1. Developing new approaches to treating multi-drug resistant infection “A journey of a thousand miles starts with a single step”- Lao-tzu (604 BC - 531 BC) David Cook Chief Scientific Officer

2. Blueberry Therapeutics Blueberry Therapeutics… Our Vision: Bring high value and innovative medicines to the market that make a positive difference to patients Our Mission: Exploit new advances in nanotechnology to develop new therapies Create a viable business able to invest long-term in tackling the huge healthcare issues of antibiotic resistance in infectious disease

3. Blueberry Therapeutics Current Portfolio *Do not require clinical development Blueberry aims to successfully deliver its OTC portfolio: 1.To generate revenue to the benefit of shareholders and to support investments in higher risk projects 2.To build knowledge and expertise around the platform

4. Blueberry Therapeutics Thinking about new ways to tackle MDR infections - The “5Rs” Cook et al. Nature Reviews Drug Discovery 13, 419–431 (2014)

5. Blueberry Therapeutics We do not lack knowledge of the “Right Target” Lots of well validated targets with historical precedent of their therapeutic exploitation For anti-bacterial effects, good translation of screens to the clinical setting If resistance is the problem…then treat resistance Many resistance gene products are well described Provide adjunct therapies to allow reuse of well described, clinically validate antibiotics Precedent for this approach e.g. augmentin (clavulanic acid) Blueberry strategy - focus on well validated targets and mechanisms of resistance

6. Blueberry Therapeutics We are lacking new molecules(!)

7. Blueberry Therapeutics Barriers to developing new molecules Dealing not just with patient PK/PD but also bacterial PK/PD Need to optimize bacterial exposure before we can test for efficacy New series against old targets have proven remarkably hard to find Some attractive targets are not always amenable to small molecule pharmaceutical intervention Safety is a problem Limits exposure - is this really a problem of poor efficacy? Are there alternative therapeutic approaches that have not been fully exploited?

8. Blueberry Therapeutics Might protein-based therapeutics offer new opportunities? Protein based therapeutics have a lot of potential IF we can overcome the problem of cell delivery Small Molecule TherapeuticsProtein Therapeutics Typical development cycle to generate a high quality lead 1-3 years6-12 months Range of pharmaceutical modalities LimitedExtensive Safety considerations Xenobiotic: every molecule has unique safety profile Target, off-target and compound safety to consider Based on naturally occurring amino acids. Safety concerns mainly focus on target based liabilities Use in diagnostics LimitedExtensive Target accessibility Intracellular Extracellular Intracellular Extracellular

9. Blueberry Therapeutics Using Nanotechnology to overcome the delivery problem Massively enhances delivery into cells, tissues and microbes Utilising Nanocin™ we can overcome the problem of cell delivery of protein therapeutics, opening up a new class of compounds for development as antibacterial agents and antibiotics: intracellular biologics Nanocin™: A non-lipid based cationic nanopolymer with high hydrogen binding capacity. Over 30 years safe use in human health. Rapidly self assembles into nanoparticles with cargo molecule to form nanoparticles in the 40nm -200nm range Can package a range of molecules including peptides and proteins

10. Blueberry Therapeutics …starts with a single step: targeting PBP2a in MRSA MRSA is a hospital and community acquired infection that can cause major complications Resistance is conferred when SA acquires the MecA gene –Codes for the PBP2A protein –A PBP with greatly reduced sensitivity to beta-lactam antibiotics Develop peptide-aptamers specifically targeting PBP2A –Target the mechanism of resistance directly Deliver these into a range of clinical isolates of MRSA using Nanocin™ Can we restore MRSA sensitivity to beta-lactam antibiotics e.g. oxacillin?

11. Blueberry Therapeutics Peptide aptamers Developed several high affinity peptide aptamers that bind PBP2A Based on two different scaffolds –Avacta Ltd –Leeds University Small (~80aa) Stable and robust scaffolds Easily produced in E. coli Can rapidly screen large libraries: >3x10 10 No disulphides Rapidly generate high affinity binders Characteristics of peptide aptamers: Use as pharmaceuticals and in diagnostics Image courtesy of Darren Tomlinson University of Leeds Variable region Scaffold (constant region)

12. Blueberry Therapeutics Restoration of oxacillin sensitivity in MRSA by peptide aptamers targeting PBP2a

13. Blueberry Therapeutics How do we identify the “Right Patients”? Current focus on development of broad-spectrum antibiotics Better point-of-care diagnostics would allow the development of narrow-spectrum drugs –Tailored to target the pathogen –Reduced the “burden” required for a new drug –Require the development of parallel specific therapies Reduce bystander effects on normal bacterial colonization (preserve the “microbiome’) Peptide-based therapeutics can also potentially be used for diagnostic purposes –parallel development of treatment and companion diagnostic

14. Blueberry Therapeutics What is the “Right Commercial Potential” for new approaches? We have been used to the availability of “cheap, broad-spectrum agents” New therapies would be “kept on the shelf for emergencies” –Limits market, drives up costs for treatment and impacts attractiveness to drug developers Need to evolve our models to allow us to create the environment which encourages the development of new therapies with which to tackle MDR infection –Payer models and health economic considerations –Business models Improved diagnostics is again a key ingredient –The “Right Patient” gets the “Right Treatment” –Our therapeutic approach has both diagnostic and treatment potential

15. Blueberry Therapeutics Learning from oncology Move away from general “broad spectrum” approaches (e.g. chemotherapy, radiotherapy) –These therapies are still routine parts of treatment Better disease understanding and diagnostics have enabled development of targeted therapies R&D concentrates on “narrow spectrum” treatments Oncology treatment value model based on frameworks like QALY (Quality Adjusted Life Years) Our product vision: tailored treatments curing patients of a life-threatening infection and returning them to many years of productive, high-quality life

16. Blueberry Therapeutics A journey of a 1000 miles…

17. Thank you www.blueberrytherapeutics.com