1

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

6

Alternatives Antibiotics

5/10

Alternatives to Antibiotics

7

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

8

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

9

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

10

• 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

11

Alternatives Antibiotics

TREAT OR ADJUNCT

12

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

13

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

14

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

15

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?

16

£1.5 bn >>£10 bn

17

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

18

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