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Learning Teams- Biologic Integration

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

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“

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

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What’s new with Sarah?

- Focus on moderate-severedisease- Topicals have failedor are medically inadvisable

How does atopicdermatitis differ from psoriasis?

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

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Atopic DermatitisDiagnosis

• 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.

Histologyp. 08

Atopic DermatitisPsoriasis

- the differences explained

Clinical Presentationp. 09


Atopic DermatitisPsoriasis

Clinical Presentationp. 010


Psoriasis

Atopic Dermatitis

Symptomsp. 011


Psoriasis Atopic Dermatitis

Comorbiditiesp. 013



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



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

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IL-13 in AD and tralokinumab

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TRALO-KIN-U-MABMonoclonal

Antibody

Variable

INN

Cytokine target

Ki(n) denotes the

target is an

interleukin

Human

How does tralokinumab work?

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https://vimeo.com/215480484

Password: TraloLeoMab

https://vimeo.com/215480484

Clinical Development Program

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

Clinical Development Program- the overview

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

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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

LP0162-1325ECZTRA1

LP0162-1326ECZTRA2

LP0162-1337LTE ECZTEND

LP0162-1342DDI

LP0162-1341Vaccine Response

LP0162-1339ECZTRA 3 (Combo)

LP0162-1334Confirm- Adolescents

LP0162-1346Cyclosporin Failures

Re-submission of PIP / PSP

Identical monotherapy trials

• Topicals have failed or aremedically 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

LP0162-1325ECZTRA1

LP0162-1326ECZTRA2

• 369 subjects

• Topicals have failed

• Primary Objective◦ To demonstrate that

tralokinumab + TCS is superior

to placebo + TCS


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

LP0162-1342DDI

LP0162-1341Vaccine Response

• 294 subjects

• Topicals have failed or aremedically inadvisable

• Primary Objective◦ To evaluate the efficacy of

tralokinumab compared with

placebo


clear) at Week 16

◦ EASI 75 at Week16

Monotherapy adolescent trialLP0162-1334Confirm- Adolescents

So what makesthis project so complex?

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

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LEO

Sites

iLab

National Eczema

Association

Quanticate

Oracle Inform

Oracle IRT

PRO Licencees

Patients

BanookECG

Almac

MedimmuneAstraZeneca

WorldCourier

Covance Labs

ACM Labs

Intellim CROJPN&KOR

DMC Members

CRF HealthPRO

Cook Pharma

Signifikans

C3i Healthcare

LionBridgeTranslations

ITF Printers

Operational Complexity- examples of the challenges that are being overcome

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• 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’

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Multiple Sources of New Information- opportunities to learn

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2016 2017 2018

Plan

ExternalInfluence

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 underlying assumptions and limitations in the

data

• Team decision◦ Amend protocol and eCRF to ensure capturing of key data at

time point of primary endpoints

◦ Update statistical methodology incl implementation of draft ICH

E9 addendum terminology on Estimands

◦ Develop a ‘’standard’’ for new trials

Clarification of exclusion criteria– an example of project learning

• Based on feedback during trial execution, exclusion criterion 18 has been modified ◦ from History of anaphylaxis to History of anaphylaxis following any

biologic therapy

• Rationale: ◦ A large proportion of subjects with moderate to severe AD will have

had food allergies and other allergies during childhood with no

relevance for later risk of anaphylactic reactions to tralokinumab

• Team decision◦ Amend current protocols and adapt in new protocols

Mastering Internal Changes- circumstances in which we’ve learned

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• New Processes

• New Project Organisation

• New Team Members

‘Dynamic Team’- The team’s knowledge has to grow in order for it to

deal with current problems in new ways and to increase it’s capacity to deal with the future.

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Tralokinumab Innovations- Investigator Meeting

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Tralokinumab Innovations- Studies&Me

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Pilot:- Dr Saddick – NYC- Dr Papp- Dr Katz

Possibility to move from pilot to regional roll out:- San Diego- Los Angeles- Miami

Why do we do what’s difficult?

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AD is now where psoriasis was 15 years ago…

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Systemics, Injectables

Phase 1 Phase 2 Phase 3 Marketed

XmAb7195 / Xencor / IgELebrkizimab / Demira (bought from

Roche 1.4bn) / IL-13

Tralokinumab / LEO Pharma

/ IL-13

Dupixent® / Sanofi-Regeneron / IL-4

R & IL-13 R

Bertillibumab / Imm. Pharma / CCL11Nemolizumab / Galderma/Maruho JP/

Roche(Chugai) / IL-31 R

CNTO-7160 / Janssen / IL-33 R Tezepelumab / AZ/Amgen / TSLP

ANB 020 / Anaptysbio / IL-33GBR-830 / Glenmark

OX-40

MEDI-931 / AZ/MedImmune / IL-4Ra Mepolizumab / GSK / IL-5

KHK 4083 / KHK / OX-40 R

MOR 106 / Morphosys-Galapagos /

IL-17C

ADSTEM Stem Cells / EHL Bio.

PF 6817024 / Pfizer

Launch 2021

However…• Unmet Need• Patient and Clinician awareness

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During the last year we have achieved a lot through learning.

AchievementsFirst subjects in Phase 3, less than12 months after acquiring tralokinumab- >10 HA interactions- First LEO tralokinumab protocol, final within 3 weeks of last HA input- First CRFs live before FSFT- First class Investigator Meetings (x4)- First use of iLab innovations to support patient recruitment via telemedicine- First roll-put of ECZchange, Investigator Portal- First Japanese subjects in global program- First S. Korean HA approval for LEO- First use of RACT and associated procedure- First use of Data Flow Plan procedure

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