The goal of this clinical trial is to learn if combined therapy with infliximab and ustekinumab works better than using these drugs alone in adult patients with ulcerative colitis. It will also learn about the safety of this combination. The main questions it aims to answer are:
Does the combination therapy improve the symptoms and heal the intestine quicker and better than these drugs administered alone? Does the combination therapy improve the quality of life better than these drugs administered alone? What medical problems do participants have when taking the combination therapy?
Participants:
Patients diagnosed with UC will be qualified to biologic therapy (infliximab/ustekinumab/infliximab + ustekinumab).
Visit the clinic in stated periods for assessment and to apply medication. Take drugs based on the schedule.

开始日期2024-07-01

申办/合作机构

Medical University of Lodz

[+3]

NCT06045754 / Recruiting临床4期

An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Dual Targeted Therapy With Vedolizumab Intravenous (IV) and Adalimumab Subcutaneous (SC) or Vedolizumab IV and Ustekinumab IV/SC in Moderate to Severe Crohn's Disease (CD)

The main aim of this study is to learn about the effect of treatment with vedolizumab IV (vedolizumab) together with adalimumab or vedolizumab together with ustekinumab in adults with moderate to severe Crohn's Disease, and the effect of treatment with vedolizumab alone, after the dual targeted treatment.
The study is conducted in two parts. In Part A, participants will receive the dual targeted treatment (vedolizumab together with either adalimumab or ustekinumab). In part B, participants will receive vedolizumab only. Part B will include participants who responded to the treatment in Part A.
Each participant will be followed up for at least 26 weeks after the last dose of treatment.

开始日期2024-04-18

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

NCT06290934 / Recruiting临床2期

A Multicenter, Randomized, Double-blind, 2-Part Phase 2 Study to Evaluate the Efficacy and Safety of GS-1427 in Adult Participants With Moderately to Severely Active Ulcerative Colitis (UC) Part 1: Placebo-Controlled, Dose-Ranging Study of GS-1427; Part 2: Active-Controlled, Combination Study Evaluating the Efficacy and Safety of GS-1427 in Combination With Ustekinumab Versus GS-1427 or Ustekinumab Monotherapy

The goal of this study is to learn if GS-1427 is effective and safe in treating participants with moderate to severe ulcerative colitis. The study will compare participants in different treatment groups treated with GS-1427 with participants treated with placebo (Part 1), and participants treated with GS-1427 or ustekinumab alone with participants treated with GS-1427 in combination with ustekinumab (Part 2).
The primary objectives of this study are:
Part 1: To assess the efficacy of GS-1427, compared with placebo control, in achieving clinical response at Week 12
Part 2: To assess the efficacy of combination therapy with GS-1427 and ustekinumab, compared with GS-1427 and ustekinumab monotherapies, in achieving clinical response at Week 12

开始日期2024-03-27

申办/合作机构

Gilead Sciences, Inc.

100 项与乌司奴单抗相关的临床结果

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100 项与乌司奴单抗相关的转化医学

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100 项与乌司奴单抗相关的专利（医药）

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2,944

项与乌司奴单抗相关的文献（医药）

2024-05-01·International journal of clinical pharmacology and therapeutics

Comparison of SB17 and reference ustekinumab in healthy adults: A randomized, double-blind, single-dose, phase I study

Article

作者: Im, Seongsik ; Kang, Taeseung ; Jeong, Hansol ; Lee, Jiyoon

OBJECTIVE:

This study compared the pharmacokinetic (PK) characteristics of SB17 (Samsung Bioepis, Incheon, Republic of Korea), a proposed biosimilar of ustekinumab (UST) against reference UST (Stelara, Janssen Biotech, Horsham, PA, USA).

MATERIALS AND METHODS:

This double-blind, three-arm, parallel-group, single-dose study randomized 201 healthy adult subjects 1 : 1 : 1 to receive 45 mg of SB17, European Union-sourced UST (EU-UST) or United States of America-sourced UST (US-UST) via subcutaneous (SC) injection. Primary endpoints were area under the concentration-time curve from time zero to infinity (AUC_inf) and maximum serum concentration (C_max). Safety, tolerability, and immunogenicity were investigated.

RESULTS:

All 90% confidence intervals (CIs) for the ratios of AUC_inf and C_max between groups were within the predefined bioequivalence margin of 0.8 - 1.25. The geometric LSMeans ratios of AUC_inf and C_max were 0.99 and 0.90 for SB17/EU-UST, 1.01 and 0.94 for SB17/US-UST, and 1.02 and 1.05 for EU-UST/US-UST, respectively. The proportion of subjects with treatment-emergent adverse events (TEAEs) was comparable between SB17, EU-UST, and US-UST (68.7, 58.2, and 65.7%). No deaths, serious adverse events (SAEs), or severe TEAEs were reported. The incidence of subjects testing positive for post-dose anti-drug antibodies (ADAs) was 26.9%, 34.3%, and 34.3% in the SB17, EU-UST, and US-UST groups, respectively. Among the subjects with a positive ADA result at day 99/end of study, 53.8% (SB17 n = 5, EU-UST n = 12, and US-UST n = 11) were positive for neutralizing antibodies (NAbs).

CONCLUSION:

This study demonstrated bioequivalence of SB17, EU-UST, and US-UST in terms of PK. Safety, tolerability, and immunogenicity were also comparable between all groups.

2024-04-23·Journal of Crohn's & colitis

Pharmacological Therapies for the Management of Fistulizing Crohn’s Disease: A Systematic Review and Meta-Analysis

Review

作者: McCurdy, Jeffrey D ; Singh, Siddharth ; Vuyyuru, Sudheer K ; Lee, Matthew J ; Ma, Christopher ; MacDonald, John K ; Jairath, Vipul ; Solitano, Virginia ; Narula, Neeraj

Abstract:

Background:

Fistulas are a debilitating complication of Crohn’s disease [CD]. We conducted a systematic review to assess the efficacy of medical therapies for fistulizing CD.

Methods:

MEDLINE, Embase, and CENTRAL were searched on May 26, 2022, for randomized controlled trials [RCTs] of pharmacological therapy in adults with fistulizing CD. The primary outcome was induction and maintenance of fistula response. Pooled risk ratios [RRs] and 95% confidence intervals [CIs] were calculated. GRADE was used to assess the certainty of evidence.

Results:

Thirty-eight RCTs were included. Nineteen trials [50%] exclusively involved perianal fistula. The remaining studies included some participants with non-perianal fistula. Pooled RRs for anti-tumour necrosis factor [TNF] agents were not statistically significant for induction [RR 1.36, 95% CI 0.97–1.91] or maintenance of fistula response [RR 1.48, 95% CI 0.97–2.27]. However, in a sensitivity analysis of studies with fistula response as the primary outcome, anti-TNFs were superior to placebo for induction [RR 1.94, 95% CI 1.10–3.41] and maintenance [RR 1.88, 95% CI 1.23–2.88] of fistula response. Oral small molecules [RR 2.56, 95% CI 1.18–5.53] and mesenchymal stem cell [MSC] therapy [RR 1.26, 95% CI 1.01–1.57] were effective for induction of fistula response. Ustekinumab was associated with maintenance of fistula response [RR 1.80, 95% CI 1.04–3.11]. Vedolizumab was not superior to placebo. The certainty of evidence ranged from very low to moderate.

Conclusion:

Very low- to moderate-certainty evidence suggests that anti-TNF therapy, oral small molecules, ustekinumab, and MSCs are effective for perianal fistulizing CD. Dedicated fistula studies evaluating biologics and small molecules are needed.

2024-04-02·Expert opinion on drug safety

Ustekinumab as induction and maintenance therapy for ulcerative colitis – national extended follow-up and a review of the literature

Review

作者: Chetwood, J D ; Paramsothy, S ; Leong, R W ; Moore, G ; De Cruz, P ; Connor, S J ; Gupta, S ; An, Y K ; Kermeen, M ; Subramaniam, K

INTRODUCTION:

Ustekinumab use in ulcerative colitis had shown low adverse event and high persistence rates to 3 years via the UNIFI long-term extension study. Outcomes beyond 3 years have not been previously described. We describe the safety signals of the entire UNIFI Australian population beyond 3 years.

METHODS:

This retrospective multicenter observational cohort study recruited from all Australian UNIFI centers. The primary outcome was safety via adverse events. Secondary outcomes included the clinical relapse rate on ustekinumab, and the need to switch from ustekinumab to an alternate agent.

RESULTS:

There were 14 patients [11 male, mean age 47 (±14) years], with a median diagnosis of 10.8 (±4.5) years prior to UNIFI enrollment. Median follow-up was 298 weeks (5.7 years) (Interquartile range (IQR): 220-311 weeks). Within the long-term extension, there were three serious adverse events and one minor event. 42.9% (6/14) patients had clinical relapses, of which clinical remission was recaptured in 83.3% (5/6). 85.7% (12/14) persisted on ustekinumab in the long-term, with 7.1% (1/14) electively ceasing ustekinumab and 7.1% (1/14) changed from ustekinumab due to clinical relapse.

CONCLUSION:

For moderate-to-severe UC in Australia, ustekinumab maintained efficacy beyond 3 years with a high persistence rate and no new safety signals.

TRIAL REGISTRATION:

The trial is registered at ANZCTR (identifier: ACTRN12622001332718).

699

项与乌司奴单抗相关的新闻（医药）

2024-07-01

·生物探索

突破自体炎症治疗新途径：口服IL-23R和IL-17拮抗剂微蛋白显现卓越疗效

IL-23R和IL-17是自体炎症性疾病的关键治疗靶点，特别是在炎症性肠病（IBD）和银屑病的治疗中，抑制IL-23和IL-17的信号通路能够显著减轻炎症反应。然而，现有的抗体疗法存在不少局限。仅约30%的IBD患者在接受抗IL-23单克隆抗体（如Stelara）治疗后可达到缓解状态，且约20%的初始响应者会由于产生抗药抗体而逐渐失去响应。此外，系统性免疫抑制增加了患者患上恶性肿瘤和严重感染的风险。由于抗体分子较大且渗透性差，无法口服，只能通过静脉注射或皮下注射，这对患者而言既不方便又容易产生压力。生产和运输抗体也相对昂贵，因为需要在哺乳动物表达系统中生产，并进行复杂的纯化过程以达到适合注射的纯度，同时还需冷藏储存和运输。 6月26日Cell报道的研究“Preclinical proof of principle for orally delivered Th17 antagonist miniproteins”旨在开发可口服的IL-23R和IL-17拮抗剂小蛋白，以应对自体炎症性疾病中的治疗需求。研究团队通过计算设计，成功设计出具有抗体水平的低皮摩尔亲和力和极高稳定性的IL-23R和IL-17微结合蛋白，这些小蛋白不仅能够有效阻断细胞信号传导，而且在加热、酸和蛋白水解条件下表现出极强的抵抗力。设计的IL-23R和IL-17小蛋白结合剂不仅具备低成本和易制造的优势，还可以通过口服途径达到治疗效果。在小鼠结肠炎模型中，口服的IL-23R微结合蛋白的疗效甚至优于临床使用的抗IL-23抗体。该研究展示了口服给药的去新设计微结合蛋白能够穿越肠上皮屏障并达到治疗靶点，具有高效力、肠道稳定性和简便制造的优点，为口服生物制剂提供了一种新的潜在模式。总的来说，该研究证明了口服IL-23R和IL-17拮抗剂小蛋白在治疗自体炎症性疾病中的巨大潜力，展示了其作为口服生物制剂的可行性和优势，为未来相关药物的开发和应用提供了重要参考。自体炎症性疾病（autoinflammatory diseases）是由自身免疫系统异常引发的疾病，如炎症性肠病（IBD）和银屑病（psoriasis）。研究发现，细胞因子IL-23和IL-17在这些疾病的发病机制中起着关键作用。IL-23由抗原呈递细胞产生，促进T辅助细胞17型（Th17 cells）的分化和维持，而IL-17则由循环中的Th17细胞和组织驻留的先天淋巴细胞（ILCs）以及γδT细胞产生，具有强烈的促炎作用。因此，靶向抑制IL-23和IL-17的信号通路已成为治疗自体炎症性疾病的重要策略。尽管现有的抗体治疗（如针对IL-23的单克隆抗体Stelara）在临床上显示出一定的疗效，但这些疗法存在诸多限制，如高成本、安全风险、疗效不持久以及给药不便（需注射）。因此，该研究旨在通过计算设计，开发能够口服的IL-23R和IL-17拮抗剂微蛋白，这些微蛋白不仅具有抗体水平的高亲和力，还具备极高的稳定性和低成本的制造优势，从而为自体炎症性疾病的治疗提供一种新型的、更加方便和安全的治疗方式。研究团队首先利用计算设计方法，设计出具有低纳摩尔亲和力和高稳定性的IL-23R和IL-17微结合蛋白。这一过程从目标蛋白的晶体或冷冻电镜（cryo-EM）结构开始，结合关键结合位点（hotspots）的信息，通过Rosetta分子建模套件优化蛋白的氨基酸序列和构象。最终，研究人员获得了数千个潜在的微结合蛋白，并将编码这些蛋白的基因转入酵母细胞，通过多轮荧光激活细胞分选（FACS）筛选出最优的结合蛋白。筛选出的微结合蛋白在大肠杆菌中表达并纯化，研究人员通过生物层干涉技术（BLI）和细胞信号传导抑制实验，定量测定这些蛋白的结合亲和力和抑制效力。结果显示，这些微结合蛋白均能以低纳摩尔的亲和力结合其目标蛋白，并在热、酸和蛋白水解条件下表现出极高的稳定性。在小鼠结肠炎模型中，研究团队评估了口服IL-23R微结合蛋白的疗效。实验结果表明，口服的IL-23R微结合蛋白在缓解小鼠结肠炎症状方面优于临床使用的抗IL-23抗体。此外，通过药代动力学和生物分布研究，发现这些微结合蛋白在大鼠体内具有良好的药代动力学特性和分布特点，能够穿越肠上皮屏障并到达目标组织。通过计算设计，研究团队成功设计出具有高亲和力和高稳定性的IL-23R和IL-17微结合蛋白。其中，IL-23R微结合蛋白23R-1和23R-2分别包含55和54个氨基酸残基，形成三个螺旋束结构，能够有效结合IL-23R。IL-17微结合蛋白17-1、17-2和17-3则分别包含43和61个氨基酸残基，能够有效结合IL-17A。体外实验结果显示，所设计的微结合蛋白能够以低纳摩尔的亲和力结合其目标蛋白。在圆二色光谱（CD）实验中，IL-23R微结合蛋白23R-1和23R-2的变性温度（Tm）分别超过95°C和极高的化学变性中点浓度（5 M Gdn for 23R-1，>6 M for 23R-2）。IL-17A微结合蛋白17-1的Tm约为90°C，化学变性中点为4 M。IL-17A微结合蛋白17-2的稳定性最弱，其Tm约为70°C，化学变性中点为2 M。体外蛋白水解稳定性：实验将每种微结合蛋白或作为对照的V565纳米抗体（目前正在开发用于IBD的口服纳米抗体）在模拟肠液（SIF）或模拟胃液（SGF）中于37°C下消化长达24小时。结果显示，部分微结合蛋白在SGF或SIF中的稳定性较好，而有些则在较短时间内降解。残余结合活性：SIF和SGF消化后的样品在不同时间点被稀释至10 nM的微结合蛋白浓度，并通过BLI（生物层干涉技术）测量其对人IL-23R的残余结合活性。结果表明，经过SGF和SIF消化后，部分微结合蛋白仍然保留对IL-23R的结合能力。大鼠体内药代动力学研究：在健康大鼠中，单剂量口服20 mg/kg的23R-72或23R-91，采用PBS或胃肠保护性载体（GPV）配方，6小时后测量血清和目标组织中的微结合蛋白浓度。结果显示，无论是PBS还是GPV配方，这些微结合蛋白在小肠内容物中的浓度为50-100 nM，在小肠组织中的浓度为40-200 nM，而在结肠组织中的浓度较低，为2-20 nM。在大鼠血清中未检测到显著浓度的微结合蛋白。血清浓度时间曲线：健康大鼠单剂量口服140 mg/kg的23R-91，在不同时间点测量血清中微结合蛋白的浓度。结果表明，微结合蛋白在15分钟后达到血清峰值浓度73 nM，随后迅速下降，半衰期约为15分钟，6小时后的浓度低于检测限。在小鼠结肠炎模型中，口服的IL-23R微结合蛋白在缓解结肠炎症状方面表现出显著的疗效。药代动力学研究表明，这些微结合蛋白在大鼠体内具有良好的药代动力学特性和分布特点，能够穿越肠上皮屏障并到达目标组织。具体数据如下：单剂量口服20 mg/kg的23R-91在健康大鼠的肠道组织和内容物中的浓度分别为50-100 nM和40-200 nM，而在结肠组织中的浓度为2-20 nM。此外，在给予单剂量140 mg/kg的23R-91后，其在大鼠血清中的浓度在15分钟后达到峰值73 nM，随后迅速下降，半衰期约为15分钟。研究团队还评估了微结合蛋白的免疫原性。23R-91具有高度的溶解性和稳定性，预计其免疫原性较低。在人体临床试验中，口服的23R-91未引发强烈的抗药反应。进一步的生物信息学分析显示，23R-91片段与多种主要组织相容性复合体（MHC）II类分子的结合亲和力较低，这与低免疫原性相关。通过计算设计开发的IL-23R和IL-17拮抗剂微蛋白展现了作为口服生物制剂的巨大潜力。相比传统的抗体疗法，这些微蛋白不仅具有高效力、低成本和易制造的优势，还能通过口服途径方便地给药，极大地提高了患者的治疗体验。该研究为自体炎症性疾病的治疗提供了一种全新的思路，展示了计算设计蛋白在生物医药领域的广泛应用前景。未来，随着更多临床前和临床研究的深入开展，这些微结合蛋白有望为广大患者带来更加安全、有效和便捷的治疗选择。参考文献 Berger S, Seeger F, Yu TY, Aydin M, Yang H, Rosenblum D, Guenin-Macé L, Glassman C, Arguinchona L, Sniezek C, Blackstone A, Carter L, Ravichandran R, Ahlrichs M, Murphy M, Pultz IS, Kang A, Bera AK, Stewart L, Garcia KC, Naik S, Spangler JB, Beigel F, Siebeck M, Gropp R, Baker D. Preclinical proof of principle for orally delivered Th17 antagonist miniproteins. Cell. 2024 Jun 23:S0092-8674(24)00631-7. doi: 10.1016/j.cell.2024.05.052. Epub ahead of print. PMID: 38936360. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2024.05.052 内容来源于网络，如有侵权，请联系删除。

临床研究临床结果

2024-07-01

·动脉网

从肿瘤换道自免疾病后，这家初创公司融了4亿

2024年，4月10日，根据Vertex Pharmaceuticals（福泰制药，以下简称Vertex）发布公告，Vertex 和Alpine Immune Sciences（以下简称Alpine）已签署收购协议，将以约49亿美元（折合人民币354亿）收购生物技术公司Alpine，以获得后者治疗肾脏自身免疫性疾病的药物。这笔交易对Alpine的估值为每股65美元。紧接着2024年5月22日，渤健（Biogen）与免疫疗法公司Human Immunology Biosciences（以下简称HI-Bio）宣布，两家公司已达成收购协议。根据协议条款，Biogen将向HI-Bio支付11.5亿美元预付款（约83亿人民币），以及6.5亿美元里程碑付款，潜在交易总价值高达18亿美元（约合130亿人民币）。预计该交易将于2024年第三季度完成。不过一个多月时间内，2024年自免领域第一大和第二大收购案就已高度亮相，不禁令业内期待下半年自免市场的表现。自身免疫疾病是由于机体对自身抗原发生免疫反应，从而引发自身组织损害所导致的疾病。全球自免疾病患病人群总数预计5亿以上，我国主要自免疾病患者近4000万人。根据对于常见的自免疾病的统计，全球自免疾病的患病率约5%—8%，是继癌症和心血管疾病外第三大慢性病。根据现有文献数据，特异性皮炎（约2%—5%）、银屑病（约2%—3%）、类风湿关节炎（约0.5%—1%）等疾病发病率较高。根据沙利文数据预测，到2030年，全球自身免疫性疾病药物市场规模有望达到1760亿美元，2022～2030年复合年增长率为3.6%，其中中国市场规模2030年有望达到近250亿美元，较2020年实现十倍增长，是全球自免药物的重要增量来源。这或许可以解释，一家专注于肿瘤的初创企业，毅然决然转换赛道，一脚踏进自免领域。 2019年，一家名为AbGenomics Holding Inc.（下称AbGenomics）的企业正式正式宣布更名为AltruBio Inc.（下称AltruBio）。AbGenomics原为位于美国旧金山的肿瘤抗体药开发商，不仅聘请国际公认的生技业资深领导专家担任新董事会成员，也和前罗氏技术营运总裁杨育民董事长搭配。而此次改名为AltruBio后，2020年，企业邀请了曾担任拜耳制药全球生技总裁要职的副总裁Judy Chou（周慧泉，下称周博士）博士为AltruBio掌舵，担任总裁兼首席执行官，积极推动公司转型，可谓换名又换帅。 AltruBio前身AbGenomics已有的两种抗体靶向疗法正在针对六个疾病领域进行研发。其中，Neihulizumab是一种免疫检查点激动剂抗体，旨在通过靶向PSGL-1调节T细胞稳态，正在进行两项针对银屑病关节炎和溃疡性结肠炎的2期临床试验。该分子之前还获得FDA快速通道资格，用于治疗类固醇难治性急性移植物抗宿主病。Neihulizumab在2020年以疫情为由终止了一项溃疡性结肠炎试验，但在重启时正在进行一项急性移植物抗宿主病研究（公司网站显示将仍会进行UC的研究）。换名换帅之后，AltruBio在周博士的带领下毅然决然进行重组，同时做了重大的决策变更，退出肿瘤学和优先考虑免疫学，包括终止靶向胃癌的ADC候选药物AbGn-107的开发。而周博士在谈到Neihulizumab时表示：“我们将肿瘤产品放在一边，以便能够100%专注于我们拥有的这一同类首创的新型分子。” 周博士曾是大型制药公司的MVP，曾在耶鲁大学获得博士学位，在德国马克斯普朗克研究所接受博士后培训，并曾担任哈佛大学医学院研究员，专注于细胞生物学和神经科学。在正式进入市场后，周博士在药物开发和生物制造领域积累了20多年的经验。在加入 AltruBio之前，她曾领导拜耳的全球生物技术组织。在拜耳，她负责该公司价值超过30亿美元的产品组合的开发、制造和分销。她还管理着3000多名员工，并领导生物制剂管线的开发和上市活动。此外，她还担任拜耳位于加利福尼亚州伯克利的工厂的现场负责人，据悉，该工厂正是拜耳在美国最大的制造基地。此外，周博士还曾在辉瑞、艾伯维、Medivation、基因泰克和惠氏生物制药公司担任领导职务。她曾多次获奖，并于2018年荣获《旧金山商业时报》颁发的“最具影响力的商界女性”奖项。她目前是加州大学伯克利分校工程学院的顾问，并通过她在硅谷女性工程协会的顾问委员会职位，致力于促进行业的多元化和包容性。据悉，就在2020 年1月，周博士接任AltruBio首席执行官一职时，放弃了拜耳提供的条件，原因是她更看好新药Neihulizumab的数据，此外，她在那时就预计公司在战略层面将发生翻天覆地的变化，但随后新冠疫情来袭，变革不得不搁置。直到2021年来临。在周博士的掌舵下，AltruBio全面“翻新”，开始由肿瘤方向转向聚焦自身免疫疾病领域。这样的大胆决策为AltruBio带来了回报。2021年4月，AltruBio宣布完成6300万美元（约4亿人民币）A轮融资。该轮融资由aMoon牵头，包括BVF Partners L.P.（BVF），CAM Capital在内的新投资者以及其他新的和现有的投资者加入了该轮。周博士表示，A轮融资的资金将用于推出第二代皮下注射型Neihulizumab——即AbGn-168H，希望能够增加器官移植适应症。该公司还将在下一阶段重点研究慢性移植物抗宿主病（SR-aGVHD）。 2024年5月21日，AltruBio宣布获得最高2.25亿美元的超额认购B轮融资。本轮融资由BVF Partners LP领投，新投资者包括RA Capital Management、Cormorant Asset Management和Soleus Capital，现有投资者aMoon Fund和Blackstone Multi-Asset Investing也参与了本轮融资。融资资金将用于推进公司首创的新型免疫检查点增强剂ALTB-268在溃疡性结肠炎（UC）中的二期临床试验。让AltruBio吸金的关键，除了从肿瘤到自免赛道的大胆转向外，也和AltruBio继承的主要管线Neihulizumab，也就是AbGn-168H有关。在AltruBio刚完成A轮融资时，其专注的抗体靶向疗法为靶向PSGL-1（P-Selectin Glycoprotein Ligand 1，中文全称为P-选择素糖蛋白配体1）/CD162的免疫检查点激动剂抗体Neihulizumab（AbGn-168H现为ALTB-168），也是优先考虑的候选免疫药物。 Neihulizumab是一种免疫检查点激动剂抗体，旨在通过靶向PSGL-1调节T细胞稳态，目前正在进行两项针对银屑病关节炎和溃疡性结肠炎的2期临床试验。2024年3月，该分子还获得FDA快速通道资格，用于治疗类固醇难治性急性移植物抗宿主病。Neihulizumab在2020年以疫情为由终止了一项溃疡性结肠炎试验，但在重启时正在进行一项急性移植物抗宿主病研究（根据AltruBio官网，其表示将仍会进行UC的研究）。而今，AltruBio的重心稍有转移，重点管线从Neihulizumab转向 ALTB-268，这是因为后者在临床中显示出更为优越的疗效。 ALTB-268是在继承ALTB-168独特的作用机制下研发的一种四价PSGL-1激动性抗体，也是第二代产品。前文提到，PSGL-1是一种免疫检查点蛋白，它的激活会下调T细胞的活性。而ALTB-268是一款能够优先下调长期激活T细胞的ICE，通过抑制T细胞效应功能，恢复免疫系统的稳态，从而从源头上治疗免疫疾病。此外，它不会下调初始T细胞和急性激活T细胞的活性，因此不会导致全身性的免疫抑制，1期临床研究已证明其在健康志愿者中的安全性和耐受性，所有队列中均未出现严重不良事件。目前，ALTB-268针对难治性UC患者的2a期探索性生物标志物研究正在招募患者， AltruBio预计将在2025年上半年报告主要临床缓解终点数据，并计划在2026年下半年进行2b阶段试验。而与此同时，ALTB-268还在进行银屑病关节炎适应症的临床试验，并已经获得了有希望的2a期结果。从Neihulizumab转向 ALTB-268，这种结构性的调整反映了AltruBio从肿瘤学转向专注于免疫学的策略性重新定位，以便充分利用其在PSGL-1途径上调节免疫反应的专业知识。根据自免性疾病特点，正常情况下，免疫系统仅对外来或者危险的物质有反应，而不会对自身组织的抗原出现反应。然而，有时候会出现免疫功能异常，把自身的组织当作外来的，而产生抗体（被称为自身抗体）或免疫细胞攻击自身的细胞或组织。这种反应被称为自身免疫反应，能各种导致炎症和组织损伤。而自免性疾病领域的药物开发思路即：抑制机体内的免疫反应和免疫细胞活性。一般情况下，抗原呈递细胞（APC）可利用MHC-II分子向T细胞展示捕获到的抗原（包括外源性/内源性抗原），且同时表达B7分子，利用B7分子与T细胞的CD28相互作用提供必要的共刺激信号。在这些因素共同作用下，T细胞被激活。随后，进入激活状态T细胞，将伴随产生细胞因子及受体。研究人员发现，在被激活的T细胞表面，PSGL-1表达显著增强。而PSGL-1是一种位于细胞表面的Ⅰ型跨膜糖蛋白，几乎能在机体内的所有白细胞（包括T细胞、B细胞、中性粒细胞、嗜酸性粒细胞等）上表达。既往研究发现，PSGL-1参与白细胞与血管内皮细胞之间的相互作用，促进白细胞向炎症部位的迁移。 AltruBio飞速发展的几年，恰逢自免疾病药物乃至全球创新药市场震荡的时段。对于自免疾病领域，随着关键市场的专利到期，修美乐（阿达木单抗）将正式交出蝉联了11年的全球销冠头衔，一代“药王”正式谢幕。修美乐是艾伯维公司研发的抗TNF-α全人源单克隆抗体药物，于2002年获FDA批准上市，用于治疗类风湿性关节炎。由于在自免疾病治疗方面展现出非凡的疗效和安全性，修美乐上市后适应症不断扩张，逐渐成为销量最高的自免药物，并于2012年登上全球药物销售额榜首。此后，为了尽可能延长修美乐的生命周期，艾伯维通过一系列市场和专利策略，推动该药物连续十年成为全球“药王”，上市以来累计销售额超过2000亿美元。根据《自然评论药物发现》发布的2023年全球创新药销量情况预测，继修美乐之后，分别以IL-4/IL-13和IL-12/IL-23为靶点的自免生物制剂Dupixent和Stelara销售额增长迅猛，预计将以超过106亿美元的销售额跻身Top10。由于业内已有“巨噬细胞重编程或将是免疫治疗耐药的解法”的观点，作为其代表性的新星靶点PSGL-1自然被寄予厚望。不过，PSGL-1能否在药王谢幕后“百家争鸣”的自免市场中争得一席之地，还需等待临床进一步有说服力的结果。当前AltruBio已走到临床2期，而另一家国内企业三生制药的国内首款PSGL-1靶向拮抗型抗体VTX-0811（SSGJ-617）也进展到临床1期。此前三生制药与Verseau达成授权协议，合作助推VTX-0811获得美国FDA批准开展临床试验，用于治疗实体瘤。内容来源于网络，如有侵权，请联系删除。

免疫疗法并购临床2期

2024-07-01

·GlobeNewswire-Health Care

FDA approves biosimilar Pyzchiva® (ustekinumab-ttwe), to be commercialized by Sandoz in US

Ad hoc announcement pursuant to art. 53 SIX Swiss Exchange Listing Rules FDA approves biosimilar Pyzchiva® (ustekinumab-ttwe), to be commercialized by Sandoz in US Pyzchiva® (ustekinumab-ttwe) is approved by FDA for all indications of reference medicineFDA granted provisional determination for interchangeability designation for Pyzchiva®Extends Sandoz immunology portfolio and further strengthens biosimilar position Expected to be among first wave of ustekinumab biosimilars to launch in US Basel, July 1, 2024 – Sandoz, the global leader in generic and biosimilar medicines, today announced that the US Food and Drug Administration (FDA) has approved biosimilar Pyzchiva®* (ustekinumab-ttwe) 45 mg/0.5 mL and 90 mg/mL pre-filled syringes for subcutaneous injection and 130 mg/26 mL (5 mg/mL) single-dose vial for intravenous infusion. Developed by Samsung Bioepis Co., Ltd, it is approved for all indications of its reference medicine and will be commercialized by Sandoz in the US. In addition, the FDA provisionally determined that Pyzchiva® would be interchangeable with the reference medicine as it is currently subject to an unexpired period of exclusivity for the first interchangeable biosimilar biological products. Sandoz intends to launch Pyzchiva® in the US in February 2025, in accordance with the settlement and license agreement with Janssen Biotech Inc. previously announced by Samsung Bioepis Co., Ltd. Pyzchiva® is expected to be among the first wave of ustekinumab biosimilars to launch in the US. Claire D'Abreu-Hayling, Chief Scientific Officer, Sandoz, said: “This approval reflects our dedication to ensuring high-quality treatments are universally accessible. By further expanding our immunology portfolio with affordable biosimilar alternatives, we continue to make significant strides towards achieving our goal of delivering life-changing medicines to the patients who need them.” Pyzchiva® is a key biosimilar value driver for the company over the mid-term, and this approval is a major step in advancing the Sandoz growth strategy by extending the US immunology portfolio. Pyzchiva® is approved by the FDA for all indications of the reference medicine Stelara®† (ustekinumab), a human interleukin (IL)-12 and IL-23 antagonist,1 including to treat adult patients with moderate to severe plaque psoriasis, active psoriatic arthritis, moderately to severely active Crohn’s disease and moderately to severely active ulcerative colitis, as well as pediatric patients with moderate to severe plaque psoriasis and active psoriatic arthritis.2 Leah M. Howard, J.D., President and CEO of the National Psoriasis Foundation, said: "Systemic medications like biologics are a key treatment option for many people to manage symptoms of psoriasis and psoriatic arthritis. Unfortunately, barriers to care, including costs, often prevent patients from getting the drug they are prescribed. Psoriatic disease is lifelong and chronic, leading to long-term treatment costs. Having more FDA-approved options can help make appropriate healthcare more affordable.” Plaque psoriasis is the most common form of psoriasis, affecting approximately 80% to 90% of patients.3 The FDA granted approval to Samsung Bioepis based on the totality of the evidence, including robust clinical studies confirming that Pyzchiva® has equivalent efficacy and comparable safety as its reference medicine. Sandoz entered into a development and commercialization agreement for biosimilar ustekinumab with Samsung Bioepis in September 2023. Under the terms of the agreement, Sandoz has the right to commercialize Pyzchiva® in the US, Canada, the European Economic Area (EEA), Switzerland and the UK. Samsung Bioepis remains responsible for development, registration, intellectual property, manufacturing and supply. *Pyzchiva® is a trademark of Samsung Bioepis Co. Ltd.†Stelara® is a registered trademark of JOHNSON & JOHNSON (USA). INDICATIONSPYZCHIVA (ustekinumab-ttwe) is indicated for the treatment of patients 6 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, patients 6 years or older with active psoriatic arthritis, adult patients with moderately to severely active Crohn’s disease, adult patients with moderately to severely active ulcerative colitis. CONTRAINDICATIONS: Clinically significant hypersensitivity to ustekinumab or to any of the excipients. WARNINGS AND PRECAUTIONS: Infections: Serious infections have occurred. Avoid starting PYZCHIVA during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue PYZCHIVA until the infection resolves. Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL-12/IL-23. Consider diagnostic tests for these infections as dictated by clinical circumstances. Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with PYZCHIVA. Initiate treatment of latent TB before administering PYZCHIVA. Malignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with a history of or a known malignancy has not been evaluated. Hypersensitivity Reactions: If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue PYZCHIVA. Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly and discontinue PYZCHIVA.Immunizations: Avoid use of live vaccines in patients during treatment with PYZCHIVA. Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. If diagnosis is confirmed, discontinue PYZCHIVA and institute appropriate treatment. ADVERSE REACTIONS: Most common adverse reactions are Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. Crohn’s Disease, induction (≥3%): vomiting. Crohn’s Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. Ulcerative colitis, induction (≥3%): nasopharyngitis. Ulcerative colitis, maintenance (≥3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea. This is not the complete list of all the safety information for PYZCHIVA. Please see full Prescribing Information for PYZCHIVA. DisclaimerThis Media Release contains forward-looking statements, which offer no guarantee with regard to future performance. These statements are made on the basis of management’s views and assumptions regarding future events and business performance at the time the statements are made. They are subject to risks and uncertainties including, but not confined to, future global economic conditions, exchange rates, legal provisions, market conditions, activities by competitors and other factors outside of the control of Sandoz. Should one or more of these risks or uncertainties materialize or should underlying assumptions prove incorrect, actual outcomes may vary materially from those forecasted or expected. Each forward-looking statement speaks only as of the date of the particular statement, and Sandoz undertakes no obligation to publicly update or revise any forward-looking statements, except as required by law. References1. Janssen Pharmaceuticals. Stelara® (Ustekinumab): Prescribing Information. Available at: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/STELARA-pi.pdf [Last accessed: June 2024]2. Pyzchiva®. Prescribing Information. Available at: BLA 761373 and BLA 761425 PI MG and IFU.pdf (sandoz.com) [Last accessed: June 2024]3. Journal of the American Academy of Dermatology. Guidelines of Care for the Management Psoriasis and Psoriatic Arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. Available at: https://www.jaad.org/article/S0190-9622(08)00273-9/fulltext [Last accessed: June 2024] About SandozSandoz (SIX: SDZ; OTCQX: SDZNY) is the global leader in generic and biosimilar medicines, with a growth strategy driven by its Purpose: pioneering access for patients. More than 20,000 people of more than 100 nationalities work together to ensure 800 million patient treatments are provided annually by Sandoz, generating substantial global healthcare savings and an even larger social impact. Its leading portfolio of approximately 1,500 products addresses diseases from the common cold to cancer. Headquartered in Basel, Switzerland, Sandoz traces its heritage back to 1886. Its history of breakthroughs includes Calcium Sandoz in 1929, the world’s first oral penicillin in 1951, and the first biosimilar in 2006. In 2023, Sandoz recorded sales of USD 9.6 billion. Global Media Relations contacts Investor Relations contacts Global.MediaRelations@sandoz.com Investor.Relations@sandoz.com Joerg E. Allgaeuer+49 171 838 4838 Karen M. King+1 609 722 0982 Chris Lewis+49 174 244 9501 Laurent de Weck+41 79 795 7364 Attachments Global Media Release Pyzchiva FDA Approval

上市批准引进/卖出免疫疗法

100 项与乌司奴单抗相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D09214	乌司奴单抗	L04AC05	DB05679

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适应症	国家/地区	公司	日期
银屑病关节炎	欧盟	Janssen-Cilag International NV	2009-01-15
银屑病关节炎	冰岛	Janssen-Cilag International NV	2009-01-15
银屑病关节炎	列支敦士登	Janssen-Cilag International NV	2009-01-15
银屑病关节炎	挪威	Janssen-Cilag International NV	2009-01-15
溃疡性结肠炎	欧盟	Janssen-Cilag International NV	2009-01-15
溃疡性结肠炎	冰岛	Janssen-Cilag International NV	2009-01-15
溃疡性结肠炎	列支敦士登	Janssen-Cilag International NV	2009-01-15
溃疡性结肠炎	挪威	Janssen-Cilag International NV	2009-01-15
克罗恩病	欧盟	Janssen-Cilag International NV	2009-01-15
克罗恩病	冰岛	Janssen-Cilag International NV	2009-01-15
克罗恩病	列支敦士登	Janssen-Cilag International NV	2009-01-15
克罗恩病	挪威	Janssen-Cilag International NV	2009-01-15
斑块状银屑病	欧盟	Janssen-Cilag International NV	2009-01-15
斑块状银屑病	冰岛	Janssen-Cilag International NV	2009-01-15
斑块状银屑病	列支敦士登	Janssen-Cilag International NV	2009-01-15
斑块状银屑病	挪威	Janssen-Cilag International NV	2009-01-15

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适应症	最高研发状态	国家/地区	公司	日期
幼年型关节炎	临床3期	美国	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	阿根廷	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	丹麦	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	法国	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	德国	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	意大利	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	波兰	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	西班牙	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	土耳其	Janssen Research & Development LLC	2022-08-30
幼年型关节炎	临床3期	英国	Janssen Research & Development LLC	2022-08-30

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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


NCT03981744 (CTgov)	临床3期	皮肌炎	51	placebo+ustekinumab (Placebo)	壓構齋膚範顧顧糧廠艱(鹽壓淵範網願製衊獵齋) = 簾鑰繭膚網製繭獵淵網獵鑰網網網齋獵蓋壓網 (鑰築獵糧夢餘鑰醖壓衊, 膚顧壓淵積簾鬱糧窪繭 ~ 鏇壓繭膚範觸簾鹹積艱) 更多	-	2024-05-13
				Ustekinumab (Ustekinumab)	壓構齋膚範顧顧糧廠艱(鹽壓淵範網願製衊獵齋) = 艱鏇膚淵艱範鑰襯糧膚獵鑰網網網齋獵蓋壓網 (鑰築獵糧夢餘鑰醖壓衊, 鏇獵構壓選窪醖製範範 ~ 艱築構選遞憲壓簾範觸) 更多
ACR2023	N/A	银屑病关节炎一线	186	UST+MTX	窪醖廠鑰夢衊構遞醖觸(鑰選廠齋製憲鑰餘顧壓) = 觸膚醖獵築鬱願窪夢憲餘顧醖鏇觸鬱鏇鹽襯淵 (糧糧簾蓋積獵淵繭壓構 ) 更多	积极	2023-11-13
				UST+PBO	窪醖廠鑰夢衊構遞醖觸(鑰選廠齋製憲鑰餘顧壓) = 衊膚醖齋築淵顧鏇範窪餘顧醖鏇觸鬱鏇鹽襯淵 (糧糧簾蓋積獵淵繭壓構 ) 更多
EADV 12023 \| EADV 22023	N/A	斑块状银屑病	581	AVT04	夢觸壓構壓艱網鹽願鹹(鏇鏇鑰餘範夢遞範鏇鬱) = 願壓襯壓醖淵鏇鏇壓製糧鏇淵窪衊齋鏇繭顧廠 (憲築築觸範願鹽壓觸鹹 )	积极	2023-10-11
				Reference Product Ustekinumab	夢觸壓構壓艱網鹽願鹹(鏇鏇鑰餘範夢遞範鏇鬱) = 糧衊繭齋衊繭蓋壓鑰鹽糧鏇淵窪衊齋鏇繭顧廠 (憲築築觸範願鹽壓觸鹹 )
NCT03782376 (CTgov)	临床3期	克罗恩病	215	Placebo (SC)+Ustekinumab 90 mg (SC) Group 1 (Group 1: Ustekinumab (IV Re-induction))	鏇鬱製築襯獵繭膚鑰憲(齋壓構範構鹹觸範廠襯) = 憲糧糧鬱積繭糧鬱積醖範餘憲膚憲築構鏇繭壓 (衊網顧積壓鬱夢膚鑰糧, 窪鏇壓窪醖壓積艱鹽膚 ~ 願醖憲壓觸網獵範齋積) 更多	-	2023-09-13
				Placebo (IV)+Ustekinumab 90 mg (SC) Group 2 (Group 2: Ustekinumab (Continuous q8w SC Maintenance))	鏇鬱製築襯獵繭膚鑰憲(齋壓構範構鹹觸範廠襯) = 鏇襯鹽積鬱築簾廠襯鹹範餘憲膚憲築構鏇繭壓 (衊網顧積壓鬱夢膚鑰糧, 窪願糧選積淵繭窪壓網 ~ 構選鑰遞鬱鑰製鑰願鏇) 更多
WCD2023	N/A	银屑病	30	Ustekinumab	構鏇醖壓鑰壓築遞構繭(鏇築餘淵夢壓獵窪鹹鏇) = 衊窪鑰窪鏇積網壓獵膚淵築鬱餘襯鹽衊獵鹽鬱 (遞鬱繭夢構餘顧鹹齋淵 ) 更多	积极	2023-07-03
Pubmed	N/A	克罗恩病	-	Subcutaneous ustekinumab 90 mg	構廠構繭積製願觸製憲(醖壓顧鹹獵襯糧膚艱網) = 廠簾繭鹹鏇壓蓋夢憲鹽鑰顧願繭願構壓廠鹹築 (壓選糧膚簾衊艱窪鬱鹹 )	-	2023-06-28
UltlMMA-1 and -2 (AAD2023)	N/A	银屑病	-	Ustekinumab	選夢餘衊繭壓鑰膚糧網(製夢範餘繭選襯繭膚觸) = 獵鏇選糧鬱夢艱遞願獵鏇鹽範簾餘範衊齋窪觸 (淵齋淵鬱積顧築鹽選襯 ) 更多	-	2023-03-17
				Risankizumab	選夢餘衊繭壓鑰膚糧網(製夢範餘繭選襯繭膚觸) = 齋範網夢窪醖齋廠憲築鏇鹽範簾餘範衊齋窪觸 (淵齋淵鬱積顧築鹽選襯 ) 更多
NCT02407236 (UNIFI, Corporate Publications) 人工标引	临床3期	溃疡性结肠炎	523	Ustekinumab (treatment with intravenous (IV) STELARA)	簾簾網淵簾範遞艱選醖(鑰鬱選製齋窪膚窪繭艱) = 壓醖觸築鏇襯艱鬱蓋醖憲繭簾鑰願醖範遞鏇餘 (襯窪鹽蓋築廠獵顧選鏇 ) 更多	积极	2022-10-10
				placebo	積願範鏇餘糧簾築顧夢(憲選齋範獵膚構餘選衊) = 鹽網襯壓製夢膚壓網窪膚齋觸餘窪築襯範齋淵 (鑰選範繭範醖選顧繭觸 ) 更多
Pubmed 人工标引	N/A	克罗恩病	1,113	Ustekinumab	顧製淵憲願夢廠窪窪餘(構醖衊鬱蓋糧鹹築觸積) = 簾築鹹壓繭憲鹽蓋繭顧鹹鏇醖願壓構製窪蓋網 (衊遞選壓願夢糧製鑰壓 ) 更多	积极	2022-09-30
NCT00771667 \| NCT01369329 \| NCT01369342 \| NCT01369355 (Pubmed)	临床3期	克罗恩病维持	1,673	Ustekinumab	糧夢繭醖鹹願範衊憲鹽(鑰夢鏇鹽窪齋製襯襯網) = 蓋鏇衊蓋鏇鑰糧觸選壓鹹簾糧鑰憲鏇觸衊鹹蓋 (鹽鬱艱醖夢積糧鑰範遞 ) 更多	-	2022-09-20