗药物疗效的评估。国内临床上仍然缺乏针对癌性腹水的药物，欧美国家推荐胸腔内给予滑石粉以使得胸膜黏连，从而抑制渗出液产生，但有较强的副作用。此前，曾有一款药物——卡妥索单抗获批欧洲药品管理局（EMA）批准用于治疗癌性腹水，但该药物实则无法解决实际需求，已退市。药物：Riliprubart（赛诺菲）靶点：C1s适应症：慢性炎症性脱髓鞘性多发性神经病Riliprubart是一款补体C1s单抗。今年3月，赛诺菲在美国神经病学会年会（AAN）上公布了Riliprubart治疗慢性炎症性脱髓鞘性多发性神经病（CIDP）的II期研究数据。结果显示，88%从标准治疗（免疫球蛋白/皮质类固醇）转换到Riliprubart的患者的病情有所改善或保持稳定。此前，赛诺菲已推出了一款C1s单抗——Sutimlimab（商品名：Enjaymo），不过其适应症为用于冷凝集素病患者降低由于溶血导致的红细胞输注需求。药物：AZD0901（石药集团）靶点：CLDN18.2适应症：CLDN18.2阳性胃癌或胃食管交界处腺癌AZD0901（CMG901）为康诺亚与乐普生物共同开发的CLDN18.2 ADC，由CLDN18.2特异性抗体、可裂解连接子及毒性载荷甲基澳瑞他汀E（MMAE）组成。该产品是首个在中国及美国均取得临床试验申请批准的CLDN18.2 ADC。2月23日，康诺亚宣布，其非全资附属公司KYM Biosciences（康诺亚拥有70%权益）与阿斯利康签署全球独家许可协议，将AZD0901研究、开发、注册、生产及商业化的全球权益授权给后者。KYM将收取6300万美元预付款、最多11.25亿美元的额外潜在付款，以及分级特许权使用费。康诺亚于2023年ASCO大会上公布的I期研究结果显示，在89例可评估疗效的CLDN18.2阳性胃癌或胃食管交界处腺癌患者中，确认的客观缓解率（cORR）为32.6%。作为热门靶点，CLDN18.2赛道的竞争已日渐激烈。根据医药魔方数据库，仅国内企业就有约59款临床在研CLDN18.2靶向药物，药物类型涵盖单抗、双抗、三抗、CAR-T疗法和ADC等。在12款已进入临床开发阶段的国产CLDN18.2 ADC中，IBI343（信达生物）与AZD0901处于第一梯队。药物：SSGJ-610（三生国健）靶点：IL-5适应症：嗜酸性粒细胞性哮喘SSGJ-610是一款IL-5拮抗剂，通过阻断IL-5与嗜酸性粒细胞表面受体的结合，从而降低血液、组织、痰液中的嗜酸性粒细胞水平，降低嗜酸性粒细胞所介导的炎症，达到治疗嗜酸性粒细胞性重度哮喘的作用。今年1月，SSGJ-610（100/300mg，每周1次）治疗嗜酸性粒细胞水平升高的重度哮喘的II期研究达到主要终点。结果显示，治疗第16周，两个剂量组与安慰剂组1秒用力呼气量（FEV1评分）较基线变化的均值分别为255ml、324ml和134ml，经协方差分析，两个剂量组相较安慰剂的组间差值分别为121ml和190ml，其中300mg剂量组显著优于安慰剂组（p<0.05），且与同靶点数据比较，显示出好于美泊利珠单抗（第32周较基线改善183ml、组间差值98ml）和Reslizumab（各剂量组第16周改善分别为187ml和248ml、相较安慰剂组的组间差值分别为93ml和137ml）的趋势。截至目前，全球已有两款IL-5单抗获批上市，即Reslizumab（Teva/默沙东/UCB）和美泊利珠单抗（GSK）。据GSK财报，2023年美泊利珠单抗销售额约为21亿美元。SSGJ-610是首款进入III期阶段的国产IL-5单抗。除了三生国健以外，恒瑞医药和融捷康生物的产品也已进入临床阶段。此外，正大天晴和百奥泰布局了美泊利珠单抗生物类似药，其产品均处于I期阶段。哮喘是由多种细胞以及细胞组分参与的慢性气道炎症性疾病，临床表现为反复发作的喘息、气急，伴或不伴胸闷或咳嗽等症状。我国成人的哮喘患病率为4.2%，推算我国有4570万成人哮喘患者。重症哮喘占哮喘人数的5.99%，是哮喘致残、致死的主要原因。嗜酸性粒细胞哮喘是最常见的临床表型，持续的气道嗜酸性粒细胞炎症极易促使哮喘进展为重度。重度哮喘的长期治疗药物包括中高剂量的吸入性糖皮质激素和长效β2受体激动剂，以及其他控制用药，但仍有5%~10%患者停药或药物减量后症状反复，且长期大量使用糖皮质激素会导致全身不良反应的发生。药物：HMPL-306（和黄医药）靶点：IDH1/IDH2适应症：急性髓系白血病IDH1/2的突变是各种类型的血液肿瘤和实体瘤中常见的基因变异，如急性髓系白血病（AML）、胆管癌、软骨肉瘤和神经胶质瘤。突变型的IDH造成2-羟基戊二酸积累，导致细胞分化受阻，从而诱导肿瘤的恶性发展。一些罕见个案中，患者同时携带IDH1和IDH2突变。在AML及胆管癌中，IDH突变亚型转化是对IDH抑制剂产生获得性耐药的主要机制之一，无论是由IDH1突变转为IDH2突变，或反之亦然。因此，同时抑制IDH1和IDH2突变可能是克服耐药性和提高临床疗效的具有潜力的策略。目前，全球已有2款IDH1抑制剂（Olutasidenib和艾伏尼布）和1款IDH2抑制剂（Enasidenib）获批上市。此外，施维雅开发的IDH1/2抑制剂Vorasidenib已于今年2月向FDA和EMA申报上市。HPML-306是目前开发进度仅次于Vorasidenib的同类产品。I期研究结果显示，100/150/200/250mg剂量组复发或难治性血液恶性肿瘤患者的ORR分别为33.3%（1/3）、40.0%（10/25）、14.3%（1/7）和42.9%（3/7）。推荐阅读2024年2月 | 15款创新药进入III期，5款来自中国药企2024年1月 | 7款创新药进入III期，4款来自中国药企2023年12月 | 13款创新药进入III期，6款来自中国药企2023年11月 | 18款创新药进入III期，8款来自中国药企2023年10月 | 28款创新药进入III期，9款来自中国药企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。

临床3期临床结果临床2期AHA会议临床1期

2024-03-19

·今日头条

今日Cell：国内团队发现新肠道激素，连起肠肝轴胆固醇代谢调控

03月19日的《热心肠日报》，我们解读了 15 篇文献，关注：肠肝轴，胆固醇，免疫耐受，IL-22，肠道应激，阿司匹林，IBD，肠脑轴，乳糜泻，Novonesis，Slimbiotics，i-Health，英赛飞影，海南三叶制药厂，百奥泰。该篇日报由R·AI辅助创作生成，人工审核校对。国内团队Cell：发现调控胆固醇代谢的新肠道激素 Cell——[64.5] ① 清华大学王一国、南方医科大学南方医院张惠杰与团队研究发现了一种新肠道激素Cholesin（肠抑脂素），其具有抑制肝脏胆固醇合成、降低血液胆固醇水平的作用；② Cholesin由此前功能未知的基因编码（人类 C7orf50 ，小鼠 3110082I17Rik ）；③ 肠道的胆固醇吸收可诱导Cholesin生成，肠细胞中，NPC1L1介导的胆固醇摄取促进Cholesin分泌；④ SNP变异rs1007765（位于 Cholesin 基因3'端附近）能上调 Cholesin 表达，并与人类血浆胆固醇水平呈负相关；⑤ 机制上，Cholesin进入肝脏后，通过结合孤儿G蛋白偶联受体GPr146，抑制cAMP/PKA-ERK1/2信号通路，从而抑制肝脏中SREBP2控制的胆固醇合成，减少极低密度脂蛋白分泌，降低血浆胆固醇水平；⑥ Cholesin治疗可改善模型小鼠血脂和动脉粥样硬化，与他汀类药物联用效果更佳；⑦ 因此，肠道胆固醇吸收通过Cholesin-GPR146轴抑制肝脏胆固醇合成，为治疗相关疾病提供了新思路。【原文信息】 A gut-derived hormone regulates cholesterol metabolism 2024-03-18 , doi: 10.1016/j.cell.2024.02.024 Science子刊：肠道细菌衍生的血清素促进生命早期的免疫耐受 Science Immunology——[24.8] ① 本研究揭示了特定肠道细菌通过增加血清素的可用性，在新生儿肠道中塑造T细胞对膳食抗原和共生菌的反应，从而促进早期生命中的免疫耐受；② 新生儿肠道中富含包括血清素在内的神经递质，且特定细菌直接产生血清素，并通过下调单胺氧化酶A以限制血清素的分解；③ 血清素直接作用于T细胞，增加细胞内吲哚-3-乙醛并抑制mTOR激活，从而促进调节性T细胞的分化；④ 新生小鼠口服血清素可产生T细胞介导的针对膳食抗原和共生菌的长期特异性免疫耐受；⑤ 本研究表明新生儿肠道细菌衍生的血清素在生命早期免疫耐受中的关键作用。【原文信息】 Gut bacteria-derived serotonin promotes immune tolerance in early life 2024-03-15 , doi: 10.1126/sciimmunol.adj4775 Nature子刊：IL-22如何调节肠道，改善肥胖相关代谢紊乱？ Nature Communications——[16.6] ① 通过构建肠上皮、肝脏和白色脂肪组织（WAT）特异性Il22ra1敲除小鼠，研究组织特异性IL-22RA1信号在介导长期高脂饮食（HFD）驱动的代谢紊乱中的重要性；② 肠上皮和肝脏特异性IL-22RA1信号可提全身高性的糖代谢；③ 肠道IL-22RA1信号以菌群依赖方式介导肝脏和WAT代谢；④ 颤杆菌属与WAT炎症增加有关，并由表达Mmp12的巨噬细胞引起；⑤ 机制上，IL-22及其诱导的IL-18调控肠道脂质代谢基因的转录，而潘氏细胞特异性IL-22RA1信号部分介导HFD后的全身性糖代谢；⑥ 本研究揭示了肠道特异性IL-22RA1信号在调节肠道代谢及缓解系统性肥胖相关疾病中的关键作用。【原文信息】 Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders 2024-02-21 , doi: 10.1038/s41467-024-45568-6 肠道应激如何导致血脂异常？ Theranostics——[12.4] ① 本研究评估核糖体应激反应在肠肝脂质调节中的作用；② 利用化学核糖体失活应激剂（RIS）处理模型，发现RIS促进肠肝脂质积累，同时降低正常和饮食诱导肥胖小鼠血液中的低密度脂蛋白胆固醇；③ 核糖体应激显著调节胆固醇输入相关途径，尤其是通过转录和转录后调控增加肠道低密度脂蛋白受体（LDLR）的水平；④ LDLR增加可促进肠肝胆固醇的积累，导致核糖体应激响应下的血脂异常；⑤ 炎症和肥胖相关的肠道模型中进一步证实以上结论；⑥ 本研究为理解慢性人类疾病中应激响应性代谢重编程提供了新的分子机制。【原文信息】 Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction 2024-01-20 , doi: 10.7150/thno.88586 国内团队：阿司匹林如何维持肠道免疫稳态？ Advanced Science——[15.1] ① 复旦大学余巍、于肖飞团队揭示了阿司匹林通过乙酰化组蛋白去乙酰化酶（HDACs）SIRT1以维持肠道免疫稳态的新机制；② 通过同位素标记的阿司匹林和质谱分析，发现阿司匹林可直接乙酰化包括SIRT1在内的10种HDACs蛋白；③ 阿司匹林乙酰化SIRT1的第408位赖氨酸，破坏其去乙酰化活性，影响底物结合亲和力；④ 阿司匹林通过抑制SIRT1，增加乙酰化p53水平，促进p53依赖的细胞凋亡；⑤ SIRT1乙酰化模拟突变小鼠中促炎细胞因子产生减少，并有助于维持肠道免疫稳态；⑥ 本研究表明SIRT1乙酰化内部功能位点在维持肠道免疫稳态中的重要性，并解释了阿司匹林作为传统抗炎药发挥作用。【原文信息】 Aspirin-Mediated Acetylation of SIRT1 Maintains Intestinal Immune Homeostasis 2024-03-14 , doi: 10.1002/advs.202306378 国内团队：自噬相关蛋白AMBRA1抑制生物制剂疗效，加重肠炎 Cell Death and Differentiation——[12.4] ① 上海交通大学医学院附属新华医院杜鹏、刘辰莹、陈颖伟与团队揭示了自噬相关蛋白AMBRA1在肠道炎症反应中的促炎作用和自噬非依赖的NF-κB激活分子机制，提示靶向AMBRA1是增强生物制剂IFX抗炎疗效的新策略；② 首先构建 Villin-Ambra1flox/flox 肠上皮细胞特异性敲除小鼠，在DSS急性小鼠肠炎模型中，证实敲除 Ambra1 显著抑制肠炎反应，并增强抗TNF-α生物制剂夫利西单抗（IFX）的靶向抗炎作用；③ AMBRA1与IKK激酶复合物及PP4R1/PP4c蛋白磷酸酶复合体互作，通过N端结构域（1-532 AA）竞争性抑制PP4R1/PP4c与IKK复合物的结合，从而拮抗了PP4R1/PP4c对IKK的去磷酸化作用，进而促进NF-κB通路激活，加重肠道炎症反应；④ 在炎症刺激条件下，IKKα通过磷酸化AMBRA1第1043位丝氨酸，抑制CUL4A与AMBRA1的蛋白互作以及CUL4A对AMBRA1的K48多聚泛素化修饰，从而增强AMBRA1的蛋白稳定性；⑤ 通过对IBD患者的IFX治疗后临床缓解及无缓解的肠道组织分析发现，AMBRA1在IFX治疗临床无缓解的肠道炎症组织中显著增高，而在IFX治疗后临床缓解的组织中表达明显减少，与IBD患者的临床治疗预后相关。【原文信息】 AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner 2024-02-29 , doi: 10.1038/s41418-024-01275-9 全面解析炎症性肠病的肠外表现 Gastroenterology——[29.4] ① 本研究是迄今为止最大规模的关于炎症性肠病（IBD）患者肠外表现（EIM）的多队列综合性分析，揭示了与EIM并发症相关的临床、血清学和遗传因素；② 大多数EIM在女性、患有结肠病变的CD患者以及需要手术的患者中更为常见，吸烟增加EIM的风险，除了原发性硬化性胆管炎PSC；③ 观察到多个血清学关联，包括PSC（ANCA, ASCA, anti-CBir1）和任何EIM（ANCA, ASCA, anti-I2）；④ 在MHC和CPEB4中发现了全基因组显著关联，遗传关联提示TNF、JAK-STAT和IL6可能是EIM的潜在治疗靶点；⑤ 与先前报道相反，这项研究的受试者中只有2%有多个EIMs，且大多数共存现象是负相关的；⑥ 研究确定了与EIMs相关的人口统计学、临床和遗传学关联，揭示了潜在的机制，并涉及新颖和现有的药物靶点，为IBD管理提供了更个性化的方法。【原文信息】 Comprehensive association analyses of extraintestinal manifestations in inflammatory bowel disease 2024-02-27 , doi: 10.1053/j.gastro.2024.02.026 溃疡性结肠炎患者的焦虑抑郁症状或与肠道菌群有关 Gut Microbes——[12.2] ① 本研究揭示出溃疡性结肠炎（UC）患者肠道菌群通过降低结肠中神经肽Y（NPY）表达，从而导致焦虑和抑郁行为；② 将UC患者（UC-FMT）和对照（HC-FMT）的粪菌移植到小鼠，通过RNA-seq检测小鼠结肠基因的表达，结果显示两组小鼠的结肠基因表达具有显著差异，UC-FMT小鼠结肠中神经肽信号通路下调，包括NPY表达下调；③ 相比于HC-FMT，UC-FMT小鼠的结肠和血浆中NPY蛋白水平也降低；④ 口服给予从UC患者粪便中分离的蒙氏肠球菌（EM）能够降低小鼠结肠中的NPY表达，并诱发肠炎、焦虑和抑郁样行为，而腹腔注射外源性NPY能显著缓解EM诱发的焦虑和抑郁样行为；⑤ EM给药的小鼠其血浆和海马中NPY蛋白水平也降低，且荚膜多糖与EM诱导的NPY表达下调相关；⑥ 与健康对照组相比，UC患者炎症性结肠中NPY表达显著降低。【原文信息】 Regulation of colonic neuropeptide Y expression by the gut microbiome in patients with ulcerative colitis and its association with anxiety- and depression-like behavior in mice 2024-02-25 , doi: 10.1080/19490976.2024.2319844 肠道菌群影响IBD相关脊柱关节炎的治疗效果 Cell Reports Medicine——[14.3] ① 本研究揭示了硫唑嘌呤治疗炎症性肠病（IBD）相关的外周脊柱关节炎（pSpA）的临床疗效与肠道菌群之间的机制联系；② 纳入22名IBD-pSpA患者中，使用硫唑嘌呤治疗后，临床反应者的肠道菌群中富含产丁酸的普拉梭菌Fp；③ 硫唑嘌呤能促进Fp中丁酸合成基因的转录和丁酸的产生，但过量的叶酸会抑制这一过程；④ 硫唑嘌呤治疗可增强粪便中丁酸的产生，并限制野生型和反应者（而非非反应者）菌群定植的小鼠结肠炎；⑤ Fp足以恢复硫唑嘌呤对非反应者菌群定植的无菌小鼠结肠炎的保护作用；⑥ 本研究为IBD-pSpA的诊断和治疗提供了新的指导。【原文信息】 The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis 2024-02-12 , doi: 10.1016/j.xcrm.2024.101431 乳糜泻自身免疫的机制（综述） Gut——[24.5] ① 乳糜泻是一种食物不耐受，也是一种自身免疫性疾病，具有高度疾病特异性的转谷氨酰胺酶2自身抗体；② 目前，如果儿童血清中含有高水平的抗转谷氨酰胺酶2的IgA抗体，就可诊断为乳糜泻；③ 抗转谷氨酰胺酶2抗体是谷蛋白免疫反应的一部分，这一过程的分子机制已经被破解；④ 谷蛋白肽是转谷氨酰胺酶2的良好底物，会被转谷氨酰胺酶2捕获，然后通过乳糜泻相关HLA分子HLA-DQ2和HLA-DQ8以脱酰胺肽的形式呈递给CD4+ T细胞；⑤ 转谷氨酰胺酶2特异性B细胞及其B细胞受体（膜结合免疫球蛋白）在谷蛋白肽呈递到T细胞的过程中至关重要；⑥ 转谷氨酰胺酶2特异性B细胞会与捕获谷蛋白肽的转谷氨酰胺酶2结合（半抗原载体样复合物），进而在T细胞的帮助下，变成产生抗转谷氨酰胺酶2抗体的浆细胞。【原文信息】 Coeliac disease: the paradox of diagnosing a food hypersensitivity disorder with autoantibodies 2024-02-20 , doi: 10.1136/gutjnl-2023-331595 Novonesis旗下益生菌新健康声明获加拿大卫生部批准 ① 3月15日，Novonesis宣布，旗下植物乳杆菌Clepius L. plantarum的2项健康声明获得加拿大卫生部批准，成为加拿大首株被认为具有缓解压力和促进胃肠健康双重益处的益生菌；② 临床前实验数据表明，该菌株具有良好的胃肠耐受性，并展现出有助于维持肠道屏障完整性以及抗病原体、抗炎和产胆盐水解酶等特性；③ 此次批准基于一系列临床研究和数据，其中一项随机双盲、安慰剂对照、多中心和剂量范围研究结果显示，该菌株无论是低剂量（1010 CFU）还是高剂量（1011 CFU）均可显著改善胃肠道症状，如腹痛和腹胀等；④ 此外，据报道，该菌株还有望通过日常补充来缓解压力。【原文信息】 Novonesis touts pioneering probiotic Clepius L. Plantarum’s approval for gut and brain health claims 2024-03-15 , nutrition insight Slimbiotics与i-Health达成益生菌商业化新合作 ① 近日，奥地利初创公司Slimbiotics与DSM旗下子公司i-Health宣布达成合作，后者将帮助前者把代谢健康益生菌引入北美和中国市场；② Slimbiotics的代谢健康益生菌为发酵乳杆菌（ L. fermentum ）K7-Lb1、K8-Lb1和K11-Lb3，筛选自肯尼亚Mbeere地区的自然发酵面团Kimere；③ 三株菌株将通过Culturelle和Estroven品牌实现商业化；④ 发表于 Nutrients 杂志上的临床研究结果显示，补充三株菌株组合3个月，能显著降低体脂肪量、体重、腰围、BMI等指标。【原文信息】 DSM i-Health partners with Slimbiotics for metabolic health probiotics 2024-03-14 , nutraingredients-usa 无线内镜厂商「英赛飞影」宣布完成天使轮融资 ① 近日，苏州英赛飞影医疗科技有限公司宣布完成天使轮融资；② 本轮融资由国仟创投、接力基金及苏州器械产业集团共同投资；③ 融资资金将用于公司核心产品智能无线硬镜和软镜的研发投入、产能扩建及市场开拓等；④ 英赛飞影的智能无线内镜产品具备无线、超低延迟、易携、高清晰度等特点，适用于多种医疗场景；⑤ 目前，两款核心产品已完成开发并进入临床试验阶段，预计将于2024年下半年获批。【原文信息】英赛飞影完成天使轮融资，开启“无线”创新之路 2024-03-18 , 动脉网海南三叶制药厂：奥美拉唑肠溶胶囊过评 ① 3月18日，国家药监局发布了新一批药品批准证明文件送达信息；② 本批次共16个受理号获批，其中海南三叶制药厂的奥美拉唑肠溶胶囊的一致性评价受理号获批；③ 奥美拉唑肠溶胶囊由阿斯利康研发，用于治疗胃、十二指肠溃疡、反流性食管炎等疾病；④ 其于1988年在欧盟和中国获批上市，是第一个上市的质子泵抑制剂。【原文信息】刚刚，国家药监局发布16个新批件，1个大品种过评！ 2024-03-18 , 新康界百奥泰2款生物类似药授权海外，达成600万美元协议 ① 3月18日，百奥泰生物宣布，已与SteinCares就2款在研生物类似药签订授权许可与商业化协议；② 百奥泰将BAT2506注射液和BAT2606注射液在巴西及拉丁美洲地区的商业化权益许可授予SteinCares；③ 此次协议总金额最高达600万美元（约合人民币4318.86万），包括120万美元首付款和最高480万美元的里程碑付款；④ 此外，双方还约定了将净销售额的两位数百分比作为收入分成；⑤ BAT2506是一款戈利木单抗生物类似药，原研戈利木单抗（Simponi）来自强生，靶向TNF-α，获批用于类风湿性关节炎、强直性脊柱炎、银屑病关节炎、溃疡性结肠炎等自免疾病；⑥ BAT2606是一款美泊利珠单抗生物类似药，原研美泊利珠单抗（Nucala）由GSK开发，主要用于嗜酸性粒细胞哮喘、支气管哮喘等免疫炎症性疾病。【原文信息】 600万美元！百奥泰2款生物类似药授权海外 2024-03-18 , 医药魔方感谢本期日报的审核者：mildbreeze，圆圈儿，章台柳，九卿臣，lxx，Alex Zhang 点击阅读过去10天的日报： 0318 | NEJM双发：大肠癌无创检测取得新突破 0317 | Cell子刊：多组学+长追踪，深度解析人体菌群动态和与宿主的互作 0316 | 国内团队34页综述详解：用饮食干预对抗疾病 0315 | 顶刊小高潮：王良静等Cell重磅突破，Science三文聚焦肠菌 0314 | 今日Nature：抵御肠道感染，菌群色氨酸代谢物有新招 0313 | 朱书/潘文等Cell子刊新发现：肠菌胆汁酸代谢如何影响大肠癌抗肿瘤免疫？ 0312 | 65分综述详解ILC3：守护肠道健康的重要免疫细胞 0311 | 分析81万人数据：根除幽门螺杆菌，还能防肠癌？ 0310 | 癌症治疗中的饮食干预：评估252项临床试验有何发现？ 0309 | AGA最新指南：基于粪便菌群的疗法在胃肠疾病中的应用

孤儿药

2024-03-14

·Pharmaceutical Technology

AstraZeneca snaps up Amolyt for $1.05bn to boost rare disease pipeline

AstraZeneca’s rare disease portfolio generated $7.76bn in global sales in 2023, as per the company’s Q4 financials. Image Credit: EllaSt / Shutterstock. AstraZeneca has signed a definitive agreement to acquire Amolyt Pharma, which specialises in therapies for rare endocrine diseases, in a deal worth $1.05bn. As per the contract, AstraZeneca will pay $800m upfront along with potential regulatory milestone payments of $250m. The deal is expected to close in Q3 2024. Amolyt’s lead candidate, eneboparatide (AZP-3601), was a central part of the acquisition. Eneboparatide is a subcutaneous parathyroid hormone receptor 1 (PTHR1) agonist for the treatment of hypoparathyroidism. This condition is caused by a deficiency in the parathyroid hormone that results in decreased calcium and elevated phosphorus levels in the blood. Dysregulation of parathyroid hormone can lead to osteoporosis and chronic kidney disease. Amolyt launched a Phase III CALYPSO trial (NCT05778071) for eneboparatide in May 2023. Topline data from the trial is expected by the end of this year. Another candidate in Amolyt’s pipeline is AZP-3813. The therapy is a peptide growth hormone receptor antagonist, which is being developed as a potential add-on to somatostatin analogues for the treatment of acromegaly, a condition associated with abnormally high secretion of growth hormone. It can lead to a variety of complications including heart failure and impaired glucose tolerance. The company initiated a Phase I trial for AZP-3813 in June 2023. See Also: Almirall to license Eloxx’s ZKN-013 for rare skin conditions Risk adjusted net present value: What is the current valuation of AstraZeneca’s AZD-3427? AstraZeneca’s rare disease portfolio generated $7.76bn in global sales in 2023, as per the company’s Q4 financials. The UK pharma giant has been investing heavily in rare disease therapies starting with the $39bn acquisition of Alexion in 2021. Last year, the company paid $1bn to acquire an early-stage gene therapy portfolio for rare diseases from Pfizer. According to a GlobalData report, innovation in rare diseases is seen as a risky investment, with rare oncology indications dominating most of the rare disease pipeline. GlobalData is the parent company of Pharmaceutical Technology . Despite this, AstraZeneca has seen some success amongst rare diseases that are not cancer-related. In September 2023, the Phase III trial for a rare vasculitis therapy, Fasenra (benralizumab), met its primary endpoint. The study found that Fasenra was non-inferior to the current standard of care, Pfizer’s Nucala (mepolizumab). Earlier this year, AstraZeneca reported positive outcomes from its Japan Phase III clinical trial of acoramidis, an investigational treatment for a rare cardiomyopathy, transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).

临床3期并购临床1期临床结果临床2期

100 项与美泊利珠单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D04923	美泊利珠单抗	R03DX09	DB06612

研发状态

适应症	最高研发状态	国家/地区	公司
嗜酸性肉芽肿	批准上市	日本更多	GSK Plc 更多
肺嗜酸性粒细胞增多	批准上市	中国更多	葛兰素史克（中国）投资有限公司更多
Churg-Strauss综合征	批准上市	澳大利亚更多	Glaxosmithkline Australia Pty Ltd. 更多
哮喘	批准上市	中国更多	葛兰素史克（中国）投资有限公司更多
肉芽肿伴多血管炎	批准上市	中国更多	GSK Plc 更多

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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


NCT03298061 (LAP/MEA116841, ATS2024) 人工标引	临床3期	肉芽肿伴多血管炎	100	Mepolizumab	(膚糧鏇艱憲遞遞製簾蓋) = 夢築積夢鑰獵鏇醖獵齋鹽選顧醖簾觸餘鏇膚積 (簾繭鹽廠網製構艱繭遞 )	积极	2024-05-19
NCT02555371 (COMET, ERS2020) 人工标引	临床3期	肺嗜酸性粒细胞增多	-	mepolizumab (stopped mepolizumab)	(鏇襯齋願鏇鏇繭鹽範鬱) = 淵壓築選鬱網衊廠選鏇簾選簾鏇鑰積壓構齋選 (齋顧製鑰構簾夢膚獵醖, 42.8 ~ 61.3)	积极	2020-12-31
				mepolizumab (continued mepolizumab)	(鏇襯齋願鏇鏇繭鹽範鬱) = 願鑰醖簾齋齋簾遞觸範簾選簾鏇鑰積壓構齋選 (齋顧製鑰構簾夢膚獵醖, 27.3 ~ 44.2)
NCT03085797 (SYNAPSE, Pubmed) 人工标引	临床3期	慢性鼻窦炎伴鼻息肉	407	SOC+Mepolizumab	鹽範範夢鏇遞遞夢蓋壓(膚觸鏇築獵衊壓繭淵觸): difference = -0.73 (95% CI, -1.11 ~ -0.34) 更多	积极	2021-10-01
				Placebo+SOC
NCT02377427 (Pubmed) 人工标引	临床2期	哮喘	30	mepolizumab	(蓋壓蓋齋鏇壓構選願壓) = 選顧築鹹選鹽蓋餘築蓋淵鹽餘憲糧鏇繭憲蓋蓋 (範憲膚獵壓願簾窪網艱 ) 更多	积极	2019-11-01
NCT03099096 (Pubmed \| J Asthma) 人工标引	临床3期	海蓝组织细胞综合征	-	mepolizumab	糧鹽淵襯憲鹹鹽淵範醖(窪鏇範餘衊鑰選遞構鹽) = 簾壓夢鹽觸蓋鑰艱顧夢製鹽遞淵遞選獵積繭夢 (廠壓願蓋網鏇積鹹淵蓋 ) 更多	积极	2020-09-01
NCT03085797 (SYNAPSE, Pubmed) 人工标引	临床3期	慢性鼻窦炎伴鼻息肉	407	standard of care+mepolizumab	衊積遞築網襯窪範築齋(蓋醖積網網構夢鏇糧簾): HR = 0.28 (95% CI, 0.09 ~ 0.84) 更多	积极	2022-07-13
				standard of care+Placebo
NCT02020889 (MIRRA, ACR2022) 人工标引	临床3期	Churg-Strauss综合征	136	SOC+Mepolizumab	-	积极	2022-09-12
				SOC+placebo
Corporate Publications 人工标引	临床3期	高嗜酸性粒细胞综合征	108	mepolizumab	築構鏇遞遞齋構簾鬱壓(製獵鏇淵顧淵繭製膚醖) = Risk of first HES flare over the study period was 66% lower for patients treated with mepolizumab compared to placebo 範鹽製憲齋廠糧願繭構 (廠構鬱願窪衊顧鹽顧願 ) 更多	积极	2019-11-13
				Placebo
NCT03292588 (MUPPITS-2, Pubmed \| Lancet) 人工标引	临床2期	肺嗜酸性粒细胞增多	290	Mepolizumab	夢鹽簾襯獵夢顧築壓廠(網膚夢鹹鏇願構築窪觸) = 鏇壓簾選襯鏇蓋製獵簾構壓蓋醖夢構膚淵齋網 (醖願鏇鏇鬱鹽鹽夢餘糧, 0.78 ~ 1.17) 更多	积极	2022-08-13
				Placebo	夢鹽簾襯獵夢顧築壓廠(網膚夢鹹鏇願構築窪觸) = 網鏇壓繭鹽窪鏇範膚憲構壓蓋醖夢構膚淵齋網 (醖願鏇鏇鬱鹽鹽夢餘糧, 1.08 ~ 1.57) 更多
NCT02555371 (COMET, Pubmed) 人工标引	临床3期	嗜酸性粒细胞性哮喘	-	mepolizumab	(糧艱網鏇餘齋憲鹹齋艱): HR = 1.77 (95% CI, 1.21 ~ 2.59) 更多	积极	2022-01-10
				Placebo