Download Dave Cook, Blueberry Therapeutics

David Cook
Chief Scientific Officer
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)
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
Blueberry Therapeutics
Current Portfolio
Risk Profile
Acute Wounds
BB1601
L
Tinea Pedis
BB2603
L
Acne Cream
BB2312
Topical Biologic*
Device*
Small Molecule*
Tropical Biologic*
M
Onychomycosis
BB0305
H
Atopic
Dermatitis
BB2702
Peptide therapeutic
H
IBD
BB0109
Peptide therapeutic
H
MDR
BB5000
Small molecule
Prescrip on
Peptide therapeutics
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
Blueberry Therapeutics
Over the counter
L
Launch
MARKET
Acne wash
BB2300
Clinical
Rapid to market
L
CTA/IND
Preclinical
*Do not require clinical
development
Thinking about new ways to tackle MDR infections - The “5Rs”
Cook et al. Nature Reviews Drug Discovery 13, 419–431 (2014)
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
Blueberry Therapeutics
We are lacking new molecules(!)
Blueberry Therapeutics
Barriers to developing new molecules
•
•
New series against old targets have proven remarkably hard to find
Some attractive targets are not always amenable to small molecule
pharmaceutical intervention
•
•
Dealing not just with patient PK/PD but also bacterial PK/PD
Need to optimize bacterial exposure before we can test for
efficacy
•
•
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?
Blueberry Therapeutics
Might protein-based therapeutics offer new opportunities?
Small Molecule Therapeutics
Protein Therapeutics
Typical development cycle to generate
a high quality lead
1-3 years
6-12 months
Range of pharmaceutical modalities
Limited
Extensive
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
Limited
Extensive
Target accessibility
Intracellular
Extracellular
Intracellular
Extracellular
Protein based therapeutics have a lot of potential IF we can overcome the
problem of cell delivery
Blueberry Therapeutics
Using Nanotechnology to overcome the delivery problem
•
Nanocin™: A non-lipid based cationic nanopolymer with high hydrogen binding capacity. Over 30 years safe
use in human health.
•
Free drug: small
number of polydispersed
particles
•
Nanoparticles
containing drug:
large number of monodispersed particles
•
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
Massively enhances delivery into cells,
tissues and microbes
Red fluorescent protein
delivered into human cells
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
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?
Blueberry Therapeutics
Peptide aptamers
Characteristics of peptide aptamers:
Variable region
Small (~80aa)
Stable and robust scaffolds
No disulphides
Easily produced in E. coli
Can rapidly screen large libraries: >3x1010
Rapidly generate high affinity binders
Use as pharmaceuticals and in diagnostics
•
•
Scaffold (constant region)
Image courtesy of Darren Tomlinson University of Leeds
Developed several high affinity peptide aptamers that bind PBP2A
Based on two different scaffolds
–
–
Avacta Ltd
Leeds University
Blueberry Therapeutics
-
-
+
-
MRSA
300
MSSA
Restoration of oxacillin sensitivity in MRSA by peptide aptamers
targeting PBP2a
+
+
+
Aptamer 1
+
-
+
+
+
+
-
+
+
+
+
-
+
MIC [Oxacillin] ug/ml
250
200
150
100
50
0
Control
Scaffold 1
Blueberry Therapeutics
Aptamer 2
Control
Scaffold 2
+ Nanocin
+ Aptamer
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
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
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
Cancer
Lung cancer
Non-small cell lung cancer
EGFR +ve NSCLC
•
R&D concentrates on “narrow spectrum” treatments
Bacterial Infec on
Current treatment paradigm
Gram+ve bacterial infec on
S. aureus infec on
MecA +ve MRSA infec on
•
•
Treatment
Treatment?
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
Blueberry Therapeutics
A journey of a 1000 miles…
Broad spectrum an bio c
Pa ent
Diagnos c screening
casse e
Aptamer
treatment panel
Nanopar cle
formula on
Tailored
therapy
An bio c
Rest inhb
+
• ID of mechanism
• Addi on to diagnos c
casse e
• Development of new aptamer
• Addi on to treatment panel
W
Emergence of new
resistance
Blueberry Therapeutics
Rapid Discovery and Development
Loop
?<4 Years
Thank you
www.blueberrytherapeutics.com