Reigniting Innovation in Antibiotics: When to Push and When to Pull

John H. Rex, MD discusses the importance of antibiotics in healthcare, emphasizing the need for innovation. He explores the concepts of pushing and pulling in antibiotic development and challenges the audience to rethink the use of antibiotics for the future. The presentation covers fundamental points on the role of antibiotics as safety nets in various medical procedures and emphasizes the critical need for advancements in this field.

• Antibiotics
• Innovation
• Healthcare
• Rethinking
• Medical

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1. Reigniting innovation in antibiotics Reigniting innovation in antibiotics When to Push and when to Pull When to Push and when to Pull John H. Rex, MD Editor-in-Chief, amr.solutions Chief Medical Officer, F2G Ltd Operating Partner, Advent Life Sciences Email: john.h.rex@gmail.com Newsletter: http://amr.solutions Slides happily shared just drop me a note! The opinions in this presentation are my own and not necessarily those of any group with which I work. 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 1

2. Disclosures John H. Rex, MD, is Chief Medical Officer & Director, F2G, Ltd.; Editor-in-Chief, AMR.Solutions; Operating Partner & Consultant, Advent Life Sciences; and Adjunct Professor of Medicine, McGovern Medical School, Houston, TX He sits on the scientific advisory boards of Bugworks Research, Inc.; Basilea Pharmaceutica; Forge Therapeutics, Inc.; Novo Holdings; and Roche Pharma Research & Early Development He is a shareholder in AstraZeneca Pharmaceuticals; F2G, Ltd; Advent Life Sciences; Zikani Therapeutis; and Bugworks Research, Inc. He has received consulting fees from Phico Therapeutics; ABAC Therapeutics; Polyphor, Ltd.; Heptares Therapeutics, Ltd.; Gangagen, Ltd.; Meiji Seika Pharma; Basilea Pharmaceutica International Ltd.; Allecra Therapeutics GmbH; Forge Therapeutics, Inc.; SinSa Labs; AtoxBio; Peptilogics; F. Hoffmann-LaRoche, Ltd.; Novo Holdings; Innocoll; Vedanta; Progenity; Nosopharm SA; Roivant Sciences; and Shionogi Inc. The opinions expressed are his own and do not necessarily reflect the opinion of any of the groups with which he works. 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 2

3. Agenda Antibiotics are the fire extinguishers of medicine How far in advance do we have to plan? Push and Pull: How and How much? 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 3

4. Pop Quiz: Have you used a fire extinguisher today? 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 4

5. Pop Quiz: Have you used a fire extinguisher today? Let s be more concrete. Are you using a fire extinguisher right now? 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 5

6. Fundamental starting points Antibiotics enable all of health care: Safety net for surgery, cancer therapy, and essentially everything else Fire extinguishers (or fire departments) of medicine Infrastructure for civilization Stated differently 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 6 Speaker personal opinion.

7. Antibiotic benefits go beyond simple use But, we don t (yet) have an agreed way to capture that value Enabling value: Many surgical and medical procedures rely on prophylaxis with effective antibiotics. Option or insurance value: We may want to have an antibiotic in reserve before we really need it, so it s ready if resistance arises or worsens. Diversity value: Having multiple antibiotics may reduce selection pressure and delay resistance. Antibiotics are the fire extinguishers of medicine! 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 7

8. Agenda Antibiotics are the fire extinguishers of medicine How far in advance do we have to plan? Push and Pull: How and How much? 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 8

9. From scratch? 10 From scratch? 10 20 years at least r r 20 years at least vancomycin 19 years Glycopeptides 19 years linezolid 40 years Oxazolidinones 40 years daptomycin 43 years Cyclic lipopeptides 43 years Time from discovery to FDA approval MRSA ceftaroline 50 years Cephalosporins 50 years ceftazidime- avibactam 14 yrs -lactam/ -lactamase inhibitors 14 years KPC-Kp No p.o. yet >13 yrs NG ciprofloxacin-resistant Fluoroquinolones-resistant NG No p.o. yet >8 yrs NG NG azithromycin-resistant Macrolides-resistant bedaquiline 20 yrs Diarylquinolines 20 years MDR TB pretomanid 27 yrs Nitroimidazoles 27 years 1960s 1970s 1980s 1990s 2000s 2010s Sources: CDC AR Threats 2019, at 35; MRSA 1960 (JevonsMP 1961. BMJ); KPC-Kp 2001 (Yigit H, et al. AAC 2001); NG-CR 2007 (CDC, MMWR 2007); NG-AR 2012 (Soge OO, et al, STD 2012); MDR-TB 1992 (Vallarino ME, et al., Pub H Rep 1992). Drug approvals: Vancomycin approved 1958, but US usage did not grow until 1979 (Kirst HA 1998. AAC). Other approvals from Drugs@FDA.gov. For emergence of MRSA resistant to ceftaroline prior to its FDA approval, see Kelley WL et al., AAC 2015. 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 9 Graphic borrowed and adapted from Kevin Outterson, July 2020

10. From scratch? 10 From scratch? 10 20 years at least And, completely new classes are higher risk and slower And, completely new classes are higher risk and slower 20 years at least vancomycin 19 years Glycopeptides 19 years linezolid 40 years Oxazolidinones 40 years daptomycin 43 years Cyclic lipopeptides 43 years Time from discovery to FDA approval MRSA ceftaroline 50 years Cephalosporins 50 years ceftazidime- avibactam 14 yrs -lactam/ -lactamase inhibitors 14 years KPC-Kp No p.o. yet >13 yrs NG ciprofloxacin-resistant Fluoroquinolones-resistant NG No p.o. yet >8 yrs NG NG azithromycin-resistant Macrolides-resistant bedaquiline 20 yrs Diarylquinolines 20 years MDR TB pretomanid 27 yrs Nitroimidazoles 27 years 1960s 1970s 1980s 1990s 2000s 2010s Sources: CDC AR Threats 2019, at 35; MRSA 1960 (JevonsMP 1961. BMJ); KPC-Kp 2001 (Yigit H, et al. AAC 2001); NG-CR 2007 (CDC, MMWR 2007); NG-AR 2012 (Soge OO, et al, STD 2012); MDR-TB 1992 (Vallarino ME, et al., Pub H Rep 1992). Drug approvals: Vancomycin approved 1958, but US usage did not grow until 1979 (Kirst HA 1998. AAC). Other approvals from Drugs@FDA.gov. For emergence of MRSA resistant to ceftaroline prior to its FDA approval, see Kelley WL et al., AAC 2015. 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 10 Graphic borrowed and adapted from Kevin Outterson, July 2020

11. Agenda Antibiotics are the fire extinguishers of medicine How far in advance do we have to plan? Push and Pull: How and How much? 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 11

12. Antibiotic paradox If you invent a bad antibiotic, use will be limited If you invent a good antibiotic, use will be very limited* In both cases, prices will be low by modern standards *And should be see next slide! 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 12

13. Rational stewardship limits sales and this is a good thing! Usage-based income will not cover costs1,2 New antibiotics often have $25m/year in sales Running costs of a drug in its first 10 years: $350m3 $100m in post-approval commitments: pediatrics, etc. $25m/year to run the plant that makes your drug, surveillance, pharmacovigilance And to repay the investors who got you here? Average cost to approval = $1.3b (Wouters, JAMA 2020)4 With the $350m in running costs, zero hope of repaying everybody even if your sales hit $50m/year Investing in antibiotics is madness! 1. AMR Solutions - Mandatory Reading: Alan Carr s Jan 2020 Antibacterial And Antifungal Market Review. Available at: https://amr.solutions/2020/01/28/mandatory-reading-alan-carrs-jan-2020-antibacterial- and-antifungal-market-review/ (Accessed August 2020); 2. AMR Solutions - What Does An Antibiotic Cost To Develop? What Is It Worth? How To Afford It? Available at: https://amr.solutions/2020/03/06/what- does-an-antibiotic-cost-to-develop-what-is-it-worth-how-to-afford-it/ (Accessed August 2020); 3. Speaker personal opinion; 4. Wouters J, et al. JAMA 2020;323:844 53. 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 13

14. Push and Pull are both needed Push is well underway: $750m: Discovery to Phase 1: CARB-X, Novo REPAIR, etc. $1b: Phase 2-3: AMR Action Fund Pull is now needed: The UK pilot as a benchmark GBP 10m/yr x 10 years = GBP 100m The UK is 3% of the G20: 100m x 33 = GBP 3.3b $4b This is right on target! Strong work, Team UK! So, how do we engage and extend? Wealthy countries need to contribute their fair share Targets must be fair and consistently available So far, the only sizeable further effort is in the US 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 14

15. Summary The problem is now well-defined After 10 years of effort, we really understand the issues The solutions are equally clear Push funding is familiar and is having an effect The big mental shift is in Pull: We must think differently about antibiotics Antibiotics are the Fire Extinguishers of Medicine Like other infrastructure, we must buy them in advance #FireExtinguishersOfMedicine 10 Sep 2020: Rethinking Antibiotics for the Future: A Global Webinar 15