Mar 9, 2015 - CMO Sally Davies, March 2013. " an. "If we fail to act, we are looking at an almost unthinkable scenario where antibiotics no longer work and ...
THREAT OF ANTIBIOTIC RESISTANCE
Chris Longshaw, PhD Associate Scientific Director, Microbiology Lunch & Learn, 9th March 2015
Positive impact of Public Heath and antibiotics on Infectious Disease…
Dawn of the Antibiotic Age
“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them…
BCE: Egyptians, Chinese etc used molds for treatment of infected wounds but did not understand efficacy 1897: Ernest Duchesne describes inhibition of E.coli by Penicillium glaucum 1928: Discovery of Penicillin from Penicillium rubens 1932: First antimicrobial „Prontosil‟ a sulphonomide from azo dyes 1943: Selman Waksman discovers Streptomycin and coins term „Antibiotics‟
There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to nonlethal quantities of the drug make them resistant” Sir Alexander Fleming, Nobel Prize speech, 1945
Antibiotic resistance in the News
“Antibiotic resistance as big a threat as Terrorism..” CMO Sally Davies, March 2013 “The post-antibiotic future means, in effect, the end to modern medicine as we know it…things as common as strep throat or a child‟s scratched knee could once again kill” Dr. Margaret Chan, Director General of the World Health Organization, March 2012
""If we fail to act, we are looking at an almost unthinkable scenario where antibiotics no longer work and we are cast back into the dark ages of medicine where treatable infections and injuries will kill once again.“ PM David Cameron, July 2014
Now antibiotics have value to society from cradle to grave
White A. et al., Effective antibacterials – at what cost? J Antimicrob Chemother. 2011;66(9):1948-53
“Left unchecked, the current trend in rising drug resistance is a crisis of global scale”
“Initial research, looking only at part of the impact of AMR shows that a continued rise in resistance by 2050 would lead to 10 million people dying every year and a reduction of 2% to 3.5% in Gross Domestic Product (GDP). It would cost the world up to 100 trillion USD*”. Jim O’Neill. Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014.‟ http://amrreview.org/publications
A history of antibiotic discovery (and resistance)
DISCOVERY VOID
Bacteria have a limited number of targets for antibiotics…
“That which does not kill me, makes me stronger” Friedrich Nietzsche, 1888 Spontaneous resistance -Target mutation - clonal spread
Acquired - resistance genes/operons - spread via plasmid or virus
Antibiotic Resistance in Europe (2012) MRSA
Klebsiella pneumoniae Carbapenem Resistant/Intermediate
Escherichia coli ESBL
Klebsiella pneumoniae MDR (3GC, FQ, AG)
Pseudomonas aeruginosa Carbapenem Resistant/Intermediate
Source: European Centre for Disease Prevention and Control (ECDC). Accessed Nov 2014
Pan-resistant bacteria exist already
Outbreak in NIH Medical Centre in 2011 resulting in 18 patients with 6 deaths linked to resistant strain. Snitkin et al (2012). Tracking a Hospital Outbreak of Carbapenem-Resistant Klebsiella pneumoniae with Whole-Genome Sequencing. Sci Tranl Med doi:10.1126/scitranslmed.3004129
How did we get in this position?
Many European countries still overuse antibiotics
Antibiotic consumption is highest in Developing world…as is Resistance • Between 2000 and 2010, consumption of antibiotic drugs increased by 36% • Brazil, Russia, India, China, and South Africa accounted for 76% of this increase • Increased consumption of carbapenems (45%) and polymixins (13%), two last-resort classes of antibiotic drugs
1. Lancet Infectious Diseases, 14 (8): 742 – 750 (2014). Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data 2. Lancet (2005) 365: 1175-1188. Hospital acquired neonatal infections in developing countries. 3. NATURE (2012); 489 : p. 192 India moves to tackle antibiotic resistance
Challenges in low-income countries • High background morbidity and mortality of infectious disease – competing challenges • Many patients don‟t have access to effective antibiotics, but often uncontrolled XS use • Poor sanitation and hygiene – 2 million people bathe in Ganges every day
„Farmed and Dangerous..?‟ Antibiotics not only for human health
Source: The Pew Charitable Trust
„Everywhere you go…always take the weather „resistant bugs‟ with you…!!‟
• Globally, 8 million people fly each day • Each passenger transports 1 kilo of bacteria (some resistant) in their gut Woerther P et al. Clin. Microbiol. Rev. 2013;26:744-758
Bacteria don‟t respect national boundaries…
“Don‟t worry, it‟ll be OK…Pharma will just develop new antibiotics like they always do”
Boucher HW, et al. Clin Infect Dis. 2013;cid.cit152
Global pipeline analysis, all therapeutic areas (ATC1), as of February 2014
Source: IMS Health Lifecycle 2013
Not a decline in Pharma R&D per se, but shift of focus away from antibiotics…
Infections can be caused by lots of different types of bacteria…
…and in many different parts of the body
Currently, each potential indication needs its own Phase 3 trials and regulatory approval… even if identical target pathogen
For antibiotics, the low hanging fruit have already been picked
Classical antibiotic discovery suffered from Law of Diminishing Returns and promises of „Genomic revolution‟ did not deliver
Developing new antibiotics takes a lot of time and investment
250
REVIEW
COMPOUNDS Phase II
ONE APPROVED DRUG
Phase III
NUMBER OF VOLUNTEERS 20 - 100 100 - 500 1,000 – 5,000
6 – 7 YEARS
NDA SUBMITTED
Phase I
3 – 6 YEARS
LG SCALE MFG
5
IND SUBMITTED
PRE - DISCOVERY
5,000 – 10,000
CLINICAL TRIALS
0.5 – 2 YEARS
PHASE 4: POST-MARKETING SURVEILLANCE
PRECLINICAL
DRUG DISCOVERY
To bring a new antibiotic to market takes 10-15 years… … and an investment of $600-$1 billion! Adapted from a slide from Barry Eisenstein, Cubist Pharmaceuticals
Therapeutic area influences drug development costs - Anti-infectives and CNS most costly
Common figure of $1 billion per drug Revised (2014) estimate = $2.9 billion - R&D expenditure =$1.4 billion - Time cost to investors = $1.16 billion - Post approval research = $0.3 billion Source: Tufts Centre for Study of Drug Development Nature reviews Drug discovery 2004 (3) p466
Unlike other therapy areas…uptake of new antibiotics is slow. Novel antibiotics are reserved as “last resort” treatment for small patient groups Empiric treatment usually starts with a broad-spectrum antibiotic
Switch antibiotic upon availability of culture results or treatment failure
In serious infections where a delay in treatment could be fatal, a judgement is made as to which broad-spectrum antibiotic(s) are suitable
Share of new class antibiotics (billion standard units in 2011)
Others medium and narrow-spectrum penicillins etc.
Where the pathogen is identified, specialists may switch to antibiotic(s) more appropriate for that pathogen
Broad-spectrum penicillins Amino-glycosides Macrolides Fluoro-quinolones Cephalosporins Carbapenems
Innovative antibiotic
New and innovative products tend to be RESERVED as last option to ensure appropriate use and minimize risk of resistance
28 Source: IMS Consulting Group report for AstraZeneca from December 2011
New classes Standard units
Every pound invested today is worth less when reimbursed in 10-12 years time… (Spend) Revenue by year
€200
€200
€100
€100
€0
€0
-€100
-€100
-€200
-€200 -€300
5 yr
8 yr
Disc.
Ph 1-3
20 years On market
Source: Citeline Pharma R&D Annual Review, 2014
-€300
But in NPV terms, it is …
5 yr
8 yr
Disc.
Ph 1-3
20 years On market
Similar number of companies in 2013 as in 1960
So is there light at the end of the Tunnel?
1,400
2.2
1,308
1,200
2.0
1,000 1.8
821 800
663 600 400
638
1.6
622
494 379
332
386
1.4
368 257
248
291
236 165
200
170
0
126
1.2
Ratio of pipeline products to originators
Number in clinical development Phase I to Pre-registration
ID still has a relatively rich pipeline, beaten significantly only by oncology
85 1.0
Number of products
Number of originators
Source: Citeline Pharmaprojects, August 29, 2014. Products are those in clinical trials from Phase 1 to pre-registration but not launched in any other indication.
ratio of products to originators
32
ID still has the best Phase 2 survival rate – markedly superior to that of oncology 80 68
70
67
65
63 61
60
Success in phase (%)
53 50
46
45
40 34
34
30 28
30
26
28
20
10
0 Infectious diseases
Autoimmune
Endocrine Phase II success
Respiratory
Neurology
Cadiovascular
Oncology
Phase III success
Phase transition success rates, 2003-2011 Source: BioMedTracker phase transitions 2003-2011, taken from Hay et al. (2014) Clinical development success rates for investigational drugs. Nature Biotechnology,32 (1): 40-51 .
33
Increasing scientific, public & political focus on antibiotic resistance and dry R&D pipeline…
Global Leadership is becoming active..! ECDC/EMEA Joint Technical report on AMR (2009)
UK DH starts update of 2002 AMR Strategy Launch of EU Antibiotic US GAIN Awareness act (QIDP) Day (EAAD)
IDSA Bad Bugs, No Drugs (2004)
BSAC Urgent BSAC Need launch Initiative Antibiotic Action
2009 2010
2011
2012
DH 5 Year AMR Strategy AMR at G8 summit
CMO Dame Sally Davies publishes Chennai Declaration Report on AMR IMI launch ND4BB initiative (1-3)
2013
WHO report on AMR
CDC report on Emerging threat from AMR
DRIVE-AB Science & Project Technology Starts Select Committee Report on AMR UK APPG on AMR
Launch of ND4BB DRIVE-AB PM launches Commission on AMR (Jim O‟Neill) -Interim June 2015 -Full report 2016
2014
O’Neill Review on AMR (UK) A. Set up a global AMR innovation fund to boost the number of early research ideas B. Make sure we are getting the most of out of existing drugs C. Improve the use of diagnostics wherever they can make a difference D. Attract and retain a high calibre skills base E. Modernise the surveillance of drug resistance globally „Review on Antimicrobial Resistance. Tackling a Global Health Crisis: Initial Steps. 2015. http://amr-review.org/publications
New Research Grants supporting AMR Government funding: • BARDA Direct Funding streams: • EU Joint Programme Initiative – AMR • UK Longitude prize for rapid diagnostics of AMR (£10 million) • Obama prize for POC diagnostics ($20 million) Public-Private Partnerships: • Innovative Medicines Initiative (EU/EFPIA)
New legislation a catalyst for recalibrating ID NPVs Capitalize on new legislation and improve ROI by in-licensing products eligible for GAIN and ADAPT Impact of US regulation/legislation on ID product lifecycles 4
5
3
Investment period
Return period 2
1
GAIN (QIDP) ADAPT (LPAD)
11 Development time
Development cost
33 Time to market
?
?
BARDA incentives
Orphan drug legislation
2 2
4 4 Volume sales
5 5 Exclusivity
38
Regulatory pathways are improving
Rex J et al (2013). Lancet Infect Dis. 13: 269-275
Wave of activity in ID drug development
Dozens of companies successfully obtain QIDP status for their products Cystic fibrosis
C. difficile infection
Respiratory P. aeruginosa Gonorrhea
Resistant orthopedic implant infections
MRSA
ABSSSI
CAP
Complicated UTI Pseudomonas aeruginosa
HAP KEY Companies with FDA approval for QIDP designated products
VAP
Adjunct to IV
Non-TB pulmonary mycobacteria
Complicated intra-abdominal infection
Invasive candidiasis and aspergillosis
Next Generation Diagnostics may be a game-changer The archetypal anti-infective model is shifting towards precision pharma
• Diagnostic capabilities are pushing infectious disease management into in an increasingly fragmented “precision” healthcare setting • This will mean massive reductions in both numbers of patients treated empirically, and potentially substantial reductions in volumes of product used per patient • This is likely to mean an end to the blockbuster empiric anti-infectives, and the start of the separation of a product’s clinical capabilities and its actual applications • Concurrent and broad-ranging indications are likely to be seen as an increasing burden, rather than an advantage, as the “one-size-fits-all” high volume approach to antimicrobials is replaced by more robust antimicrobial stewardship
41
Non-Industry Partners
EFPIA Partners
http://drive-ab.eu/
How do we win the war against infectious disease…? • Reduce global consumption and mis-use of antibiotics – Animals & plants – Human medicine • Improve sanitation in developing countries • Quicker diagnosis of bacterial infection and resistance so patients treated with right drug • Better infection control to prevent resistance spread • Increased R&D into new antibiotics and alternatives (vaccines, virulence inhibitors, resistance breakers) • Revolutionise anti-infective market – de-link return from sales
Thank you for your attention
