Learning Teams - Biologic Integration. p. 01

Transcription

1 Learning Teams - Biologic Integration p. 01

2 p. 02 Expanding our portfolio to include both biologics and topicals...

3 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

4 Reaching New Patients p. 04

5 What s new with Sarah? - Focus on moderate-severe disease - Topicals have failed or are medically inadvisable

6 How does atopic dermatitis differ from psoriasis? - age of onset - clinical signs and symptoms - co-morbidities

7 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: Br J Dermatol 1994; 131(3): JAAD 2014; 70 (2):

8 Histology p the differences explained Psoriasis Atopic Dermatitis

9 Clinical Presentation p the differences explained Psoriasis Atopic Dermatitis

10 Clinical Presentation p the differences explained Atopic Dermatitis Psoriasis

11 Symptoms p the differences explained Psoriasis Atopic Dermatitis

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13 Comorbidities p the differences explained Psoriasis Psoriatic arthritis Chrohn s disease Uveitis Vitiligo Cardiovascular diseases Diabetes Hypertension Obesity Metabolic syndrome Atopic Dermatitis Asthma Conjunctivitis/blepharitis Rhinitis and Chronic Sinusitis Allergies (false positive prick test) Vitiligo Alopecia Areata Urticaria Depression Depression

14 Therapies p the differences explained Psoriasis Emollients TCS, TCI Tar Dithranol, vitamin D, Tarzarotene salicylic acid and urea Phototherapy MTX, CyA, Retinoids, Apremilast Biologics Atopic Dermatitis Emollients TCS, TCI, Crisaborole Tar Phototherapy Azathioprine, MTX, CyA, Mycophenolate, Glucocorticosteroids Biologics

15 Immune Responses - the differences explained p. 015 Psoriasis Atopic Dermatitis

16 IL-13 in AD and tralokinumab p. 016

17 TRALO-KIN-U-MAB Variable INN Cytokine target Ki(n) denotes the target is an interleukin Human Monoclonal Antibody

18 How does tralokinumab work? p. 018

19 p Password: TraloLeoMab

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21 Clinical Development Program p. 021

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

23 Clinical Development Program - the overview p. 023

24 12 month activity plan - all ongoing / new clinical activities in this period p. 024 Description / Rationale Subjects FSFV LP ECZTRA1 LP ECZTRA2 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 /05/ /06/2017 LP LTE ECZTEND LP DDI LP Vaccine Response LP ECZTRA 3 (Combo) LP Confirm- Adolescents LP Cyclosporin Failures Subjects from ECZTRA1/2 may be invited to join a LTE protocol [ECZTEND] /10/2018 FDA cite a disease-drug-drug interaction potential through cytokines affecting CYP /05/2018 Trial included in adult program to ensure that no limitation is placed in label, needed for Paeds /05/2018 CHMP guided that real-life use in combination with TCS to be studied /02/2018 Confirmatory trial in adolescents, including 2 doses; 150mg and 300mg /05/2018 Trial planned to provide data required for access from a more severe sub-population /09/2018 Re-submission of PIP / PSP 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

25 LP ECZTRA1 Identical monotherapy trials LP ECZTRA2 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 subjects per trial IGA: Investigator s Global Assessement; EASI: Eczema Area and Severity Index

26 LP TCS Combination Combination with topical corticosteroid 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 Week subjects

27 LP DDI Other trials for initial regulatory submission LP Vaccine Response 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 AUC last and C max at Day 105 and Day -7 for the five substrates 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

28 LP Confirm- Adolescents Monotherapy adolescent trial 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 subjects

29 So what makes this project so complex?

30 Operational Complexity - the number of handovers/touch-points/interfaces p. 030 PRO Licencees CRF Health PRO Patients National Eczema Association ilab Quanticate Banook ECG Sites DMC Members Signifikans Oracle Inform Intellim CRO JPN&KOR LEO Almac World Courier Oracle IRT ACM Labs AstraZeneca Medimmune Cook Pharma C3i Healthcare Covance Labs LionBridge Translations ITF Printers

31 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

32 The Learning Team p. 032

33 Multiple Sources of New Information - opportunities to learn p

34 Flow of information & project integration External Influence - AZ experience (e.g phase 2b) - Competitor intelligence - FDA, EMA, PDMA advice - Advisory Boards Execution / Implementation - FDA review - protocols - trial outlines - PIP / PSP negotiation - New dupixent data - KOL input Plan - Update plan - Amend protocols - Adapt new trials

35 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

36 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

37 Mastering Internal Changes - circumstances in which we ve learned p. 037 New Processes New Project Organisation New Team Members

38 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. p. 038

39 Tralokinumab Innovations - Investigator Meeting p. 039

40 Tralokinumab Innovations - Studies&Me p. 040 Pilot: - Dr Saddick NYC - Dr Papp - Dr Katz Possibility to move from pilot to regional roll out: - San Diego - Los Angeles - Miami

41 Why do we do what s difficult? p. 041

42 AD is now where psoriasis was 15 years ago p. 042 Systemics, Injectables Phase 1 Phase 2 Phase 3 Marketed XmAb7195 / Xencor / IgE Bertillibumab / Imm. Pharma / CCL11 CNTO-7160 / Janssen / IL-33 R ANB 020 / Anaptysbio / IL-33 MEDI-931 / AZ/MedImmune / IL-4Ra Lebrkizimab / Demira (bought from Roche 1.4bn) / IL-13 Nemolizumab / Galderma/Maruho JP/ Roche(Chugai) / IL-31 R Tezepelumab / AZ/Amgen / TSLP GBR-830 / Glenmark OX-40 Mepolizumab / GSK / IL-5 Tralokinumab / LEO Pharma / IL-13 Launch 2021 Dupixent / Sanofi-Regeneron / IL-4 R & IL-13 R KHK 4083 / KHK / OX-40 R MOR 106 / Morphosys-Galapagos / IL-17C ADSTEM Stem Cells / EHL Bio. PF / Pfizer

43 However Unmet Need Patient and Clinician awareness p. 043

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

45 Achievements First 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