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Key questions to ask
What if there were no new:• Antibiotics?• Antibiotic classes?• Targets?
Is resistance the only problem?What are the alternatives to antibiotics?
What if there are no new antibiotics?
Highlights of a Wellcome Trust & Department of Health (England)initiated & sponsored
review & reportinto
“Alternatives to Antibiotics”
SWON Industry Workshop23 Sept 2016
Dr Lloyd Czaplewski
Alternatives Antibiotics
Alternatives to Antibiotics (A2As)
• Review scope– Non-compound approaches that target bacteria– Approaches that target the host
– Suitable to treat systemic or invasive infection– Administered intravenously, orally or by inhalation– Mono-therapy, combination therapy and/or
prophylactic use– External topical administration excluded
• Formation of a Working Group to consider and to provide a consensus on A2As to inform development of policy in the AMR area
The Working Group (24)
Generalists A2A SpecialistsMartha Clokie
Heather Fairhead
Vince Fischetti
Simon Foster
David HarperIan Henderson
Bob HancockKai Hilpert
Chris Thomas
Brian Jones
Aras KadiogluBrendan Gilmore
Sunil Shaunak
John Rex
Lloyd Czaplewski
Trevor Trust
Richard Bax
Steve ProjanJared Silverman
David Knowles
Sigga OlafsdottirMike Dawson
David Payne
Peter Warn
Review process
• 50-page technical report on 19 A2A approaches • Meeting at the Wellcome Trust 10 December 2014• Collective email “debate” & iterative maturation of the technical report• Transformation of the report into a “consensus” Lancet ID manuscript• Publication of the review in Lancet ID online Jan 12 2016
Lancet Infectious Diseases Volume 16, No. 2, p239–251, February 2016
A2As versus traditional approaches
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Alternatives Antibiotics
5/10
Alternatives to Antibiotics
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Mat
urity
Time
Widely adoptedMature market
A2AsDiscoveredEfficacy in an animal modelPatentedPublishedAlmost a therapy
Led by innovators/visionaries
A2AsUnprovenDon’t understand the risksNeeds wider evidence baseOnly 6 published PK studies and 2 safety studiesCommercially unattractiveClinical trials largely negative
Where are A2As?
Portfolio analysisProbability of success
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Phase Preclinical Phase I Phase II Phase III RegistrationYears 5 1 2 3 1
Stage probability of success
23% 45% 47% 71% 90%
Accumulative probability of success
23% 10% 4.7% 3.3% 3%
Cost of Phase £m 12.5 6 10 45 1.3
Alternatives Antibiotics
LysinsTreat
Approach Probability of Registration by 2025 and Sponsor
Target Recommended pipeline investment to enable additional Phase 2 validationand Name
Phase at Q1 2015
Earliest Anticipated Registration
Lysins 26% £135m Intron
BiotechnologyS. aureus SAL200 P1 ongoing 2022
Contrafect S. aureus CF-301 P1 ready 2022
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Phase Preclinical Phase I Phase II TotalStage probability of success 23% 45% 47% Rounded number of projects
9 2 1
Cost of Phase £m 12.5 6 10 Portfolio cost £m 112.5 12 10 £134.5
Alternatives Antibiotics
TREAT
AntibodiesPrevent
Approach Probability of Registration by 2025+ and Sponsor
Target Recommended pipeline investment to enable additional Phase 2 validation and Name
Phase at Q1 2015
Earliest Anticipated Registration
Antibodies 170% - Merck C. difficile MK-3415A P3 ongoing 2017 MedImmune S. aureus MEDI4893 P2 ongoing 2021 Aridis P. aeruginosa AR-101 P2a
complete2021
Aridis S. aureus AR-301 P2a ready 2022 MedImmune P. aeruginosa MEDI3902 P1 ongoing 2023 Aridis P. aeruginosa Aerucin IND ready 2025
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• Antibodies are being developed to prevent infection• May find use as adjuncts in combination with antibiotics• Not currently being developed to replace antibiotics
Alternatives Antibiotics
PREVENT
Antimicrobial PeptidesTreat or Adjunct
Approach Probability of Registration by 2025 and Sponsor
Target Recommended pipeline investment to enable additional Phase 2 validation and Name
Phase at Q1 2015
Earliest Anticipated Registration
Antimicrobial Peptides
52%* £135m?
Roche/Polyphor P. aeruginosa POL7080 P2 ongoing 2022 Novacta
BiosystemsC. difficile NBV302 P1 ongoing 2022
Adenium S. aureus AP-138 Pre-P1 2023 Adenium UTI AP-139 Pre-P1 2023 Adenium C. difficile AP-114 Pre-P1 2023
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Alternatives Antibiotics
TREAT OR ADJUNCT
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Bacterial versus host targeting
• Direct targeting of bacteria a more traditional approach• Targeting host is innovative but….
– Side-effects– Potency– Polymorphisms– Immunocompromised patients– Suitability of animal models - need for non-human primates?– Costs/risks
Alternatives Antibiotics
Host Defense/Innate & Antibiofilm Peptides
Approach Probability of Registration by 2025 and Sponsor
Target Recommended pipeline investment to enable registration
Phase at Q1 2015
Earliest Anticipated Registration
Host Defense & Antibiofilm
Peptides
0 Gram-ve and Gram+ve
£604m Preclinical
2027
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Phase Preclinical Phase I Phase II Phase III Registration TotalStage probability of success
23% 45% 47% 71% 90%
Rounded number of projects
34 8 4 2 1
Cost of Phase £m 12.5 6 10 45 1.3 Portfolio cost £m 425 48 40 90 1.3 £604
Alternatives Antibiotics
ADJUNCT
Given the current A2A portfolio we cannot expect a new therapeutic to treat systemic or invasive bacterial infection within the next 10 years
ApproachProbability of registration by
2025 %First in man use Target bacteria
Antibodies 170 Prevent P. aeruginosa, S. aureus, C. difficileProbiotics 124* Treat or Prevent C. difficileLysins 26 Treat Gram-positive & Gram-negative?Bacteriophages 9 Treat P. aeruginosa, C. difficileImmune Stimulation 43 Prevent or Adjunct C. difficile, Broad-spectrumVaccines 188 Prevent C. difficile, P. aeruginosa, S. aureusPeptides <20 Treat or Adjunct P. aeruginosa, C. difficile, S. aureus
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With adequate funding into antibodies, probiotics and vaccines, we expect
registration of:-1 new medicines for C. difficile (probiotic and antibody or vaccine) by 2019
1 for P. aeruginosa (antibody or vaccine) by 20211 for S. aureus (antibody or vaccine) by 2022
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The A2A experiment
• Antibiotics have provided multiple medicines over 70 years & a huge investment• A2As have not had the same investment• Insufficient experience and literature of preclinical to clinical transition• Clinical potential unproven• Challenging investment argument
• BUT potentially a new source of medicines
• Identify which approaches are most attractive; • Develop diagnostics to enable use of targeted therapies• Refocus healthcare from treatment to prophylaxis• Multiple products will be required to replace a single antibiotic• Funding should focus on market pull rather than research push• Invest in experimental clinical medicine not just drug discovery• Develop A2A networks and a more collegiate approach• Without adequate funding we cannot act as if there will be replacements for antibiotics
Opportunity – just not enough activity?
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£1.5 bn >>£10 bn
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Achieving impact
• Proactive marketing– Emailed 765 in academia, industry, government, non-governmental, charities, policymakers– LinkedIn >1200 connections– Facebook– Twitter, posts, likes, retweets
Lancet Infectious Diseases Volume 16, No. 2, p239–251, February 2016
• O’Neill AMR Team – Article informed the Vaccine & Alternatives report (11 th Feb 2016)– A2A’s to be treated on par with antibiotics with access to the
proposed Global Innovation Fund
• Elsevier Atlas Award for research impact• Top 2% of article reads & downloads• Twitter/Facebook• Top 5% of all research outputs scored
A2A Review/Lancet ID Article Impact
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DNDi/GARD
Solving the problem of antibiotic resistance
• Partnerships• experience, skills and insights
• International• Coordinated• Sustained• Generational challenge• Big science budgets
LHC £6 bn ISS £96 bn>>£10 bn