Nathalie Seigneuret 30.10.2014 Japan Health Sciences Foundation Visit IMI JU Office, Brussels, Belgium

Project Overview NEW DRUGS FOR BAD BUGS ND4BB PROGRAMME

Antibiotics resistance 'as big a risk as terrorism' – UK medical chief -

Antibiotic resistance: we must act now, says WHO

Three million Europeans catch infections in hospital annually

The rising threat of AMR

17 Janvier 2008: La résistance des bactéries aux antibiotiques a atteint une dimension planétaire

• Mortality: resistant infections are more often fatal • Morbidity: prolonged illnesses, greater chance for to spread,

complications of diseases • Cost: increased costs in care • Limiting solutions

The rising threat of AMR

Thursday 25 April 2013

The rising threat of AMR

25 000 Europeans killed / year

€1.5 bn costs to economy / year

2 new classes of antibiotics in the last 30 years

What are the challenges in R&D?

1. Significant scientific challenges, innovation gap – More focus on fundamental science & explore new approaches 2. Regulatory & clinical trial challenges – Pursue new regulatory paths & create diagnostics to streamline AB trials 3. Low return on investment – New ‘de-linked’ commercial models; diagnostics driving appropriate use

Challenges too great for any single entity to solve, collaboration is essential

EU Action Plan – Nov 2011

The 12 actions Human Veterinary

1. Appropriate use 2. & 3. Appropriate use and legal changes

4. Prevention of infection 5. Prevention of infection

6. New antibiotics

9. Surveillance

8. International cooperation

11. Research and innovation

12. Communication, education

7. Need for new antibiotics, alternatives

10. Surveillance

The 12 actions Human

1. Appropriate use 2. & 3. Appropriate use and legal changes

4. Prevention of infection 5. Prevention of infection

6. New antibiotics

9. Surveillance

8. International cooperation

11. Research and innovation

12. Communication, education

7. Need for new antibiotics, alternatives

10. Surveillance

Action 6: To promote, in a staged approach, unprecedented collaborative research and development efforts to bring new antibiotics to patients by: – Launching rapidly with EFPIA, within the IMI-Joint Undertaking, a programme for research on new antibiotics aimed at improving the efficiency of research and development of new antibiotics through unprecedented open sharing of knowledge.

EU Action Plan – Nov 2011

New Drug for Bad Bugs programme: ND4BB

Overall vision of ND4BB: to create an innovative collaborative Public-Private Partnership (PPP)-based approach that will encompass all aspects from the discovery of new antibiotics to Phase 2 and 3 clinical trials to reimbursement and appropriate us with the aim of reinvigorating antibiotic R&D

IMI already invested > €600 million in New Drugs for Bad Bugs projects aiming at:

Solving scientific challenges

Fostering new models of industrial collaborations for antibiotic development

Developing networks for clinical trials

Revisiting regulatory environment

Providing necessary incentives for industry to reinvest in the area

Overview of the ND4BB programme ND4BB cross topic collaboration and dissemination

Topic 1: COMBACTE a) Enabling

Clinical Collaboration and refining clinical

trial design b) Clinical

Development of GSK1322322

c) Clinical Development of

MEDI4893

Topic 2 : TRANSLOCATION

Research penetration and efflux Gram-

negatives Data Hub and

Learning from R&D experience

Topic 4: Driving re-

investment in R&D and

Responsible use of Antibiotics

Topic 5: Clinical

development of antibacterial

agents for Gram-negative antibiotic

resistant pathogens

Topic 6: Systemic molecules against HAIs due to clinically challenging

Gram-negative pathogens

Topic 7: Inhaled

Antibacterials in CF and non-CF BE

Discovery Economics & stewardship Development

Topic 3 : ENABLE Discovery &

development of new drugs combatting

Gram–negative infections

Development

ND4BB Information Centre – Submission of legacy and ND4BB data for shared learnings and best practices

6th Call (Projects started Jan 2013) 8th Call (Project started Feb 2014) 9th Call (Project starts Q3 2014)

11th Call (Call launched Dec 2013)

Overview of the ND4BB programme

Translocation penetration and efflux Gram-neg

bacteria & ND4BB Information Centre

COMBACTE + ND4BB Topics 5,6,7 creating sustainable clinical investigator and laboratory networks to increase efficiency;

clinical trials

ENABLE Progressing the most promising ‘hit’

molecules from academia and SME’s to early clinical development

DRIVE-AB options for a new economic model of

antibiotic development

• RAPP-ID (rapid point-of-care test platforms)

• Predict-TB (modeling to predict drug combinations)

• Zoonosis anticipation and preparedness initiative (Zapi)

• ND4BB Topics 1-7

The IMI portfolio

Project Overview COMBACTE

Facts on the project COMBACTE = COMBatting AntibiotiC resisTance in Europe

Participants 33

academic institutions 29

large pharmaceutical companies 3

SME 1

Led by: University Medical Centre Utrecht, NL (+ University Hospital Centre of Limoges, FR) GlaxoSmithKline (+AstraZeneca)

Budget & timelines € 243.36 million (€109.43 million IMI JU + € 133.92 million EFPIA) started Jan 2013, runs 7 years

Project AIMS

• Self-sustaining antibacterial development network (clinical investigator and laboratories network)

• Increase efficiency of antibiotic development

• Conduct clinical trials using the network

• Information sharing within the consortium the wider ND4BB programme external environment

1. To establish a sustainable high-quality investigator network & surveillance programmes 2. To increase the efficiency of antibiotic development through:

Analysing shared pre-clinical and clinical data sets and making recommendations Enhancing the application of PK/PD to pre-clinical data Utilizing comparator data to inform novel clinical trial designs to reduce the

burden on Phase 2 and Phase 3 trials, therefore making the development of antimicrobials more feasible and efficient

3. To conduct trials with a new investigational agent against MRSA 4. To optimise application of rapid diagnostic tests in the context of clinical trials to better target patients for (early)inclusion in clinical trials

Project Overall Objectives

5. To explore potential biomarkers to enhance diagnostic and prognostic assessment of patients

6. Increase probability of success & efficiency of clinical development of a new monoclonal antibody for prevention of S. aureus infections (MEDI4893) through Evaluation of burden of disease and potential target population, utilizing targeted

active surveillance, followed by Interventional Phase 1b/2 studies in the populations of interest, using study

designs informed by the data collected from the epidemiologic surveillance studies

7. Establish population‐specific surveillance programs

8. Conduct prospective clinical studies

Project Overall Objectives

Project Overall Structure

Self-sustaining network CLIN-NET expansion throughout Europe Development of baseline questionnaire and of web-based GCP

training tool LAB-net development of baseline questionnaire and of antibiotic

resistance workshop

Increase efficiency of antibiotic development Review of the challenges, access to historical antibiotic development

Conduct clinical trials using the network: 1st clinical trial with MEDI4893 initiated

Project Results/Achievements

COMBACTE CLIN-Net: 294 hospital sites in 34 countries

Project Results/Achievements

https://www.combacte.com/

Project Overview TRANSLOCATION

TRANSLOCATION

• develop new technologies to measure the transport of molecules across the cell envelope of Gram-negative bacteria

• Improve understanding of bacterial mechanisms to flush out molecules through the identification of key proteins

Merging the best science of microbiology, structural biology and biophysics increasing overall probability of success to deliver novel antibacterials

all atom kinetic modeling electrophysiology mass spec X-ray

crystallography

Main Objectives

Molecular basis of the bacterial cell wall permeability

Translocation - Project tasks

Research and Discovery Development of assays to study penetration and efflux in multi-resistant

Gram-negative pathogens.

Understanding the impact of Porin structure and intrinsic permeability

Hijacking bacterial transport mechanisms to import antibiotics

Novel penetration and/or efflux targets from a genetic approach

Understanding penetration and efflux via modelling and simulation

Project management, collaboration, ethics, and dissemination

Creation of a ND4BB Information Centre: to compile and analyze antibacterial R&D information from across multiple companies

Analysis of shared data to provide best practices for efficacy models, translational approaches, dose selection, etc.

Efficiency

TRANSLOCATION - Achievements TRANSLOCATION Project: How to Get Good Drugs into Bad Bugs (ScienceTranslationalMedicine.org) Diphenyl-benzo[1,3]dioxole-4-carboxylic acid pentafluorophenyl ester: a convenient catechol precursor in the synthesis of siderophore vectors suitable for antibiotic Trojan horse strategies (Organic &Biomolecular Chemistry, 2014) Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa (Metallomics, 2014) Role of the Central Arginine R133 toward the Ion Selectivity of the,Phosphate Specific Channel OprP: Effects of Charge and Solvation (Biochemistry, 2013) Role of the Central Arginine R133 toward the Ion Selectivity of the Phosphate Specific Channel OprP: Effects of Charge and Solvation (Biochemistry, 2013) RND Efflux Pumps: Structural Information Translated into Function and Inhibition Mechanisms (Current Topics in Medicinal Chemistry, 2013)

14 Academic Centres Universities, research organisations, public bodies, non-profit groups Assistance Publique - Hôpitaux de Paris, France Centre National de la Recherche Scientifique, France Société Civile Synchrotron SOLEIL, France Fundacio Centre de Recerca en Salut International de Barcelona, Spain Jacobs University Ggmbh, Germany Johann Wolfgang Goethe Universität Frankfurt am Main, Germany University of St Andrews, United Kingdom Universita degli Studi di Cagliari, Italy Universität Basel, Switzerland Universitätsklinikum Freiburg, Germany Université d'Aix-Marseille, France Université de Genève, Switzerland University College Dublin, Ireland University of Newcastle upon Tyne, United Kingdom

TRANSLOCATION Participants

5 EFPIA member companies AstraZeneca AB, Sweden Basilea Pharmaceutica AG, Switzerland Glaxosmithkline Research and Development Ltd, United Kingdom Janssen Infectious Diseases – Diagnostics BVBA, Belgium Sanofi-Aventis Research and Development, France 1 Non EFPIA company Bruker Daltonik GmbH, Germany 5 Small and medium-sized enterprises (SMEs) European Screening Port GmbH, Germany Ionovation GmbH, Germany Nanion Technologies GmbH, Germany Nanospot GmbH, Germany Yelen, France

Project Overview Enable

Facts on the project ENABLE = European Gram-negative Antibacterial Engine Participants 32

academic institutions 18

large pharmaceutical companies 4

SME 10

Led by: GSK Uppsala University

Budget & timelines

€ 81.9 million (€58.9 million IMI JU + € 23.0 million EFPIA) started Jan 2014, runs 6 years

Project AIMS

One of the major challenges in antibiotic discovery is turning ‘Hits’ and ‘Leads’ into development candidates

ENABLE aims : • Create a collaborative drug discovery platform • Increase the overall pipeline of new antibiotics

Drug development Drug discovery

max 8 max 3 max 2 max 2

ELF ENABLE

Joint forces public-private : exchange and learnings between best European academic scientists and scientists from ‘big pharma’

Joint forces private-private: pharma companies discover their historically different approaches

Strong governance + Open Calls: ensures that only best programmes are funded at any given time

Unprecedented intellectual property agreement: taking full advantage of flexibilities in IMI IP policy

ENABLE – A UNIQUE DRUG DISCOVERY MODEL OF COLLABORATION

Project Overall Objectives

To increase the pipeline of medicines against Gram-negative infections :

• three antibacterial Leads

• two antibacterial Candidates • at least one compound into preclinical and Phase 1 clinical

studies

Novel ‘hit’ molecule

Optimized ‘Lead’ molecule

Clinical candidate

Phase 1 clinical trial

Novel molecules (SMEs,

universities)

Drug Discovery Platform

GSK / Sanofi

Alliance Portfolio

Management Committee

Project Overall Structure

Open Calls to attract best programmes

Controls Progression

decisions

Resources at GSK / Sanofi + Drug

Discovery Platform

Supported by Drug Discovery

Platform Supporting multiple programmes

Multiple program teams • Open sharing of ideas & data— no silos • Highly supportive of novel approaches

Project Overall Structure

• Each participant remains exclusive owner of Background

• Compound Foreground arising within a programme will be owned by original Hit Owner

• Compensation schemes worked out to compensate for contributions made in case of future commercialization

Platform scientists Hit owners

Project Results/Achievements

3rd Open Call ongoing for interesting and innovative potential Gram negative programmes to join the project and enter the pipeline for: • Hit to Lead programmes

• Lead to Candidate programmes Deadline December 19 2014; 1700 CET

www.imi.europa.eu @IMI_JU

Thank you

Nathalie Seigneuret Senior Scientific Project Manager Maria-Teresa De Magistris Principal Scientific Manager

Angela Wittelsberger Scientific Project Manager

Nathalie.seigneuret@imi.europa.eu MariaTeresa.DeMagistris@imi.europa.eu

Angela.Wittelsberger@imi.europa.eu