This study is a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of ensifentrine inhalation suspension (3 mg) delivered twice daily via standard jet nebulizer over at least 24 weeks, compared to placebo, in subjects with non-cystic fibrosis bronchiectasis (NCFBE).

开始日期2024-09-11

申办/合作机构

Verona Pharma Plc

NCT06460493

/ Active, not recruiting临床3期

A Study Assessing the Effect of Ensifentrine on CAT™ Scores Over 12 Weeks in Subjects with Moderate to Severe COPD

This is an open-label study at one study center that will assess the effect of twice-daily nebulized ensifentrine on COPD Assessment Test (CAT™) scores over 12 weeks in subjects with moderate to severe COPD. Subjects will continue their long-acting dual or triple COPD maintenance treatments during study participation.

开始日期2024-06-11

申办/合作机构

Verona Pharma Plc

[+1]

CTR20230006

/ Active, not recruiting临床3期

一项在中度至重度慢性阻塞性肺疾病患者中评价Ensifentrine给药24周有效性和安全性的III期随机、双盲、安慰剂对照临床研究

评估Ensifentrine 3 mg每日两次（BID）24周治疗中度至重度慢性阻塞性肺疾病（COPD）患者的有效性、安全性及耐受性

开始日期2023-03-10

申办/合作机构

The Ritedose Corp.

[+2]

100 项与恩塞芬汀相关的临床结果

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100 项与恩塞芬汀相关的转化医学

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100 项与恩塞芬汀相关的专利（医药）

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项与恩塞芬汀相关的文献（医药）

2025-12-01·Chronic Respiratory Disease

Ensifentrine in COPD patients taking long-acting bronchodilators: A pooled post-hoc analysis of the ENHANCE-1/2 studies

Article

作者: Rickard, Kathleen Ann ; Dransfield, Mark ; Anzueto, Antonio ; Marchetti, Nathaniel ; Dixon, Amy L ; Reyner, Daniel ; Rheault, Tara ; Kalhan, Ravi

Background:

The efficacy and safety of ensifentrine, a novel PDE3/PDE4 inhibitor, were previously evaluated in the ENHANCE-1 (NCT04535986) and ENHANCE-2 (NCT04542057) trials. Here, we present a pooled post-hoc subgroup analysis of patients according to background chronic obstructive pulmonary disease (COPD) maintenance medication regimens.

Objective:

This analysis aimed to explore the efficacy and safety of ensifentrine in patients receiving long-acting muscarinic antagonists (LAMA) or long-acting beta-agonists with inhaled corticosteroids (LABA + ICS).

Methods:

Eligible patients had moderate to severe COPD, were aged 40–80 years, and were symptomatic at randomization. Patients were randomized 5:3, receiving twice-daily ensifentrine 3 mg or placebo via standard jet nebulizer over 24 weeks.

Results:

The pooled post-hoc analysis included 485 LAMA patients and 272 LABA + ICS patients. Ensifentrine showed lung function improvement over placebo at week 12, including average FEV1 AUC0–12 h in the LAMA (placebo-corrected least squares mean change from baseline [LSMC], 92 mL; 95% CI, 54, 131; p < 0.001) and LABA + ICS subgroups (LSMC, 74 mL; 95% CI, 27, 121; p = 0.002). Ensifentrine reduced the rate and risk of exacerbations in both LAMA (48% and 50%, respectively) and LABA + ICS (51% and 56%, respectively) subgroups. Ensifentrine-treated patients reported improvement in symptoms and quality of life over 24 weeks. The safety profile of ensifentrine in each subgroup was similar to the profile in the pooled modified intention-to-treat population.

Conclusions:

Nebulized ensifentrine offers a novel non-steroidal anti-inflammatory and bronchodilator treatment added to existing LAMA or LABA + ICS treatment options in patients with moderate to severe, symptomatic COPD.

2025-04-01·TISSUE & CELL

Development of a rat airway organoids model for studying chronic obstructive pulmonary disease

Article

作者: Ren, Zirui ; Xian, Yangling ; Pan, Dequan ; Lin, Yanzhen ; Zhao, Huan ; Yang, Hongwei ; Yu, Kang ; Cheng, Tong ; Yang, Chuanlai ; Fang, Changjian ; Zhang, Yali ; Xia, Ningshao ; Wang, Wei ; Tan, Haoyin ; Huang, Xiumin ; Liu, Nanyi

Chronic obstructive pulmonary disease (COPD) poses global health challenges owing to limited treatment options and high rates of morbidity and mortality. Airway organoids have recently become a valuable resource for the investigation of respiratory diseases. However, limited access to clinical tissue samples hinders the use of airway organoids to study COPD. Therefore, alternative models that can mimic human airway pathology without relying on human tissues are needed. In this study, airway organoids were developed from tracheal epithelial cells obtained from 8-week-old Sprague-Dawley rats and exposed to lipopolysaccharide (LPS) to induce COPD-like characteristics. Exposure to LPS leads to structural changes in organoids, including an increase in goblet cells, a decrease in ciliated cells, increased mucin production, and elevated levels of pro-inflammatory cytokines. The COPD drugs erdosteine and R-HP210 effectively reduced mucin secretion, although none was able to restore the function of ciliated cells. Inflammatory markers responded differently, with ensifentrine and erdosteine significantly reducing cytokine levels. These results demonstrate that rat airway organoids replicate important aspects of human COPD pathology, thus providing an accessible, ethical, and clinically relevant alternative to human tissues and traditional animal models to enhance our understanding of COPD pathogenesis and evaluate potential treatments.

2025-02-01·CHEST

Effect of Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine on Exacerbation Rate and Risk in Patients With Moderate to Severe COPD

Article

作者: Sciurba, Frank C ; Rickard, Kathleen ; Barjaktarevic, Igor Z ; Bengtsson, Thomas ; Rheault, Tara ; Christenson, Stephanie A

BACKGROUND:

Exacerbations in COPD can be life-threatening and can lead to irreversible declines in lung function and quality of life. Medications that reduce exacerbation burden are an unmet need, because exacerbations put patients at risk of more exacerbations and decrease quality of life. Ensifentrine is a first-in-class selective dual inhibitor of phosphodiesterase 3 and 4 with demonstrated nonsteroidal antiinflammatory activity and bronchodilatory effects.

RESEARCH QUESTION:

Does ensifentrine reduce the rate or risk of COPD exacerbations?

STUDY DESIGN AND METHODS:

A prespecified, pooled analysis of the phase 3 clinical trials Ensifentrine as a Novel Inhaled Nebulized COPD Therapy (ENHANCE)-1 (ClinicalTrials.gov Identifier: NCT04535986) and ENHANCE-2 (ClinicalTrials.gov Identifier: NCT04542057) was conducted to assess the effect of ensifentrine on exacerbation rate and risk (time to first exacerbation). The trials included symptomatic patients aged 40 to 80 years with moderate to severe COPD who received 3 mg twice-daily ensifentrine over 24 weeks or placebo. Subgroup analyses and frequent exacerbator transition risk assessment were conducted post hoc.

RESULTS:

In total, 975 patients treated with ensifentrine and 574 patients who received placebo were included in the pooled analysis, including 62% of patients receiving concomitant long-acting muscarinic antagonist or long-acting β₂-agonist therapy and 18% receiving concomitant inhaled corticosteroid therapy. Ensifentrine was associated with significant reductions in the rate (rate ratio, 0.59; 95% CI, 0.43-0.80; P < .001) and risk (hazard ratio, 0.59; 95% CI, 0.44-0.81; P < .001) of moderate to severe exacerbations compared with placebo. Reductions in the rate and risk of exacerbations generally were consistent across patient subgroups, including age, sex, race, background maintenance medication use, chronic bronchitis, eosinophil count, COPD severity, and exacerbation history. Ensifentrine was associated with a numerical delay in transitioning from an infrequent exacerbator (Global Initiative for Chronic Obstructive Lung Disease group B) to a frequent exacerbator (Global Initiative for Chronic Obstructive Lung Disease group E) compared with placebo.

INTERPRETATION:

Ensifentrine reduced the rate of exacerbations and increased the time to first exacerbation among patients with COPD across a broad range of clinically relevant subgroups.

246

项与恩塞芬汀相关的新闻（医药）

2025-03-09

·药智网

慢阻肺治疗的「破局时刻」

慢性阻塞性肺疾病（简称慢阻肺，COPD）是全球第三大死因[1]，传统治疗以支气管扩张剂和激素为主，但患者仍面临急性加重频繁、肺功能进行性下降等困境[2]。2025版慢性阻塞性肺疾病全球倡议（GOLD）迎来历史性更新：首次纳入两款靶向创新制剂——恩塞芬汀（Ensifentrine）和度普利尤单抗（Dupilumab）[3]。这意味着COPD治疗正式迈入“精准靶向时代”，也为中国超1亿COPD患者带来新希望[4]。注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 1 划时代的2款靶向创新制剂 1. 恩塞芬汀（Ensifentrine）：全球首个吸入式PDE3/4双抑制剂 Ensifentrine[5]由美国Verona Pharma研发，靶向磷酸二酯酶3/4（PDE3/4），适用于成人COPD患者的维持治疗，不区分治疗背景及急性加重史，不同细分人群均可获益。Ensifentrine于2024年6月获得FDA批准用于中重度COPD，于2025年2月在中国澳门获批。（1）核心优势：全球首个吸入式双靶点药物（PDE3/4），一药三效。PDE主要通过调控cAMP（环磷酸腺苷）和cGMP（环磷酸鸟苷）来起到支气管平滑肌扩张和抗炎作用，而且还可以激活囊状纤维化跨膜转导调节子（CFTR）以降低黏液粘度和增强黏膜纤毛清除功能[6]。图1 Ensifentrine的作用机制图片来源：Verona Pharma官网（2）关键临床试验数据（ENHANCE系列研究）：本次FDA批准主要基于 ENHANCE-1和 ENHANCE-2 两项RCT III期临床试验，数据显示Ensifentrine 可显著改善肺功能并降低疾病恶化率和发作风险，且安全性较高[7]。主要终点—改善肺功能：相较于安慰剂组，用药12小时后ENHANCE-1中第一秒用力呼气容积（FEV1）改善了87mL，ENHANCE-2中改善了94mL。次要终点—降低急性加重风险：相较于安慰剂组，24周内，Ensifentrine治疗组显著降低了中重度COPD 患者急性加重率，ENHANCE-1中降低了36%，ENHANCE-2中降低了43%。此外，汇总分析显示，Ensifentrine治疗24周，未来急性加重风险降低41%[8]。安全性：与安慰剂组不良反应率相当，总体安全性、耐受性表现良好。图2 ENHANCE系列临床试验疗效数据图片来源：Verona Pharma官网（3）临床意义：填补空白：首个同时改善症状和减少加重的吸入制剂，推动COPD管理迈入“去激素化”时代，尤其适合不耐受激素的患者（如糖尿病、骨质疏松患者的较佳选择）。便捷高效：其治疗方式是使用标准喷射雾化器将药物直接输送到肺部，这使得药物更容易吸入，不需要高吸气流速或复杂的手呼吸协调。 2. 度普利尤单抗（Dupilumab）：全球首个获批的COPD生物靶向药 Dupilumab[9]赛诺菲/再生元联合开发，靶向白细胞介素-4受体亚基α（IL-4Rα），适用于血嗜酸性粒细胞升高且控制不佳的成人COPD患者。Dupilumab的首个获批适应症是中重度特应性皮炎（2017年3月FDA批准），此后不断拓展适应症—哮喘、慢性鼻-鼻窦炎伴鼻息肉、慢性自发性荨麻疹、结节性痒疹、嗜酸性食管炎。直至2024年7月，Dupilumab的第7个适应症率先在欧盟获批，成为首个用于治疗 COPD 的生物靶向药，2024年9月该适应症获得中国国家药品监督管理局（NMPA）批准。（1）核心优势：全球首个获批的慢阻肺病靶向治疗药物。Dupilumab可特异性结合IL-4Rα亚基，阻断IL-4、IL-13信号传导，抑制嗜酸性粒细胞（EOS）活化，从而减轻慢阻肺病患者的2型炎症反应，抑制疾病进展[10]。图3 Dupilumab靶向治疗COPD机制图片来源：参考文献10 （2）关键临床试验数据（BOREAS & NOTUS研究）：本次Dupilumab的获批主要是基于两项具有里程碑意义的Ⅲ期临床试验BOREAS和NOTUS，数据显示[11][12]Dupilumab可有效降低COPD患者的病情恶化率，还能显著提高肺功能（如FEV1值）且安全性较高。主要终点—降低急性加重风险：两项研究结果显示，当背景治疗中所有患者均接受了最佳标准吸入治疗（几乎所有患者均接受三联疗法）时，相较于安慰剂组，Dupilumab组患者的中重度急性加重发生率在52周内均显著降低，BOREAS研究降低了30%，NOTUS研究降低了34%。随着慢阻肺病患者基线血EOS和呼出气一氧化氮（FeNO）水平升高，Dupilumab治疗对于患者急性加重率的降低越明显。次要终点—改善肺功能：相较于安慰剂组，BOREAS研究显示Dupilumab组患者的肺功能改善情况可从第2周持续到第52周。在第12周时，Dupilumab组患者的支气管舒张剂前第一秒用力呼气容积（pre-BD FEV1）较基线提升160mL。NOTUS研究结果与BOREAS相似，均提示Dupilumab可为患者带来早期且持续的肺功能改善。安全性：两项研究中Dupilumab组患者的不良事件发生情况均与安慰剂组类似。（3）临床意义：精准治疗：锁定Th2炎症型COPD（约占30%患者），标志着“生物标志物指导治疗”的落地。跨界价值：合并哮喘、湿疹的COPD患者可“一药多治”。注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 2 COPD生物制剂研发管线：百花齐放目前，慢阻肺领域，全球共有超50条生物制剂研发管线，覆盖不同炎症通路。靶向Th1型炎症通路的生物制剂尚未在慢阻肺病领域显示出显著疗效，探索主要集中在Th2型炎症通路，以及可同时覆盖Th1型/Th2型炎症通路的相关靶点，如IL-5/IL-5R、IL-4(R)/IL-13、TSLP、IL-33、ST2等。本文只讨论热门靶点研发管线。 1. 靶向Th1型炎症通路的COPD生物制剂普遍疗效不佳在COPD患者中，以中性粒细胞驱动为主的Th1型炎症类型较为常见，因此早期探索集中在TNF-a、IL-8、IL-1等Th1型靶点。但是2001年以IL-8为靶点的 ABX-IL8、2002年的TNF-α抑制剂英夫利昔单抗以及2011年开发的IL-1单抗 MEDI8968 针对 COPD 展开的探索研究均以失败告终。三种药物与安慰剂相比，临床获益欠佳。 2.靶向Th2型炎症通路的COPD生物制剂取得突破随着研究的深入，靶向Th2型炎症通路相关细胞因子的生物制剂在慢阻肺病领域中逐步展现出积极结果。其中IL-5/IL-5R、IL-4(R)/IL-13是Th2通路的热门靶点。 2.1 靶向IL-5/IL-5R，研发竞争小，美泊利珠单抗有望今年获批目前针对 COPD 开发的 IL-5/IL-5R 靶点药物仅有三款，贝纳利珠单抗和美泊利珠单抗的研发速度较快。其中GSK在2025年2月宣布中国NMPA已受理美泊利珠单抗注射液的一项新适应症上市申请，用于具有嗜酸性粒细胞表型的慢性阻塞性肺疾病（COPD）患者的维持治疗。如果获批，美泊利珠单抗有望成为首个获批的每月一次的 COPD生物制剂。表1 靶向IL- 5/IL- 5R的COPD生物制剂研发进展数据来源：药智数据，药智咨询整理 2.2 靶向IL-4(R)/IL-13，国内企业研发进展较快 IL-4和IL-13是Th2型炎症通路的关键驱动因子。目前靶向IL-4(R)/IL-13 靶点的药物共有10款。目前仅有度普利尤单抗已上市，国内公司康诺亚/石药集团的司普奇拜单抗和三生国健研发的SSGJ-611研发进度较快，分别处于临床Ⅲ期和临床Ⅱ期。表2 靶向 IL-4(R)/IL-13的COPD生物制剂研发进展数据来源：药智数据，药智咨询整理 3.靶向上皮警报素类细胞因子，全球研发进度相近，国产跟进速度快上皮细胞来源的警报素类细胞因子，位于炎症级联反应顶端，可同时参与Th1和Th2炎症反应。近年来，靶向该阶段的生物制剂亦在慢阻肺病领域展开探索，其中TSLP、IL-33、ST2是热门靶点。目前针对TSLP靶点研发的药物共有8款，其中4款已进入临床Ⅱ期阶段（3 款属于跨国药企）；针对IL- 33/ST2 靶点研发的药物共有7款，其中3款已进入临床Ⅲ期阶段，均为跨国药企开发，国内公司迈威生物开发的9MW1911已进入临床Ⅱ期阶段。表3 靶向上皮警报素类细胞因子的COPD生物制剂研发进展数据来源：药智数据，药智咨询整理 4.靶向PDE3/4的生物制剂研发管线目前仅有PXSTPI-1100这1条，处于临床I期，由Pharmaxis Ltd公司发起，但自2009年后未再更新研发进展。针对PD3/PD4靶点的化药研发管线较多（30条），可能随着新药恩塞芬汀投入临床应用，减轻COPD患者疾病负担，市场的良好反馈或许能引发针对PDE3/4生物制剂的研发热潮。注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 3 结语：COPD治疗的范式革命 2025版GOLD指南对生物制剂的正式纳入，标志着COPD治疗将从“一刀切”的时代，逐渐迈入个体化精准治疗新纪元。国内外企业争相布局IL-5/IL-5R、IL-4(R)/IL-13、TSLP、IL-33、ST2等热门靶点，未来研发将呈现两大趋势：其一，临床研究设计可能会偏向于患者分层，便于后续临床基于生物标志物（如血嗜酸粒细胞、FeNO）选择靶向药物；其二，生物制剂与传统药物联用，延长疗效并减少激素依赖。以恩塞芬汀和度普利尤单抗为代表的新型靶向药物和生物制剂，不仅为患者提供了全新的治疗选择，更深刻揭示了COPD异质性炎症机制的本质。随着更多精准靶向药物的研发上市，以“对因治疗”为核心的精准医学范式，或将重构呼吸系统疾病的整体诊疗格局。参考文献： [1] Li M, et al. BMJ Open Respir Res. 2023 Jul;10(1):e001698. [2] 中华医学会呼吸病学分会慢性阻塞性肺疾病学组等.中华结核和呼吸杂志, 2021,44(3) : 170-205. [3] GOLD.https://goldcopd.org/2025-gold-report/. [4] Wang C, et al. Lancet. 2018 Apr 28;391(10131):1706-1717. [5] Ensifentrine说明书 [6] Cazzola, M.et al. Int J Chron Obstruct Pulmon Dis. 2023 Jun;18:1333–1352. [7] Anzueto A, et al. Am J Respir Crit Care Med. 2023;208(4):406-416. [8] Sciurba FC, et al. Chest. 2025;167(2):425-435. [9] Dupixent approved in the US as the first-ever biologic medicine for patients with COPD. Retrieved September 27, 2024. [10]中华医学会变态反应学分会过敏性疾病基础研究与转化医学学组(筹). 中国临床实用医学，2023，14(04):1-22. [11]Bhatt SP, et al. N Engl J Med. 2024;390(24):2274-2283. [12]Bhatt SP,et al. N Engl J Med. 2023;389(3):205-214. 声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 斯蒂文合作、投稿、转载开白 | 马老师 18323856316（同微信）如需定制医药咨询服务，请扫描下方二维码咨询！阅读原文，是受欢迎的文章哦

临床3期临床结果

2025-03-03

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成为香饽饽的COPD新药，局面如何？

2024年6月26日，全球首个双重PDE3/4抑制剂Ensifentrine（恩塞芬汀）在FDA获批上市。这款号称“一药双效”的创新药物，成功打破COPD治疗僵局，开启了“抗炎+扩支”的整合治疗时代。 2024年9月27日，赛诺菲宣布，达必妥®（度普利尤单抗注射液）获得中国国家药品监督管理局（NMPA）批准，用于血嗜酸性粒细胞升高且控制不佳的慢性阻塞性肺疾病成人患者，借此开启了COPD生物治疗时代。 2024年12月20日，这款由健康元与拜耳合作开发的慢阻肺（COPD）治疗药物，是目前单靶点口服药市场仅有的新药产品，也可能成为中国首款创新机制的COPD口服药。 2025年2月21日，GSK宣布其IL-5单抗Nucala（美泊利珠单抗）的新药上市申请获国家药监局受理，用于作为嗜酸性粒细胞表型慢性阻塞性肺病（COPD）患者的附加维持治疗，再次将COPD领域的靶向生物药疗法推向了高潮。不到一年，COPD领域的新药研究似乎就成为了香饽饽，不仅MNC接连布局，国内Biotech企业更是将其作为赶超全球的大好机会，这是为何？更关键的是，COPD领域背后究竟有何魅力？如今的在研领域又是怎样一个局面？庞大的患者群体所谓慢阻肺，即一种常见的、可预防和治疗的慢性气道疾病，其特征是持续存在的气流受限和相应的呼吸系统症状，是一种较常见的慢性疾病，病死率较高，且严重影响患者的生命质量，并给其家庭与社会带来沉重的经济负担。据悉，COPD已成为全球第三大死亡原因，全球约有3.9亿例COPD患者，中国约有1亿例COPD患者，占全球COPD病例的近25%，潜在用药市场庞大。而随着慢阻肺规范化诊疗的推行，虽然慢阻肺死亡率逐年下降，但随着空气指数下降、吸烟等因素，其整体发病率却出现反向上涨的趋势。更关键的是，由于目前慢阻肺的发病机制尚未完全明确，氧化应激、炎症反应、蛋白酶/抗蛋白酶失衡等多种因素均可导致组织重构，进而致病，相对复杂的致病原理也为COPD新药研究带来巨大困难。局限严重的传统治疗一直以来，临床上针对稳定期慢阻肺病治疗基本围绕两个目标进行，即减轻症状和降低风险，两个目标相互关联、相互促进，共同构成了慢阻肺病管理的重要内容。尽管这些药物及干预措施虽能显著改善慢阻肺病患者的症状，但其局限性也相对比较大，比如治疗精准性不足、疾病异质性高、无法逆转病程、传统治疗副作用明显、耐药性严重等。更关键的是现阶段临床药物治疗无法覆盖所有慢阻肺病疾病表型，并且鉴于慢阻肺病的发病机制相当复杂且尚未完全阐明，目前临床上仍缺乏针对病因的有效治疗药物。这也使取得一定临床成就的创新疗法无法复制到 COPD 治疗领域，相关新药临床研究推进异常缓慢。两极分化的在研方向在历史上，COPD新药主要分为三个时代，即传统支气管扩张剂时代、抗炎治疗兴起时代、生物制剂革命时代。而围绕三个时代的发展，也演变出如今在研COPD新药的两大方向，即老药新发展与生物靶向药替代。图片来源：博药（点击查看大图）老药新发展首先，有一点需要明确：老药并非“不行”。事实上，在几十年临床使用上的经久不衰已是老药的最佳证明，而老药新发展，既是指临床目标不变（减轻症状+降低风险），针对不良反应、临床有效性等方向进行了诸多优化性设计。新型吸入 β2 受体激动剂（LABA）由于β2受体激动剂主要作用于气道平滑肌细胞、肥大细胞膜表面的β2受体，其在缓解COPD临床症状方面有着广泛认可的作用，也是目前COPD临床治疗主力药物之一。从短效β2受体激动剂到长效β2受体激动剂，临床上用于COPD治疗的LABA在频繁用药、药物剂量、实用性、患者依从性、安全性方面做出系列产品更迭，也确定了新型LABA的主线方向。药品名称靶点适应症最高临床阶段原研单位最新临床进展时间（近三年有进展即“活跃管线”）阿贝特罗 Abediterol ADRB2 临床Ⅱ期 Almirall Ltd;阿斯利康 2019-12-12 琥珀酸巴芬特罗 Batefenterol Succinate ADRB2;CHRM2;CHRM3 临床Ⅱ期 Innoviva Inc 2016-01-21 AZD-2115 ADRB2;mAChR 临床Ⅱ期 Pearl Therapeutics Inc;阿斯利康 2017-03-06 卡莫特罗 Carmoterol ADRB2 临床Ⅱ期田边三菱制药株式会社 2011-10-19 维兰特罗 Vilanterol ADRB2 临床Ⅱ期葛兰素史克 2007-08-21 数据来源：公开数据整理、药智数据时至今日，研发端上仍有药企致力于新型β2受体激动剂方向，但受限于临床替代难度较大，其中大多数管线的临床推进已不再积极。其中，比较具有代表意义的有几种新型β2受体激动剂：卡莫特罗（Carmoterol）活性及对β2受体的选择性高，起效快，作用时间达30h，治疗过程中耐受性和安全性与沙美特罗无显著差异。维兰特罗（Vilanterol）较沙美特罗起效快、治疗指数高、内在活性好，作用时间超过24h。但从目前该领域的研发活跃情况来看，可以预见的是未来新型LABA大概率将不再是COPD新药研发的主要方向，至少已很少有企业愿意在朝这方面努力了。新型长效抗胆碱药（LAMA）抗胆碱能药物主要通过阻断M1-M3胆碱受体，进而扩张气道平滑肌、改善气流受限和慢阻肺症状，20世纪70年代，短效抗胆碱药物（SAMA）开始被用于慢阻肺的治疗，但虽起效迅速，但作用时间仅6—8小时，对于COPD这样的慢病而言，局限性较大，因此21世纪初，长效抗胆碱能药物（LAMA）问世，作用时间大幅增长，部分产品甚至可超过24小时。比如，2017年获批上市的格隆溴铵（Glycopyrrolate），对M3受体的选择性较噻托溴铵高，起效时间较噻托溴铵快4.8倍，安全性好；GSK的乌美溴铵改善FEV1的效果与噻托溴铵相似，效果与剂量无相关性，吸收迅速（Tmax=5～15min），在血液中代谢迅速，耐受性好。药品名称靶点适应症最高临床阶段原研单位最新临床进展时间（近三年有进展即“活跃管线”）乌美溴铵 Umeclidinium Bromide CHRM1;CHRM2;CHRM3;CHRM4;CHRM5 已上市葛兰素史克 2023-11-08 阿地溴铵 Aclidinium Bromide CHRM3 已上市 Almirall SA；精鼎医药（许可） 2024-08-13 噻托溴铵 Tiotropium Bromide CHRM3 已上市勃林格殷格翰 2025-02-06 TRN-157 CHRM3 临床Ⅱ期 Theron Pharmaceuticals Inc；山东鲁抗医药（许可）；长风药业（许可） 2024-08-09 数据来源：公开数据整理、药智数据而目前，在新型长效抗胆碱能药（LAMA）研发层面，其整体情况与LABA的局面类似，绝大多数管线的临床进展并不积极，仅少数产品还在持续推进，其中山东鲁抗的TRN-157，目前其已在美国完成了I期和IIa期临床试验，在国内已完成了健康受试者单次给药的I期临床试验，安全性均良好，本品已获得国家药品监督管理局同意开展IIa期临床试验。双靶点支气管扩张剂（MABA） MABA是一类新型具有毒蕈碱拮抗剂和β2激动剂双重作用的双靶点药物，能够实现在一个分子上同时作用两大靶点的创新设计，具有M受体拮抗和β受体激动两种功能，可协同扩张气管和抗炎。对比LABA与LAMA单靶点产品，从机制上其具备了核心的三大优势：双靶点协同，疗效提升：双靶点机制不仅成功规避了LAMA、LABA单药治疗可能面临的疗效局限性和潜在副作用风险，更通过“双靶点”的协同作用，实现COPD疾病症状以及肺功能的双重改善，大幅提升治疗效果和患者的治疗依从性。兼顾速效与长效，治疗优势凸显：数据显示，该药物兼具速效与长效的双重治疗优势，能够迅速响应急性期的需求实现快速缓解，同时亦适合作为长期维持治疗的选择，有望对现有治疗方案形成强有力的补充甚至替代。安全设计、无忧治疗：该药物独特的季铵盐结构设计能够有效避免药物进入中枢神经系统，从而大幅降低对中枢神经系统产生副作用的可能性，提升了治疗的安全性，为慢阻肺患者带来更加高效、便捷且安全的治疗新选择。药品名称靶点关键适应症与阶段适应症最高临床阶段原研单位最新临床进展时间（近三年有进展即“活跃管线”）琥珀酸巴芬特罗 Batefenterol Succinate ADRB2;CHRM2;CHRM3 临床Ⅱ期：慢性阻塞性肺病临床Ⅱ期 Innoviva Inc 2016-01-21 CHF-6366 ADRB2;CHRM3 临床Ⅱ期：哮喘;慢性阻塞性肺病临床Ⅱ期意大利凯西制药公司 2017-12-14 DBM-1152A ADRB2;CHRM3 临床Ⅰ期：慢性支气管炎;慢性阻塞性肺病;支气管痉挛;肺气肿引起支气管痉挛临床申请：哮喘临床Ⅰ期硕佰医药 2024-08-08 TQC-3927 ADRB2;CHRM3 临床Ⅰ期：慢性阻塞性肺病临床申请：哮喘临床Ⅰ期正大天晴 2024-12-02 数据来源：公开数据整理、药智数据目前，MABA类双靶点制剂相对前两类药物的研发热情明显更高，是COPD新药研究的重要方向之一，其中Innoviva的Batefenterol、阿斯利康的Navafenterol与凯西制药的CHF-6366临床进度较靠前，但进展相对不那么积极。而对比之下，部分国内管线明显更加活跃，比如硕佰医药与健康元的DBM-1152A、正大天晴的TQC-3927，目前均已进入临床I期，且临床推进迅速。 PDE双靶点抑制剂 PDE主要分布于体内各种炎症细胞内，家族的成员多达11位，每位成员各司其职，参与不同的生理过程，其中PDE-4抑制剂可以阻止PDE-4对cAMP/cGMP的水解作用，使cAMP/cGMP在炎症细胞内聚集。因此，PDE4抑制剂对于治疗慢性阻塞性肺疾病（COPD）非常有吸引力。但由于PDE4在全身多处组织中广泛表达，导致其具备潜力的同时，不良反应也极大地限制了其发展。因此，寻求一款兼具高有效性与低不良反应的PDE4抑制剂成为该领域的主线任务。多项研究表明，相比于单独抑制PDE3或PDE4，同时抑制PDE3和PDE4产生的抗炎和松弛平滑肌作用更强，同时较低的副作用也使得PDE3/4双重抑制剂顺势成为COPD新药研发的趋势之一。数据来源：公开数据整理、药智数据（点击查看大图）其中，2024年全球首个获FDA获批上市的PDE3/4抑制剂Ensifentrine（恩塞芬汀）就是显著代表，“一药双效”的创新药物，成功打破COPD治疗僵局，开启了“抗炎+扩支”的整合治疗时代。国内领域，目前也有多家企业有所布局，进入临床阶段的产品包括正大天晴的TQC-3721与恒瑞医药的HRS-9821，不出意外的话，首款国产PDE3/4抑制剂将在两者中产生。 PI3Kδ 抑制剂虽然PI3K药物大多集中肿瘤领域（包括实体瘤和血液肿瘤），目前已获批上市的PI3K抑制剂适应症也均为肿瘤，但近年来的研究表明PI3K在慢性阻塞性肺疾病（COPD）、哮喘、特发性肺纤维化（IPF）以及神经系统疾病病理过程中也扮演重要角色，这也导致部分企业对上述适应症的临床试验兴趣大涨。其中，在一些COPD患者中对诸如皮质类固醇的常规疗法的抗性已被归因于PI3Kδ/γ途径的上调。另外，PI3Kδ/γ的双重抑制强烈地涉及气道及其他自身免疫性疾病的过敏及非过敏性炎症作为干预策略。因此，针对PI3Kδ/γ信号传导的抑制提供了一种旨在对抗免疫炎性反应的新手段。药品名称靶点关键适应症与阶段产品最高临床阶段适应症最高临床阶段原研单位最新临床进展时间（近三年有进展即“活跃管线”）奈米利司 Nemiralisib PI3Kdelta 临床Ⅱ期：PI3Kδ过度活化综合征;哮喘;慢性阻塞性肺病临床Ⅱ期临床Ⅱ期葛兰素史克 2018-10-23 RV-6153 PI3K 临床Ⅰ期：慢性阻塞性肺病临床Ⅰ期临床Ⅰ期 RespiVert Ltd 2015-07-28 RV-1729 PI3K;PI3Kdelta;PIK3CG 临床Ⅰ期：慢性阻塞性肺病临床Ⅰ期临床Ⅰ期 RespiVert Ltd 2014-05-14 数据来源：公开数据整理、药智数据目前，在该领域中涉及COPD的临床阶段管线数量不多，且绝大多数管线临床状态并不活跃，其中GSK的Nemiralisib是目前临床阶段最靠前的创新疗法，其次则是RespiVert的RV-6153与RV-1729。 CXCR拮抗剂早些年，小分子趋化因子受体（CXCR）拮抗剂在呼吸系统疾病中的作用仍是一个活跃的研究领域，研究发现COPD患者体内CXCL8、CXCL1和CXCL5的水平升高，与CXCR2受体结合后，使中性粒细胞和单核细胞增多并激活。口服CXCR拮抗剂具有抑制肺部慢性中性粒细胞性炎症的作用，临床研究还发现CXCR2拮抗剂同样具有抑制肺部慢性中性粒细胞性炎症的作用，提示对COPD具有潜在的治疗作用。药品名称靶点关键适应症与阶段产品最高临床阶段适应症最高临床阶段原研单位最新临床进展时间（近三年有进展即“活跃管线”）多西帕司他钠 Dociparstat Sodium CXCL12;CXCR4 临床Ⅲ期：SARS-CoV-2感染;急性肺损伤;急性髓系白血病临床Ⅱ期：慢性阻塞性肺病临床Ⅲ期临床Ⅱ期 Cantex Pharmaceuticals Inc;Chimerix Inc 2021-02-26 AZD-5069 CXCR2 临床Ⅱ期：呼吸系统疾病;哮喘;慢性支气管炎;慢性阻塞性肺病;支气管扩张;肝癌;肺气肿;肺病临床Ⅱ期临床Ⅱ期阿斯利康 2022-03-07 达尼利星 Danirixin CXCR2 临床Ⅱ期：慢性阻塞性肺病;流感病毒感染临床Ⅰ期：呼吸道合胞病毒感染临床Ⅱ期临床Ⅱ期葛兰素史克 2018-03-01 QBM-076 CXCR2 临床Ⅱ期：慢性阻塞性肺病临床Ⅰ期：三阴性乳腺癌;结直肠癌;肾细胞癌;非小细胞肺癌临床Ⅱ期临床Ⅱ期诺华制药 2016-05-09 数据来源：公开数据整理、药智数据但随着研究深入，目前大多数针对趋化因子受体和介质的药物研究已经停止，仅有少数几个针对CXCR1与CXCR2拮抗剂的研究还在继续。生物靶向药崛起对COPD生物药的开发探索，一直都是当前创新药研发的重点方向，但由于创新疗法的局限性，对新开发项目来说，不确定因素往往更多，这也导致十数年里全球制药企业在COPD生物药研发过程中折戟无数。不过，随着医药基础研究水平的进步，靶向生物药市场验证机会也越来越多，近年来COPD生物靶向药逐渐有了新的希望，相关疗法也陆续取得不错的成绩，目前来看“IL/TSLP单抗”与“靶向双抗”是现阶段最被寄予厚望的技术方向。单抗多项研究表明，COPD患者的整个气道、肺实质和肺血管中都存在慢性炎症。这就表示包括1型细胞因子肿瘤坏死因子α(TNF-α)，2型细胞因子IL-4、IL-5、IL-13及其警报素IL-33、TSLP等都会参与COPD病理生理，而随着研究深入，TNF-α抑制剂单抗在COPD实际治疗中的临床疗效相对有限，逐渐被研究者放弃。因此，COPD单抗的相关研究开始集中转向2型炎症，IL-4、IL-5、IL-33与TSLP逐渐成为COPD单抗研究的“四强”。 IL-5单抗方面，由于率先在嗜酸性粒细胞表型重症哮喘方面取得突破，如阿斯利康、GSK等MNC都希望能一鼓作气，将其药物用途拓展至COPD领域，彼时IL-4也被认为是最可能应用于COPD领域的IL单抗方向。但现实却是多个IL-5单抗在COPD适应症上接连失利。数据来源：公开数据整理、药智数据（点击查看大图）直至2024年9月，GSK的Mepolizumab治疗COPD的Ⅲ期MATINEE研究取得了积极结果，并于2025年2月11日在中国申报上市。 IL-4单抗方面，由于IL-5单抗在COPD领域的接连失利，其幸运地迎来了反超机会，2024年7月赛诺菲/再生元合作开发的IL-4Ra单抗Dupixent（Dupilumab/度普利尤单抗）在全球率先获得欧洲药品管理局（EMA）批准用于治疗血液嗜酸性粒细胞（BEC）升高且未得到控制的COPD成人患者，从而摘得首款COPD生物药桂冠。数据来源：公开数据整理、药智数据（点击查看大图）在其主要临床终点中，度普利尤单抗AECOPD平均年恶化率分别降低30%和34%，且肺功能（支气管扩张剂前FEV1）在12周时较基线改善160mL和139mL，而基线时分别为77mL和57mL。Dupixent的成功进一步通过试验验证了IL-4和IL-13信号传导在COPD中的作用。 IL-33单抗方面，作为驱动病毒感染和诱发AECOPD的关键细胞因子，在COPD患者的血浆和支气管上皮中可明显观察到IL-33的过度表达。目前已有多款靶向IL-33的单抗正处于COPD的Ⅲ期临床试验阶段数据来源：公开数据整理、药智数据（点击查看大图）赛诺菲的IL-33单抗Itepekimab，目前已处于临床Ⅲ期阶段，其临床数据显示其虽对急性加重率降低无统计学意义，但对曾吸烟者COPD急性加重率降低>40%，赛诺菲对其年销售峰值预期达50亿欧元。而国内领域的布局管线虽临床进度较上述两者有所不及，但也极具潜力，其分别是正大天晴的TQC-2938、荃信生物的QX-007-N与三生国健的SSGJ-621。 TSLP单抗方面，相比于IL-4R等靶点，TSLP位于更上游，位于多个炎症级联反应顶端，是2型炎症重要驱动因素，在各种类型的炎症和免疫类疾病中充当促炎细胞因子。图片来源：《TSLP: from allergy to cancer》靶向TSLP抗体通常是通过阻断TSLP与其受体之间的相互作用来抑制TSLP介导的信号通路，从而抑制DC细胞、肥大细胞、自然杀伤细胞、TH2细胞介导炎症反应。目前TSLP靶点肿瘤适应症开发布局较为集中，其中哮喘适应症的临床进展最快，而由于COPD与哮喘的关联性，导致TSLP单抗用于COPD治疗的研究也同样火热。数据来源：公开数据整理、药智数据（点击查看大图）截止目前，全球领域尚无任何一款TSLP单抗获批用于治疗COPD，临床推进最快的是安进与阿斯利康的Tezepelumab、博奥信生物的BSI-045B、诺华制药的Ecleralimab、荃信生物的QX-008-N，均已进入临床Ⅱ期。但同时，值得注意的是，在TSLP单抗用于COPD治疗的在研药物领域中，国内Biotech企业得管线数目却占比较高，后续有望成为全球该领域的主要力量。双抗原则上来讲，双抗较单抗，确实具备诸多技术优势，比如双重靶向下的协同作用使得它在处理肿瘤的异质性和复杂生物学特性时，比单抗有更全面的覆盖、在增强治疗效果、克服耐药性等方面优势明显。也正是因此，全球制药企业不出意外的均将其作为潜在创新疗法布局，而在COPD领域，目前已有少数企业开始积极推进，靶点主要主要集中于TSLP+IL、IL+IL两大方向。分类药品名称靶点关键适应症与阶段产品最高阶段适应症最高临床阶段原研单位最新临床进展时间（近三年有进展即“活跃管线”）双抗 HB-0056 IL11;TSLP 临床Ⅰ期：哮喘;慢性阻塞性肺病;特发性肺纤维化;特应性皮炎临床Ⅰ期临床Ⅰ期华奥泰生物 2025-01-24 RC-1416 IL4RA;IL5 临床Ⅰ期：哮喘临床申请：慢性阻塞性肺病;特应性皮炎;肿瘤临床Ⅰ期临床申请融捷康生物 2024-10-17 PM1017 IL4RA;IL5 临床前：哮喘;嗜酸粒细胞增多症;慢性阻塞性肺病临床前临床前普米斯生物 2022-08-12 数据来源：公开数据整理、药智数据据不完全统计，COPD双抗领域目前以华奥泰生物的HB-0056推进最快，前已处于临床I期，其次是融捷康生物的RC-1416与普米斯生物的PM1017，分别处于临床申请与临床前阶段。华奥泰生物的HB-0056，是以抗TSLP人源化单克隆抗体为亲本抗体，在N端连接抗IL-11（白细胞介素-11）单链纳米抗体的双特异性抗体，能高特异性地靶向TSLP和IL-11这两个靶点。而TSLP和IL-11均以不同的机制参与诱导Th2（辅助型T细胞2）反应、气道炎症和COPD的发病机制，两者可以互补作用来影响该疾病。融捷康生物的RC-1416，可以选择性结合IL-4R和IL-5，同时下调由IL-4、IL-5和IL-13诱导的信号，显著抑制炎症性Th2（2型炎症因子）细胞，以及下游的参与炎症反应的嗜酸性粒细胞、肥大细胞、嗜碱性粒细胞的活性，对多种Th2通路诱导的疾病都具备治疗效果。而IL-5目前被认为是Th2通路的关键驱动因子之一，IL-5与其受体结合后进一步激活下游JAK-STAT信号通路。普米斯生物的PM1017，可以同时阻断慢性阻塞性肺病患者体内IL-4/IL-13/IL-4Rα/IL-13Rα1，以及IL-5/IL-5Rα两条非冗余的信号通路，从而更大限度地抑制疾病进展，同时避免临床上使用度普立尤单抗治疗，患者发生的嗜酸性粒细胞增多症等副作用。皮下注射剂型加上工程化改造的Fc片段缩短给药频率，PM1017可以为患者提供更加便捷，安全，有效的治疗方案。难以看清的未来趋势对于绝大多数自免、慢病而言，其患者群体庞大是其最大的优势，更何况其临床上还存在大量未满足的临床需求，因此近年来逐渐成为全球创新技术领域除肿瘤外的最大竞争地。而对于COPD新药研发而言，虽然现阶段IL、TSLP等靶向制剂均以单抗技术为主，但就疗法未来而言，其患者顺应性的弊端或许也将成为限制其发展的关键之处（调查显示至少超过20%的患者不愿意使用注射剂型）。放眼隔壁的IL-17领域，目前全球范围内已有多家创新药企在尝试推进IL-17口服制剂，且不乏辉瑞、礼来、赛诺菲等MNC药企的身影。比如礼来DC-806折戟后寄希望的小分子IL-17靶向药DC-853，赛诺菲以700万美金首付从C4X引进的IL-17A临床前小分子抑制剂；强生/Protagonist首个口服IL-23受体的靶向口服肽JNJ-2113。当然，考虑到COPD用药特殊性，此处的IL单抗口服趋势不一定完全适用（毕竟长久以来吸入制剂制在呼吸系统的临床地位明显高于口服小分子），未来大概率会做出因地制宜的改变，比如IL单抗的吸入制剂、TSLP吸入单抗等。但可以肯定的是，随着未来COPD靶向生物药的发展，COPD单抗制剂的竞争加剧，关于患者顺应性的考虑或许会在恰当的时候，进入研究者的视野中。小结综上所述，从数十年前LABA、LAMA被临床应用于COPD治疗，再到如今临床上LABA+LAMA+ICS的临床联用方案，很明显COPD的新药研发较肿瘤、自免疾病而言，明显慢了很多。固然，这一方面是由于COPD相关基础临床研究不足，另一方面也是由于COPD短期研发收益低于肿瘤、肥胖、自免等风口疾病领域。但这并不表示COPD领域的市场不大，不存在临床需求。相反，长时间的无药可用的压抑之下，或许还会造就COPD领域更加迫切的临床需求。而从目前COPD新药在研的情况来看，一部分企业选择继续沿用传统研发路线，对老药进行新的优化与升级，过程中诞生了一系列新型LABA、新型LAMA以及双靶点支气管扩张剂（MABA）等等，比如成功打破COPD治疗僵局的恩塞芬汀；而另一部分企业则倾向于将在肿瘤、自免新药开发上获得的经验复制于COPD领域，积极推进IL单抗、TSLP单抗与靶向双抗，比如赛诺菲与再生元的度普利尤单抗、GSK的美泊利珠单抗。目前来看，就老药新发展与靶向生物药两方面发展而言，预计未来很长一段时间，靶向生物药或将成为COPD新药的主线剧情，直到双抗同质化那天，而过程中也必将有越来越多中国Biotech企业从中崛起。当然，无论是老药新用，还是靶向生物药的大趋势，对于目前COPD的临床需求而言，仍不够完美，或未来，在逆转COPD病程、针对病因治疗、解决患者顺应性需求方面，小分子与生物药能协同一起，为更核心的需求服务。来源 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上市批准

2025-02-27

·veronapharma.com

Verona Pharma Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update

OhtuvayreTM (ensifentrine) recorded net product sales of $36.6 million in Q4 and $42.3 million in 2024 More prescriptions filled through February 2025 than in Q4 2024 Over 4,600 unique prescribers with ~55% of Tier 1 HCPs prescribing Ohtuvayre through February 2025 Phase 2 programs in bronchiectasis and fixed-dose combination in COPD advance Conference call today at 9:00 a.m. EST / 2:00 p.m. GMT LONDON and RALEIGH, N.C., Feb. 27, 2025 (GLOBE NEWSWIRE) — Verona Pharma plc (Nasdaq: VRNA) (“Verona Pharma” or the “Company”), a biopharmaceutical company focused on respiratory diseases, announces its financial results for the fourth quarter and full year ended December 31, 2024, and provides a corporate update. “2024 was another transformational year for Verona Pharma with the US approval and launch of Ohtuvayre (ensifentrine), the first novel inhaled therapy available for the maintenance treatment of Chronic Obstructive Pulmonary Disease (“COPD”) in over 20 years,” said David Zaccardelli, Pharm. D., President and Chief Executive Officer. “We are very pleased to report the extremely strong start to the launch continues to build momentum with more prescriptions dispensed through February 2025 than in the entire fourth quarter of 2024. “More than 4,600 unique healthcare professionals (“HCPs”) including approximately 55% of our Tier 1 HCPs have prescribed Ohtuvayre. Additionally, to date, more than 275 HCPs have prescribed Ohtuvayre to over 20 patients in their practice. Ohtuvayre is being prescribed for maintenance therapy across a broad COPD population including those receiving background single, dual and approximately 50% on triple therapy. These data strengthen our belief that ensifentrine’s novel bronchodilator and non-steroidal anti-inflammatory activity will redefine the treatment paradigm for COPD. “Alongside our commercialization efforts, in the third quarter we initiated two Phase 2 clinical trials: a dose-ranging trial with glycopyrrolate, a long-acting muscarinic antagonist (“LAMA”), to support a nebulized fixed-dose combination of ensifentrine and glycopyrrolate for the maintenance treatment of COPD, and a study assessing the safety and efficacy of nebulized ensifentrine in patients with non-cystic fibrosis bronchiectasis (“bronchiectasis”). We are pleased to report the glycopyrrolate dose-ranging trial was successfully completed and we plan to initiate a dose ranging Phase 2b trial with a fixed-dose combination of ensifentrine and glycopyrrolate in the second half of 2025. “In addition to our successful Ohtuvayre launch, our development partner in Greater China, Nuance Pharma, announced in February 2025 that Ohtuvayre was approved in Macau, the first approval outside of the US, for the maintenance treatment of COPD. In addition, Nuance Pharma has completed enrollment in its own pivotal Phase 3 trial in China to evaluate ensifentrine for the maintenance treatment of COPD and expects to report results in mid-2025. “In 2025, we will continue to build on the successful commercialization of Ohtuvayre in the US while progressing our Phase 2 programs. We are also initiating activities with regulatory authorities in the European Union and the UK for potential marketing authorization application submissions for Ohtuvayre.” Program Updates and Key Milestones The Company’s near-term milestones include: In the second half of 2025, the Company plans to start a dose-ranging Phase 2b trial to assess the safety and efficacy of a fixed-dose nebulized combination of ensifentrine with glycopyrrolate. The Company has successfully completed a Phase 2 dose-ranging trial with glycopyrrolate to support this program. The Company continues to enroll subjects in a Phase 2 trial to assess the efficacy and safety of nebulized ensifentrine in patients with bronchiectasis. In 2025, the Company plans to progress the regulatory activities for potential marketing authorization application submissions for Ohtuvayre for the maintenance treatment of COPD in the European Union and in the UK. In mid-2025, the Company’s development partner in Greater China, Nuance Pharma, is expected to report results from its pivotal Phase 3 trial evaluating ensifentrine for the maintenance treatment of COPD in China. Fourth Quarter and Recent Highlights In October 2024, the Company gave four oral presentations and presented two posters on analyses from the ENHANCE studies at CHEST Annual Meeting 2024. These included subgroup data supporting improvements in lung function, symptoms and quality of life, as well as reductions in the rate of exacerbations, regardless of COPD severity (moderate or severe), smoking status (current or former) and chronic bronchitis (with or without). An analysis of Ohtuvayre’s impact on reducing exacerbation rates and COPD-related healthcare resource utilization was also presented. In November 2024, the 2025 GOLD report added Ohtuvayre to the COPD treatment algorithm. Also in November 2024, the Company completed enrollment in a Phase 2 dose-ranging trial with glycopyrrolate, a LAMA, supporting a fixed-dose combination program for the maintenance treatment of COPD via a nebulizer. On January 1, 2025, Ohtuvayre’s product specific J-code became effective. In February 2025, the Company’s development partner in Greater China, Nuance Pharma, announced Ohtuvayre has been approved in Macau for the maintenance treatment of COPD in adult patients. This is the first regulatory approval outside of the US. Fourth Quarter 2024 Financial Results Cash position: Cash and cash equivalents at December 31, 2024, were $399.8 million (December 31, 2023: $271.8 million). Product sales: Net sales of Ohtuvayre were $36.6 million for the fourth quarter ended December 31, 2024 (Q4 2023: $0 million). The Company received FDA approval on June 26, 2024 and the product was commercially available beginning in August 2024. Cost of sales: Cost of sales was $2.0 million for the fourth quarter ended December 31, 2024 (Q4 2023: $0 million), which included Ohtuvayre manufacturing costs incurred after US approval, inventory overhead costs and sales-based royalties. R&D Expenses: Research and development (“R&D”) expenses were $7.9 million for the fourth quarter ended December 31, 2024 (Q4 2023: $4.1 million). This increase of $3.8 million was primarily due to an increase of $3.2 million in clinical trial and other development costs as we initiated two Phase 2 studies in the third quarter of 2024 related to the combination of nebulized ensifentrine and glycopyrrolate and for Ohtuvayre in patients with bronchiectasis, and an increase of $1.1 million in share-based compensation. SG&A Expenses: Selling general and administrative expenses (“SG&A”) were $45.1 million for the fourth quarter ended December 31, 2024 (Q4 2023: $15.0 million). The increase of $30.1 million was driven primarily by an increase of $9.8 million in marketing and other commercial related activities, including travel, primarily related to the launch of Ohtuvayre, and an increase of $2.6 million in professional and consulting fees, information technology costs and other support costs due to the continued buildout of our commercial organization. Additionally, we had an increase of $8.8 million in people-related costs as we built out our commercial organization including much of the field sales team as well as an increase of $7.8 million related to share-based compensation. Net loss: Net loss was $33.8 million for the fourth quarter ended December 31, 2024 (Q4 2023: Net loss $14.1 million). Full Year 2024 Financial Results Product sales: Net sales were $42.3 million for the year ended December 31, 2024 (2023: $0 million) related to product sales of Ohtuvayre. Cost of sales: Cost of sales was $2.6 million for the year ended December 31, 2024 (2023: $0 million), which included Ohtuvayre manufacturing costs incurred after US approval, inventory overhead costs and sales-based royalties. R&D Expenses: R&D expenses were $44.6 million for the year ended December 31, 2024 (full year 2023: $17.2 million), an increase of $27.4 million. This increase was primarily due to an increase of $17.5 million in clinical trial and other development costs we incurred related to the two Phase 2 studies which were initiated in the third quarter of 2024 related to the combination of nebulized ensifentrine and glycopyrrolate and for Ohtuvayre in patients with bronchiectasis, the $6.3 million approval milestone, $3.1 million increase in share-based compensation, $2.0 million increase for people-related costs and $1.1 million related to pre-launch manufacturing costs for commercial supply. This was partially offset by a decrease of $1.3 million in consultant and professional fee costs which were higher in the prior year due to service costs associated with our New Drug Application and the related approval process. SG&A Expenses: SG&A expenses were $149.8 million for the year ended December 31, 2024 (full year 2023: $50.4 million), an increase of $99.4 million. This increase was driven primarily by an increase of $29.7 million in marketing and other commercial related activities, including travel, primarily related to the launch of Ohtuvayre, a charge of $15.0 million for the first sale milestone and an increase of $7.3 million in professional and consulting fees, information technology costs and other support costs due to the continued buildout of our commercial organization. Additionally, we had an increase of $26.8 million in people-related costs as we built out our commercial organization including much of the field sales team as well as an increase of $18.8 million related to share-based compensation. Net loss: Net loss was $173.4 million for the year ended December 31, 2024 (full year 2023: $54.4 million). Conference Call and Webcast Information Verona Pharma will host an investment community webcast and conference call at 9:00 a.m. EST / 2:00 p.m. GMT on Thursday, February 27, 2025, to discuss the fourth quarter and full year 2024 financial results and the corporate update. To participate, please dial one of the following numbers and ask to join the Verona Pharma call: +1-800-836-8184 for callers in the United States +1-646-357-8785 for international callers A live webcast will be available on the Events and Presentations link on the Investors page of the Company’s website, www.veronapharma.com, and the audio replay will be available for 90 days. An electronic copy of the fourth quarter and full year 2024 results press release will also be made available today on the Company’s website. Important Safety Information Indication Ohtuvayre is a prescription medicine used to treat COPD in adults. COPD is a chronic (long-term) lung disease that includes chronic bronchitis, emphysema, or both. What is the most important information I should know about Ohtuvayre? Ohtuvayre can cause serious side effects, including: Sudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop using Ohtuvayre and call your healthcare provider right away or go to the nearest hospital emergency room right away. Mental health problems including suicidal thoughts and behavior. You may experience mood or behavior changes when taking Ohtuvayre. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts of suicide or dying, attempt to commit suicide, trouble sleeping (insomnia), new or worse anxiety, new or worse depression, acting on dangerous impulses, and/or other unusual changes in your behavior or mood. Do not use Ohtuvayre to treat sudden breathing problems. Always have a rescue inhaler with you. Who Should Not use Ohtuvayre? Do not use Ohtuvayre if you have had an allergic reaction to ensifentrine or any of the ingredients in Ohtuvayre. What should I tell my healthcare provider before using Ohtuvayre? Before you use Ohtuvayre, tell your healthcare professional if you have or have had a history of mental health problems including depression and suicidal behavior; have liver problems; are pregnant or plan to become pregnant; are breastfeeding. It is not known if Ohtuvayre may harm your unborn baby. It is not known if the medicine in Ohtuvayre 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. What are the most common side effects of Ohtuvayre? The most common side effects of Ohtuvayre include back pain, high blood pressure, bladder infection and diarrhea. These are not all the possible side effects of Ohtuvayre. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. This summary does not include all the information about Ohtuvayre and is not meant to take the place of a discussion with your healthcare provider about your treatment. For further information, please see the full Prescribing Information, including the Patient Information Leaflet. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. For further information please contact: About Verona Pharma Verona Pharma is a biopharmaceutical company focused on developing and commercializing innovative therapies for the treatment of chronic respiratory diseases with significant unmet medical needs. OhtuvayreTM (ensifentrine) is the Company’s first commercial product and the first inhaled therapy for the maintenance treatment of COPD that combines bronchodilator and non-steroidal anti-inflammatory activities in one molecule. Ensifentrine has potential applications in non-cystic fibrosis bronchiectasis, cystic fibrosis, asthma and other respiratory diseases. For more information, please visit www.veronapharma.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. All statements contained in this press release other than statements of historical fact should be considered forward-looking statements. Words such as “anticipate,” “believe,” “plan,” “expect,” “intend,” “may,” “potential,” “prepare,” “possible” and similar words and expressions are intended to identify forward-looking statements. These forward-looking statements include, but are not limited to, statements regarding the potential benefits and efficacy of our drug Ohtuvayre to treat adult patients in the US with COPD, statements regarding our two recently initiated Phase 2 clinical trials, the Company’s plans to initiate a Phase 2b clinical trial, potential regulatory approvals in the EU and UK, and Nuance Pharma’s results from its pivotal Phase 3 trial, and the timing of any of the foregoing. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from our expectations expressed or implied by the forward-looking statements, including, but not limited to, the following: risks related to our limited operating history; our need for additional funding to complete development and commercialization of Ohtuvayre which may not be available and which may force us to delay, reduce or eliminate our development or commercialization efforts; our reliance on the success of Ohtuvayre, our only commercial product; our reliance on third-party manufacturers and suppliers; the efficacy of Ohtuvayre compared to competing drugs; our ability to successfully commercialize Ohtuvayre; serious adverse, undesirable or unacceptable side effects associated with Ohtuvayre which could adversely affect our ability to commercialize Ohtuvayre; failure to develop Ohtuvayre for additional indications, alternate delivery methods, or as a combination therapy; failure to obtain approval for and commercialize Ohtuvayre in multiple major pharmaceutical markets; our commercial capabilities and infrastructure, including sales, marketing, operations, distribution, and reimbursement infrastructure, may not be adequate to successfully commercialize Ohtuvayre; lawsuits related to patents covering Ohtuvayre and the potential for our patents to be found invalid or unenforceable; lawsuits related to our licensing of patents and know-how from third parties for the commercialization of Ohtuvayre; changes in our tax rates, unavailability of certain tax credits or reliefs or exposure to additional tax liabilities or assessments that could affect our profitability, and audits by tax authorities that could result in additional tax payments for prior periods; the terms of our credit agreement and the revenue interest purchase and sale agreement (“RIPSA”) place restrictions on our operating and financial flexibility, and if we fail to comply with certain covenants in the RIPSA, our results of operations and financial condition may be harmed; our vulnerability to natural disasters, global economic factors, geo-political actions and unexpected events, including health epidemics or pandemics; and the other important factors discussed under the caption “Risk Factors” in our Annual Report on Form 10-K for the period ended December 31, 2024, filed with the Securities and Exchange Commission (“SEC”) on February 27, 2025, as such factors may be updated from time to time in our other filings with the SEC. We disclaim any obligation to update or revise any forward-looking statement contained in this press release, even if subsequent events cause our views to change, except as required under applicable law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Verona Pharma plc Consolidated Financial Summary (unaudited) (in thousands, except share and per share amounts)

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KEGG	Wiki	ATC	Drug Bank
D11743	恩塞芬汀	-	DB16157

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适应症	国家/地区	公司	日期
慢性阻塞性肺疾病	美国	Verona Pharma, Inc.	2024-06-26
慢性阻塞性肺疾病	美国	Verona Pharma Plc	2024-06-26

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适应症	最高研发状态	国家/地区	公司	日期
非囊性支气管扩张	临床2期	美国	Verona Pharma Plc	2024-09-11
新型冠状病毒感染	临床2期	美国	Verona Pharma, Inc.	2020-09-04
囊性纤维化	临床2期	英国	Verona Pharma Plc	2017-02-08
中度慢性阻塞性肺疾病	临床2期	-	Verona Pharma Plc	2017-01-01
慢性哮喘	临床2期	瑞典	Verona Pharma Plc	2015-04-01
慢性哮喘	临床2期	英国	Verona Pharma Plc	2015-04-01
哮喘	临床2期	荷兰	Verona Pharma Plc	-
哮喘	临床2期	-	Ligand UK Ltd.	-
过敏性鼻炎	临床2期	荷兰	Verona Pharma Plc	-
炎症	临床1期	英国	Verona Pharma Plc	2014-12-01

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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


NCT04535986 \| NCT04542057 (ENHANCE-2, FDA_CDER) 人工标引	临床3期	慢性阻塞性肺疾病	1,553	OHTUVAYRE (ENHANCE-1)	鹽製淵窪願醖餘餘顧顧(壓鹽遞醖壓獵簾願繭鹹) = 範願壓簾鹹醖範壓獵製餘憲鏇繭繭衊獵壓簾獵 (窪範積襯艱觸夢糧繭餘, 25 ~ 97) 更多	积极	2024-06-26
				Placebo (ENHANCE-1)	鹽製淵窪願醖餘餘顧顧(壓鹽遞醖壓獵簾願繭鹹) = 選餘鏇願餘鏇顧淵憲鏇餘憲鏇繭繭衊獵壓簾獵 (窪範積襯艱觸夢糧繭餘, -64 ~ 13) 更多
ATS2024	N/A	慢性阻塞性肺疾病	-	Ensifentrine 3 mg + LAMA	願衊簾艱簾夢餘糧憲製(淵壓蓋選積範衊願餘觸) = 製壓網鹽蓋膚製糧艱顧積積選獵醖遞憲顧願壓 (願觸壓網蓋淵窪構壓膚 ) 更多	-	2024-05-19
ATS2024	N/A	慢性阻塞性肺疾病	-	Nebulized ensifentrine 3 mg	艱願憲範鏇淵襯鹽鑰衊(鑰鬱繭積鏇衊鑰壓範淵) = 壓鏇齋壓獵鬱餘壓網廠淵壓壓淵遞願鑰願艱積 (醖選鏇齋襯願憲製鹽築 ) 更多	-	2024-05-19
ATS2024	N/A	慢性阻塞性肺疾病	-	Nebulized Ensifentrine 3 mg	夢鏇鹹網淵蓋壓遞鏇選(鏇觸遞製襯鏇鑰夢築壓) = 壓糧憲選繭壓襯鹹蓋鑰鏇餘積築鹹構淵選獵範 (製膚艱獵製膚夢窪齋鏇 ) 更多	-	2024-05-19
				Placebo	夢鏇鹹網淵蓋壓遞鏇選(鏇觸遞製襯鏇鑰夢築壓) = 襯鏇窪衊壓鏇積繭簾鑰鏇餘積築鹹構淵選獵範 (製膚艱獵製膚夢窪齋鏇 ) 更多
ATS2024	临床3期	-	-	Ensifentrine 3 mg	範製淵鏇膚夢憲繭鏇構(鏇廠鹽壓願窪遞獵淵淵) = 鏇觸鬱顧醖觸憲遞壓選獵膚衊齋夢艱壓鹽鏇淵 (膚築鑰選鹹網鑰淵壓糧 )	积极	2024-05-19
ATS2024	N/A	慢性阻塞性肺疾病	-	Nebulized ensifentrine 3 mg	餘餘夢鏇鹹窪遞築憲鹹(築鏇簾餘艱夢鏇範遞獵) = 遞糧膚鬱願簾鹹選簾齋遞衊範構憲夢鑰艱廠繭 (繭鏇餘窪憲衊衊製範簾, -8.5 ~ -3.3) 更多	-	2024-05-19
				Placebo	餘餘夢鏇鹹窪遞築憲鹹(築鏇簾餘艱夢鏇範遞獵) = 網築獵夢艱蓋夢製獵鏇遞衊範構憲夢鑰艱廠繭 (繭鏇餘窪憲衊衊製範簾, -7.3 ~ -1.7) 更多
ATS2024	N/A	慢性阻塞性肺疾病	-	Nebulized ensifentrine 3 mg	憲簾夢醖鏇簾蓋鏇製積(築鏇選觸範獵夢糧積願) = 積構鏇簾夢鏇網鹽壓齋鑰醖壓選膚選築餘醖鹽 (鏇遞廠鑰鹽鬱廠遞廠選 )	-	2024-05-19
ATS2024	N/A	慢性阻塞性肺疾病	-	Ensifentrine 3 mg	獵遞鹹醖壓餘蓋廠襯窪(鏇艱鹽鏇蓋鬱顧網鹹艱) = showed larger reductions with ensifentrine+LABA/ICS vs placebo+LABA/ICS at Weeks 6 and 12 遞製糧願餘醖衊壓構鏇 (夢淵餘壓鹹壓廠廠簾齋 )	-	2024-05-19
				Placebo
NCT04535986 (ENHANCE-1, ERS2023) 人工标引	临床3期	慢性阻塞性肺疾病	760	ENHANCE-1 was a 24-week (+48-wk subset), multi-center, randomized, double-blind, placebo-controlled trial to evaluate nebulized ensifentrine-3mg twice-daily (randomized 5:3) in subjects 40-80 years with symptomatic moderate-to-severe COPD (post-bronchodilator FEV1 30–70% predicted, FEV1/FVC ratio <0.7, >2mMRC), and smoking history >10 pack-years. Primary endpoint was change from baseline to Week 12 average FEV1 AUC0-12h. Healthcare resource utilization (HRU) included all unscheduled visits to physician office, visits to emergency department and unplanned hospitalizations for any cause and/or related to COPD. Exacerbation rate and time to first event were assessed. 760 subjects were randomized and treated. Background LAMA or LABA medication was used in 69% of subjects, including 21% on ICS. Results: The primary endpoint was met. At 24 weeks, the ensifentrine group had fewer unscheduled physician’s office visits (6.5% vs 10.6%) and emergency room attendance resulting in hospital admission (3.6% vs 4.9%) vs placebo. Ensifentrine reduced moderate/severe exacerbation rate (36%, p=0.050) and instant risk, as assessed by time to first exacerbation (38%, p=0.038) vs placebo. Ensifentrine reduced moderate exacerbation rate (RR=0.59 [95% CI 0.36, 0.97], p=0.036) and instant risk (HR=0.57 [0.35, 0.93], p=0.025) vs placebo. Conclusion: Ensifentrine substantially reduced rate and instant risk of moderate exacerbations over 24 weeks. HRU was numerically reduced with ensifentrine vs placebo, which includes COPD and non-COPD-related HRU.	範遞選餘積鹽窪膚觸艱(壓鏇齋鑰繭夢獵築觸製) = 構憲築夢製齋鏇廠鹽鏇齋範積壓淵獵繭餘簾糧 (選觸製簾廠壓願鑰糧淵 ) 更多	积极	2023-09-11
				Placebo	範遞選餘積鹽窪膚觸艱(壓鏇齋鑰繭夢獵築觸製) = 簾窪糧繭餘獵製製積簾齋範積壓淵獵繭餘簾糧 (選觸製簾廠壓願鑰糧淵 ) 更多
NCT04535986 \| NCT04542057 (ENHANCE Trials, Pubmed)	临床3期	慢性阻塞性肺疾病	-	Ensifentrine	範築夢鹹淵遞壓觸齋繭(鹽壓鹹憲積積鹽齋壓鑰) = 窪構築築衊壓範製壓淵遞網糧餘壓網範壓積廠 (膚鹽襯鹽窪膚艱鑰夢夢, [55 ~ 119])	-	2023-06-26
				Placebo	-