Case Study of a Cambridge Biotech Startup

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• Case Study of a Cambridge Biotech Start-up

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Funxional Therapeutics Ltd (FXT)
A company with products entering clinical
development, based upon a strategy exploiting
functional screening to develop novel new classes
of drugs
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Pre -1980s
Select compounds which have a desirable effect on
the function of the individual Optimise the lead
candidates

• Aspirin from willow
• Penicillin from mould
• Vitamins

Inefficient
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Pre -1980s
Select compounds which have a desirable effect on
the function of the individual Optimise the lead
candidates
How do I find new lead compounds? How do I
evaluate safety? How do I reduce the risk
associated with costly late stage clinical trials?
Inefficient
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Today
Reduce the organism to a simple collection of
molecules Choose a molecular target (receptor or
enzyme) Perform a high-throughput
screen Optimise the lead candidates
Inefficient
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Today
Reduce the organism to a simple collection of
molecules Choose a molecular target (receptor or
enzyme) Perform a high-throughput
screen Optimise the lead candidates
Inefficient
How do I validate my molecular targets? What
happens if no single receptor/enzyme is
responsible for the function I need to modulate?
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Select Target
Design screening assays Screen library Select
promising hits Synthesise directed
sub-libraries Re-screen
Development lead
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Select Target
Design screening assays Screen library Select
promising hits Synthesise directed
sub-libraries Re-screen
Development lead
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Select Target
Design screening assays Screen library Select
promising hits Synthesise directed
sub-libraries Re-screen
Development lead
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Pharmaceutical companies have grown by optimising
every stage of the process EXCEPT target selection
Everyone knows you need to target the adrenalin
receptor to modulate blood pressure. The winners
in this game will be the ones who find the best
compound for the job, and develop it into the
best product.
Senior Executive, 1968
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Select Target
Design screening assays Screen library Select
promising hits Synthesise directed
sub-libraries Re-screen
Development lead
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Pitfalls of molecular target selection

• If its obvious to you, its probably obvious to
  everyone
• Dependent on good hypotheses
• Validation paradigm
• - Knockout the gene
• - Look for effect in animal model
• How good is the animal model?
• How many genes are developmental lethal?
• Closely related isoforms?

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Scarring following incisional wounding Traumatic
brain injury Ischemic stroke Atherosclerosis Ca
ncer Asthma Rheumatoid arthritis
GOOD
BAD
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Scarring following incisional wounding Traumatic
brain injury Ischemic stroke Atherosclerosis Ca
ncer Asthma Rheumatoid arthritis
GOOD
BAD
Species? Cell types involved? Conserved
trigger?
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Tomorrow
Reduce the organism to a simple collection of
functions Choose a function to modulate Perform
a functional screen Optimise the lead candidates
Efficient
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Tomorrow
Reduce the organism to a simple collection of
functions Choose a function to modulate Perform
a functional screen Optimise the lead candidates
Efficient
Finds drugs with unexpected or complex molecular
targets, but highly desirable functional
properties
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Functional screening
Side-steps bottleneck of molecular target
selection Opens access to a different
space Finds useful agents acting at unexpected
targets Identifies agents acting simultaneously
at multiple molecular targets
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Functional screening
Side-steps bottleneck of molecular target
selection Opens access to a different
space Finds useful agents acting at unexpected
targets Identifies agents acting simultaneously
at multiple molecular targets Functional
screening is hard to do!
BUT
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Enabling Skillsets
Hurdle Functional assays are not as
straightforward to perform in high-throughput
format as molecular assays

• Solutions
• Expertise in parallel microtitre format
  functional assays
• Use peptides to aid rational design, rather than
  rely on vast random libraries
• Well-validated general methods of designing
  peptidomimetic small molecules which retain
  function
• Use proprietary small molecule libraries which
  are not random, but heavily enriched in bioactive
  NCEs

FXT has all these skillsets
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Molecular screening technology is only faster
because billions of pounds have been spent by the
pharmaceutical industry optimising that paradigm.
Functional screening can be made just as cheap,
just as high throughput given even a fraction of
that investment.
Jason Avery, FXT CEO, 2005
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Example 1 Anti-inflammatory Drug
Hypothesis Chemokines are important for
orchestrating leukocyte recruitment to sites of
inflammation
Molecular approach Select a chemokine receptor
and screen for antagonists
BUT Which chemokine? Which receptor?
Functional approach Set up a functional assay
for leukocyte recruitment and search for
functional Inhibitors of chemokine-dependent
migration
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Functional Cell Migration Assay
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Alignment Strategy to Identify Chemokine
Inhibitors
AQPDAINAPV TCCYNFTNRK ISVQRLASYR
RITSSKCPKE .. . .
. AQPDAVNAPL TCCYSFTSKM IPMSRLESYK
RITSSRCPKE AVIFKTIVAK EICADPKQKW VQDSMDHLDK
QTQTPKT . . . .
AVVFVTKLKR EVCADPKKEW VQTYIKNLDR NQMR...
PEPTIDE 1
PEPTIDE 2
human
mouse
PEPTIDE 3
Alignment of different chemokines from more than
10 species identified regions of homology across
the whole superfamily
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Properties of Peptide 3
The first broad-spectrum chemokine inhibitor
(BSCI)

• Sequence specific
• Effective against all chemokines tested, with
  similar potency
• Completely inhibits migration
• Not very potent

Reckless Grainger (1999) Biochem. J. 340803-10
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Conventional Medicinal Chemistry Optimises Lead
Candidate
PEPTIDES
AMINO-GLUTARIMIDES

• NR58-3.14.3
• BIM 58171
• BIM 58189

• NR58,4
• NR58,33

YOHIMBAMIDES
AMINO-CAPROLACTAMS

• Yohimban-
• 16-amide

• Olfoxamide
• BN 83250
• BN 83470

BN83470 most promising candidate for further
development
Grainger et al. (2005) Mini Rev. Med. Chem.
5825-32
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BSCIs A New Family of Anti-inflammatory drugs

• BN83470 is an orally acting anti-inflammatory
  agent
• Efficacy data in 10 animal models of
  inflammation
• Active at 1µg/kg doses - equivalent to
  corticosteroids
• Excellent side effect profile
• Beginning Phase I trials in 2007
• Development programme in place for allergic
  rhinitis, asthma, COPD
• Other aminocaprolactam BSCIs being developed for
  surgical adhesions, stroke and heart disease

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BSCIs Mechanism of Action

• Not known a priori (unlike products of molecular
  screens)
• Identify molecular targets by conventional
  pharmacology
• BSCIs are receptor AGONISTS!
• Function by deafening the cell to the chemokine
  signal
• Molecular target is a known GPCR, but not one
  anyone has ever considered targeting to inhibit
  inflammation
• Functional screening has opened up a whole new
  space for anti-inflammatory medications

IDENTITY REMAINS CONFIDENTIAL TO FXT
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Example 2 Alzheimers Drug
Hypothesis Failure to clear apoptotic cells in
the absence of apoE triggers neurodegeneration
Molecular approach ???
How is apoE modulating phagocytosis?
Functional approach Set up a functional assay
for phagocytosis and search for
functional agonists equivalent to apoE
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Functional screen for phagocytosis

• Label thymocytes with CellTracker Green
• Induce apoptosis, for example by serum
  withdrawal, and confirm by Annexin V staining
• Expose cultured macrophages to labelled apoptotic
  cells for 30mins at 37ºC in presence or absence
  of candidate agonists
• Detect cells that are taken up by flow cytometry

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A small molecule apoE mimetic
Wild type
ApoE deficient
With apoE mimetic
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IBBs New Drugs for Alzheimers

• Conventional medicinal chemistry used to refine
  the peptidic apoE mimetics
• Yielded a family of indolylbisbenzamidine
  (IBBs), the first submicromolar, non-peptide apoE
  mimetics
• IBBs stimulate phagocytosis of apoptotic cells
  up to 3-fold in vitro, and compensate for loss of
  apoE in vivo
• Acceptible safety profile?
• Potent and effective in animal models of AD

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IBBs Mechanism of Action

• Not known a priori (unlike products of molecular
  screens)
• Identify molecular targets by conventional
  pharmacology
• IBBs target just one of the 10 receptors known
  to bind apoE
• Precise mode of action still unknown
• Molecular target well known, but never
  previously considered as a target for AD
  therapeutics
• Functional screening has opened up a whole new
  space for AD medications

IDENTITY REMAINS CONFIDENTIAL TO FXT
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GAEL Technology
GPCR-Agonist Enriched Library

• Enabling platform technology for functional
  screening
• Proprietary library of NCEs enriched in candidate
  GPCRs agonists
• Based on facile chemistry, allowing introduction
  of vast diversity into GAEL library
• Library elements based on scaffold with intrinsic
  low toxicity and excellent PK/PD properties
• A pipeline of valuable NCEs in diverse,
  pre-selected therapeutic classes

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Natural Ligand
ANTAGONIST
AGONIST
Receptor
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GAEL Core Structure
Carbon
Diversity
Oxygen
Nitrogen
Hydrogen

• Core structure of an ideal GPCR agonist,
  identified by molecular modeling of several
  hundred known agonists at wide range of GPCRs
• Create a proprietary library where every element
  contains this ideal core
• Elements distinguished by diverse substitutions
  which control selectivity for different GPCRs

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Finding the Ideal Insulin Secretagogue
Our first application of the GAEL technology

• Huge market in diabetes, obesity and metabolic
  disorders for insulin secretagogues (gt100 million
  people, 10B worldwide market)
• Competitors (DPP-IV inhibitors and GLP-1
  analogues) have disadvantages
• DPP-IV involved in metabolising other bioactive
  peptides, so inhibitors have unwanted
  side-effects
• Current GLP-1 analogs are peptides
• GLP-1 and GIP double knock-out mice retain
  glucose-sensitive insulin secretion - so other
  receptors are important too
• Ideal profile for applying GAEL technology in a
  functional screen - aim to find mixed GIP/GLP
  agonists

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Research Plan

• Synthesize 1,000 element GAEL library (6 months)
• Screen library in functional assay for
  stimulation of insulin production by RIN 1046-38
  cells (3 months)
• Screen positive hits for ability to suppress
  blood glucose levels in fasted Zucker rats (3
  months)
• In parallel, synthesise further analogues of lead
  candidates and screen in vitro and in vivo (6
  months)

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Funxional Therapeutics Ltd (FXT)

• Committed to the new functional screening
  paradigm
• Toolbox of proprietary screening tools
• Microtitre parallel functional assays
• Peptidomimetic chemistries
• Enriched libraries
• Family of aminocaprolactam BSCIs with unique,
  proprietary mechanism of action
• BN83250 s.c. product in surgical adhesions
• BN83250 i.v. product in ischemic stroke
• BN83470 product in asthma, allergic rhinitis,
  COPD
• Family of IBBs with proprietary mechanism of
  action
• EOL1 product in traumatic brain injury
• FXT173 product in Alzheimers Disease

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Funxional Therapeutics Ltd (FXT)

• Founded in 2005 and currently privately held
• Ipsen Group are major shareholders
• TCP Innovations
• Cambridge University
• Founders
• VC Investors
• Strong management team
• CEO Jason Avery
• VP RD Callum Campbell
• CSO David Grainger
• VP Business Development Bob Schroff
• Completed 5.5M series A financing October 2006
• First Phase II proof of concept Q4 2009
• First product 2012?