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Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Inhaled Therapeutic Leadership; Spearheading Immunology Biologics

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Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Inhaled Therapeutic Leadership; Spearheading Immunology Biologics Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Inhaled therapeutic leadership; spearheading immunology biologics Bing Yao, Head of MedImmune Respiratory, Inflammation & Autoimmunity iMED Respiratory: Transform patient outcomes in asthma, COPD & IPF 1 2 3 Deliver inhaled Expand with innovative Transforming disease therapies precision therapies management Short term Medium term Long term 2 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Respiratory: Industry-leading portfolio Phase I Phase II Phase III / Registration Small molecule Large molecule Small molecule Large molecule Small molecule AZD1419 brodalumab* AZD2115 benralizumab PT003 TLR9 IL17R MABA IL5R LAMA/LABA asthma asthma COPD severe asthma COPD AZD7624 AZD9412 PT008 tralokinumab PT001 ip38 Inhaled IFNβ ICS IL13 LAMA COPD COPD asthma severe asthma COPD AZD7594 tralokinumab AZD0548 benralizumab Duaklir iSGRM IL13 (abediterol) LABA IL5R LAMA/LABA asthma IPF asthma COPD COPD AZD7594 MEDI9929* AZD0548 iSGRM TSLP (abediterol) LABA COPD asthma COPD PT010 AZD9412 PT010 Marketed LAMA/LABA/ICS Inhaled IFNβ LAMA/LABA/ICS asthma asthma COPD AZD8999 PT009 MABA ICS/LABA asthma COPD Disease area AZD8999 MABA Asthma COPD IPF COPD *In partnership with Amgen 3 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) COPD: Inhaled portfolio addresses all disease severities and provides device choice Diagnosed Adapted from GOLD with LABA/ICS LAMA/LABA/ICS guidelines exacerbation Increased risk of exacerbation Diagnosed with LAMA LAMA/LABA symptoms Symptoms worsening “Passive” dry powder ”Active” device, pMDI, inhaler, DPI, most preferred for elderly and for commonly used severe disease LAMA/LABA/ICS+ + PT009 PT010 PT001 PT003 4 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Asthma: Inhaled portfolio addresses all GINA steps and provides device choice Adapted from GINA LAMA/ICS LAMA/LABA/ICS guidelines ’As Needed’ LABA/ICS ICS GINA classification 1 2 3 4 5 “Passive” dry powder ”Active” device, pMDI, inhaler, DPI, most preferred for young, elderly commonly used and for severe disease LAMA/ICS + LAMA/ICS PT010 ’As Needed’ + PT009 PT008 - budesonide 5 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Severe asthma: Targeting distinct patient subsets High Th2 driven | EOS low Th2 driven | EOS dominant B A 20% 35% level Anti-IL-13 Anti-IL-5 Anti-IL-13 Th2 low | EOS low Th2 low | EOS high periostin D C Serum 30% 15% Anti-IL-5 Low Low High Blood eosinophil level 6 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Benralizumab (severe asthma): Only IL5 receptor mAb in Phase III Phase IIb data Exacerbation rate reduction • Potent reduction in eosinophils • Reduction in asthma exacerbation • Improvement in lung Annual exacerbation rate rate exacerbation Annual function relative to reduction placebo Baseline blood eosinophil count cutoff (cells per μL) Regulatory submission expected 2016 Source: M. Castro et al., Lancet Resp Med, 2014 7 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Benralizumab (COPD): First mAb to show eosinophilic inflammation reduction Mean change from baseline in FEV1 over time Phase IIa data (PP population) • First anti-IL5 / IL5R to demonstrate lung function improvement P = 0.014 • Primary endpoint not achieved, but trend toward reduction of exacerbations with elevated eosinophils • Improvement in symptom scores Phase III on track for completion 2018 Source: Brightling et al., Lancet Resp Med, 2014 8 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Tralokinumab (severe asthma): Targeting IL13, a central TH2 cytokine AER for tralokinumab 300 mg Q2W vs Phase IIb data placebo over 52 weeks Periostin- low (15) 40% 32% DPP-4 • Identified potential (273, -53) low (8) 20% responder population 7% 0% (886, -88) • Identified promising -20% biomarkers -40% (22,-74) -44% (30,-86) • Efficacy across AER, -60% (-2, -89) All (33) -57% FEV1, ACQ-6 and -80% -67% DPP-4 AQLQ in subgroups Periostin- high (24) high (18) Phase III on track for completion 2017 Phase II ongoing in IPF AER – Asthma Exacerbation Rate, FEV1 – Forced Expiratory Volume in 1 second, ACQ-6 – Asthma Control Questionnaire, AQLQ – Asthma Quality of cycle Questionnaire 9 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Inflammation & Autoimmunity: Series of first & best-in-class assets Phase I Phase II Phase III / Registration Large molecule Large molecule Small molecule Large molecule Small molecule MEDI5872* mavrilimumab RDEA3170 brodalumab* lesinurad B7RP1 GM-CSFR SURI IL17R SURI SLE rheum arthritis gout psoriatic arthritis gout MEDI4920 sifalimumab brodalumab* CD40L IFNa IL17R Sjögren’s SLE psoriasis MEDI-551 anifrolumab CD19 IFNaR MS SLE MEDI7183* α4β7 Crohn’s disease MEDI7183* α4β7 Disease area ulcerative colitis MEDI2070* Rheumatology Dermatology IL23 Crohn’s disease Gastroenterology Neuroscience *In partnership with Amgen 10 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Lesinurad (gout): Progressing to regulatory submission CLEAR 1 and CLEAR 2: Proportion Lesinurad in gout of patients achieving sUA <6 mg/dL at Month 6 – NRI 60% 54% 55% • Gout affects ~15m patients 50% − Potential to cause bone, joint, kidney damage and 40% associated with CV disease and its co-morbidities 28% 30% 23% • Xanthine oxidase (XO) inhibitors act to control 20% production of uric acid 10% • 40–70% of patients are not at goal on XO 0% inhibitors alone CLEAR 1 CLEAR 2 PBO + Allo LESU200 + Allo • Lesinurad and RDEA3170 increase excretion of uric acid − AE profile, incl. renal AE of lesinurad 200mg+allopurinol comparable to allopurinol • RDEA3170 Ph II studies progressing with focus alone in mono and FDC − Increases in serum creatinine observed lesinurad • Lesinurad EU / US submission planned Q4 200mg plus allopurinol vs. allopurinol alone (5.9- 2014 for use w/XO 6.0% vs. 1.0-3.4%, >1.5x increase vs. baseline) 11 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Targeting IFNα / IFNαR in lupus Sifalimumab binds directly to Anifrolumab targeting broader spectrum IFNα neutralising IFNα subtypes of interferons (IFNα, IFNβ, and IFNω) IFN-β IFN-ω IFN-α Phase IIb lupus study validates Receptor-targeting potentially better interferon targeting: Primary and efficacy: Greater PD suppression secondary endpoints achieved (70–90% vs. 30–40% for sifalimumab) Anifrolumab Phase II presentation expected mid-2015 Phase III start expected 2015 12 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Sifalimumab (lupus): Significant improvement in SLE responder index and organ specific measurements Endpoint at day 365 Day 1 SRI (4) SRI (6) SRI (8) All-comers population Placebo (%) 45.4 37.4 24.5 (N=98 - 108) 1200 mg dose (%), 59.8 53.3 41.8 (N=98 - 107) Effect size (%) 14.4 15.9 17.3 P-value* 0.031 0.016 0.008 Day 169 Dx+ population Placebo (%), 42.0 33.3 20.3 (N=79 - 88) 1200 mg dose (%), 57.5 51.7 41.3 (N=80 - 87) Effect size (%) 15.4 18.4 21.0 24.5% treatment difference in P-value* 0.038 0.012 0.004 CLASI-4 response SRI(x) SLE Responder Index(x=reduction in SLEDAI required for response) 1200 mg dose vs placebo** *P-value < 0.098 is considered to be statistically significant for the final analysis after adjusting for the interim analysis using O’Brien-Fleming type Lan-DeMets alpha spending function approach to control type I error rate at 0.1 for the primary endpoint **mITT Population with a CLASI Activity Score ≥10 at Baseline 13 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Mavrilimumab (RA): First-in-class anti-GM-CSFRα antibody • Phase IIb data ACR efficacy responses at day 169 80 73.4 • 45–74% of patients on Placebo (N=81) 70 anti-TNF fail to achieve 61.2 Mav. 30mg (N=81) 60 Mav. 100mg (N=85) an ACR50 50.6 50 Mav. 150mg (N=79) 40.5 • Mavrilimumab inhibits 40 28.4 macrophage activation, 30 24.7 25.9 Subjects (%) Subjects 20 13.9 differentiation and 12.3 12.3 10.6 survival 10 3.7 0 ACR20 ACR50 ACR70 Phase IIb results • Co-primary endpoints: DAS28, ACR20 highly significant • Significant benefit after one week • Significant improvements in patient-reported outcomes • No apparent safety signals Source: Clin Pharmacol Ther. 92(3):352-9, 2012 14 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Brodalumab (psoriasis, psoriatic arthritis, asthma): Unique receptor-targeting approach Psoriasis IL-17A/F • Three Phase III studies; two with IL-17A IL-17F IL-25 H2H superiority study design vs. Stelara (ustekinumab) and placebo • First and second Phase III studies achieved primary and secondary endpoints • Remaining Phase III psoriasis H2H comparator data in Q4 2014 IL-17R alpha Psoriatic arthritis • Phase III on track Targeting IL17 receptor and inhibiting Asthma signaling of multiple ligands • Opportunity for lifecycle management In partnership with Amgen 15 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Brodalumab (psoriasis): Positive Phase III data AMAGINE-1TM Phase III psoriasis data AMAGINE-3TM Phase III H2H may offer new level of skin clearance ustekinumab comparator 90 Placebo (N=81) 83.3 90 85.1 Broda. 140mg 80 Broda. 210mg 80 70.3 Placebo 70 69.3 69.2 70 Ustekinumab 60.3 60 60 Broda. 140mg Broda. 210mg 50 50 42.5 41.9 40 36.7 40 30 27.0 30 18.5 23.3 20 Percent (%) (%) Percent of with subjects PASI at 75/100 12 weeks PASI PASI 75/90/100 at 12 weeks at 75/90/100 PASI 20 (%) Percent of with subjects 10 6.0 0.3 10 0 2.7 0.5 0.9 PASI 100 PASI 75 0 PASI 100 PASI 90 PASI 75 Phase III AMAGINE-2TM H2H comparator study expected in Q4 2014 In partnership with Amgen 16 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA)
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