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The Need to Increase R&D Push Incentives and Effective Pipeline Co-Ordination

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The Need to Increase R&D Push Incentives and Effective Pipeline Co-Ordination 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 Scientific definition . Innovation No cross-resistance to existing antibiotics • New class/target/MoA • Substantial improvement of existing class without cross-resistance . Novelty Improved antibiotics from existing classes • Reduced class-specific resistance New App . Usefulness Improved features, e.g. • Oral formulation • Improved pharmacokinetics Definition not uniformly agreed! 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 Players in Antibacterial Drug Discovery . „Antibacterial“ SMEs Number of SMEs (estimate) . No estimate available: ~20 ~90 o Academic institutions ~200 ~80 o Publicly funded research institutions o Non-profit research institutions o Public-Private Partnerships . 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 Clinical pipelines - WHO critical priority pathogens ß-lactams, ß-lactam-inhibitor combinations Ph Class Compound Pathogen activity WHO critical priority pathogens CR-E | CR-PA| CR-AB Carbapenem resistant Vaborbactam/merop CR-E: Enterobacteriaceae Carbapenems CR-PA: Pseudomonas aeruginosa 3 Relebactam/imip CR-AB: Acinetobacter baumannii group 1 VNRX-5133/merop 3 Sulopenem Activity 1 Cephalosporins Zidebactam/cefep Unclear 1 Nacubactam/cefep No or insufficient activity 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 Clinical pipeline: Specific solutions for specific patients for specific situations in specific regions Based on the WHO pipeline analysis 2017, to be published in October 2017 Clinical pipelines - WHO critical priority pathogens WHO critical priority pathogens CR-E|CR-PA|CR-AB Carbapenem resistant Delafloxacin Fluoroquinolone CR-E: Enterobacteriaceae 3 Sulopenem Carbapenem ESBL CR-PA: Pseudomonas aeruginosa 3 Plazomicin Aminoglycoside CR-AB: Acinetobacter baumannii group 3 Lascufloxacin Fluoroquinolone 3 Eravacycline Tetracycline 3 Omadacycline Tetracycline 3 Solithromycin Macrolide Activity 3 Iclaprim DHFR-inhibitor Unclear 3 Lefamulin Pleuromutilin* No or insufficient activity 2/3 MRX-I/MRX-IV Oxazolidinone 2 Gepotidacin NBTI (Triazaacenaphthylene) New chemical or 2 Zoliflodacin NBTI (Spiropyrimidenetrione) functional class 2 Murepavidn Novel membrane targeting AB 2 Brilacidin Novel membrane targeting AB 2 Afabicin FabI inhibitor Mostly developed by companies with <500 employees (most 2 Nafithromycin Macrolide companies <100) 2 Finafloxacin Fluoroquinolone 1 SPR-741 + antibiotic? Polymyxin + antibiotic? 1 TP-271 Tetracycline Biologics, C. diff. drugs, 1 TP-6076 Tetracycline combinations or off-patent 1 KBP-7072 Tetracycline drugs not included * New for systemic infections Gram-pos 1 TNP-2092 Rifamycin-quinolone hybrid Based on the WHO pipeline analysis 2017, to be published in October 2017 Preclinical pipelines, n=254 CARB-X submissions 2016, n=254 60 200 180 160 50 140 120 100 40 80 60 40 30 20 0 Small Academic Large Non-profit Medium 20 10 0 U. Theuretzbacher et al: Innovation potential of the preclinical antibiotic pipeline. Nature Reviews Drug Discovery. 2017. In press Recommendation: push mechanisms ICO Increase, Coordinate, Optimise resources Priority grants • Address drug discovery and early development hurdles: scientific and financial • Global coordination hub Discovery Optimisation Discovery grants improve the entry rates into Preclinical dev. the preclinical phase, improve the effect of pull mechanisms Phase 1 Phase 2 Additional annual push funding ~200-500 million Phase 3 Recommendation: Push incentives - ICO Push vs pull: Risk due to high attrition rate vs relative certainty what we get broad Research Applied research around AMR • Mostly broad topics, add ICO: addressing the most difficult scientific questions Drug Discovery Broad + priority topics • Academic, non-profit institutions: ICO, knowledge hub, partnerships • SMEs: ICO, support with expertise and experience Drug development Priority pathogens and TPPs • Preclinical: ICO • Clinical: ICO, clinical trial networks, sustainable use and equitable access conditions apply priority 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 G20, global Integrated public health-driven R&D organisation GARD-P Model: Global Collaboration hub on AMR R&D Coordinate, align, streamline, increase funding and incentives Prioritise: Identify Align Co-ordinate Co-ordinate Policies for WHO PPL gaps and existing new new push sustainable WHO PLA duplication, funding funding and pull use and WHO TPP mapping incentives access Global Collaboration Hub on AMR R&D Inform public, private, philanthropic decision making, increase efficiency Increase therapeutic options and tackle AMR PPL: priority pathogen list G20, Global PLA: pipeline analysis TPP: target product profiles WHO, IACG, TATFAR, OECD, EU, JPIAMR, CARB-X, GARD-P, … Model: Integrated public health-driven R&D organisation Public and philanthropic funding Public health focus in all phases Global Discovery Preclinical Clinical dev. Registration Marketing Virtual AFFORDABLE, EQUITABLE, SUSTAINABLE 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 .
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