IL-22Rα1

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

MADISON, N.J.--( BUSINESS WIRE )-- NOT FOR UK USE – NOT INTENDED FOR UK MEDIA LEO Pharma A/S, a global leader in medical dermatology, will present a breadth of new data on moderate-to-severe chronic hand eczema (CHE), congenital ichthyosis (CI) and atopic dermatitis (AD) at the upcoming 82 nd American Academy of Dermatology (AAD) Annual Meeting. The event is being held from March 8 th to 12 th in San Diego, California. “ Our growing body of clinical evidence reinforces our passion and commitment to advancing the standard of care in medical dermatology ,” said Kreesten Meldgaard Madsen, LEO Pharma’s Chief Development Officer. “ We are incredibly excited to have this opportunity at the 2024 AAD Annual Meeting to showcase our efforts to address patient needs across multiple skin conditions, including two late-breaker presentations regarding the potential treatment of CHE and CI, both of which are well known to disrupt the lives of countless people around the world.” With eight abstracts accepted in total for the meeting, 1-8 AAD is the latest major dermatology congress in which LEO Pharma will underscore a commitment to advancing scientific innovation and development in medical dermatology, with the aim of making a fundamental difference for people living with skin conditions. “ The AAD meeting is one of the most important milestones in the medical dermatology calendar in the United States, a country where skin conditions are estimated to affect as many as 1 in 3 people. I am proud that we can follow up on our 2023 AAD program with this level of critical data,” s aid Brian Hilberdink, EVP and President, Region North America, LEO Pharma. “ The opportunity to collaborate and deliberate with the research community and healthcare professionals at the scale that this meeting allows is key to bringing about meaningful change and improved outcomes for people living with skin conditions. We are honored to share our latest findings and look forward to engaging with the community while gathering more insights that will help benefit patients.” The first late-breaker presentation on March 9 th will outline the key results of the DELTA-3 trial, which assessed the long-term safety and efficacy of investigational delgocitinib cream in adults with moderate-to-severe CHE. This is the first time the key results have been shared at a medical congress. 1 Additional data for delgocitinib cream will also be presented as e-posters, including pooled analyses of the pivotal phase 3 DELTA-1 and DELTA-2 trials. 4,5,6 An additional late-breaker presentation on March 10 th will outline the preliminary results from the maximum use arm of the ASCEND trial, which examined the efficacy, safety and pharmacokinetics of investigational TMB-001 in adult and adolescent subjects with moderate-to-severe X-linked and Autosomal Recessive CI. 2 Additional data, presented as an e-poster, also based on the ASCEND trial, will examine the pharmacokinetics of TMB-001 compared to oral isotretinoin. 7 Adbry ® (tralokinumab-ldrm) data will be shared during the annual meeting as an e-poster summarizing results from the ECZTEND trial investigating the stability of long-term therapeutic responses to tralokinumab in adults with moderate-to-severe AD. 3 Finally, one temtokibart (LEO 138559) e-poster will be delivered and will analyze individual patient responses to IL-22RA1 inhibition in a phase 2a monotherapy trial for moderate-to-severe AD, 8 following up on the late-breaking presentation of the phase 2a trial that was presented at AAD 2023. The company’s full roster of accepted presentations at the 2024 AAD Congress includes: Delgocitinib Long-term safety and efficacy of delgocitinib cream for up to 36 weeks in adults with Chronic Hand Eczema: results of the Phase 3 open-label extension DELTA-3 trial Author: Melinda Gooderham Abstract #: 56059 LB presentation: Saturday March 09 at 11:10 – 11:20 AM PST Location: Room 20BCD Efficacy and safety of delgocitinib cream in adults with moderate-to-severe chronic hand eczema: pooled results of the Phase 3 DELTA-1 and -2 trials Author: Robert Bissonnette Abstract #: 52715 E-poster presentation​ Delgocitinib cream reduces itch and pain in adults with moderate-to-severe chronic hand eczema: pooled analyses of the Phase 3 DELTA-1 and -2 trials Author: Andrea Bauer Abstract #: 53696 E-poster Systemic exposure and safety profile of delgocitinib cream in adults with moderate-to-severe chronic hand eczema in the Phase 3 DELTA-2 trial Author: Melinda Gooderham Abstract #: 53695 E-poster Adbry ® (tralokinumab-ldrm) Stability of long-term therapeutic responses to tralokinumab in adults with moderate-to-severe atopic dermatitis Author: Andrew Blauvelt Abstract #: 53133 E-poster Temtokibart Individual patient responses to IL-22RA1 inhibition in a Phase 2a monotherapy trial for moderate-to-severe atopic dermatitis Author: Melinda Gooderham Abstract #: 53111 E-poster TMB-001 Efficacy, Safety and Pharmacokinetics of First 17 Adult and Adolescent Subjects in Maximal Use Portion of Vehicle Controlled ASCEND Trial of Polyethylene Glycol (iPEG™)-Based Topical Isotretinoin 0.05% (TMB-001) for Treatment of Congenital Ichthyosis Author: Christopher G. Bunick Abstract #: 56255 LB presentation: Sunday March 10 at 03:00 – 03:10 PM PDT Location: Room 20BCD The Phase 3 Vehicle-Controlled ASCEND Trial of Polyethylene Glycol (iPEG™) Based Topical Isotretinoin (TMB-001 0.05% ointment) for Treatment of X-Linked and Autosomal Recessive Congenital Ichthyosis: Analysis of Pharmacokinetic Results Compared with 80 mg Oral Isotretinoin ​ Author: Christopher G. Bunick Abstract #: 51523 E-poster About chronic hand eczema Chronic hand eczema (CHE) is defined as hand eczema (HE) that lasts for more than three months or relapses twice or more within a year. 9,10 HE is the most common skin disorder of the hands 11 with a one-year prevalence rate of approximately 9%. 12 In a substantial number of patients, HE can develop into a chronic disease. 11 CHE is a fluctuating disorder characterized by itch and pain, and patients may experience signs such as erythema, scaling, lichenification, hyperkeratosis, vesicles, edema, and fissures on hands and wrists. 13 About atopic dermatitis Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense itch and eczematous lesions. 14 Atopic dermatitis is the result of skin barrier dysfunction and immune dysregulation, leading to chronic inflammation. 15 Type 2 cytokines, including IL-13, play an important role in the key aspects of atopic dermatitis pathophysiology. 15,16 Excessive IL-22 production is also known to contribute to the pathogenesis of AD. 17 About congenital ichthyosis Congenital ichthyosis (CI) is a group of rare genetic keratinization disorders that can lead to dry, thickened, and scaling skin. 18-21 Most cases of ichthyosis are inherited, but some types develop in association with genetic syndromes or diseases, such as Hodgkin's Lymphoma. 22,23 People living with CI may have limited range of motion, chronic itching, an inability to sweat normally, high risk of secondary infections, and impaired eyesight or hearing. 18-21 About delgocitinib Delgocitinib cream is an investigational, potential first-in-class, topical pan-Janus kinase (JAK) inhibitor for CHE. It inhibits the activation of JAK-STAT signaling, which plays a key role in the pathogenesis of CHE. 24 Delgocitinib has not been approved by any health authority. The pathophysiology is characterized by skin barrier dysfunction, inflammation of the skin, and alterations of the skin microbiome. 25 LEO Pharma is currently developing delgocitinib in a cream formulation for the treatment of moderate-to-severe chronic hand eczema (CHE) in adults, which is currently not approved by any health authority. In 2014, LEO Pharma A/S and Japan Tobacco Inc. (JT) entered into a license agreement in which LEO Pharma gained exclusive rights to develop and commercialize delgocitinib for topical use in dermatological indications worldwide, excluding Japan, where JT retains rights. About Adbry ® (tralokinumab-ldrm) Adbry ® (tralokinumab-ldrm), which is marketed outside of the U.S. under the tradename Adtralza ® (tralokinumab), is a high-affinity fully human monoclonal antibody developed to bind to and inhibit the interleukin (IL)-13 cytokine, which plays a role in the immune and inflammatory processes underlying atopic dermatitis signs and symptoms. 15,16 Adbry ® specifically binds to the IL-13 cytokine, thereby inhibiting interaction with the IL-13 receptor α1 and α2 subunits (IL-13Rα1 and IL-13Rα2). 26 Adbry is approved for the treatment of adults and pediatric patients (12 years and above) with moderate-to-severe AD in the U.S., Canada, the European Union, the United Arab Emirates, Great Britain, and South Korea. Adtralza is approved for use in adults with moderate-to-severe AD in Saudi Arabia, Switzerland, and Japan. U.S. INDICATION AND IMPORTANT SAFETY INFORMATION What is ADBRY? ADBRY ® (tralokinumab-ldrm) injection is a prescription medicine used to treat people 12 years of age and older with moderate-to-severe atopic dermatitis (eczema) that is not well controlled with prescription therapies used on the skin (topical), or who cannot use topical therapies. ADBRY can be used with or without topical corticosteroids. It is not known if ADBRY is safe and effective in children under 12 years of age. Do not use ADBRY if you are allergic to tralokinumab or to any of its ingredients. What should I discuss with my healthcare provider before starting ADBRY? Tell your healthcare provider about all your medical conditions, including if you: have eye problems. have a parasitic (helminth) infection. are scheduled to receive any vaccinations. You should not receive a “live vaccine” if you are treated with ADBRY. are pregnant or plan to become pregnant. It is not known whether ADBRY will harm your unborn baby. There is a pregnancy exposure registry for women who use ADBRY during pregnancy. The purpose of this registry is to collect information about the health of you and your baby You or your healthcare provider can get information and enroll you in this registry by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/adbry-tralokinumab/ . are breastfeeding or plan to breastfeed. It is not known whether ADBRY passes into your breast milk and if it can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I use ADBRY? See the detailed “Instructions for Use” that comes with ADBRY for information on how to prepare and inject ADBRY and how to properly store and throw away (dispose of) used ADBRY prefilled syringes. Use ADBRY exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how much ADBRY to inject and when to inject it. ADBRY comes as a single-dose (150 mg) prefilled syringe with needle guard. ADBRY is given as an injection under the skin (subcutaneous injection). If your healthcare provider decides that you or a caregiver can give the injection of ADBRY, you or your caregiver should receive training on the right way to prepare and inject ADBRY. Do not try to inject ADBRY until you have been shown the right way by your healthcare provider. If you miss a dose, inject the missed dose as soon as possible, then continue with your next dose at your regular scheduled time. If you inject -too much ADBRY than prescribed, call your healthcare provider or call Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. Your healthcare provider may prescribe other medicines to use with ADBRY. Use the other prescribed medicines exactly as your healthcare provider tells you to. What are the possible side effects of ADBRY? ADBRY can cause serious side effects including: Allergic reactions (hypersensitivity), including a severe reaction known as anaphylaxis. Stop using ADBRY and tell your healthcare provider or get emergency help right away if you get any of the following symptoms: breathing problems itching skin rash swelling of the face, mouth, and tongue fainting, dizziness, feeling lightheaded (low blood pressure) hives Eye problems. Tell your healthcare provider if you have any worsening eye problems, including eye pain or changes in vision. The most common side effects of ADBRY include: Upper respiratory tract infections Eye and eyelid inflammation, including redness, swelling, and itching Injection site reactions High count of a certain white blood cell (eosinophilia) These are not all the possible side effects of ADBRY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Please click here for full U.S. Prescribing Information, including Patient Information and Instructions for Use. About temtokibart Temtokibart (LEO 138559) is an investigational monoclonal antibody that targets the IL-22RA1 receptor subunit, currently in Phase 2 development for the potential treatment of moderate-to-severe atopic dermatitis. 27 It blocks the IL-22RA1 subunit and thereby inhibits the effects of the IL-22 cytokine, and potentially also to some extent the effects of IL-20 and IL-24. 27 Temtokibart does not bind to the IL-22 cytokine itself. 27 LEO Pharma has obtained a worldwide exclusive license to develop and commercialize temtokibart from argenx. About TMB-001 TMB-001, topical isotretinoin in the company’s investigational patented polyethylene glycol (IPEG™) delivery system, is being developed for the treatment of moderate-to-severe subtypes of congenital ichthyosis (CI). During Q4 2021, the positive topline results for its Phase 2b CONTROL Study were announced. In Q1 2022, TMB-001 received both Breakthrough Therapy Designation and Fast Track Status from the U.S. Food and Drug Administration (FDA). The Phase 3 ASCEND clinical trial was initiated in Q2 2022. A bout LEO Pharma LEO Pharma is a global company dedicated to advancing the standard of care for the benefit of people with skin conditions, their families and society. Founded in 1908 and majority owned by the LEO Foundation, LEO Pharma has devoted decades of research and development to advance the science of dermatology, and today, the company offers a wide range of therapies for all disease severities. LEO Pharma is headquartered in Denmark with a global team of 4,300 people, serving millions of patients across the world. In 2023, the company generated net sales of DKK 11.4 billion. References Gooderham M, et al. Long-term safety and efficacy of delgocitinib cream for up to 36 weeks in adults with Chronic Hand Eczema: results of the Phase 3 open-label extension DELTA-3 trial. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Bunick G , et al. Efficacy, Safety and Pharmacokinetics of First 17 Adult and Adolescent Subjects in Maximal Use Portion of Vehicle Controlled ASCEND Trial of Polyethylene Glycol (iPEG™)-Based Topical Isotretinoin 0.05% (TMB-001) for Treatment of Congenital Ichthyosis. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Blauvelt A, et al. Stability of long-term therapeutic responses to tralokinumab in adults with moderate-to-severe atopic dermatitis. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Bissonnette R, et al. Efficacy and safety of delgocitinib cream in adults with moderate-to-severe chronic hand eczema: pooled results of the Phase 3 DELTA-1 and -2 trials. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Bauer A, et al. Delgocitinib cream reduces itch and pain in adults with moderate-to-severe chronic hand eczema: pooled analyses of the Phase 3 DELTA-1 and -2 trials. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Gooderham M, et al. Systemic exposure and safety profile of delgocitinib cream in adults with moderate-to-severe chronic hand eczema in the Phase 3 DELTA-2 trial. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Bunick G, et al. The Phase 3 Vehicle-Controlled ASCEND Trial of Polyethylene Glycol (iPEG™) Based Topical Isotretinoin (TMB-001 0.05% ointment) for Treatment of X-Linked and Autosomal Recessive Congenital Ichthyosis: Analysis of Pharmacokinetic Results Compared with 80 mg Oral Isotretinoin. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Gooderham M, et al. Individual patient responses to IL-22RA1 inhibition in a Phase 2a monotherapy trial for moderate-to-severe atopic dermatitis. Presented at the 2024 American Academy of Dermatology Annual Meeting; March 8-12 2024; San Diego, CA. Lynde C, Guenther L, Diepgen TL, et al. Canadian hand dermatitis management guidelines. J Cutan Med Surg. 2010;14(6):267-284 Diepgen TL, Andersen KE, Chosidow O, et al. Guidelines for diagnosis, prevention and treatment of hand eczema. J Dtsch Dermatol Ges. 2015;13(1):e1-e22. Bissonnette R, Diepgen TL, Elsner P, et al. Redefining treatment options in chronic hand eczema (CHE). J Eur Acad Dermatol Venereol. 2010;24 Suppl 3:1-20. Thyssen JP, Johansen JD, Linneberg A, Menné T. The epidemiology of hand eczema in the general population—prevalence and main findings. Contact Dermatitis. 2010;62(2):75-87. Thyssen JP, Schuttelaar MLA, Alfonso JH, et al. Guidelines for diagnosis, prevention, and treatment of hand eczema. Contact Dermatitis. 2022;86(5):357-378. Weidinger S, et al. Atopic dermatitis. Lancet. 2016;387:1109-1122. Boguniewicz M, et al. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011;242(1):233-46. Bieber T. Interleukin-13: targeting an underestimated cytokine in atopic dermatitis. Allergy. 2020; 75:54-62. Dudakov JA, Hanash AM, van den Brink MR. Interleukin-22: immunobiology and pathology. Annu Rev Immunol. 2015;33:747-785. Oji V, Traupe H. Ichthyosis: clinical manifestations and practical treatment options. Am J Clin Dermatol. 2009;10(6):351-364. Takeichi T, Akiyama M. Inherited ichthyosis: Non-syndromic forms. J Dermatol. 2016;43(3):242-251. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm Venereol. 2008;88(1):4-14. Lilly E, Bunick CG. Congenital Ichthyosis: A Practical Clinical Guide on Current Treatments and Future Perspectives. Clin Cosmet Investig Dermatol. 2023;16:2473-2479. Haber R, Feghali J, Nadir U, Yi MD, Cahn BA. Acquired ichthyosis: a clinical review. Arch Dermatol Res. 2023;315(9):2529-2543. Mishra K, Jandial A, Gupta K, Prakash G, Malhotra P. Ichthyosis: A Harbinger of Lymphoma. BMJ Case Rep. 2018;2018:bcr2018224229. Dubin C, Del Duca E, Guttman-Yassky E. Drugs for the Treatment of Chronic Hand Eczema: Successes and Key Challenges. Ther Clin Risk Manag. 2020;16:1319-1332. Lee GR, Maarouf M, Hendricks AK, Lee DE, Shi VY. Current and emerging therapies for hand eczema. Dermatol Ther. 2019;32(3):e12840. Popovic B, et al. Structural characterisation reveals mechanism of IL-13-neutralising monoclonal antibody tralokinumab as inhibition of binding to IL-13Rα1 and IL-13Rα2. J Mol Biol. 2017; 429:208-19. Thaçi D, et al. Efficacy and safety of IL-22R inhibition in patients with moderate-to-severe atopic dermatitis: results from a phase 2a monotherapy trial. 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「  本文共：17条资讯，阅读时长约：3分钟 」今‍日‍头条君圣泰肝-肠抗炎新药Ⅱ期临床积极。君圣泰医药自研肝-肠抗炎代谢调节剂HTD1801，在治疗非酒精性脂肪性肝炎（NASH）合并2型糖尿病（T2DM）的Ⅱa期临床达到主要终点和多个次要终点。与安慰剂相比，HTD1801（1000mg）显著减少患者18周后的肝脏脂肪含量，两组校正T1加权成像（cT1）分别减少60.9[75.9]ms和14.7[68.9]ms，两组cT1至少减少80ms的患者比例分别为39%和16%。HTD1801总体耐受性良好。详细结果将于EASL2023大会上公布。‍‍‍国‍‍‍‍‍‍‍‍‍内‍‍‍‍药‍‍讯‍‍‍‍1.诺华IgE单抗获批慢性寻麻疹NDA。诺华创新生物制剂奥马珠单抗（茁乐）预充式注射液获国家药监局批准新增适应症，用于慢性自发性荨麻疹患者（CSU）在家注射使用奥马珠单抗，方便快捷地控制荨麻疹症状。奥马珠单抗是一款IgE靶向抗体，它通过特异性结合血清内游离的IgE、阻断其致炎通路发挥作用。2022年8月，该剂型已获批用于过敏性哮喘的治疗。2.百济神州BTK抑制剂新适应症报产。百济神州BTK抑制剂泽布替尼胶囊的新适应症上市申请获CDE受理，推测适应症为联合奥妥珠单抗适用于既往接受过至少二线系统性治疗的复发或难治性滤泡性淋巴瘤（R/R FL）患者。公布于ASCO2023年会上的全球Ⅱ期ROSEWOOD临床更新数据显示，中位随访为20.2个月时，联合疗法ORR为69.0%(vs45.8%)，完全缓解率为39.3%(vs19.4%)。今年6月初，CDE已将泽布替尼联合治疗R/R FL适应症纳入优先审评。3.恒瑞PCSK-9抑制剂报降脂NDA。恒瑞医药PCSK 9抑制剂recaticimab（瑞卡西单抗）上市申请获CDE受理。目前，恒瑞医药针对recaticimab已开展3项III期临床，旨在评估recaticimab用于治疗高胆固醇血症（CTR20210702）、单药治疗非家族性高胆固醇血症和混合型高脂血症（CTR20210703）以及联合降脂药稳定治疗血脂控制不佳的高胆固醇血症和高脂血症（CTR20210932）的有效性与安全性。据悉，这是第4款申报上市的国产PCSK9单抗。4.武汉滨会溶瘤病毒获FDA快速通道资格。FDA授予滨会生物溶瘤病毒候选药物BS001（OH2）注射液快速通道资格，用于治疗PD-1单抗治疗后耐药或进展的不可切除的Ⅲ期或IV期黑色素瘤。该产品以Ⅱ型单纯疱疹病毒为载体，运用分子克隆、DNA同源重组等技术改造而成，具有直接溶瘤、诱导局部和全身性抗肿瘤免疫应答、广谱抗肿瘤的效果。此前FDA已授予该新药孤儿药资格，用于治疗IIb期至IV期黑色素瘤。5.先为达GLP-1R激动剂最新临床数据积极。先为达生物将在ADA2023年会上公布长效GLP-1类似物Ecnoglutide（XW003）三项临床研究的积极结果。其中在评估Ecnoglutide与利拉鲁肽（Saxenda®）相比治疗成年肥胖患者的II期研究中，26周治疗数据显示，Ecnoglutide（1.2mg、1.8mg和2.4mg）组的受试者体重分别较基线降低11.5%、11.2%和14.7%（2.4mg组，P<0.001），而利拉鲁肽3.0mg组的受试者体重较基线降低8.8%。Ecnoglutide的总体安全性与其他GLP-1类药物相似。6.利奥制药IL-22RA1单抗中国报IND。LEO Pharma制药1类生物制品LEO 138559的临床试验申请获CDE受理。LEO 138559是一款IL-22RA1单抗，通过阻断IL-22RA1受体亚单位，从而抑制白细胞介素-22（IL-22）细胞因子的作用。目前，LEO 138559治疗中重度特应性皮炎的IIa期研究已达到主要终点，与安慰剂相比，LEO 138559治疗患者的EASI评分较基线变化显著改善（-15.3VS-3.5）。详细结果将在AAD年会上公布。‍‍‍‍国‍‍‍‍‍‍‍‍‍‍际‍‍‍‍药‍讯‍‍1.首款DMD基因疗法获FDA批准上市。Sarepta公司与罗氏联合开发的基因疗法Elevidys（SRP-9001）获FDA加速批准上市，成为首个用于治疗杜氏肌营养不良（DMD）4-5岁患者的一次性基因疗法。Elevidys通过AAV病毒载体将表达微抗肌萎缩蛋白（micro-dystrophin）的转基因递送到患者肌肉，生成具有部分抗肌萎缩蛋白功能的重组蛋白，治疗对携带任何类型DMD致病基因变异的患者。在临床试验中，SRP-9001显著提高患者肌肉中微抗肌萎缩蛋白的表达水平。2.辉瑞斑秃新药获FDA批准上市。辉瑞口服JAK3/TEC双激酶抑制剂Litfulo（ritlecitinib）获FDA批准上市，用于治疗12岁以上严重斑秃患者。在一项Ⅱb/Ⅲ期ALLEGRO临床中，与安慰剂相比，接受50mg的ritlecitinib治疗达到头皮毛发覆盖面积超过80%的患者比例显著更高（23%vs1.6%）。青少年（12-17岁）和成人使用Litfulo的疗效和安全性一致。该新药也是FDA首次批准用于重度斑秃青少年（12+）的治疗药物。3.低剂量秋水仙碱获批用于心血管疾病。FDA批准AGEPHA公司抗炎药物LODOCO®（秋水仙碱，0.5mg片剂）新适应症，用于预防动脉粥样硬化。2022年2月，发表在《美国心脏协会》上的一项秋水仙碱（0.5mg）治疗慢性冠心病患者的LoDoCo2研究长期疗效数据显示，与安慰剂相比，秋水仙碱（0.5mg）治疗2年、3年和4年使患者发生心肌梗死(MI)、中风、冠状动脉血运重建和心血管死亡的风险降幅分别为68%、61%和53%。4.THR-β激动剂治疗NASH的Ⅲ期临床积极。Madrigal公司在EASL 2023年会上公布其潜在“first-in-class”口服选择性甲状腺激素受体（THR）-β激动剂resmetirom治疗非酒精性脂肪肝炎（NASH）的Ⅲ期临床（MAESTRO-NASH）52周治疗数据。与安慰剂相比，resmetirom（80mg和100mg）治疗达到非酒精性脂肪肝活动评分（NAS）降低≥2分，且肝纤维化无恶化的患者比例更多（26%和30%，vs10%）；达到肝纤维化至少改善一个阶段，且NAS无恶化的患者比例更高（24%和26%，vs14%）。其中resmetirom（100mg）组患者肝脏脂肪水平平均降低51%。该公司将在今年第二季度向FDA递交新药申请。5.诺和诺德胰岛素周制剂IIIa期临床积极。诺和诺德在ADA会议上公布每周1次超长效胰岛素icodec治疗2型糖尿病的IIIa期临床积极数据，并同步发表在《新英格兰医学杂志》上。与每日一次甘精胰岛素U100相比，每周一次icodec治疗具有非劣效性（P<0.001）和优效性（P=0.02），两组患者Hb1Ac水平的平均降幅分别为1.55%和1.35%，估计的组间差异为-0.19%，95% CI：-0.36~-0.03。临床中没有发现新的安全信号。6.礼来口服GLP-1R激动剂II期临床积极。礼来非肽口服胰高血糖素样肽-1（GLP-1）受体激动剂orforglipron用于肥胖或超重患者的慢性体重管理II期临床达到主要终点和所有关键的次要终点。与安慰剂相比，orforglipron（12mg, 24mg, 36mg或45mg）治疗组患者第26周时体重减幅更大【8.6%（9.0公斤）至12.6%（13.3公斤），vs2.0%（2.1公斤）】。药物的安全性与其他以肠促胰岛素为基础的治疗相似。详细结果将公布在美国糖尿病协会年会上和同时发表在《新英格兰医学杂志》上。7.FIC口服小分子药耳科概念验证临床积极。Sensorion公司潜在“first-in-class”小分子药物SENS-401在用于中重度听力损伤患者保持耳蜗植入后剩余听力的概念验证Ⅱa期临床初步结果积极。数据显示，所有接受治疗的5例患者中，他们的骨膜下淋巴液中的SENS-401水平均达到产生治疗效果的水平。这些结果确认，SENS-401可以到达耳蜗，并可能对保留剩余听力产生影响。此前，该药已获得FDA孤儿药资格，用于预防儿童铂类药物引起的耳毒性。‍‍‍‍‍‍‍‍‍医‍‍‍‍‍‍药‍‍‍‍‍‍‍‍‍‍‍‍‍热‍‍‍‍‍‍‍点‍‍‍‍‍‍‍‍‍1.上海3家三甲综合性医院宣布新一任党委书记。21日，复旦大学附属中山医院、上海交通大学医学院附属第九人民医院和上海市第六人民医院等3家三甲综合性医院分别召开医院干部会议，宣布新一任党委书记的任免决定。顾建英同志任复旦大学附属中山医院党委书记，汪昕同志因年龄原因不再担任复旦大学附属中山医院党委书记。马延斌同志任上海交通大学医学院附属第九人民医院党委书记，郭莲同志因年龄原因不再担任上海交通大学医学院附属第九人民医院党委书记。马昕同志任中共上海市第六人民医院委员会书记，免去陈方同志中共上海市第六人民医院委员会书记职务。2.浙大邵逸夫医院牙周中心揭牌成立。6月23日，浙江大学医学院附属邵逸夫医院牙周中心正式揭牌。该中心以口腔综合诊疗为基础、牙周专业为特长，配套拥有国际一流的牙周病检查和治疗器械（FLORIDA电子牙周探诊系统、水激光、EMS无痛超声、超声骨刀等），根据患者个体及牙周疾病类型差异，提供种植术、引导组织再生术、引导骨再生术、植骨术、游离瓣移植术、美学牙周外科手术等临床领先技术，并结合多样化的健康促进、随访和维护治疗，为患者提供长期而稳定的疗效。3.四川加强孤独症筛查干预全链条服务。近日，四川省卫健委联合省残联召开0～6岁儿童孤独症筛查干预服务现场会。会议要求，积极搭建儿童心理保健信息网络，逐步建立儿童孤独症筛查干预健康电子档案，推广使用四川省妇幼卫生信息平台；持续加强健康宣教和政策解读，大力开展儿童心理保健科普知识、孤独症医疗保障和救助政策等宣传教育，提高儿童家长孤独症知识知晓率。‍‍‍‍‍‍‍评‍‍‍‍‍审‍‍‍‍动‍‍态‍‍‍‍‍‍‍  1. CDE新药受理情况（06月22日) 2. FDA新药获批情况（北美06月22日）股市资讯上个交易日 A 股医药板块 -1.46%涨幅前三     跌幅前三凯普生物+13.79%  一 品 红  -8.26%华神科技+10.00%  凯 莱 英 -7.19%必 康 退 +9.59%   翰宇药业 -6.95%【浙江医药】子公司收到关于在研药物注射用NCB003的注册临床申请《受理通知书》。【信立泰】公司收到创新小分子药物SAL0119片的FDA受理。【海思科】收到HSK31679片的《药物临床试验批准通知书》。【康希诺】收到关干吸附无细胞百(组分)白破联合疫苗(6岁及以上人群用)的《药品临床试验批准通知书》。【恒瑞医药】子公司提交的注射用瑞卡西单抗药品上市许可申请获国家药监局受理。- The End -戳“阅读原文”，了解更多医药研发及股市资讯。