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  • Learning Teams - Biologic Integration

    p. 01

  • Expanding our portfolio to include both biologics and topicals...

    p. 02

  • The NME Innovation Pipeline features 3 biologics, which are all at very different stages in development

    This presents as an opportunity to pass on learnings across projects and within teams

  • Reaching New Patients

    p. 04

  • What’s new with Sarah?

    - Focus on moderate-severe disease - Topicals have failed or are medically inadvisable

  • How does atopic dermatitis differ from psoriasis?

    - age of onset - clinical signs and symptoms - co-morbidities

  • Change/Insert Date/Location

    Check in Date & Time

    Click Apply to All

    Insert Location/Footer:

    Check in Footer

    Atopic Dermatitis Diagnosis

    • AD is a clinical diagnosis

    • Patient history (seasonal variation, early onset, family history)

    • Characteristic morphology and distribution of skin lesions

    • Associated clinical signs and symptoms

    • There is no specific test that can establish a diagnosis of AD

    • Formal diagnostic criteria have been developed to help Classification in clinical trials and epidemiologic studies (Hanifin 1980, Williams 1994, Eichenfield 2014)

    These are not used in daily clinical practice

    Acta Derm Venerol 1980; 92: 44-47. Br J Dermatol 1994; 131(3): 383-96. JAAD 2014; 70 (2): 338-51.

  • Histology p. 08

    Atopic DermatitisPsoriasis

    - the differences explained

  • Clinical Presentation p. 09

    - the differences explained

    Atopic DermatitisPsoriasis

  • Clinical Presentation p. 010

    - the differences explained

    Psoriasis

    Atopic Dermatitis

  • Symptoms p. 011

    - the differences explained

    Psoriasis Atopic Dermatitis

  • Comorbidities p. 013

    - the differences explained

    Psoriasis Atopic Dermatitis

    Psoriatic arthritis

    Chrohn’s disease

    Uveitis

    Vitiligo

    Cardiovascular diseases

    Diabetes

    Hypertension

    Obesity

    Metabolic syndrome

    Depression

    Asthma

    Conjunctivitis/blepharitis

    Rhinitis and Chronic Sinusitis

    Allergies (false positive prick test)

    Vitiligo

    Alopecia Areata

    Urticaria

    Depression

  • Therapies p. 014

    - the differences explained

    Psoriasis Atopic Dermatitis

    Emollients

    TCS, TCI

    Tar

    Dithranol, vitamin D, Tarzarotene

    salicylic acid and urea

    Phototherapy

    MTX, CyA, Retinoids, Apremilast

    Biologics

    Emollients

    TCS, TCI, Crisaborole

    Tar

    Phototherapy

    Azathioprine, MTX, CyA,

    Mycophenolate,

    Glucocorticosteroids

    Biologics

  • Immune Responses - the differences explained

    p. 015

    Psoriasis Atopic Dermatitis

  • IL-13 in AD and tralokinumab

    p. 016

  • TRALO-KIN-U-MAB Monoclonal

    Antibody

    Variable

    INN

    Cytokine target

    Ki(n) denotes the

    target is an

    interleukin

    Human

  • How does tralokinumab work?

    p. 018

  • p. 019

    https://vimeo.com/215480484

    Password: TraloLeoMab

    https://vimeo.com/215480484

  • Clinical Development Program

    p. 021

  • FSFV achieved on 29-May-2017 Dr Zirwas, Bexley OH, USA

  • Clinical Development Program - the overview

    p. 023

  • 12 month activity plan - all ongoing / new clinical activities in this period

    p. 024

    Description / Rationale Subjects FSFV

    The phase 3A clinical program provides pivotal data from 2

    replicate Phase 3 Monotherapy RCTs which support BLA,

    MAA and JNDA submissions. Endpoints a 16W and

    maintenance claim at 52W

    780 30/05/2017

    780 29/06/2017

    Subjects from ECZTRA1/2 may be invited to join a LTE

    protocol [ECZTEND] 320 - 1600 02/10/2018

    FDA cite a disease-drug-drug interaction potential through

    cytokines affecting CYP450 30 16/05/2018

    Trial included in adult program to ensure that no limitation is

    placed in label, needed for Paeds 200 09/05/2018

    CHMP guided that ‘real-life’ use in combination with TCS to

    be studied 369 08/02/2018

    Confirmatory trial in adolescents, including 2 doses; 150mg

    and 300mg 294 24/05/2018

    Trial planned to provide data required for access from a

    ‘more severe’ sub-population. 200 19/09/2018

    The plan for paediatric research must be approved by time

    of submission (but we should not start trials that would not

    be accepted). We need to align in EU and USA

    - Submission

    Nov 2017

    LP0162-1325 ECZTRA1

    LP0162-1326 ECZTRA2

    LP0162-1337 LTE ECZTEND

    LP0162-1342 DDI

    LP0162-1341 Vaccine Response

    LP0162-1339 ECZTRA 3 (Combo)

    LP0162-1334 Confirm- Adolescents

    LP0162-1346 Cyclosporin Failures

    Re-submission of PIP / PSP

  • Identical monotherapy trials

    • Topicals have failed or are medically inadvisable

    • Primary Objective ◦ To evaluate the efficacy of

    tralokinumab compared with

    placebo

    • Primary Endpoints ◦ IGA score 0 (clear) or 1 (almost

    clear) at Week 16

    ◦ EASI 75 at Week 16 • 780 subjects per trial

    IGA: Investigator’s Global Assessement; EASI: Eczema Area and Severity Index

    LP0162-1325 ECZTRA1

    LP0162-1326 ECZTRA2

  • • 369 subjects

    • Topicals have failed

    • Primary Objective ◦ To demonstrate that

    tralokinumab + TCS is superior

    to placebo + TCS

    • Primary Endpoints ◦ IGA score 0 (clear) or 1 (almost

    clear) at Week 16

    ◦ EASI 75 at Week16

    Combination with topical corticosteroidLP0162-1339TCS Combination

  • Other trials for initial regulatory submission

    • Randomized double-blind, placebo controlled, Vaccine trial, n=200

    • Primary Objective ◦ To demonstrate immune

    responses to vaccines during

    tralokinumab treatment

    • Primary Endpoints ◦ Positive anti-tetanus response ◦ Positive meningococcal

    serogroup C serum bactericidal

    assay response at Week 16

    • Open label, drug-drug interaction trial, n=30

    • Primary Objective ◦ To evaluate if tralokinumab after

    14 weeks of treatment (steady

    state) changes the metabolism of

    substrates of CYP 1A2, 2C9,

    2C19, 2D6 or 3A4 pathways

    • Primary Endpoints ◦ Ratio of AUClast and Cmax at Day

    105 and Day -7 for the five

    substrates

    LP0162-1342 DDI

    LP0162-1341 Vaccine Response

  • • 294 subjects

    • Topicals have failed or are medically inadvisable

    • Primary Objective ◦ To evaluate the efficacy of

    tralokinumab compared with

    placebo

    • Primary Endpoints ◦ IGA score 0 (clear) or 1 (almost

    clear) at Week 16

    ◦ EASI 75 at Week16

    Monotherapy adolescent trialLP0162-1334Confirm- Adolescents

  • So what makes this project so complex?

  • Operational Complexity - the number of handovers/touch-points/interfaces

    p. 030

    LEO

    Sites

    iLab

    National Eczema

    Association

    Quanticate

    Oracle Inform

    Oracle IRT

    PRO Licencees

    Patients

    Banook ECG

    Almac

    MedimmuneAstraZeneca

    World Courier

    Covance Labs

    ACM Labs

    Intellim CRO JPN&KOR

    DMC Members

    CRF Health PRO

    Cook Pharma

    Signifikans

    C3i Healthcare

    LionBridge Translations

    ITF Printers

  • Operational Complexity - examples of the challenges that are being overcome

    p. 031

    • Delivery of dataset to medical monitoring • EDC access & training • IMP supply chain • ePRO equipment & data upload • Updating lab kits because of CTP amendment • CMC amendment, EU • IMP import • Recruitment planning • CRO access to CTMS and eTMF • AZ collaboration of RSI

  • The ‘Learning Team’

    p. 032

  • Multiple Sources of New Information - opportunities to learn

    p. 033

    2016 2017 2018

  • Plan

    External Influence

    Execution / Implementation

    - AZ experience (e.g phase 2b) - Competitor intelligence - FDA, EMA, PDMA advice - Advisory Boards

    - FDA review - protocols - trial outlines

    - PIP / PSP negotiation - New dupixent data - KOL input

    - Update plan - Amend protocols - Adapt new trials

    Flow of information & project integration

  • Capture key data for all subjects, regardless of IMP discontinuation – an example of project learning

    • FDA raised questions to monotherapy protocols with regard to sensitivity analyses ◦ How to evaluate sensitivity of primary analysis results to

    deviations from underly