醫(yī)學(xué)交流課件：For internal discussion with MSL

1、New Products Development Introduction overview 1 New products Development Introduction - Yangshan Clinical study on new products of asthma - Wupeibei Clinical study on new products of COPD - Tianweiwei Confidentiality Notice This file is private and may contain confidential and proprietary informati

2、on. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 King

3、dom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, StudyTypeObjectiveTarget populationLeading PIStatus Symbicort as needed Phase III IMCT 327/3750 Well controlled asthma weeks Budesonide/formoterol as needed superior to terbutaline as needed and non-inferior to budesonide

4、 bid plus terbutaline as needed Mild asthmaticsZhong Nanshan Actively recruiting 2016Q2 LPI Observational cohort study 525/725 Severe asthma registry in Chinese Uncontrolled severe asthmatics Zhong Nanshan Actively recruiting Benralizumab anti-IL-5R Phase III RMCT Reduce asthma exacerbation when add

5、 on to mId to high dose ICS/LABA Uncontrolled severe asthmatics with higher level of blood eosinophils 2016Q3 CTP-Approval 2017Q1 FSI Tralokinumab anti-IL-13 Phase III RMCT Reduce asthma exacerbation when add on to mId to high dose ICS/LABA Uncontrolled severe asthmatics with positive Th2 biomarkers

6、 2016Q2 CTP-Submission 2 Asthma - ongoing and upcoming studies 3 4 5 Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distrib

7、ute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, 6 研究設(shè)計(jì)研究設(shè)計(jì) Confidentiality Notice This file is private

8、 and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not

9、 permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, 7 研究終點(diǎn)和觀察變量研究終點(diǎn)和觀察變量 1. 臨床特征 肺功能：FEV1和PEF 哮喘控制：哮喘發(fā)作次數(shù)、 ACQ、AQLQ 醫(yī)療資源利用情況 ：急診、 住院、藥物改變 2. 生物標(biāo)志物 血液和痰中炎性細(xì)胞計(jì)數(shù), FENO 氣道活檢中炎性細(xì)胞和基質(zhì)重塑的組織學(xué)分 析 多重檢測方法分析血液和痰中的炎癥標(biāo)志物 Th2介質(zhì), 包括IL

10、-5, IL-4, IL-13,periostin等 Th17細(xì)胞因子IL-17A 巨噬細(xì)胞介質(zhì), 包括IL-1, TNF, IFN等 削弱Th2反應(yīng)的細(xì)胞因子（IL-12和IL-10） MMP2和MMP9 急性期蛋白CRP 氣道上皮細(xì)胞轉(zhuǎn)錄組學(xué)分析 血細(xì)胞的全基因組關(guān)聯(lián)研究(GWAS) 應(yīng)用qPCR 檢測血細(xì)胞中特定的mRNA (Cyp11a1, ORMDL3) 哮喘發(fā)作時(shí)痰液病毒檢測 HRCT評估氣道結(jié)構(gòu)(氣道壁和管腔） 3、表型 .基于臨床特征和生物標(biāo) 志物特征，通過聚類分析 定義重度哮喘患者的表型 8 25 Confidentiality Notice This file is pri

11、vate and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is

12、 not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, 9 預(yù)期研究結(jié)果預(yù)期研究結(jié)果 深入了解具有不同發(fā)病機(jī)制和臨床特征的重度哮喘表型 獲得用于疾病表型分類和預(yù)測的信號包括生物標(biāo)志物 促進(jìn)研發(fā)直接針對特定疾病特征的個(gè)體化精準(zhǔn)治療方案 10 IL-5可促進(jìn)嗜酸性粒細(xì)胞的生長、成熟、遷移，并抑制 嗜酸性粒細(xì)胞凋亡 benralizumab是一種單克隆抗體，能夠與白細(xì)胞介素5 受體的

13、亞基（IL-5R）結(jié)合，消耗嗜酸性粒細(xì)胞 其他抗IL-5藥物： v GSK 美泊利單抗 (mepolizumab)， FDA于2015.11批 準(zhǔn) v Teva 制藥 Cinquil(reslizumab)， FDA于2016.3批準(zhǔn) v 通過阻斷IL-5結(jié)合至嗜酸性表面上表達(dá)的IL-5受體復(fù)合 物的鏈抑制IL-5生物活性，減低嗜酸性的生產(chǎn)和生存 Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received th

14、is file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD,

15、 UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, 11 Benralizumab是我們公司呼吸領(lǐng)域的第一個(gè)生 物制劑 兩個(gè)關(guān)鍵的III期臨床試驗(yàn)（SIROCCO和 CALIMA研究）在減少重度未控制哮喘患者的 急性加重方面獲得了顯著的結(jié)果 將在今年下半年向美國和歐洲提交 Benralizumab的注冊申請 https:/azusgb01- me=Intranet&name=heartbeat_may2016_ Benralizumab&r=true&r=true#/ 12 Aug 2016 Aug 2016 Aug 2016 13 Prim

16、ary endpoint: Annual asthma exacerbation rate Study drug: 30mg/mL solution for injection in accessorized pre-filled syringe Patient population: Severe asthma uncontrolled on medium-to-high dose ICS/LABA with 2 exacerbations in the previous year required use of systemic corticosteroid. Tralokinumab:

17、mechanism and indication Tralokinumab is a full human IgG4 monocolonal antibody targeting IL-13. IL-13 blockade has been shown to reduce the downstream signals that may mediate the central pathological features of persistent asthma: o Smooth muscle contraction and proliferation o Th2-type inflammati

18、on o IgE production o Mucus hypersecretion o Collagen synthesis and deposition 14 Proposed indication: Adults and adolescents with inadequately controlled asthma on medium-high-dose inhaled corticosteroid/long acting 2 agonist (ICS/LABA) Dose regimen: 300 mg, Q2W, sub-cutaneous formulation, with an

19、aim for self-administration at home. Periostin and DPP4: possible biomarkers for IL-13 Periostin is a matricellular protein belonging to the fasciclin family. Periostin secretion by bronchial epithelial cells is induced by IL-13 oSerum periostin levels may reflect IL-13 pathway activation oSerum per

20、iostin levels may predict response to tralokinumab 15 DPP-4 is a multifunctional enzyme involved in the activation of T cells. DPP-4 is highly induced by IL-13 in healthy and asthmatic epithelial lung cells DPP-4 could be a biomarker for asthmatic patients with IL-13 pathway activation Tralokinumab

21、development in China 20142015201620172018201920202021202220232024 12341234123412341234123412341234123412341234 Study recruitmentTreatmentDBL- CSR BLA Regional Asthma Program Readout 26,Sept DSR Global Asthma Program IDLCTP BM and cut off selection 22, Aug Execute one of the four Ph3 protocols and th

22、e PK protocol according to global readout STRATOS 1 - MD/HD ICS, N=1140, 2 Tralo doses, 3 arm: 300mg Q2w / 300mg Q4w / Placebo, AERR STRATOS 2 - MD/HD ICS (+JPN), N=770, 1 Tralo dose, 2 arm: 300mg Q2w / Placebo, AERR CPP CTP submission CTP approval IDL submission (both PFS & LVB by referring US data) IDL approval of both PFS & LVBI CTP PhIII study PK study DSR Submit 5 protocols in Tralo CTP package (tralo 300mg, SC, Q2W): 1. D2210C00023 PK in HV, single dose 2. D2