Download Phylogica - Moodle Lille 2

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BUSINESS
MODEL
March 14th 2013
Alexandre Chavatte - Julie Mouton
Hélène Pauchet – Céline Renard
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PLAN
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•
•
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Introduction
Technology
Partnership
Examples of applications
Financial situation
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Introduction
-
What is Phylogica?
-
Historic
-
Management team
Introduction
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
Phylogica is a biotechnology company based in Perth, Australia
and
Oxford,
peptides,
there is UK.
around a USD 2 million sign-on fee, then there are milestone payments of
up to USD 150 million which the company will receive if any compounds make it to market.
This can include around USD 10 million when a Phase II trial commences and around USD
20 million at the start of a Phase III trial. The company will also receive somewhere between
3%-5% royalties from any future sales of products.
The company aims to capitalize on recurring revenues from its partnerships with

pharmaceutical companies, which enabled it to achieve profitability as early as next year and
Provides
peptide drug discovery services to the Pharmaceutical
fund internal R&D activities.
industry.
Historic
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
Collaboration between
&
Perth, Western Australia

Philadelphia, USA
Was spun out in 2001.
&

March 2005
Frankfurt Stock, Germany

Currently 25 employees
Historic
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Phylogica partnered with researchers from the University of
Cambridge in a spin-off company named Phenomica.
combination of Phylogica’s Phylomer® libraries with
technology from Cambridge to identify vulnerable points in a disease
that can be the focus for new drug development.
Management team
Dr Doug
Wilson
Executive
Chairman
CEO
Dr Paul Watt
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Mr Nick Woolf
CFO & VP Corporate
Development
Dr Richard
Hopkins
COO and VP
Research
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Technology
•
Phylomer®
•
Screening
•
Applications
Using Phylomers to expand the
druggable landscape
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Technology = Phylomer®
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
New class of biological therapeutics

Bioactive fragments of naturally occurring proteins that
are encoded in the genomes of evolutionary diverse
microbes.

Highly enriched for stable secondary and tertiary
structures

Act as high affinity peptide disruptors of protein-protein
interactions and binders of protein targets.
Target validation tool
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Origin of Phylomer® Peptides
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From 25 characterised bacterial genomes we have derived up to 260 million
distinct Phylomer® peptides from thousands of protein structural folds
Source of Phylomer® Peptides
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Diverse and often harsh environments
 volcanic streams
 geysers
 deep sea volcanic vents


Subject to intense natural selection  optimal
protein structures required for cell survival
Thermophile genomes may encode more
thermostable folds
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Phylomer properties
•
•
•
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Structure
Stability
Immunogenicity
Efficacy
Technology = Phylomer®
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
Encoded structural motifs within Phylomer® sequences
may allow stable folding as they bind to a particular
target (via an induced fold), even if peptides don’t fold
autonomously by themselves
Pharmacological properties:
Stability
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RETROINVERSO
Retro inverso peptide
Inverso peptide
Retro peptide
Pharmacological properties:
Stability
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RETROINVERSO

plasma stability with more than 50 % of the Phylomer
peptide present after 12 hrs incubation (vs 10 to 30 min for
unmodified phylomer)

Protease-resistant in human plasma

In vivo half-life without further modification (eg :
PEGylation)
Pharmacological properties:
In vitro stability
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Pharmacological properties:
Pharmacokinetic in rats
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InSymbiosis, Canada
In vivo Phylomer® half-life
Pharmacological properties:
Immunogenicity
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In silico testing against :
 Multiple HLA

MCH Class II
- More than 60% of Phylomer® peptides were not modeled
as significantly immunogenic
- More than 85% of Phylomer® peptides, including PYC35
and PYC36 were potentially less immunogenic than
currently marketed peptide drugs
Efficacy
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
Global model of ischemic stroke

Focal cortical model of CNS injury

Full thickness burns model

Inhaled LPS model of ARDS
Synthesis
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Pepsets
Synthetic
High Purity
Synthesis
Recombinant
Protein
Synthesis
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Screening
From phenotype to pharmacophore
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Phylomer screening
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Intracellular targets:
Forward two hybrid, Reverse two hybrid

Extracellular targets:
Lytic Phage Display (T7) , Secreted Phage Display (M13)


Phenotype driven: synthetic Phylomer library

Mammalian expression vector (phenotypic complementation)
Sreening extracellular target using phage display
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médecine/sciences 1998 ; 14 : 300-9
Screening intracellular targets using yeast
two-hybrid assays
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Target discovery screening method
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Arrayed Phylomer Libraries
Phenotypic screen in mammalian
cells
Target identification
Validate target
Structural studies to determine
binding interface
Phylomer against intracellular targets
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
Activator protein-1 (AP-1) signalling pathay


MAL/TLR signalling pathway


AP-1 is a transcription factor involved in cancer and
inflammatory diseases
MAL is implicated in a range of infectious and other
diseases
Sonic hedgehog pathway
Sonic hedgehog is involved in cancer and other
diseases

Phylomer against extracellular targets
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
Screening Phylomers® to inhibit the function of targets that play a
crucial role in inflammation :

TNFα

CD40

CD28 receptor

GM-CSF
Phage display identifies target-specific hits
Evaluation of relative binding and specificity using Phage ELISA
Interests
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Highest functional hit
rates for peptides
Higher stability
More structural diversity
(contain multiple scaffold
classes)
Can be used for
intracellular and
extracellular disease
targets
Alternative delivery
potential (Patient
Friendly) inhaled, buccal,
transdermal, nasal, oral
delivery routes
Easy to Synthesis:
Reduced costs
Bio-informatic advantages
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Partnership
•
•
•
Technology partners
Pharmaceutical partner
License and agreement
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Technological partners
WHY?
1)
Stability
2)
Structural diversity
3)
Optimization
1) Stability
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Computer model of a PASylated Fab fragment

German biotech company

The revolutionary 'PASylation' technology :
a biological alternative to PEGylation for biopharmaceuticals with extended
plasma half-life

‘PASylation’ = Pro/Ala-rich Sequences composed of Proline, Alanine, and
Serine

L- amino-acids  PAS left

can be fused with a therapeutic protein or peptide
1) Stability
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Similar to PEG: PAS sequences adopt a stable random
structure with large hydrodynamic volume
 size of the resulting fusion protein
 size beyond the threshold of kidney filtration
 prolongation of the half-live
PASylation with 200-600 residues leads to a plasma half life
extension by a factor of 10-100 !
Drawbacks of PEG:
- Expensive
- PEGylation can change the protein properties
- In vitro: additional procession and purification steps (lower the yield, raise the cost)
- Decomposition by oxidation upon storage, not biodegradable  side effects
1) Stability
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2) Structural diversity
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 Dutch biopharmaceutical firm focusing on protein mimicry technology
 CLIPS technology
To optimise novel therapeutic Phylomer drug candidates against CD40-ligand for the
treatment of rheumatoid arthritis and other disease-associated targets
 CLIPS = Chemical Linkage of Peptides onto Scaffolds
 To mimic discontinous active sites

Performance of a peptide:
binding activity and/or a proteolytic stability
Majority of small peptides (20-30 AA) : lack a well-defined secondary structure in solution
CLIPS : a conformation story
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CLIPS technology…allows protein to be locked into a desired biologically
active conformation including alpha-helice, loop, double loop, triple loop
A little chemistry…
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The orange ball is a synthetic peptide
Reaction:
 lasts no longer than 30 min
 runs at room temperature
 no catalysis
 hight yields
 one step
Scaffolds :
 they have to be composed of:
1 phenyl ring with 2 bromo methyls groups
 they have to be soluble in aqueous solvents
 It would be preferable to use a non-chiral
scaffold
Pepscan = 70 different types of Clips-scaffolds
varying mainly in polarity, solubility and thiol-thiol spanning distance
3) Optimization
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 UK company
 CIS display technology:
rapid construction of new peptide, polypeptide and antibody libraries and the
selection of lead compounds.
Aim of the cooperation: Optimize the performance of three of
Phylogica’s lead
optimize the exact chemical and three dimensional structure
improving drug properties such as affinity, stability and potency
Cis display
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CIS display is an acellular, in vitro display
technology

Uses biochemical process of E. coli

No cloning, therefore larger librairies (> 1013)
are rapidly generated

CIS display is a powerful discovery engine for
peptides and other protein scaffolds
Cis display
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Pharmaceutical Partners
Payment
December 2009
Aim
cell-penetrating peptides
for delivery across the
blood-brain barrier.
Extended in May 2011
August 2010
$1.5 millions
to discover novel
antibiotic peptides for the
treatment of hospital
acquired infection
December 2010
$0.5 millions
11/12: Phylogica received
an undisclosed milestone
payment for successfully
completing the first stage
of the collaboration
to discover novel peptide
vaccines
December 2011
$1.7 millions
to develop multiple
Phylomer -based drug
candidates using novel
cell-penetrating peptides
Extended in january 31,
2013
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License and agreement
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September 12, 2012
Phylogica has licensed
its skin-repair
Phylomer® peptide
PYC35 for use in
cosmetics products.
anti aging cream
February 05,2013
Phylogica has entered
an agreement to
commercialise a family
of anti inflammatory
Phylomer® peptides for
pharmaceutical use.
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Examples of applications
•
•
AP1  Brain
 Skin
Antimicrobial Phylomer
AP1
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Neuroprotection: AP1 inhibitory peptides
Study of their efficacy in preventing cell death in cortical neuronal cultures following
glutamate excitotoxicity
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Glutamate
excitotoxicity
Activation
of JNK
Dimerization
c-Jun/c-Fos
Transcriptional
activation of
AP1
APOPTOSIS
Various neurological
disorders,
neuronal cell death
 Two-hybrid screen
 identification of 19 AP-1 inhibitory peptides, fused to the cell penetrating
peptide TAT
These peptides bind to the c-Jun dimerization domain and down regulate AP1
transcription
AP1 neuroprotection
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Neuronal
viability
Dosedependent
neuroprotection
 5 peptides
(PYC19D-TAT, PYC35D-TAT, PYC36D-TAT, PYC38D-TAT, PYC41D-TAT)
display neuroprotective activity in both L- and retro-inverso D-isoforms with increasing levels
of neuroprotection peaking at 83%
AP1 : wound healing
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Phylomer®
peptide
C-Jun



Cost associated with burn
injury: +++
Need for treatments that
can reduce the tissue
damage and subsequent
scarring
Peptide: isolated by a
reverse yeast-2 hybrid
screen for peptide
disruptors of c-Jun
dimerization
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
Peptide was tested for interaction with c-Jun by
• Co-Immuno precipitation
• Inhibition of AP-1 reporter gene activity in the K562 cell line
Results
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TUNEL is a common method for detecting DNA fragmentation that results from
apoptotic signaling cascades
Wound Rep Reg (2008) 16 58–64
Anti microbial Phylomer ®
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Screen
Screening
Biopanned
Phylomer-T7 Phage
Library
Against Live
Bacteria
Synthesis
Activity
Synthesise hits in
Pepset Format
Screen for
Antimicrobial
Activity
Structure
23 aa peptide with
5-6 aa progression
Haemolytic Activity
Mechanism
Average of 3-4
Pepsets/sequence
Mammalian toxicit
Analysis
Selection of Phylomer® peptides inhibit the growth
Significant antibacterial activity by screening for cell binding
of bacteria
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Bactericidal activity was confirmed in live cell plating assays
Assessment of antimicrobial
activity and haemolytic activity
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Financial situation
Evolution of Income Statement
Variation of commercial income
2500000
2000000
Commercial income,
1918368
$
1500000
1000000
500000
0
2009
2010
2011
Government grant income,
0
2012
Financial Situation
o Licence skin repair peptide to « le métier de la beauté »
o Milestones from existing partners
o New deals
Plan to lay off Stock Exchange
33,33% each year, during 2014 to 2016
 The
Stock Exchange does not offer any more one
sufficient liquidity to the shareholders.
 Quotation very theoretical :
http://www.zonebourse.com/PHYLOGICA-LIMITED-8528277/cotations/
 The
quoted market price do not reflect the intrinsic
value of the company.
Gamble to benefit at lower cost of most part of the
future value of the company.
Comparison with other biotechnology company
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Strategy


Don’t contract any loan
Strategy focus on communication
Deals with little firms


Not big financial interest…
…But publicity impact?
Problems
 Not
ambitious enough
 Not enough fund (no loan)
 Too much time with no return on their investment
 No source of income (share price are worth)
Force to inject cash in their the capital.
Solutions ?
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SWOT
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Strengths
Opportunities
•
•
•
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Strong patent position in Phylomer
peptide library
No known direct competitors in Phylomer
technology
Strong management and deal making
Successful in early partnering with big
pharma which reduces overall business
risk
Weakness
•
•
Partnerships and license agreement with
large pharmaceuticals and early stage
bio-tech companies.
Transition from conservative business
model to potential drug developer allows
for potential significant valuation re-rating
Potential markets for phylomer peptides
for therapeutic use are enormous
Threats
• Uncertainty with regards to patent protection
• Early partnering reduces potential
and proprietary rights.
revenues after commercialization phase
• Uncertainty of the outcome of Phylogica’s
• Most of the products are still at the initial
research result.
development phase
• Uncertainty about the outcome of
•
negotiations with future partners.
Higher level of expenditure than budgeted
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Point of view
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THE END
Any questions ?
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Example: PAS 201
16126,8
Monodisperse
ESI mass spectrum  a single peak
MM: 16126,8 Da +/- 0,18 (16126,89 Da)