DRIVE-AB conference in Brussels, 5.-6. September 2017

The need to increase R&D push incentives and effective pipeline co-ordination

U. Theuretzbacher, Center for Anti-Infective Agents and DRIVE-AB

DRIVE-AB is supported by the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115618, resources of which are

composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA (European Federation

of Pharmaceutical Industries and Associations) companies’ in kind contribution. DRIVE-AB is part of the New Drugs for Bad Bugs (ND4BB) program.

Innovation

Innovation

Novelty

Usefulness New App

U. Theuretzbacher Antibiotic innovation for future public health needs. Clin Microbiol Infect. 2017 Jun 24. U. Theuretzbacher: New drugs – will they solve the problem of resistance to antibiotics? Clin Microbiol Infect. 2017 August 19

No cross-resistance to existing antibiotics • New class/target/MoA • Substantial improvement of existing class without

cross-resistance

Improved antibiotics from existing classes • Reduced class-specific resistance

Improved features, e.g. • Oral formulation • Improved pharmacokinetics

Scientific definition

Definition not uniformly agreed!

Players in Antibacterial Drug Discovery

„Antibacterial“ SMEs

~90 ~200

~20

~80

Number of SMEs (estimate)

Global pharmaceutical corporations: Novartis, Roche/Genentech, Sanofi, Medimmune (biologics), GSK, Merck

Large companies: Shionogi, Wockhardt

Amount of public and philanthropic funding for drug discovery and preclinical development is not known

No estimate available:

o Academic institutions

o Publicly funded research institutions

o Non-profit research institutions

o Public-Private Partnerships

Clinical pipelines - WHO critical priority pathogens

Ph Class Compound Pathogen activity CR-E | CR-PA| CR-AB

Carbapenems Vaborbactam/merop

3 Relebactam/imip

1 VNRX-5133/merop

3 Sulopenem

1 Cephalosporins Zidebactam/cefep

1 Nacubactam/cefep

2 AAI-101/cefep

1 Tazo/cefep

1 C-Scape

3 Ceph-siderophore Cefiderocol

2 Monobactams Avibactam/aztreon

1 LYS228

1 BLIs ETX-2514SUL

KPC|NDM

Activity

Unclear

No or insufficient activity

WHO critical priority pathogens Carbapenem resistant CR-E: Enterobacteriaceae CR-PA: Pseudomonas aeruginosa CR-AB: Acinetobacter baumannii group

Based on the WHO pipeline analysis 2017, to be published in October 2017

Clinical pipeline: Specific solutions for specific patients for specific situations in specific regions

ß-lactams, ß-lactam-inhibitor combinations

Delafloxacin Fluoroquinolone

3 Sulopenem Carbapenem ESBL

3 Plazomicin Aminoglycoside

3 Lascufloxacin Fluoroquinolone

3 Eravacycline Tetracycline

3 Omadacycline Tetracycline

3 Solithromycin Macrolide

3 Iclaprim DHFR-inhibitor

3 Lefamulin Pleuromutilin*

2/3 MRX-I/MRX-IV Oxazolidinone

2 Gepotidacin NBTI (Triazaacenaphthylene)

2 Zoliflodacin NBTI (Spiropyrimidenetrione)

2 Murepavidn Novel membrane targeting AB

2 Brilacidin Novel membrane targeting AB

2 Afabicin FabI inhibitor

2 Nafithromycin Macrolide

2 Finafloxacin Fluoroquinolone

1 SPR-741 + antibiotic? Polymyxin + antibiotic?

1 TP-271 Tetracycline

1 TP-6076 Tetracycline

1 KBP-7072 Tetracycline

1 TNP-2092 Rifamycin-quinolone hybrid

CR-E|CR-PA|CR-AB

Clinical pipelines - WHO critical priority pathogens

Gram-pos

Activity

Unclear

No or insufficient activity

Based on the WHO pipeline analysis 2017, to be published in October 2017

Biologics, C. diff. drugs, combinations or off-patent drugs not included

Mostly developed by companies with <500 employees (most companies <100)

Carbapenem resistant CR-E: Enterobacteriaceae CR-PA: Pseudomonas aeruginosa CR-AB: Acinetobacter baumannii group

WHO critical priority pathogens

New chemical or functional class

* New for systemic infections

Preclinical pipelines, n=254

CARB-X submissions 2016, n=254

U. Theuretzbacher et al: Innovation potential of the preclinical antibiotic pipeline. Nature Reviews Drug Discovery. 2017. In press

0

10

20

30

40

50

60

0

20

40

60

80

100

120

140

160

180

200

Small Academic Large Non-profit Medium

Priority grants

Recommendation: push mechanisms ICO

Optimisation

Discovery

Preclinical dev.

Phase 1

Phase 2

Phase 3

Discovery grants improve the entry rates into

the preclinical phase, improve the effect of

pull mechanisms

Increase, Coordinate, Optimise resources

• Address drug discovery and early development hurdles: scientific and financial

• Global coordination hub

Additional annual push funding ~200-500 million

Recommendation: Push incentives - ICO

Push vs pull: Risk due to high attrition rate vs relative certainty what we get

broad

priority

Applied research around AMR Research • Mostly broad topics, add ICO: addressing the most difficult scientific

questions

Broad + priority topics Drug Discovery • Academic, non-profit institutions: ICO, knowledge hub, partnerships

• SMEs: ICO, support with expertise and experience

Priority pathogens and TPPs Drug development • Preclinical: ICO

• Clinical: ICO, clinical trial networks, sustainable use and equitable access conditions apply

ICO – Increase, Coordinate, Optimise resources

Recommendation: Pipeline coordinating models

Public health outcome-driven coordination of pipeline activities

- Identifying gaps in the current R&D pipelines according to public health needs

- Addressing these gaps by

Global Collaboration Hub on AMR R&D

Integrated public health-driven R&D organisation

G20, global

GARD-P

Model: Global Collaboration hub on AMR R&D

Global Collaboration Hub on AMR R&D

Coordinate, align, streamline, increase funding and incentives

Prioritise: WHO PPL WHO PLA WHO TPP

PPL: priority pathogen list PLA: pipeline analysis TPP: target product profiles

Identify gaps and duplication, mapping

Align existing funding

Co-ordinate new funding

Inform public, private, philanthropic decision making, increase efficiency

Co-ordinate new push and pull incentives

Policies for sustainable use and access

Increase therapeutic options and tackle

AMR G20, Global

WHO, IACG, TATFAR, OECD, EU, JPIAMR, CARB-X, GARD-P, …

Model: Integrated public health-driven R&D organisation

Discovery Preclinical Clinical dev. Registration Marketing

Public health focus in all phases

AFFORDABLE, EQUITABLE, SUSTAINABLE

Glo

bal V

irtu

al

Point of entry to patient delivery

In- house scientific and R&D capacity (project management, clinical trials, discovery and preclinical, CMC expertise)

Equal partnerships with agreed principles and based on economically sustainable models

Public and philanthropic funding