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 , 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 * AZD2115 PT003 TLR9 IL17R MABA IL5R LAMA/LABA asthma asthma COPD severe asthma COPD AZD7624 AZD9412 PT008 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

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 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

• 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

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* RDEA3170 brodalumab* lesinurad B7RP1 GM-CSFR SURI IL17R SURI SLE rheum arthritis gout psoriatic arthritis gout MEDI4920 brodalumab* CD40L IFNa IL17R Sjögren’s SLE MEDI-551 CD19 IFNaR MS SLE MEDI7183* α4β7 Crohn’s disease

MEDI7183* α4β7 Disease area

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

Sifalimumab binds directly to Anifrolumab targeting broader spectrum IFNα neutralising IFNα subtypes of (IFNα, IFNβ, and IFNω)

IFN-β IFN-ω IFN-α

Phase IIb lupus study validates Receptor-targeting potentially better 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 () 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)

Respiratory, Inflammation & Autoimmunity: Lifecycle management of first & best-in-class medicines

Highlighted Phase III and Phase II molecules:

benralizumab severe asthma COPD

tralokinumab severe asthma IPF atopic derm

brodalumab* psoriasis psoriatic arthritis asthma

sifalimumab/ SLE lupus nephritis myositis Sjögren’s anifrolumab

MEDI7183* Crohn’s disease ulcerative colitis

LCM pursuing Lead indication LCM for future now

* In partnership with Amgen

17 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA)

2015: Duaklir launch, potential approval, submissions and Phase III starts

Duaklir Launch of LAMA-LABA in Genuair device in EU

lesinurad Potential approval of first new MOA for gout in combination with XO

brodalumab* Submission of IL17R for psoriasis

PT003 Submission of first pMDI LAMA-LABA

Phase III starts PT010 triple COPD, sifalimumab/anifrolumab, mavrilimumab

* In partnership with Amgen

18 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA)

Summary

Strong respiratory portfolio broadened through Pearl and Almirall

Positive data for first and best-in-class molecules in portfolio

Most comprehensive portfolio of personalised precision therapies

19 – Pipeline: Respiratory, Inflammation & Autoimmunity (RIA)

Pipeline: Respiratory, Inflammation & Autoimmunity (RIA) Inhaled therapeutic leadership; spearheading immunology biologics

Bing Yao, Head of MedImmune Respiratory, Inflammation & Autoimmunity iMED