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New Germs, Old Drugs, Tough Business
Brief Reflections on AMR Work
1st September 2015
J W Scannell
J W Scannell, [email protected] ) OSP 2 September 2015
Good Old Fashioned Exhaustion? The Antimicrobial “Discovery Void”
Source: Silver, L. L. (2011). Challenges of antibacterial discovery. Clinical Microbiology Reviews, 24, 71–109. doi:10.1111/j.1749-6632.2010.05828.x
J W Scannell, [email protected] ) OSP 2 September 2015
The White Heat of Modern Scientific Failure: Genomics and HTS GSK Experience from 1995 to 2002
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Target identification
Target validation
Screen development
Screening Lead
optimization Preclinical
development Clinical trials
Phase I-III
Source: Payne, D. J., Gwynn, M. N., Holmes, D. J., & Pompliano, D. L. (2007). Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Reviews. Drug Discovery, 6, 29–40. doi:10.1038/nrd2201. See also: Silver, L. L. (2011). Challenges of antibacterial discovery. Clinical Microbiology Reviews, 24, 71–109. doi:10.1111/j.1749-6632.2010.05828.x Note, this was not just a GSK problem. GSK has simply published its experience. According to Payne et al. (2007): “GSK was not the only company that had difficulty finding antibacterial leads from HTS. A review of the literature between 1996 and 2004 shows that >125 antibacterial screens on 60 different antibacterial targets were run by 34 different companies. That none of these screens resulted in credible development candidates is clear from the lack of novel mechanism molecules in the industrial antibacterial pipeline.”
First bacterial genome sequenced in ’95 Several major pathogens sequenced over next few years > 350 candidate target genes identified from comparative sequence analysis
127 “essential” genes identified Prioritised those with close homologues across variety of bacteria but without close homologues in man
67 High throughput screening campaigns conducted Each involved testing gene products against up to ~500,000 compounds from the GSK compound libraries Only 16 “hits” across all targets
16 “hits” led to only 5 “leads” with potentially attractive drug-like properties However, leads had only narrow spectrum activity
No clinical trials initiated
J W Scannell, [email protected] ) OSP 2 September 2015
Antimicrobial Resistance is Now A First World Problem
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J W Scannell, [email protected] ) OSP 2 September 2015
The O’Neill Review
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“The UK Prime Minister announced a Review on Antimicrobial Resistance in July [2014], calling for ideas to bring this growing threat under control…. We want to explore the following 5 themes…
1. The impact of antimicrobial resistance on the world’s economy if the problem is not tackled
2. How we can change the use of antimicrobial drugs to reduce the rise of resistance…
3. How we can boost the development of new antimicrobial drugs
4. The potential for alternative therapies to disrupt the rise in resistance…
5. The need for coherent international action that spans drugs regulation, and drugs use across humans, animals, and the environment…”
J W Scannell, [email protected] ) OSP 2 September 2015
A Major Policy Challenge is Solving the Incentive Problem
Small Markets
• New antimicrobials likely to face intense “stewardship”
• New antimicrobials likely to face price-sensitive buyers – Most hospitals in the developed
world are reimbursed out of a fixed per-patient fee
– Poor countries are poor
• New antimicrobials will often be narrow spectrum – Further limits market size
– Demands effective microbiological diagnosis before treatment
Policy Choices
• Balance of “push” versus “pull” incentives?
• Market-based pull incentives to increase antibiotic sales? – GAIN & QDIP
– NTAP/DISARM
– RADARS
• Or “delinkage” to separate profits from usage? – Antibiotics as Public Goods
– WHO Global Consortium
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J W Scannell, [email protected] ) OSP 2 September 2015
O’Neill Review – Some Emerging Recommendations
• Pull incentives – Review favours some kind of de-linkage
• $16bn - $37bn from public sources, for lump sum payments for ~15 new molecules, including 4 new classes, over 10 years
• Probably mixed model; up-front “prize” plus controlled sales
• Push incentives - $2bn over 5 years for discovery and research
• High risk, “blue sky”, not yet commercial
• Paid for by levy on the drug industry
• And a possible “open source” opportunity
– Systematically screen combinations of old antibiotics for useful clinical profiles against resistant pathogens
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J W Scannell, [email protected] ) OSP 2 September 2015
