A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Assess Efficacy and Safety of Atuliflapon Given Orally Once Daily for Twelve Weeks in Adults With Moderate to Severe Uncontrolled Asthma

This is a randomised, placebo-controlled, double-blind study to assess the efficacy and safety of Atuliflapon administered once daily over a 12-week treatment period to adult participants with moderate to severe uncontrolled asthma.

开始日期2022-01-27

申办/合作机构

AstraZeneca PLC

NCT04601467

/ Terminated临床2期IIT

PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE

This is a multi-center study conducted at 8 sites in 2 countries (Singapore, New Zealand). Patients with an acute myocardial infarction (AMI) were randomized in a ratio of 1:1 ratio to receive AZD5718 (Atuliflapon) 125 mg or placebo for 12 months to assess the efficacy of AZD5718 to prevent coronary plaque progression as measured on serial computer tomographic coronary angiography.

开始日期2021-07-12

申办/合作机构

University of Otago

[+1]

NCT04734275

/ Completed临床1期

A Randomised, Single-dose, Open-label, Single-centre, Crossover Study to Assess the Relative Bioavailability and Safety of Different Formulations of AZD5718 in Fasted and Fed State in Healthy Volunteers

This study will be a randomised, open-label, 3-period, 3-treatment, single-dose, crossover study in healthy subjects The study will be performed at a single study centre in the United Kingdom.

开始日期2021-02-01

申办/合作机构

AstraZeneca PLC

[+1]

100 项与 Atuliflapon 相关的临床结果

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100 项与 Atuliflapon 相关的转化医学

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100 项与 Atuliflapon 相关的专利（医药）

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项与 Atuliflapon 相关的文献（医药）

2024-11-01·Journal of Computational Biophysics and Chemistry

Molecular Docking, Quantum Mechanics and Molecular Dynamics Simulation of Anti-CAD Drugs Against High-Risk Xanthine Dehydrogenase Variants Associated with Oxidative Stress Pathways

作者: Sudhan, M. ; Ahmed, Shiek S. S. J. ; Emran, Talha Bin ; Attia, Sabry M. ; Ahmad, Sheikh F. ; Janakiraman, V.

Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings.

2024-10-01·Pharmacology Research & Perspectives

Disposition of orally administered atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor in healthy participants

Article

作者: Heijer, Maria ; Nelander, Karin ; Gränfors, Malin ; Sidhu, Sharan ; Li, Xue‐Qing ; Samuelsson, Kristin ; Ericsson, Hans ; Amilon, Carl ; Lindstedt, Eva‐Lotte ; Lindmark, Bo ; Garkaviy, Pavlo ; Weidolf, Lars ; Knöchel, Jane ; Bragg, Ryan A.

Abstract:

In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half‐life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug‐related exposure (DRE), while a direct N‐glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.

2024-09-01·BRITISH JOURNAL OF CLINICAL PHARMACOLOGY

A drug–drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5‐lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam

Article

作者: Lindstedt, Eva‐Lotte ; Connolly, Kat ; Ödesjö, Helena ; MacPhee, Iain ; Aurell, Malin ; Nelander, Karin ; Heijer, Maria ; Ericsson, Hans ; Forte, Pablo ; Panduga, Vijender ; Ali, Hodan ; Knöchel, Jane

Aims:

Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre‐clinical profiling suggests that time‐dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co‐administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time‐/dose‐dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity.

Methods:

Open‐label, fixed‐sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug–drug interaction.

Results:

Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co‐administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co‐administrations with two predicted therapeutically relevant doses of Atuliflapon.

Conclusions:

Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.

项与 Atuliflapon 相关的新闻（医药）

2025-11-03

·生物通

无定形VHL基SMARCA2 PROTAC关键功能结构的确定——揭示大分子降解剂固态稳定化新机制

在当今药物研发领域，靶向蛋白降解技术（PROTAC）正掀起一场革命。这类双功能分子能够将疾病相关靶点蛋白与E3连接酶拉近，促使靶蛋白被泛素化标记进而被蛋白酶体降解。与传统抑制剂相比，PROTAC的优势在于它不需要直接抑制靶蛋白的活性位点，而是利用细胞自身的降解机制来清除致病蛋白，这使得一些原本被认为"不可成药"的靶点成为了可能治疗的对象。目前已有20多种PROTAC化合物进入临床试验阶段，展现出巨大的治疗潜力。然而，PROTAC分子在制剂开发过程中面临着一个严峻挑战：它们通常难以结晶，大多以无定形形式存在。无定形固体虽然避免了结晶的难题，但其原子级结构不明确，存在自发结构重排的风险，可能影响药物的生物利用度和稳定性。传统的结构解析手段如X射线衍射和冷冻电镜（cryo-EM）虽然能够解析PROTAC与蛋白质形成的三元复合物结构，但对纯固态无定形PROTAC却无能为力。这种结构信息的缺失严重制约了高效、稳定PROTAC制剂的设计与开发。为了解决这一难题，来自瑞士洛桑联邦理工学院（EPFL）和阿斯利康的Daria Torodii、Jacob B. Holmes等研究人员在《Nature Communications》上发表了最新研究成果。他们采用核磁共振（NMR）晶体学方法，首次在原子水平上解析了一种基于Von Hippel-Lindau（VHL）的SMARCA2 PROTAC（PROTAC 2）的无定形结构，揭示了其独特的稳定化机制。研究人员主要运用了核磁共振晶体学技术，结合动态核极化（DNP）增强的固态核磁共振方法和分子动力学模拟，通过机器学习模型ShiftML2预测化学位移，对无定形PROTAC 2粉末样品进行了全面的结构表征。研究还使用了差示扫描量热法（DSC）测定玻璃化转变温度，并通过X射线衍射验证样品性质。研究结果 NMR谱图指认研究人员首先通过溶液态和固态NMR谱图的系统比较，成功指认了PROTAC 2无定形粉末中41个碳原子和31个氢原子的化学位移。由于分子较大（含48个碳原子和35个不等价质子），谱图存在严重重叠，研究团队采用变温NMR和DNP增强技术提高了检测灵敏度，并通过高斯拟合获得了各原子位点的化学位移分布。最佳匹配结构筛选通过分子动力学模拟生成372，864个候选结构，利用机器学习模型预测各结构的化学位移，并与实验值比较，筛选出5，000个与实验数据最吻合的结构（NMR集合）。这些结构不仅能量合理，而且能很好地再现实验观测到的化学位移分布。结构 motif 分析研究发现，PROTAC 2分子中存在一个显著 promoted 的分子内氢键相互作用（H1-N53），出现在80%的NMR集合分子中。这一氢键将酚环部分锁定在特定构象，使得SMARCA2结合区域相对有序。与之前研究的无定形小分子药物AZD4625和Atuliflapon不同，PROTAC 2中分子间氢键相互作用不再是主要的稳定化机制。相反，研究团队提出，类似于玻璃态聚合物，PROTAC 2无定形形式的主要稳定化机制是整体柔韧性引入的熵贡献，特别是在分子的连接区域。肽样区域构象分析在VHL结合区域，五元脂肪环表现出广泛的二面角分布，表明该区域存在较大程度的无序。主链二面角分布显示三个峰值中心，与蛋白质中脯氨酸的构象分布相似但更为分散。有趣的是，在PROTAC 2与SMARCA和VHL形成的三元复合物中观察到的构象（PDB：6HAX）在无定形固体中较为罕见，表明结合过程中的氢键相互作用显著影响了PROTAC的构象偏好。连接区域的高度无序性对连接区域二面角（C20-C23-C26-C27）和原子间距离（C7-C26、C7-C50、C18-C39）的分析表明，该区域几乎完全无序，所有可能的构象和距离均有分布，没有明显的促进或抑制现象。这种高度柔韧性使得PROTAC 2的整体行为类似于玻璃态聚合物，其玻璃化转变温度（Tg约-105°C）与聚苯乙烯（约-100°C）等聚合物相似。研究结论与意义本研究首次在原子水平上解析了无定形PROTAC 2的完整结构，揭示了其三个功能单元具有截然不同的结构类型：SMARCA2结合区域有序度最高，由强分子内氢键（H1-N53）稳定；肽样VHL结合区域较为无序；连接区域则几乎完全无序。与之前研究的小分子无定形药物不同，PROTAC 2的主要稳定化机制不是分子间氢键相互作用，而是整体柔韧性引入的熵贡献，特别是在连接区域。这种聚合物般的特性使得PROTAC 2的无定形形式能够通过构象熵来稳定，这一发现为理解大分子降解剂的固态行为提供了新视角。研究还发现，无定形固体中PROTAC 2的最主要构象与其在蛋白质三元复合物中的构象存在显著差异，突显了环境对PROTAC构象的重要影响。这些发现不仅增进了对PROTAC无定形制剂稳定化机制的理解，也为设计更高效、更稳定的靶向蛋白降解剂提供了重要结构基础，特别是对于那些靶向传统"不可成药"蛋白的降解剂开发具有指导意义。这项研究展示了NMR晶体学在解析复杂无定形药物结构方面的强大能力，为未来研究其他难以结晶的生物大分子制剂提供了可靠的方法学基础。随着更多PROTAC化合物进入临床开发阶段，对这种新型降解剂固态行为的深入理解将直接影响其制剂设计和临床应用前景。

蛋白降解靶向嵌合体

2024-11-06

·PRNewswire

Severe Asthma Clinical Trial Pipeline Appears Robust With 40+ Key Pharma Companies Actively Working in the Therapeutics Segment | DelveInsight

The severe asthma market is fueled by the rising prevalence of the condition, particularly in urban areas, alongside the emergence of innovative therapies like biologics targeting IgE and cytokine modulators. A growing demand for personalized medicine enhances treatment efficacy and patient compliance. Government initiatives and increased awareness improve access to care, while advancements in inhaler technology boost medication adherence. Collaborative efforts in R&D are also vital for driving innovation in asthma treatments. LAS VEGAS, Nov. 6, 2024 /PRNewswire/ -- DelveInsight's ' Severe Asthma Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline severe asthma therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the severe asthma pipeline domain. Key Takeaways from the Severe Asthma Pipeline Report DelveInsight's severe asthma pipeline report depicts a robust space with 40+ active players working to develop 50+ pipeline therapies for severe asthma treatment. Key severe asthma companies such as Kinaset Therapeutics, Bio-Thera Solutions, CSPC ZhongQi Pharmaceutical Technology, AB Science, GlaxoSmithKline, Oneness Biotech, Biosion, Lanier Biotherapeutics, Kymera Therapeutics, Suzhou Connect Biopharmaceuticals, Upstream Bio, Teva Branded Pharmaceutical Industries, Sanofi, Jiangsu Hengrui Medicine, AstraZeneca, Advagene Biopharma, Genrix (Shanghai) Biopharmaceuticals, and others are evaluating new severe asthma drugs to improve the treatment landscape. Promising severe asthma pipeline therapies such as KN-002, BAT2606, CM326, Masitinib, GSK3511294, FB 704A, BSI-045B, LNR 125.38, KT 621, CBP-201, Verekitug, TEV'248, Rilzabrutinib, SHR-1905, Atuliflapon, AD17002, GR1802, and others are under different phases of severe asthma clinical trials. In September 2024, Kinaset Therapeutics announced two oral presentations and a late-breaking poster presentation at the 2024 European Respiratory Society (ERS) Congress. The presentations demonstrate the potential of Kinaset's lead clinical candidate, frevecitinib ( KN-002), to treat all patients with moderate to severe asthma and patients with COPD. In May 2024, GSK announced positive headline results from the phase III clinical trials SWIFT-1 and SWIFT-2, which assessed the efficacy and safety of depemokimab versus placebo in adults and adolescents with severe asthma with type 2 inflammation characterized by blood eosinophil count. In April 2024, Twenty-five abstracts across approved and investigational medicines will be presented at this year's American Thoracic Society (ATS) International Conference. Notable data presentations for Sanofi's immunology pipeline include the first presentation of phase IIb moderate to severe asthma data for rilzabrutinib. In October 2023, Upstream Bio announced positive interim results in its Phase Ib clinical study of UPB-101, a thymic stromal lymphopoietin receptor (TSLPR) inhibitor. The Phase Ib study is a randomized, double-blinded, placebo-controlled multiple ascending dose (MAD) study with subcutaneous (SC) administration conducted in asthma patients. In October 2023, Aiolos Bio with an asthma drug in clinical trials, announced that it raised $245 million in Series A funding. Atlas Venture, Bain Capital Life Sciences, Forbion Capital Partners and Sofinnova Investments led the round, with additional investment from RA Capital Management Request a sample and discover the recent advances in severe asthma treatment drugs @ Severe Asthma Pipeline Report The severe asthma pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage severe asthma drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the severe asthma clinical trial landscape. Severe Asthma Overview Severe asthma is a chronic respiratory condition characterized by persistent symptoms that are difficult to control, even with high-dose medications. Unlike milder forms of asthma, severe asthma can significantly impair the quality of life and may result in frequent exacerbations requiring hospitalization. The exact cause of severe asthma is not entirely clear, but it often arises from a combination of genetic and environmental factors. These may include respiratory infections, allergens (pollen, mold, dust mites), pollutants (tobacco smoke, air pollution), occupational irritants, and lifestyle factors such as obesity and stress. Severe asthma can also develop in people whose milder asthma is not well-controlled over time. Diagnosis of severe asthma begins with a comprehensive medical history, physical examination, and pulmonary function tests like spirometry to assess lung function. Doctors may also order additional tests, such as chest X-rays, blood tests, and allergy tests to identify triggers. A key factor in diagnosing severe asthma is the persistence of symptoms despite the optimal use of standard asthma treatments. Managing severe asthma typically requires a multifaceted approach. Inhaled corticosteroids and long-acting bronchodilators are the mainstays of treatment. For those who do not respond to these medications, biologic therapies (such as omalizumab, mepolizumab, or dupilumab) may be prescribed to target specific pathways involved in the inflammatory response. In addition, patients with severe asthma may benefit from lifestyle modifications, including weight management, avoiding triggers, and pulmonary rehabilitation. In extreme cases, systemic corticosteroids may be necessary, although long-term use can have serious side effects. Find out more about severe asthma treatment drugs @ Drugs for Severe Asthma Treatment A snapshot of the severe asthma Pipeline Drugs mentioned in the report: Learn more about the emerging severe asthma pipeline therapies @ Severe Asthma Clinical Trials Severe Asthma Therapeutics Assessment The severe asthma pipeline report proffers an integral view of the severe asthma emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Severe Asthma Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous, Parenteral, Topical Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Therapeutics Assessment By Mechanism of Action: Interleukin 5 receptor antagonists, Thymic stromal lymphopoietin inhibitors, Thymic stromal lymphopoietin inhibitors, Thymic stromal lymphopoietin modulators, Interleukin 6 inhibitors, STAT6 transcription factor degraders, Interleukin 4 receptor alpha subunit antagonists Key Severe Asthma Companies: Kinaset Therapeutics, Bio-Thera Solutions, CSPC ZhongQi Pharmaceutical Technology, AB Science, GlaxoSmithKline, Oneness Biotech, Biosion, Lanier Biotherapeutics, Kymera Therapeutics, Suzhou Connect Biopharmaceuticals, Upstream Bio, Teva Branded Pharmaceutical Industries, Sanofi, Jiangsu Hengrui Medicine, AstraZeneca, Advagene Biopharma, Genrix (Shanghai) Biopharmaceuticals, and others. Key Severe Asthma Pipeline Therapies: KN-002, BAT2606, CM326, Masitinib, GSK3511294, FB 704A, BSI-045B, LNR 125.38, KT 621, CBP-201, Verekitug, TEV'248, Rilzabrutinib, SHR-1905, Atuliflapon, AD17002, GR1802, and others. Dive deep into rich insights for new drugs for severe asthma treatment, visit @ Severe Asthma Drugs Table of Contents For further information on the severe asthma pipeline therapeutics, reach out @ Severe Asthma Treatment Drugs Related Reports Severe Asthma Market Severe Asthma Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key severe asthma companies including AstraZeneca plc, GlaxoSmithKline plc, Sanofi S.A., Novartis AG, Roche Holding AG, Teva Pharmaceutical Industries Ltd., Merck & Co., Inc., Boehringer Ingelheim International GmbH, Regeneron Pharmaceuticals, Inc., Johnson & Johnson, Pfizer Inc., Bristol Myers Squibb, Eli Lilly and Company, Vertex Pharmaceuticals Incorporated, Amgen Inc., AbbVie Inc., Genentech, Inc., Gilead Sciences, Inc., Biogen Inc., CSL Limited, among others. Asthma Market Asthma Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key asthma companies including GlaxoSmithKline, 4D Pharma plc, AstraZeneca, Suzhou Connect Biopharmaceuticals, Avillion, Pearl Therapeutics, ARS Pharmaceuticals, Sinomab, Avalo Therapeutics, Kymab, Sanofi, Cumberland Pharmaceuticals, Genentech, Inc. , among others. Asthma Pipeline Asthma Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products, and the key asthma companies, including Jiangsu Hengrui Medicine, GlaxoSmithKline, Immunotek SL, AB Science, EMS, Avalo Therapeutics, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., ARS Pharmaceuticals, Sanofi, Zura Bio Ltd., AstraZeneca, EURRUS Biotech GmbH, T-Balance Therapeutics GmbH, Gossamer Bio, Aldeyra Therapeutics, Inc., Trio Medicines, Janssen Research & Development, Arrowhead Pharmaceuticals, Hoffman-La-Roche, GlaxoSmithKline, Biohaven Pharmaceutical, TAK-Circulator Co., Shanghai Hengrui Pharmaceutical, among others. Acute Respiratory Distress Syndrome Market Acute Respiratory Distress Syndrome Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key ARDS companies, including MediciNova, Edesa Biotech, Light Chain Biosciences, Boehringer Ingelheim, Genentech, Windtree Therapeutics, Biomarck Pharmaceuticals, Athersys, Healios, Direct Biologics, Biohaven Pharmaceutical, Arch Biopartners, APEPTICO Forschung und Entwicklung GmbH, Staidson (Beijing) Biopharmaceuticals, Veru, Mesoblast Limited, Avalo Therapeutics, Pluristem Therapeutics, ILTOO Pharma, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床结果临床2期临床3期临床1期

2022-10-15

·医药观澜

辉瑞、阿斯利康、复宏汉霖、锦篮基因等公司1类新药获批临床丨CDE周报

▎药明康德内容团队编辑根据中国国家药监局药品审评中心（CDE）官网数据，本周有多款1类创新药临床试验申请通过“默示许可”。这些产品包括IL-13中和抗体、FLAP抑制剂、抗GARP单抗、长效活化七因子、AAV基因治疗药物等，针对适应症包括艾滋病、脊髓性肌萎缩症、血友病等。本文中，我们将挑选其中部分1类新药作介绍，供读者参阅（排名不分先后）。辉瑞：ARV-471（PF-07850327）片作用机制：蛋白降解靶向嵌合体适应症：ER+/HER2-乳腺癌公开资料显示，ARV-471（PF-07850327）片是一款靶向降解雌激素受体（ER）的蛋白降解靶向嵌合体。辉瑞（Pfizer）公司已经与Arvinas公司达成数额可超过20亿美元的研发协议，共同开发ARV-471。蛋白降解靶向嵌合体的一端可以与靶点蛋白结合，另一端可以募集E3泛素连接酶，给靶点蛋白打上泛素的“标签”，促进它们被蛋白酶体降解。这一作用方式可能提供靶向以往“不可成药”靶点的新手段。据辉瑞早先新闻稿，ARV-471是一款潜在“best-in-class”蛋白降解剂。此前在1期临床试验中，无论肿瘤表达野生型ER还是突变型ER，ARV-471最高可将ER水平降低90%。在34名可以评估临床获益的患者中，临床获益率为41%。该药目前正在开展单药治疗ER+/HER2-乳腺癌的剂量扩展2期临床试验。本次在中国，该药获批临床的适应症为ER+/HER2-乳腺癌。复宏汉霖：HLX60作用机制：抗GARP单抗适应症：实体瘤和淋巴瘤根据复宏汉霖公开资料，HLX60是其开发的一款创新型抗GARP单抗。在健康人体内，调节性T细胞（Treg细胞）能可以通过多种机制来抑制炎症和自身免疫反应的发生。然而，癌细胞则能够利用Treg细胞的这一机制躲避人体免疫系统的攻击。研究发现，Treg细胞的功能主要得益于它们细胞表面的一种叫做GARP的分子。GARP可指导Treg细胞发挥其抑制功能。因此，通过抑制Treg细胞表面的GARP功能，GARP抑制剂有可能重新激活癌症患者的免疫系统，以消灭癌细胞。HLX60可通过特异性结合GARP，阻断GARP介导的TGF-β1的释放，逆转肿瘤微环境中的免疫抑制效应，提高抗肿瘤免疫应答。该产品还可以通过抗体依赖细胞介导的细胞毒作用（ADCC）清除GARP阳性肿瘤细胞和Tregs等免疫抑制性细胞，发挥抗肿瘤作用。该药与抗PD-1单抗斯鲁利单抗联用的抗肿瘤效果明显优于单药疗效。据悉，HLX60此前已经在海外获批并启动1期临床试验。本次在中国，该药获批临床的适应症为实体瘤和淋巴瘤。图片来源：123RF百时美施贵宝公司：cendakimab注射液作用机制：IL-13中和抗体适应症：中重度特应性皮炎由百时美施贵宝（BMS）公司旗下新基（Celgene）公司申报的cendakimab注射液获批临床，适用于治疗对外用处方药控制不佳，或不建议使用外用处方药的成人和12岁及以上青少年的中重度特应性皮炎。公开资料显示，cendakimab是一款白介素13（IL-13）中和抗体，它可与IL-13配体结合，抑制其与IL-13Ra1和IL-13Ra2亚基结合，从而起到抗炎和抗纤维化作用。IL-13是2型炎症的关键驱动因子，而2型炎症在特应性皮炎等免疫性疾病中起着主要作用。在特应性皮炎患者中，IL-13蛋白过度表达，并通过促进2型辅助性T细胞（Th2）反应，驱动炎症并导致皮肤屏障功能障碍。目前，cendakimab正在海外开展一项针对中重度特应性皮炎适应症的2期临床试验。阿斯利康：AZD5718片作用机制：FLAP抑制剂适应症：慢性肾脏病根据阿斯利康（AstraZeneca）公开资料介绍，AZD5718是一种选择性、可逆的5-脂氧合酶激活蛋白（FLAP）抑制剂，可以抑制白三烯的生成。在海外，该药此前已经在针对伴有或不伴有2型糖尿病的蛋白尿性慢性肾脏病患者的2期临床试验中显示出积极疗效。本次该药在中国获批临床，拟开发适应症为慢性肾脏病。据文献报道，在现有的治疗方法下，慢性肾脏病（CKD）患者仍有因残留白蛋白尿而发生肾脏和心血管事件的风险。在人体内，5-脂氧合酶及其激活蛋白会影响白三烯的产生。白三烯是促炎和血管收缩的脂质介质，其生物作用包括刺激白细胞趋化性、中性粒细胞激活、促进血管通透性和血管收缩等，与慢性炎症疾病的病因学有关，而慢性炎症会导致CKD加重和进展。诺华：JDQ443片、TNO155片作用机制：KRAS G12C共价抑制剂、SHP2抑制剂适应症：KRAS G12C突变的晚期实体瘤根据诺华（Novartis）公司公开资料，JDQ443是一款口服选择性KRAS G12C共价抑制剂，它能够不可逆地将KRAS G12C锁定在失活状态，在临床前研究中表现出良好的抗癌活性；TNO155是诺华在研的一款SHP2抑制剂。研究表明，SHP2是间接抑制KRAS活性的主要靶点，与KRAS G12C抑制剂联用具有治疗广泛携带KRAS突变癌症患者的潜力。此外，与SHP2抑制剂联合用药也是学术界较公认的解决KRAS G12C抑制剂耐药的方案。在海外，JDQ443和TNO155正在开展多项单药或联合用药的3期临床研究。本次，JDQ443片、TNO155片和TNO155胶囊均在中国获批临床，针对适应症为KRAS G12C突变的晚期实体瘤。图片来源：123RF天境生物：普那利单抗注射液作用机制：抗GM-CSF中和抗体适应症：巨噬细胞活化综合征普那利单抗注射液（plonmarlimab，又称TJM2）是天境生物自主开发的抗人粒细胞巨噬细胞集落刺激因子（GM-CSF）的中和抗体。GM-CSF是一种重要的细胞因子，在自身免疫性疾病的慢性炎症和损伤中发挥重要作用。研究表明，GM-CSF可以诱导巨噬细胞极化为促炎性M1表型，并且促进包括其它炎症性细胞因子如TNF、IL-1、IL-6、IL-12和IL-23在内的炎性连锁反应。中和GM-CSF可以抑制炎症反应并让患有类风湿关节炎等自身免疫疾病的患者临床获益。据天境生物公开资料介绍，普那利单抗具有高亲和力，可特异性结合GM-CSF，并能阻断GM-CSF与其受体结合，从而阻断下游的信号传导和靶细胞激活。因此，它可以有效地抑制巨噬细胞、中性粒细胞和树突细胞介导的炎症反应，从而减少组织炎症和损伤。此前，该药已经在中国开展了治疗类风湿关节炎的1b期临床研究，以及在美国开展治疗重症新冠肺炎的2/3期临床研究。本次，该药获批临床的适应症为：风湿免疫性疾病相关噬血细胞性淋巴组织细胞增多症（又称巨噬细胞活化综合征，MAS）。晟斯生物：注射用重组人凝血因子VIIa-Fc融合蛋白作用机制：长效活化七因子适应症：血友病晟斯生物研发的“注射用重组人凝血因子Ⅶa-Fc融合蛋白”（简称晟斯109）获批临床，拟开发适应症为：血友病A和血友病B伴有凝血因子VIII或IX抑制物的成人及青少年患者的出血控制。抑制物是血友病患者针对外源性凝血因子产品（八因子/九因子）输注后，产生的中和性抗药抗体。抑制物产生后，常规的因子替代治疗疗效会降低、无效，患者出血性相关病变的发生率增加，大大增加出血治疗难度，也是血友病替代治疗中最严重的并发症之一。在中国，伴抑制物患者止血治疗的一线药物为活化重组七因子。然而现有产品存在半衰期较短的瓶颈，给临床治疗带来不便。据晟斯生物新闻稿介绍，晟斯109是一款长效活化七因子产品，它通过独创的双头同源二聚Fc融合技术，可在维持活化七因子止血疗效的同时，大大提高其体内半衰期。该产品本次获批临床后，晟斯生物将在12岁以上青少年和成年伴抑制物的血友病A/B患者（先天性八因子/九因子缺乏）中开展临床研究。锦篮基因：GC101腺相关病毒注射液作用机制：AAV基因治疗药物适应症：1型SMA锦篮基因研发的AAV基因治疗药物GC101腺相关病毒注射液（简称“GC101注射液”）获批临床，针对适应症为1型脊髓性肌萎缩症。脊髓性肌萎缩症（SMA）是由于运动神经元存活基因1（SMN1）突变导致SMN蛋白功能缺陷所致的遗传性神经肌肉病，它会影响神经元功能，造成患者肌肉神经源性萎缩，是造成婴幼儿死亡的常染色体隐性遗传疾病之一。据锦篮基因公开资料介绍，GC101注射液是一种基于AAV病毒载体的基因替代治疗药物，通过鞘内给药方式直接向中枢神经系统递送和补充SMN蛋白，改善SMA患者呼吸功能及运动能力。该药的结构和给药方式均针对疾病特征和生物分布特点进行了优化，以达到更安全、更有效的目的。除了上述产品，近期还有多款1类新药在中国获批临床，包括真实生物研发的新一代口服长效人类免疫缺陷病毒（HIV）候选药物CL-197、ObsEva公司与育源生命公司正在开发的潜在“first-in-class”的口服催产素受体拮抗剂nolasiban分散片等，本文不再一一介绍。期待这些在研创新疗法后续临床试验顺利进行，早日造福患者。参考资料：[1]中国国家药监局药品审评中心（CDE）官网.Retrieved Oct 14，2022, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c[2]各公司官网及公开资料本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文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。

创新药抗体基因疗法免疫疗法蛋白降解靶向嵌合体

100 项与 Atuliflapon 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
哮喘	临床2期	美国	AstraZeneca PLC	2022-01-27
哮喘	临床2期	日本	AstraZeneca PLC	2022-01-27
哮喘	临床2期	阿根廷	AstraZeneca PLC	2022-01-27
哮喘	临床2期	澳大利亚	AstraZeneca PLC	2022-01-27
哮喘	临床2期	保加利亚	AstraZeneca PLC	2022-01-27
哮喘	临床2期	智利	AstraZeneca PLC	2022-01-27
哮喘	临床2期	克罗地亚	AstraZeneca PLC	2022-01-27
哮喘	临床2期	德国	AstraZeneca PLC	2022-01-27
哮喘	临床2期	匈牙利	AstraZeneca PLC	2022-01-27
哮喘	临床2期	荷兰	AstraZeneca PLC	2022-01-27

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临床结果

适应症

分期

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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


NCT04492722 (CTgov)	临床2期	慢性肾病	613	AZD5718+Dapagliflozin 10 mg (AZD5718 Dose 1 + Dapagliflozin 10 mg)	網醖構積選願遞衊鹽夢(窪襯齋淵遞顧餘壓積鏇) = 鹽鹽範選艱觸淵醖鏇壓憲憲構憲觸構夢窪鹽衊 (顧獵膚製顧築範齋鹹壓, 襯窪齋衊鏇憲鑰選製網 ~ 選簾窪壓鹹鬱膚觸願醖) 更多	-	2023-12-26
NCT04492722 (CTgov)	临床2期	慢性肾病	613	AZD5718+Dapagliflozin 10 mg (AZD5718 Dose 2 + Dapagliflozin 10 mg)	網醖構積選願遞衊鹽夢(窪襯齋淵遞顧餘壓積鏇) = 範醖憲顧觸構夢範壓壓憲憲構憲觸構夢窪鹽衊 (顧獵膚製顧築範齋鹹壓, 鏇壓鑰網遞鏇獵淵壓積 ~ 衊簾艱廠廠網衊蓋鏇鏇) 更多	-	2023-12-26
NCT03317002 (FLAVOUR, CTgov)	临床2期	冠心病	129	Placebo	鑰願糧糧範鏇鏇壓膚夢(製鹹顧夢廠繭窪鬱齋糧) = 蓋鬱憲鑰鏇蓋獵襯鬱鹹鏇糧製鹽餘觸壓積範鏇 (積壓夢獵蓋網鏇蓋願襯, 44.38) 更多	-	2021-06-30