ABPI POI Project Recommendations

ABPI POI Project Recommendations

Antimicrobial resistance (AMR) a pharmaceutical industry perspective 17th November 2018 Dr Bryan Deane Dept of Research, Medical & Innovation Contents Introduction the ABPI; the biopharmaceutical industry AMR: the issue AMR initiatives and recent progress Looking ahead 2 Association of the British Pharmaceutical Industry (ABPI) The ABPI represents innovative research-based biopharmaceutical companies, We represent large, medium or small companies who research and develop the majority of the current medicines pipeline supply more than 80% of all branded medicines

used by the NHS bring life-saving and life-enhancing medicines to patients. Recognised by government as the industry body negotiating on behalf of the branded pharmaceutical industry for statutory consultation requirements e.g. UK pricing scheme for medicines Global medicines development The rapid advance of medical progress over the last half-century means that the average child born in the UK in 2030 is expected to live to over 97 years of age. With over 7,000 medicines and vaccines in development globally for a wide range of diseases, an exciting new wave of medical innovation will play a key role in addressing the challenges faced by patients and by the NHS. Globally, the biopharmaceutical industry is set to invest 142 billion a year on R&D by 2022. New medicines offer the potential to revolutionise what it means to be a patient. Going beyond chemotherapy, a blister pack of pills and the often costly, intrusive intervention of surgery, doctors and scientists are discovering new ways to harness the power of the very latest breakthroughs in science to deliver truly personalised treatment. Within the next 5 years cutting edge developments in medicine will transform the lives of patients. Some of the most impactful new therapies in development are: combination therapies for cancer; disease-modifying therapies for Alzheimers; antibacterial monoclonal antibodies to target antimicrobial resistance; gene therapies against haemophilia; cell therapies against diabetes; and CAR-T therapies targeting blood cancers.

4 Drug Discovery Process 5 Developing a new medicine Average global cost of development: 1.2 Billion per approved new medicine UK R&D investment is over 5bn per annum 15% of sales UK industry employs 61,000 people (2016) 6 New medicine Life Cycle Investment / profit over the life cycle of a medicine (illustrative) 600 400 net profit (000s)

200 0 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1

0 1 2 3 4 5 6 7 8 9 10

11 12 -20 -40 year (0 = launch) -60 preclinical phase III trials phase I & II trials launch registration

Sales growth Patent expiry 7 Five major (most widely used) classes Penicillins (beta-lactams, oral & injectable) 1942 penicillin; amoxicillin Aminoglycosides (injectable) 1950 streptomycin; gentamicin Macrolides (oral) 1952 erythromicin; azithromycin Quinolones (oral & injectable)

1962 nalidixic acid; ciprofloxacin Cephalosporins (beta-lactams, mostly injectable) 1964 cephalothin; ceftriaxone 1945 tetracyclines 1949 chloramphenicol The modern pharmaceutical industry 1959 hydrochlorthiazide (diuretic) hypertension (beta-blocker) hypertension

1964 Inderalpropranolol 1969 Ventolin salbutamol (beta-agonist) asthma 1972 Becotide beclamethasone (corticosteroid)

asthma 1976 Tagamet cimetidine (H2 antagonist) ulcers 1984 Vasotec enalapril (ACE inhibitor) hypertension

1986 Prozacfluoxetine 1986 zidovudine (SSRI) depression (NRTI) HIV/AIDS [first blockbuster] [also subject to resistance] 1990

Norvasc 1991 Imitrexsumatriptan (5HT rec ag) migraine 1991 Zofran ondansetron (5HT3 rec antag) emesis 1992 Zocor simvastatin

(HMG CoA reduc inhib) lipid lowering 1995 Cozaarlosartan (Angioten II rec antag) hypertension 1998 Herceptin trastuzumab (mAb) 1998

Remicade infliximab (TNF-inhib mAb) Crohns disease 2002 Humira adalimumab (TNF inhib mAb) rheumatoid arthritis 2014 Jardiance

empagliflozin (SGLT2 inhib) type II diabetes amlodipine (Ca++ channel blocker) hypertension breast cancer many blockbusters, all generic and most on the WHO essential drugs list 9 Contents Introduction the ABPI; the biopharmaceutical industry AMR: the issue AMR initiatives and recent progress

Looking ahead Mortality rates and life expectancy Life expectancy has increased due to our ability to prevent & treat infection (Lister, Pasteur, Koch) Discovery of penicillin by Sir Alexander Fleming and its subsequent development by Florey & Chain revolutionised treatment of infectious disease Antibiotics enable other procedures (surgery, transplants, cancer therapy etc) Crude mortality rates for all causes, noninfectious causes and infectious diseases over the period 1900-1996. Slide 11 Infectious disease is different When considering prescribing an antibiotic, we need to consider

Treating the patient, eradicating the pathogen Minimising the effect on the patients natural microbiome Potential impact on the overall population Primary Care Otherwise healthy patients Usually common pathogens (incl Streptococcus, Haemophilus etc) Secondary Care Seriously ill patients Opportunistic pathogens (incl Staphylococcus, Escherichia, Klebsiella) Appropriate prescribing the right patient, receiving the right medicine, at the right dosage, in the right formulation, at the right time, for the right duration, for the right indication (pathogen and infection site) 12 Infectious disease is different Appropriate prescribing the right patient, receiving the right medicine, at the right dosage, in the right formulation, at the right time, for the right duration,

for the right indication (pathogen and infection site) Primary Care Secondary care Use only if bacterial (clinically likely or bacteriologically confirmed) Use only if bacterial (clinically likely or bacteriologically confirmed) Avoid using if pathogen is likely viral

Need new antibiotics to combat resistant pathogens Will minimise further resistance to currently used ABs (mostly long-established, generic) New antibiotics will need clear Appropriate Use ad Stewardship plans to preserve efficacy 13 Gram positive or negative? Gram +ve Staphylococcus Streptococcus Clostridium Enterococcus Gram -ve

Acinetobacter Enterobacter Escherichia Haemophilus Klebsiella Moraxella Neisseria Pseudomonas Salmonella Antibiotic Classes Antibiotic mechanisms of action Antibiotic resistance mechanisms Antibiotic resistance A major public health threat Slide 18 18 Antimicrobial resistance poses a catastrophic threat. If we don't act now,

any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can't be treated by antibiotics Professor Dame Sally Davies. Chief Medical Officer, England. March 2013 A post-antibiotic era means in effect an end to modern medicine as we know it. Things as common as Strep Throat or a childs scratched knee could kill once again Dr Margaret Chan. Director General, World Health Organisation Owing to the massive threat that it poses to world health and the economy, antimicrobial resistance has finally started to receive the attention it deserves. But awareness is only the first step; to solve the problem, governments, drug makers, and health-care professionals will have to start taking more concrete action Lord Jim ONeill, Author, the UK AMR Review Global Antimicrobial Resistance Threats ONeil Report 2014 (final report 2016) Slide 19 19

Impact of AMR on World Economy Slide 20 20 $20 billion in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year US estimate AMR Impact on World GDP In trillions of USD ONeill 2014 New antibiotic targets (WHO 2017)*: priority resistant pathogens Priority 1: CRITICAL Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant, ESBL-producing

Priority 2: HIGH Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter spp., fluoroquinolone-resistant Salmonellae, fluoroquinolone-resistant Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant Priority 3: MEDIUM Streptococcus pneumoniae, penicillin-non-susceptible Haemophilus influenzae, ampicillin-resistant Shigella spp., fluoroquinolone-resistant *CDC (USA) has 18 targets in its Feb 2018 list 21 A Global issue; case - Klebsiella 22 Contents Introduction the ABPI; the biopharmaceutical industry AMR: the issue AMR initiatives and recent progress

Looking ahead Our collective efforts to develop a framework for evaluating and reimbursement antibiotic treatments started in 2013 2014 2015 Annual report of AMR risks Nov 2013: Publication of UK 5-Year AMR Strategy following CMO Report July 2014: PM commissions Jim ONeill to assess economic impact of AMR July 2014: PM briefs G7 on AMR Global report on AMR Surveillance AB Network established

Annual report of AMR risks Feb 2015: ONeill Report (Interim) Publication of Global Action Plan & Country Analysis 2016 Annual report of AMR risks National Action Plans 2017 Annual report of AMR risks Priority Pathogen list Essential Antibiotic list & Pipeline summary 2018 Development, Access &

Stewardship Framework (expected) Jan 2016: Industry Declaration Sept 2016: Industry Roadmap AMR Alliance launched Access to Medicines AMR Benchmark AMR Alliance Report; DRIVEAB May 2016: ONeill Report (Final)

EEPRU AMR joint sub-groups o Reimbursement and Evaluation o Appropriate Use and Stewardship 24 UK Five Year AMR Strategy, 2013-2018 - refresh Click to edit Master subtitle style 25 UK Five Year Antimicrobial Resistance Strategy 2013 to 2018 The 7 Key Areas for Future Action Key area 1*: improving infection prevention and control practices Key area 2*: optimising prescribing practice Key area 3*: improving professional education, training and public engagement Key area 4: developing new drugs, treatments and diagnostics Key area 5*: better access to and use of surveillance data Key area 6: better identification and prioritisation of AMR research needs

Key area 7: strengthened international collaboration *Appropriate Use workstream Reimbursement workstream 26 DHSC / industry collaboration DH / Industry Working Group on AMR DH / Industry Subgroup Appropriate Use / Stewardship Membership: DH, PHE; NHSI; ABPI, Companies Objective: to identify areas of alignment and potential collaboration between DH, PHE, NHSI and industry on the issue of stewardship and appropriate use of antibiotics DH / Industry Subgroup Reimbursement & Evaluation Membership: DH; NICE; ABPI; GSK; Pfizer; MSD;

Shionogi, J&J Objective: to explore the feasibility and potential design of de-linked models of reimbursement, together with a consideration of HTA reform for antibiotics 27 AMR A One Health Approach: Humans, animals, agriculture & the environment 28 2018 Update The commercial reality: By 1990, the diminishing return on investment was leading to a decline in investment in R&D In 1990, 18 major companies were committed to AB R&D; by 2013 this had dropped to 4 However; some activity has been stimulated since 2013 UK has had a leading voice in the global community (David Cameron, Sally Davies, Jim ONeill) AMR is a global issue, and many of our members are UK affiliates of global companies

29 2018 Update Most recently, input to: Health & Social Care Select Committee inquiry 5 year AMR strategy refresh NHS 10-year plan We work with and through other Industry associations IFPMA, EFPIA, PhRMA, JPMA 30 2018 Industry Progress AMR Industry Alliance (100 plus companies/associations) Research & Science o US$2bn invested in AMR related R&D in 2016 (across 22 companies) Appropriate Use o 80% of companies are engaged in activities to support Appropriate Use

o 90% support surveillance work Access o Supporting WHO Action plan to improve access to essential drugs Manufacturing & Environment o 24 Sep 2018: Alliance launched the first list of discharge targets to guide environmental risk assessments for the manufacture of antibiotics 31 2018 Industry Progress AMR Benchmark (Access to Medicines Foundation) Research & Development (18 companies assessed) o 40 antimicrobials (28 antibiotics) targeting priority resistant pathogens in clinical development o Vaccines against 12 of the 19 priority pathogens are either in development or on the market

o 66 out of 130 projects are being carried out in partnership Appropriate Access and Stewardship o Access is geographically broader for older products (see WHO EDL) o All 18 companies assessed conduct educational programmes around stewardship o 9 companies support surveillance programmes in a total of 147 countries Manufacturing & Production o Most companies have environmental risk management plans; discharge limits have now been agreed 32 Contents Introduction the ABPI; the biopharmaceutical industry AMR: the issue AMR initiatives and recent progress Looking ahead

What would you expect from Industry? Discover new medicines (new mechanisms/classes)? Develop new medicines, through clinical trials, formulation and manufacture, to regulatory approval? Champion Appropriate Use and stewardship support education to help make the most of what we have? Support surveillance? Investigate new/different approaches vaccines, phage therapy, oligonucleotides, microbiome transplant? Commercial reality (to do all this with diminishing returns?) o Need to create an economic environment in which investment in antibiotic R&D is

sustainable 34 What is a good antibacterial target? The target should be present in a required spectrum of organism. It should be absent in humans. It should be essential for bacterial growth. It should be expressed and relevant to be infection process. Some thing about the function of target should be known. Bypass resistance mechanisms? Completely new approaches? 35 Solutions? 36 Antibiotic resistance mechanisms and approaches to avoiding them Resistance has always been with us; Fleming warned us in 1945

Efflux pump inhibitors? Beta-lactamase inhibitors eg clavulanate/ amoxicillin 1981 tazobactam/ piperacillin 1993 Iron chelator eg cefiderocol 2018 Membrane permeabilisers? (eg PA-beta-N) 37 Antimicrobial therapy; potential new approaches Value element

Definition Antibodies; vaccines Antibodies that bind to and inactivate the pathogen, its virulence factors or its toxins; inactivated bacteria or bacterial proteins that stimulate the immune system Immune stimulation Proteins or bacterial extracts that boost the immune system

Microbiome/ probiotics Live micro-organisms (or a set of micro-organisms, incl faecal transplant) that compete with harmful bacteria Lysins Enzymes used by bacteriophages to destroy the cell walls of target bacteria Bacteriophages

Viruses to infect and kill bacteria(wild type or engineered) Oligonucleotides Transcription Factor Decoys prevent expression of genes needed for the bacteria to survive and multiply Peptides Antimicrobial (direct effect); host defence peptides (enhance host immune response); antibiofilm peptides

Antibiofilm peptides Benefits of avoiding the spread of infection to the wider population (reduced onward transmission) 38 ABPI Industry commitment to a global approach Commitment o Industry is playing its part in R&D, Access, Appropriate Use and Manufacturing o Need to maintain momentum, we have a fragile consensus, at a tipping point Collaboration

o Industry is ready and willing - with Government and all stakeholders Commercial reality o Need to create an economic environment in which investment in antibiotic R&D is sustainable Next Steps o Need to confirm commitment to market entry rewards; pilot a new economic model, de-linking reimbursement from volume usage o Maintain activity - in R&D and education for Appropriate Use o Broaden mandatory surveillance 39 Close

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