A Randomized, Subject- and Investigator-blinded, Placebo-controlled, Parallel Group Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QBW251 in Patients With Bronchiectasis

The purpose of this study is to determine whether potentiating the cystic fibrosis transmembrane conductance regulator (CFTR) with QBW251 in patients with bronchiectasis will demonstrate clinical safety and efficacy related to improved mucociliary clearance with reduced bacterial colonization as potential drivers of airway obstruction, reduced airway inflammation, exacerbations and mucus load, improved lung function, clinical symptoms and quality of life to support further development in bronchiectasis.

开始日期2021-02-02

申办/合作机构

Novartis Pharmaceuticals Corp.

[+1]

NCT04587622

/ Completed临床1期

A Phase 1, Open-label, Single-dose, Parallel-group Study to Evaluate the Systemic Pharmacokinetics of Icenticaftor in Participants With Mild, Moderate, or Severe Hepatic Impairment Compared to Matched Healthy Control Participants

The primary purpose of this study is to evaluate the effect of hepatic impairment on the systemic pharmacokinetics, safety, and tolerability of icenticaftor in participants with varying degrees of hepatic impairment.

开始日期2020-10-30

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT04268823

/ Terminated临床2期

A Randomized, Subjects and Investigator Blinded, Placebo Controlled Parallel Group Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD)

The purpose of this study was to determine whether potentiating the cystic fibrosis transmembrane conductance regulator (CFTR) with QBW251 in subjects with COPD would be efficacious with regards to reducing lung and systemic inflammation and bacterial colonization as potential drivers of airway obstruction, airway destruction, remodeling and exacerbations.
Furthermore, this study provided supportive data to investigate the relationship of COPD phenotype and the response in small airway structure, function, mucus load and spirometry indices as well as in improvement of overall COPD symptoms and quality of life.

开始日期2020-09-10

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 Icenticaftor 相关的临床结果

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100 项与 Icenticaftor 相关的转化医学

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100 项与 Icenticaftor 相关的专利（医药）

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项与 Icenticaftor 相关的文献（医药）

2024-12-01·DRUG METABOLISM AND DISPOSITION

Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites

Article

作者: Hackling, Melissa ; Eggimann, Fabian ; Leuthold, Luc Alexis ; Bebrevska, Lidiya ; Glaenzel, Ulrike ; Huth, Felix ; Meissner, Axel

Icenticaftor (QBW251) is a potentiator of the CFTR protein and is currently in clinical development for the treatment of chronic obstructive pulmonary disease and chronic bronchitis. An absorption, distribution, metabolism, and excretion (ADME) study was performed at steady state to determine the pharmacokinetics, mass balance, and metabolite profiles of icenticaftor in humans. In this open-label study, six healthy men were treated with unlabeled oral icenticaftor (400 mg b.i.d.) for 4 days. A single oral dose of [¹⁴C]icenticaftor was administered on Day 5, and unlabeled icenticaftor was administered b.i.d. from the evening of Day 5 to Day 12. Unchanged icenticaftor accounted for 18.5% of plasma radioactivity. Moderate to rapid absorption of icenticaftor was observed (median T_max: 4 hours), with 93.4% of the dose absorbed. It exhibited moderate distribution (Vz/F: 335 L) and was extensively metabolized, principally through N-glucuronidation, O-glucuronidation, and/or O-demethylation. The metabolites M8 and M9, formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively, represented the main entities detected in plasma (35.3% and 14.5%, respectively) in addition to unchanged icenticaftor (18.5%). The apparent mean T_1/2 of icenticaftor was 15.4 hours in blood and 20.6 hours in plasma. Icenticaftor was eliminated from the body mainly through metabolism followed by renal excretion, and excretion of radioactivity was complete after 9 days. In vitro phenotyping of icenticaftor showed that cytochrome P450 and uridine diphosphate glucuronosyltransferase were responsible for 31% and 69% of the total icenticaftor metabolism in human liver microsomes, respectively. This study provided invaluable insights into the disposition of icenticaftor. Significance Statement The ADME of a single radioactive oral dose of icenticaftor was evaluated at steady state to investigate the nonlinear pharmacokinetics observed previously with icenticaftor. [¹⁴C]Icenticaftor demonstrated good systemic availability after oral administration and was extensively metabolized and moderately distributed to peripheral tissues. The most abundant metabolites, M8 and M9, were formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively. Phenotyping demonstrated that [¹⁴C]icenticaftor was metabolized predominantly by UGT1A9 with a remarkably low K_m value.

2024-09-01·CTS-Clinical and Translational Science

Drug–drug interactions of icenticaftor (QBW251) with a 5‐probe cytochrome P450 cocktail and oral contraceptives

Article

作者: Weis, Wendy ; Glaenzel, Ulrike ; Huth, Felix ; Drollmann, Anton ; Zack, Julia ; Bebrevska, Lidiya

Abstract:

A drug–drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5‐probe cytochrome P450 (CYP) substrate cocktail, guided by in vitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static‐mechanistic DDI assessment indicated that icenticaftor may moderately induce the metabolic clearance of co‐medications metabolized by CYP3A4 (area under the concentration–time curve [AUC] ratio: 0.47) and potentially CYP2C; icenticaftor may also weakly inhibit the metabolic clearance of co‐medications metabolized by CYP1A2 and CYP3A4 (AUC ratio: 1.35 and 1.86, respectively) and moderately inhibit CYP2B6 (AUC ratio: 2.11). In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 (AUC ratio: 3.35) and CYP2C19 (AUC ratio: 2.70). As expected from the results of the in vitro studies, weak induction was observed for CYP3A4 (AUC ratio: 0.51) and CYP2C8 (AUC ratio: 0.66). In the OC DDI study, co‐administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30‐μg EE and 150‐μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle‐stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs.

2024-05-01·Clinical pharmacology in drug development

Concentration‐QTcF Modeling of Icenticaftor from a Randomized, Placebo‐ and Positive‐Controlled Thorough QT Study in Healthy Participants

Article

作者: Julia Zack ; Wendy Weis ; Ganesh R. Iyer ; Hongqi Xue ; Jean Lecot ; Borje Darpo ; Ieuan Jones ; Anton Drollmann ; Lidiya Bebrevska

Abstract:

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo‐ and positive‐controlled, 4‐way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration‐corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration‐QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: –0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be −1.3 milliseconds at the icenticaftor 300‐mg twice‐daily peak concentration (geometric mean was 1094 ng/mL) and −5.5 milliseconds at the 750‐mg twice‐daily peak concentration (geometric mean Cmax was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by‐time‐point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from –7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750‐mg dose group compared with –3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300‐mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3‐fold increase in peak plasma concentration observed at the icenticaftor 750‐mg twice‐daily dosage compared with Icenticaftor 300 mg twice daily (2.3‐fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration–QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

项与 Icenticaftor 相关的新闻（医药）

2026-01-25

·哽啾糖水铺

慢性阻塞性肺疾病（COPD）的治疗：当前研发管线与新机遇

前言慢性阻塞性肺疾病（COPD）是一种影响约10%成年人口的重大公共卫生问题，已成为全球第三大死亡原因。传统观念认为COPD是老年吸烟男性的疾病，但近十年的研究已颠覆此看法，揭示了其作为一种复杂、异质性疾病的全生命周期本质。其发病机制涉及基因（G）与多种环境（E）因素在整个生命周期（T）中的动态相互作用（即GETomics），这决定了个体的肺功能发展轨迹。关键的病理生理机制包括两大类炎症反应：以中性粒细胞为主的1型炎症和与嗜酸性粒细胞相关的2型炎症。新兴的治疗策略正从传统的支气管扩张剂和吸入性皮质类固醇（ICS）转向更为精准的生物制剂。针对2型炎症的单克隆抗体已取得突破，如靶向IL-4Rα的Dupilumab和靶向IL-5的Mepolizumab均已获批用于特定COPD患者亚群（如血嗜酸性粒细胞计数（BEC）≥300个/μl），能显著减少急性加重事件。当前的药物研发管线十分丰富，重点关注抗炎通路。除了已获批的药物，针对上皮警报素（如IL-33和TSLP）的抗体（如Tozorakimab、Itepekimab、Tezepelumab）也显示出潜力，尤其是在非吸烟者或具有特定生物标志物的患者中。此外，靶向激酶、磷酸二酯酶（PDE）、CFTR功能障碍和氧化应激的小分子药物也在积极开发中。未来的治疗机遇在于更早期的干预，包括解决异常肺部发育问题、靶向慢性支气管炎、调节肺部微生物组失调、治疗多病共存以及探索抗衰老和肺再生等前沿领域。为了提高新药研发的成功率，未来的临床试验设计必须充分考虑COPD的生物学和临床异质性，利用生物标志物进行精准的患者分层，并探索更全面的复合终点。1. 对慢性阻塞性肺疾病（COPD）的全新理解 COPD的传统认知——一种由吸烟引起、以肺功能加速衰退为特征的老年男性疾病——现已被证明是不全面的。现代观点强调了其复杂性和全生命周期性。1.1. GETomics：全生命周期的视角 GETomics模型强调COPD是基因（G）、环境（E）在个体整个生命周期（T）中复杂动态相互作用的结果。多重风险因素：除吸烟外，遗传、表观遗传及多种环境因素（如感染、污染物暴露）均是风险因素。全球约三分之一的COPD患者从不吸烟。多基因背景：已发现超过100个基因与低肺功能和COPD相关，但单个基因影响较小，需多个基因共存才会增加风险。多基因风险评分（PRS）正被用于研究其遗传背景。生命早期的起源：在成人COPD中发现的PRS同样能在肺功能下降的儿童中被识别，这支持了COPD的生命早期起源理论。1.2. 肺功能轨迹（Trajectome）个体一生中的肺功能发展存在多种轨迹，统称为“trajectome”。正常轨迹：肺功能在婴幼儿期和青春期发育，于20-25岁达到峰值，之后随生理性衰老而缓慢下降。异常轨迹：发育不良型：部分患者因产前或产后事件导致从未达到正常的肺功能峰值，从而发展为COPD。加速衰退型：约50%的COPD患者表现为成年后肺功能的加速下降，常与吸烟等环境暴露有关轨迹与预后：高于正常轨迹与更健康的衰老相关，而低于正常轨迹则与呼吸系统、心血管和代谢系统疾病以及过早死亡相关。这一新认知为COPD的预防、早期诊断和及时治疗开辟了新的机遇窗口。2. COPD的关键病理生理机制 COPD的病理生理学核心是肺部异常、复杂且持续的炎症反应，主要分为两种类型：中性粒细胞炎症和嗜酸性粒细胞炎症。2.1. 中性粒细胞炎症（1型炎症）这是COPD中常见的炎症类型，涉及先天免疫系统的过度反应。中性粒细胞作用：吸烟会诱导中性粒细胞在肺部聚集，释放中性粒细胞弹性蛋白酶等蛋白酶，导致气道重塑和肺泡壁破坏（肺气肿）。 α1-抗胰蛋白酶（AAT）缺乏：AAT是保护肺部免受中性粒细胞弹性蛋白酶破坏的关键抗蛋白酶。AAT缺乏是一种遗传性病因，会导致早发性肺气肿。巨噬细胞作用：吸烟会增加肺部巨噬细胞数量，促进中性粒细胞募集。COPD患者的巨噬细胞吞噬和杀灭病原菌的能力下降，易导致慢性细菌感染，进一步加剧1型免疫反应。 T细胞反应：T辅助细胞1（TH1）和TH17反应也参与其中。TH1细胞产生IFNγ等细胞因子激活巨噬细胞和中性粒细胞，而TH17细胞产生的IL-17则直接参与中性粒细胞的募集。2.2. 嗜酸性粒细胞炎症（2型炎症）部分COPD患者存在以嗜酸性粒细胞增多为特征的2型炎症，这与ICS治疗反应更佳相关。核心细胞因子：T辅助细胞2（TH2）和2型先天性淋巴样细胞（ILC2s）分泌IL-4、IL-5和IL-13，这些细胞因子是嗜酸性粒细胞、肥大细胞和嗜碱性粒细胞的激活与生存信号。 IL-5：在嗜酸性粒细胞的分化、成熟、生存及从骨髓释放中起核心作用。 IL-4和IL-13：通过共享的IL-4Rα受体链发挥作用。其信号通路（STAT6通路）能诱导IgE产生、嗜酸性粒细胞浸润、气道炎症、支气管收缩、杯状细胞化生和黏液过度分泌。生物标志物：血嗜酸性粒细胞计数（BEC）是临床上用于识别2型炎症的常用生物标志物。BEC较高（如≥100个/μl）的患者使用ICS获益更大。2.3. 上皮警报素警报素是气道上皮细胞在受到微生物、颗粒物等刺激后释放的内源性蛋白质，能启动和放大免疫反应。 IL-33：作用机制：通过ST2受体激活NF-κB等通路，调节2型（如ILC2s、嗜酸性粒细胞）和非2型（如巨噬细胞、CD8+ T细胞）炎症。临床相关性：COPD患者肺部IL-33水平升高，尤其在重度患者中。有趣的是，其表达在当前吸烟者中可能降低，这提示抗IL-33治疗可能对前吸烟者更有效。胸腺基质淋巴细胞生成素（TSLP）：作用机制：通过TSLPR/IL-7Rα复合物激活JAK/STAT通路，被认为是启动2型免疫反应的核心调节因子，但其作用广泛，也影响中性粒细胞、巨噬细胞和CD8+T细胞等。临床相关性：病毒等刺激可诱导COPD患者气道上皮过度表达TSLP。 2.4. 其他关键病理通路磷酸二酯酶（PDEs）：PDE4通过降解cAMP促进炎症。PDE3则更多影响平滑肌，具有支气管舒张潜力。激酶：MAPK家族、Janus激酶（JAKs）和IL-1受体相关激酶4（IRAK4）等是细胞内信号转导的关键节点，参与多种细胞因子的促炎信号传导。 CFTR功能障碍：吸烟可导致获得性囊性纤维化跨膜电导调节因子（CFTR）功能障碍，减少气道表面液体，导致黏液清除障碍和慢性支气管炎症状。氧化应激：COPD患者肺部存在高负荷的氧化应激。NRF2是抗氧化反应的关键转录因子，而NLRP3炎症小体则是一种对氧化应激等危险信号作出反应的促炎复合体。全身性炎症：约16%的COPD患者存在持续性全身炎症（以CRP、IL-6等标志物升高为特征），这与更高的全因死亡率和急性加重频率显著相关。3. 当前COPD药物研发管线分析当前的研发管线主要集中在抗炎药物，特别是借鉴了哮喘治疗中单克隆抗体的成功经验，并强调精准医疗。3.1. 研发中的重点药物概览药物公司作用机制状态抗中性粒细胞 Mitiperstat AstraZeneca 髓过氧化物酶（MPO）抑制剂 II期抗嗜酸性粒细胞 Mepolizumab GlaxoSmithKline 抗IL-5抗体 FDA批准 Benralizumab AstraZeneca 抗IL-5Rα抗体 III期 T2细胞因子拮抗剂 Dupilumab Sanofi 抗IL-4Rα抗体 FDA和EMA批准抗警报素 Astegolimab Roche 抗ST2抗体 III期 Itepekimab Sanofi 抗IL-33抗体 III期 Tozorakimab AstraZeneca 抗IL-33抗体 III期 Tezepelumab AstraZeneca 抗TSLP抗体 II期 PDE抑制剂 Ensifentrine Verona Pharma PDE3和PDE4抑制剂 FDA批准 Tanimilast Chiesi PDE4抑制剂 III期激酶抑制剂 Frevecitinib Kinaset Therapeutics 泛JAK抑制剂 I期 AZD6793 AstraZeneca IRAK4抑制剂 I期黏液靶向 GDC-6988 Roche TMEM16A II期3.2. 靶向嗜酸性粒细胞炎症的生物制剂这类药物已成为COPD治疗的重大突破。 Mepolizumab (抗IL-5)：在MATINEE研究中，对于BEC≥300个/μl的患者，在三联疗法基础上加用Mepolizumab可使中重度急性加重年化率降低21%。现已获得FDA批准，用于伴有嗜酸性粒细胞表型的COPD患者的附加维持治疗。 Benralizumab (抗IL-5Rα)：在GALATHEA和TERRANOVA两项III期研究中，未能对BEC≥220个/μl的预设人群达到主要终点。事后分析显示，在既往急性加重≥3次且接受三联疗法的高风险亚组中，可观察到30%的急性加重率下降。 Dupilumab (抗IL-4Rα)：在BOREAS和NOTUS两项III期研究中，针对BEC≥300个/μl且接受三联疗法的高风险患者，Dupilumab可使急性加重率降低30-34%（P < 0.001），并改善肺功能（FEV1）和生活质量。已获得FDA和EMA批准，并被GOLD指南推荐用于特定患者群体。3.3. 靶向警报素的生物制剂这是目前研发的热点，旨在从炎症级联反应的上游进行干预。抗IL-33/ST2通路：Itepekimab (抗IL-33)： II期研究显示，在前吸烟者中可将急性加重率降低42%，但在当前吸烟者中无获益。这与吸烟者IL-33表达较低的观察结果一致。Tozorakimab (抗IL-33)： II期研究未达到改善FEV1的主要终点，但在既往急性加重≥2次的亚组中观察到获益。其III期临床试验正在进行中。Astegolimab (抗ST2)： II期研究未显著影响急性加重率或FEV1，但能降低血和痰中的嗜酸性粒细胞计数。 Tezepelumab (抗TSLP)：在II期COURSE研究中，总体人群的急性加重率未显著降低。但预设的亚组分析显示，在BEC≥150个/μl的患者中观察到更显著的预防效果。3.4. 新型小分子药物 PDE抑制剂：Ensifentrine (PDE3/4双重抑制剂)：作为雾化剂，主要发挥支气管舒张作用，已获FDA批准。但其在标准三联疗法基础上的获益和对高危患者的抗炎效果尚待明确。Tanimilast (吸入性PDE4抑制剂)：旨在通过吸入给药减少口服PDE4抑制剂的全身副作用。III期研究正在招募伴有慢性支气管炎和较高BEC的患者。激酶抑制剂：p38 MAPK抑制剂的试验多以失败告终。吸入性JAK抑制剂旨在提供广泛的抗炎作用，同时通过局部给药降低全身性副作用风险。 CFTR调节剂：Icenticaftor的II期试验未达到主要终点，但显示出改善症状的趋势。开发此类药物需要更精准地识别具有CFTR功能障碍的目标人群。4. 未来治疗干预的新机遇对COPD病理生理学的深入理解揭示了多个潜在的治疗新靶点和干预窗口。异常肺部发育：识别影响生命早期肺功能轨迹的因素，探索促进肺部正常发育和“追赶性生长”的干预措施，可能从根本上预防COPD。慢性支气管炎和黏液高分泌：这是一个明确的未满足需求。新的治疗目标包括：减少黏液过度产生、增加黏液清除、降低黏液粘度（如新型黏液溶解剂、CFTR增强剂）。慢性支气管感染与肺部微生物组：COPD患者存在肺部微生物组失调（dysbiosis），与更严重的中性粒细胞炎症和不良预后相关。通过抗生素、益生菌或“痰菌移植”来恢复微生物组平衡是潜在的新策略。免疫适应性（Immune Fitness）：通过疫苗接种（如流感、RSV、肺炎球菌等）不仅可以预防特定感染，还可能通过“训练免疫”来增强先天免疫应答，改善老年COPD患者的整体免疫功能。 COPD急性加重（ECOPD）的精准治疗：ECOPD可分为细菌性、病毒性、嗜酸性粒细胞为主和炎性不明显等不同生物学亚型。开发快速床旁检测技术以识别这些亚型，将有助于实现急性加重的精准治疗（如在嗜酸性粒细胞型ECOPD中使用Benralizumab）。多病共存：COPD常与其他心血管、代谢等疾病共存。未来的治疗可能需要考虑全身性给药，以同时处理肺部和肺外表现。例如，二甲双胍或GLP-1激动剂因其潜在的呼吸和心血管双重获益而受到关注。加速的肺部衰老：COPD表现出多种衰老特征，如端粒损耗、细胞衰老和线粒体功能障碍。靶向这些衰老机制的药物（如Senolytics）为减缓疾病进展提供了新思路。肺再生：虽然极具挑战性，但利用干细胞疗法或CAR-T细胞疗法等前沿技术来修复受损肺结构、逆转疾病，是未来值得探索的终极目标。5. 对未来临床试验设计的考量为提高新药研发成功率，未来的随机对照试验（RCTs）设计需进行优化。考虑生物学异质性：必须放弃“一体适用”的试验设计。应利用生物标志物（如BEC、FeNO、血清CXCL10、痰IL-1β）选择最有可能从特定作用机制中获益的患者亚群。Dupilumab的成功III期试验正是精准医学策略的典范。考虑临床异质性关注年轻患者：在50岁以下的患者中进行RCT因为早期干预可能更有效。纳入肺功能轨迹：区分肺功能加速衰退型和低水平稳定型的患者。前者炎症水平更高，可能对抗炎治疗反应更好。探索新的临床终点复合终点：结合症状、肺功能、急性加重等多个指标创建复合终点，以更敏感地衡量药物反应。影像学终点：利用定量CT等先进影像技术，将黏液栓塞等结构性改变作为试验终点，以更直观地评估疗效

临床研究临床结果

2023-02-01

·Endpoints

Updated: Novartis rejigs late-stage plans for Cosentyx, next-gen CAR-T, TIGIT antibody and more

Novartis has cleaned up its Phase III slate, shelving late-stage plans for programs across inflammatory diseases and cancer, the Swiss pharma giant disclosed in its quarterly update — while also putting a mid-stage Huntington’s drug to bed and switching things up for a key rare disease candidate. The biggest change came in the decision to abandon a Phase III trial for Cosentyx, Novartis’ blockbuster IL-17A antibody, in active peripheral spondyloarthritis. It didn’t end up recruiting any of the 324 patients planned before terminating the trial earlier this month due to a “strategic decision of senior management,” according to records on clinicaltrials.gov. Cosentyx is already approved for multiple diseases, including plaque psoriasis and active psoriatic arthritis, bringing in more than $1 billion in revenue in the fourth quarter of 2022 alone. A development strategy update is also cited as the reason why Novartis didn’t start a pivotal trial for its next-gen CD19 CAR-T in second-line diffuse large B-cell lymphoma as planned. Dubbed YTB323 or rapcabtagene autoleucel, the cell therapy hits the same target as Novartis’ approved Kymriah but is made using a simplified manufacturing process. The change-up pushes back the anticipated regulatory submission for YTB323 from 2025 to beyond 2026, according to an investor presentation, with high-risk large B-cell lymphoma being the new lead indication. In an early trial, a high dose of YTB323 registered a 73% complete response rate among 15 patients. While Novartis had planned to start a new Phase III study for ociperlimab , the TIGIT antibody it licensed from BeiGene, for solid tumors in late 2022, it didn’t end up doing so — although it didn’t specify a reason. Moving into Phase II, Novartis revealed it’s officially discontinued branaplam in Huntington’s disease, “based on an overall assessment of potential benefit-risk” from the Phase II VIBRANT-HD study. Back in August, Novartis suspended dosing in the VIBRANT-HD study, citing fears of neuronal damage, but said it would need time to determine next steps. On iptacopan, the factor B inhibitor also known as LNP023 that CEO Vas Narasimhan has spotlighted as a top program, Novartis said it is shuttering a Phase II program in membranous nephropathy, citing “uncompellingcompetitive profile.” Meanwhile, it also expects a few months delay for the submissions in C3 glomerulopathy and IgA nephropathy, but noted that Phase III readouts are still expected in 2023. The planned submission for atypical haemolytic uraemic syndrome, though, is being pushed out to beyond 2026 as the company revealed slower than anticipated trial recruitment. The company also noted that it is still looking to out-license icenticaftor, a potentiator for the cystic fibrosis transmembrane conductance regulator (CFTR) protein that it developed to treat chronic obstructive pulmonary disease, or COPD. As remarked last quarter, Phase IIb data indicated a dose response across multiple endpoints. Editor’s note: Story updated to note that Novartis also reported updates to the branaplam and iptacopan programs.

临床2期细胞疗法临床3期临床结果免疫疗法

100 项与 Icenticaftor 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
支气管扩张	临床2期	中国	Novartis Pharmaceuticals Corp.	2021-02-02
支气管扩张	临床2期	德国	Novartis Pharmaceuticals Corp.	2021-02-02
支气管扩张	临床2期	西班牙	Novartis Pharmaceuticals Corp.	2021-02-02
支气管扩张	临床2期	英国	Novartis Pharmaceuticals Corp.	2021-02-02
慢性支气管炎	临床2期	美国	Novartis Pharmaceuticals Corp.	2019-09-12
慢性支气管炎	临床2期	日本	Novartis Pharmaceuticals Corp.	2019-09-12
慢性支气管炎	临床2期	阿根廷	Novartis Pharmaceuticals Corp.	2019-09-12
慢性支气管炎	临床2期	澳大利亚	Novartis Pharmaceuticals Corp.	2019-09-12
慢性支气管炎	临床2期	奥地利	Novartis Pharmaceuticals Corp.	2019-09-12
慢性支气管炎	临床2期	比利时	Novartis Pharmaceuticals Corp.	2019-09-12

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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


NCT04396366 (CTgov)	临床2期	支气管扩张	42	QBW251 (QBW251 300 mg b.i.d)	艱憲構夢觸網餘築鏇窪(繭繭齋艱積鬱鹹餘顧衊) = 衊鹽觸膚選選憲積鹽顧鬱築願鹹觸鹹選夢鹹夢 (糧願築艱餘鹽網觸觸鹽, 1.4621) 更多	-	2025-03-06
				Placebo (Placebo)	艱憲構夢觸網餘築鏇窪(繭繭齋艱積鬱鹹餘顧衊) = 鬱鑰糧網憲衊蓋壓醖鬱鬱築願鹹觸鹹選夢鹹夢 (糧願築艱餘鹽網觸觸鹽, 1.6476) 更多
NCT04268823 (CTgov)	临床2期	慢性阻塞性肺疾病 \| 慢性支气管炎	54	Placebo	糧選衊鹹鹹壓遞廠餘選(齋蓋鑰鹽鑰製憲鹽糧獵) = 選艱襯齋鏇糧窪艱齋憲餘鬱網艱顧醖齋廠衊衊 (遞艱簾醖鑰繭鑰衊選壓, 0.1365) 更多	-	2023-10-04
NCT04072887 (CTgov)	临床2期	慢性阻塞性肺疾病 \| 慢性支气管炎	974	COPD maintenance background therapy+QBW251 (QBW251 450 mg)	築製鬱鹽艱鹽遞簾艱夢(蓋獵積鹽願鹽構廠選齋) = 築糧膚蓋餘憲壓憲蓋憲蓋醖網餘遞鹽糧選膚繭 (蓋築築築範夢鹽夢窪觸, 0.021) 更多	-	2023-04-28
				COPD maintenance background therapy+QBW251 (QBW251 300 mg)	築製鬱鹽艱鹽遞簾艱夢(蓋獵積鹽願鹽構廠選齋) = 淵簾鹽膚選築廠鹹網廠蓋醖網餘遞鹽糧選膚繭 (蓋築築築範夢鹽夢窪觸, 0.0103) 更多
NCT02190604 (Pubmed \| J Cyst Fibros)	临床1/2期	囊性纤维化	153	Icenticaftor 450 mg bid	積廠艱廠淵顧構齋觸膚(醖選構鏇廠鏇簾築鬱糧) = 壓醖鏇糧獵鹹鹹憲廠鹹醖鹹憲艱襯憲衊範觸壓 (鹽顧襯鑰網獵範顧鑰窪 )	-	2020-12-05
NCT02449018 (Pubmed) 人工标引	临床2期	慢性阻塞性肺疾病	92	QBW251	簾願鏇餘夢餘醖鹽淵構(製遞築築獵選觸繭餘築): difference = 0.28 更多	积极	2020-10-05
				Placebo
ERS2018	临床4期	慢性阻塞性肺疾病	-	QBW251	衊窪遞鹽鑰積壓齋餘憲(簾鹹觸範簾獵蓋簾觸壓) = 鬱構壓壓夢鬱夢觸糧積觸壓鑰網願壓衊獵醖選 (艱糧鹹醖廠選鹹鏇齋願 ) 更多	积极	2018-09-15
NCT02449018 (CTgov)	临床2期	慢性阻塞性肺疾病	92	QBW251 (QBW251)	範醖蓋簾製憲獵範蓋廠(選遞鬱鏇艱鹹醖衊鏇願) = 蓋顧齋餘繭糧糧艱艱壓築遞壓憲齋艱齋蓋鬱鹹 (簾願窪鹽淵獵鑰鹽遞襯, 1.28) 更多	-	2018-04-02
				Placebo (Placebo)	範醖蓋簾製憲獵範蓋廠(選遞鬱鏇艱鹹醖衊鏇願) = 繭繭簾窪願製窪顧網蓋築遞壓憲齋艱齋蓋鬱鹹 (簾願窪鹽淵獵鑰鹽遞襯, 1.15) 更多