2011 06 20 Addex Corp Slides by Dy6H5O

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									Addex Pharmaceuticals
    Corporate Presentation
         June 2011
Vision

Goal: allosteric modulators for human health


How: proprietary discovery platform


Focus: CNS, metabolic disorders & inflammation




                                               2
    Financials & Stock
•   Cash through early 2013
      CHF63.8 (US$68/€50) million in cash as of Dec 31, 2010
      2011 burn guidance CHF28-32 million
•   Market cap (20 June): CHF81 (US$92/€65) million
•   Traded on SIX Swiss Exchange: ADXN (ISIN:CH0029850754)
•   7,835,878 shares outstanding
      Biotechnology Value Fund holds 30%
•   Five analysts covering:
          Jefferies          Peter Welford & Philippa Gardner
          Helvea             Olav Zilian
          Bank Vontobel      Andrew C. Weiss
          Bank am Bellevue   Bob Pooler
          Edison             Robin Davison


                                                                3
   Management & Boards
                                  Executive Management
André J. Mueller, Executive Chairman         Jean-Philippe Rocher, Head of Core Chemistry
Tim Dyer, Chief Financial Officer            Robert Lütjens, Head of Core Biology
Charlotte Keywood, Chief Medical Officer Tatiana Carteret, Head of Human Resources
Sonia Poli, Head of Non-Clinical Development Chris Maggos, Business Development & Communication
Laurent Galibert, Head of Inflammation & Metabolic Disorders

                  Board of Directors
                                                             Scientific Advisory Board
André J. Mueller, Executive Chairman
Andrew Galazka, SVP Scientific Affairs, Merck-Serono       George F. Koob, Chairman
Ray Hill, former Head of EU Licensing, Merck & Co., Inc.   Bernhard Bettler
Hoyoung Huh, BiPar Sciences Inc. and Geron Corp.           Mark A. Geyer
Vincent Lawton, former MD of Merck Sharp & Dohme U.K.      Barbara J. Mason
                                                           Jean-Philippe Pin
Oleg Nodelman, Biotechnology Value Fund
Antoine Papiernik, Sofinnova Partners

                                                                                         4
Small molecule drug discovery is
an important bottleneck
•   Industry does not have all the discovery tools it needs
     – There is no shortage of exciting targets
     – Incremental innovations help but have largely failed to open the
       bottleneck

•   Allosteric discovery tools represent a paradigm shift
     – Standard techniques are most efficient for finding molecules that
       bind the “active site” (or “binding pocket”)
         •   The active site is a relatively small part of the target receptor
         •   The active site can be highly conserved within a receptor family (e.g.
             mGluR & cytokine receptors), making subtype selectivity via the active
             site challenging
     – Addex tools identify molecules that bind anywhere on the target
     – Our tools are more sensitive because they can detect molecules
       that modify receptor activity without fully activating/blocking it


                                                                                5
    Allosteric modulators (AM) are an
    emerging new therapeutic class
                                                       Allosteric Modulation Explained
•   AM are different from traditional
    “orthosteric” drugs
     – AM bind to different sites on cell surface
         receptors
     –   AM have structurally different
         characteristics
•   Modulatory not binary
     – Like a dimmer switch not an on/off switch
     – Positive allosteric modulators (PAM)
         increase activity of receptors
     –   Negative allosteric modulators (NAM)
         inhibit receptor activity
•   AM are proven drugs
     – Sensipar/Mimpra cinacalcet (Amgen/NPS)
         is a PAM of CaSR
     –   Selzentry/Celsentri maraviroc (Pfizer) is a
         NAM of CCR5
•   But AM are hard to find with classical
    tools!


                                                                                         6
                 Allosteric Advantages
                                  Orthosterics are steady state
            Biological response




                                              Agonist                  • AM have better specificity/selectivity
                                                                          – e.g. mGluRs
                                              Natural ligand
                                              Antagonist               • AM can target receptors considered
                                                                       intractable for small molecules
                                                 Time                     – e.g. GLP-1 and TNF
                                  Allostery preserves natural rhythm
                                                                       • AM act like dimmer (not “on/off”) switch
Biological response




                                            PAM + natural ligand          – better control = better drugs
                                            Natural ligand

                                            NAM + natural ligand


                                                 Time

                                                                                                             7
Platform: Unique Library + Proprietary HTS
 • 70,000+ compound allostery-biased library
    Physicochemical Comparison        Structural Comparison

                        drug-like
                                                               Intellectual
                                                               property is
                                                              un-exploited!




             Addex HTS Platform Assays - Patent Portfolio
                   Assay                      Filing #
    APRA                           WO 2010/082133
    Phoenyx                        EP09178233
    ProxyLite for GPCRs            EP10160519
    ProxylLite for non GPCRs       EP10191973
    AddeLite                       EP10162068
                                                                        8
  Platform Performance
• Addex has received partnering revenue every year since 2004
• Cash inflows generated to date: CHF46.5 (US$53/€37) million
• All three partnerships are fully funded by our partners
• Addex is eligible for up to about $1 billion in milestones plus royalties

                                    Summary of Partnerships
                                                                              Fees and           Total
                                                      Status      Upfront
      Partner          Product     Indication(s)                              milestones       Potential      Royalty
                                                    at signing     Cash
                                                                              receiveda       Milestones

   Ortho-McNeil-     mGluR2 PAM     Anxiety &                       €3 M                                       low
                                                   Hit-to-Lead                 €7.2 M           €112 M
     Janssen         (ADX71149)   schizophreniab                 (Dec 2004)                                 double-digit

                                   Parkinson’s                      $3 M
 Merck & Co., Inc.   mGluR4 PAM                    Hit-to-Lead                 $3.3 M          $167.5 M          ND
                                    diseaseb                     (Dec 2007)

                                                     Clinical      $22 M
 Merck & Co., Inc.   mGluR5 PAM   Schizophreniab    Candidate                     -             $680 M           ND
                                                   (ADX63365)    (Jan 2008)

                                                                                      anot   including upfront payment
                                                                                      band    undisclosed indications

                                                                                                                         9
                                                                  Pipeline
                                                                                      Preclinical                                           Clinical
                                                   Assay                   Lead       Clinical
  Partner      Molecule / Mechanism             Development Hit-to-Lead                                                    Phase I         Phase IIa   Milestone
                                                                        Optimization Candidate
                                                & Screening
             Dipraglurant-IR (ADX48621)          Parkinson’s Disease Levodopa Induced Dyskinesia (PD-LID)                                              Ph II data
             mGluR5 NAM                          partially funded by The Michael J. Fox Foundation                                                       1H12
             Dipraglurant-ER (ADX48621)                                                                                                                 Start Ph I
                                                 Dystonia
             mGluR5 NAM                                                                                                                                   2H11
                                                 Schizophrenia
Ortho-McNeil-
              ADX71149 mGluR2 PAM                funded & developed by OMJPI*
  Janssen
                                                 Anxiety

Merck & Co. ADX63365 mGluR5 PAM                  Schizophrenia ‡
                                                 funded & developed by Merck

             FSHR/LHR NAM                        Endometriosis

             GABA-BR PAM                         Pain / Anxiety

             mGluR2 NAM                          Alzheimer’s / Depression

                                                 Parkinson’s Disease ‡
Merck & Co. mGluR4 PAM                                                                                                                                   CNS
                                                 Depression
             mGluR7 NAM
                                                 Generalized Anxiety Disorder
             Receptor tyrosine kinase
                                                 Neurodegenerative & other diseases
             superfamily

             GLP1R PAM                           Type II Diabetes
                                                 Rheumatoid Arthritis, Psoriasis, Inflammatory Bowel Disease                               Metabolism
             TNF receptor superfamily
                                                 Alzheimer’s, Multiple Sclerosis                                                                &
             A2A PAM                             Psoriasis, Osteoarthritis
                                                                                                                                          Inflammation
             Interleukin receptor family
             NAM = negative allosteric modulator (an inhibitor)   ‡   and undisclosed additional indications
             PAM = positive allosteric modulator (an activator)    * Ortho-McNeil-Janssen   Pharmaceuticals, Inc., a Johnson & Johnson subsidiary

                                                                                                                                                        10
Selected development milestones

   Product        Indication(s)   Milestone     When
Dipraglurant-ER
                    Dystonia      Ph I start    2H11
 mGluR5 NAM
  ADX71149
                  Schizophrenia   Ph IIa data    ND
 mGluR2 PAM
Dipraglurant-IR
                     PD-LID       Ph IIa data   1H12
mGluR5 NAM
Dipraglurant-ER
                    Dystonia      Ph I data     1H12
 mGluR5 NAM




                                                       11
Metabotropic Glutamate Receptors (mGluR)
  •   Glutamate - like dopamine & serotonin - is a major neurotransmitter that has
      therapeutic potential in a variety of important indications
       – Blockbuster antipsychotics work via dopamine receptors
       – Blockbuster antidepressants (SSRIs) work via serotonin receptors
  •   Metabotropic glutamate receptors (mGluR) have been challenging drug targets
      but have clinical/preclinical validation in many indications after decades of study
       – mGluR2 PAM (OMJPI)             – mGluR2 NAM
            •   Schizophrenia                •   Alzheimer’s disease
            •   Anxiety                      •   Depression
            •   Addiction
       – mGluR5 PAM (Merck)             – mGluR5 NAM
                                           (dipraglurant/ADX48621 & backups)
            •   Schizophrenia
                                             • PD-LID / dystonia
            •   Cognitive impairment
                                             • Fragile X syndrome / autism
       – mGluR4 PAM (Merck)                  • Anxiety / depression / addiction
            •   Parkinson’s disease          • GERD
            •   Anxiety                      • Pain
                                        – mGluR7 NAM
                                             •   Generalized Anxiety Disorder
                                             •   Depression
                                             •   Addiction



                                                                                        12
Schizophrenia
• Prevalence
    – Schizophrenia 1%
    – Bipolar mania 3%
• Worldwide antipsychotic drug sales >$16 billion
    –   J&J’s Ripserdal franchise ~$5 billion/year
    –   Eli Lilly’s Zyprexa franchise ~$5 billion/year
    –   Antipsychotics are off patent
    –   Atypical antipsychotics are going off patent now
• Typical and atypical antipsychotics inhibit dopamine D2 receptor
    –   Address negative symptoms
    –   Address positive symptoms
    –   Side effects can include: prolactinemia (lactation); weight gain; extrapyramidal symptoms
    –   Do nothing to address cognitive impairment
• mGluR2 activation is the first novel mechanism to show significant
   efficacy in decades
    –   Efficacy on negative symptoms
    –   Efficacy on positive symptoms
    –   No prolactinemia, no weight gain, no extrapyramidal symptoms
    –   Potential synergies with antipsychotics could lead to cognitive benefit

                                             Source: Nature Reviews Drug Discovery 7, 471-472 (2008)



                                                                                                    13
   ADX71149 mGluR2 PAM for
   Schizophrenia

  Normal Neurotransmission                                 Disease State    Treated


                               glutamate
                                                                                              ADX71149




                                                                           Marketed antipsychotic drugs
                                                                           exert efficacy predominantly
                                                                           via dopamine D2 receptors



Adapted from Nature Reviews Drug Discovery 7, 471-472 (2008)




                                                                                                   14
ADX71149 Schizophrenia Study
An ongoing EU Phase IIa study
• Part A (n=15): open label for 12 weeks
    – 15 subjects with (sub)acute positive symptoms
    – 50mg ADX71149 bid increasing to up to 150mg bid
• Part B (n=90) double-blind placebo-controlled for 10 weeks
    – Subjects with stable but symptomatic schizophrenia
    – Patients continue on their currently prescribed antipsychotic
    – 50mg ADX71149 bid increasing to up to 150mg bid
• Endpoints will examine safety, tolerability and efficacy
    – Primary outcome measures
        • Safety
        • Tolerability
    – Secondary outcome measures
        • Positive and negative syndrome scale (PANSS)
        • Clinical Global Impression – Schizophrenia (CGI-SCH)
        • Subjective well-being under neuroleptics scale (SWN)
• Data 1H12
                                                        Source: http://1.usa.gov/dOAMIi


                                                                                          15
Dipraglurant (ADX48621) Overview
•   Dipraglurant inhibits metabotropic glutamate receptor 5
    (mGluR5) via negative allosteric modulation (NAM)
• mGluR5 inhibition is clinically validated in multiple
    indications including
     – Parkinson’s disease levodopa-induced dyskinesia (PD-LID)
     – Gastroesophageal reflux disease (GERD)
     – Generalized anxiety disorder (GAD)
•   Initial Phase I program of dipraglurant sucessful
     – Three studies: SAD, MAD, gender & food effects
     – 132 subjects studied to date, including 30 older subjects
     – Safety & tolerability support further clinical study
•   Exceptional preclinical data in PD-LID model

                                                                   16
Why PD-LID & Dystonia?

•   PD-LID
    –   Clinically validated by another mGluR5 NAM (AFQ056 from Novartis*)
    –   Attractive specialty pharma commercial opportunity
    –   The Michael J. Fox Foundation grant
         •   MJFF advisors, PD key opinion leaders (KOLs), reviewed the dipraglurant
             preclinical data and Ph IIa trial design
         •   Publicity & KOL familiarity (via grant review) with dipraglurant could facilitate
             enrollment
•   Dystonia
    –   Dipraglurant is the first drug-candidate to report efficacy for dystonia in
        LID models
    –   Brain circuits for non PD dystonias are similar to those found in PD-LID
    –   Third most common movement disorder (following PD and essential
        tremor)
    –   Potential Orphan Drug and Fast Track status opportunities within
        subtypes of dystonia
                                                         *for data: http://bit.ly/dgEVbH


                                                                                            17
Dipraglurant (ADX48621) in PD-LID model
                                                                                  Chorea
                                                                        (rapid uncontrolled movements)

• Parkinsonian (MPTP-treated) macaques with
  levodopa-induced dyskinesia (LID) received
   – dipraglurant or vehicle (e.g. placebo)
   – levodopa

• Behavioral assessment began upon levodopa
  administration
   – trained observers performed video review                                     Dystonia
                                                                        (sustained muscle contractions)
   – dyskinesia & PD scoring (10 min every 30 min for 4hrs)
        • lower scores (left axis) indicate fewer symptoms/disability
        • dyskinesia symptoms are side effects from levodopa

• Dipraglurant is the first compound reported to show
  statistically significant efficacy for dystonia


                                                                                               18
Dipraglurant Phase IIa PD-LID Trial
Study ADX48621-201 (n=90)
   •   Phase IIa trial in the EU and US ongoing
        –   Randomised, double-blind, placebo-controlled, muliticenter
        –   Patients with moderate to severe LID
        –   Treatment duration 4 weeks
   •   Placebo or dipraglurant
        –   Taken with 3 of the patients’ daily levodopa doses
        –   Dose titration from 50mg q.d. to 100mg t.d.s over the 4 weeks
   •   Primary objective: safety & tolerability
   •   Secondary objective: exploratory efficacy
        –   Objective evaluation in the clinic on day 1 and after 2 and 4 weeks
             • Trained observer scores LID severity
             • Abnormal Involuntary Movement Score (AIMS)
        –   Patient diaries
            • PD rating scales (including dystonia)
            • Evaluation of mood
   •   Data 1H12



                                                                                  19
FSHR NAM
  GnRH                                          GnRH, FSH & Endometriosis

                                        •   FSHR NAM offer a more specific approach
                                            to estradiol control compared to GnRH
                                            antagonists
                                        •   Endometriosis is linked to excess estradiol
                                        •   GnRH antagonists have been shown to
                                            reduce estradiol & endometriosis
                                            symptoms
                                        •   FSHR is downstream from GnRh and is
                                            more directly responsible for production of
                                            estrogen/estradiol



                                     ADX68692
     •   ADX68692 is a follicle stimulating hormone receptor (FSHR) NAM
     •   Orally available non-steroid molecule with drug-like characteristics
     •   In late preclinical development
     •   ADX68692 and backups are available for partnering

                                                                                 20
FSHR NAM efficacy in rats
4 weeks treatment - effect on estrus cycle duration
    20

    18
                                                                                                      ***
    16

    14

    12
                                                                                            ***
    10

     8

     6                                  ***
     4
                                                 ***
     2

     0
         Number of Estrous cycles during treatment duration          Mean duration of Estrous cycle (days)

                0 mg/kg/day    2x10 mg/kg/day     2x30 mg/kg/day   2x100 mg/kg/day    2x300 mg/kg/day



ADX68692 disrupts the estrus cycle leading to complete blockade at
high dose

                                                                                                             21
mGluR2 NAM

• Data from Addex and others show that mGluR2 inhibition can
  reverse cognitive deficit in preclinical models
   –   in models of cognitive deficit
   –   in physiologically relevant models of AD
   –   mechanism may be complementary to marketed drugs
• Published data suggest that mGluR2 inhibition may reduce
  generation of beta-amyloid* and may be synergistic with donepezil**
   –   mGluR2 NAM may be disease modifying
   –   greater magnitude of effect possible via combination therapy

             *The Journal of Neuroscience, March 17, 2010; 30(11):3870-3875
             **Bioorganic & Medicinal Chemistry Letters, Dec 1, 2010; 20(23):6969-6974




                                                                                  22
ADX92639 reverses β amyloid-induced
deficit
 Rat novel object recognition (NOR) test
                                Exploration of novel vs familiar objects                                                          Locomotor activity during the test
                           18
                                  sham                        β-Amyloid*                                                    120
                           15
                                    ***                                                                                           sham                   β- Amyloid*
  Exploration time (sec)




                           12
                           9




                                                                                                             Line crosses
                                                                                                                             90
                           6
                           3
                           0
                                  veh                veh                veh                veh                               60

                           18
                           15           ***                              ***                                                 30
                           12                                                             ***
                            9
                            6
                            3                                                                                                 0
                                                                                                                                   t1    t2   t1    t2    t1   t2    t1   t2
                            0
                                 veh                  10             30                                                            Veh             10          30        Donepezil
                            Donepezil               ADX92639 (mg/kg, p.o.)          (1 mg/kg, ip)                                             ADX92639 (mg/kg, p.o.) (1 mg/kg, ip)

                                        *Single administration into the lateral ventricle of 8 μl solution
                                                          Final concentration of b amyloid = 2 mg/ml

Familiar object                         ADX92639 reverses cognitive impairment induced by intracebroventricular
Novel object                            (icv) β-amyloid in the rat NOR test after oral administration:
                                                • Full and donepezil-like reversal of the memory deficit at 30 mg/kg
                                                • No effect on locomotor activity observed during the test
                                                                                                                                                                                     23
GABA-B Receptor PAM
 • Activation of gamma-aminobutyric acid subtype B
   (GABA-B) receptor is clinically & commercially
   validated
    – generic GABA-B receptor agonist, baclofen, is marketed for spasticity &
        some spinal chord injuries
    –   other orthosteric GABA-B agonists showed clinical validation in
        gastroesophageal reflux disease (GERD)

 • GABA-B receptor PAM are differentiated from
  baclofen
    – Allostery may reduce/eliminate development of tolerance &
        dependence
    –   Allostery may reduce other tolerability issues, like somnolence
    –   ADX71943 demonstrated potential for chronic pain (e.g. osteoarthritis)
    –   Has potential for GERD and urinary incontinence



                                                                                 24
     ADX71943 demonstrated antihyperalgesic
     effects in a model of osteoarthritis
                                                       350
                                                                            Pre-treatment                                       Treatment
                 Maximum response bewteen 1 and 2 hr                                                                      ***
                                                       300
                                                                                                                  **
                                                                                                              *        *
                      Withdrawal threshold (g)



                                                       250



                                                       200
                                                                                                                                             ***
                                                                                           ###                                         **
                                                       150



                                                       100



                                                        50



                                                         0

                                                                    Pre-MIA              Post-MIA                 Day 1              Day 8
Days post-monosodium iodocate (MIA)
                                  -1                                                       14                      14                 21
                                                                  Vehicle                          1 mg/kg ADX71943                3 mg/kg ADX71943
                                                                  10 mg/kg ADX71943                30 mg/kg ADX71943               Celecoxib (30 mg/kg)
                                                               ###p<0.001 vs. Pre-MIA baseline; paired t-test, n=10 rats per group.
                                                             *p<0.05, **p<0.01, ***p<0.001 vs. vehicle;one-way ANOVA with Dunn's multiple comparison n=10 per group.

                                                                                                                                                                       25
Oral GLP1R PAM in ogtt test in
diabetic db/db mouse model
•   ADX91886 is a specific orally available GLP1R PAM, which we successfully used to
    establish the first in vivo proof of concept for an oral GLP1R PAM in a model of diabetes
     – ADX91886 has been discontinued
     – New GLP1R PAM are in lead optimization at Addex
•   In vivo POC performed in db/db knockout mice
     –   no leptin receptors
     –   develop human Type II diabetes mellitus
     –   develop hypertension and obesity
     –   have disrupted circadian blood pressure (BP) rhythm

•   Oral Glucose Tolerance Test (ogtt)
     – Diabetic db/db KO mice received orally
           •   ADX91886 GLP-1R PAM
           •   sitagliptin (Januvia) DPP IV inhibitor
           •   or vehicle
     – 15 min later oral glucose (2 g/kg) was administered
     – Blood glucose + insulin levels were measured: 10; 20; 30; 60; 90 min after glucose
         administration




                                                                                            26
GPL-1R PAM vs. sitagliptin in ogtt
test in diabetic db/db mice




                                     27
                                            Disclaimer

These materials do not constitute or form part, or all, of any offer or invitation to sell or issue,
neither in the United States of America nor elsewhere, or any solicitation of any offer to
purchase or subscribe for, any securities, nor shall part, or all, of these materials or their
distribution form the basis of, or be relied on in connection with, any contract or investment
decision in relation to any securities.

These materials contain forward-looking statements based on the currently held beliefs and
assumptions of the management of Addex Pharmaceuticals Ltd, which are expressed in good
faith and, in their opinion, reasonable. Forward-looking statements involve known and unknown
risks, uncertainties and other factors, which may cause the actual results, financial condition,
performance, or achievements of Addex Pharmaceuticals Ltd, or industry results, to differ
materially from the results, financial condition, performance or achievements expressed or
implied by such forward-looking statements. Given these risks, uncertainties and other factors,
recipients of this document are cautioned not to place undue reliance on these forward-looking
statements. Addex Pharmaceuticals Ltd disclaims any obligation to update these forward-
looking statements to reflect future events or developments.

These materials are strictly confidential and must not be disclosed or distributed to third parties.




                                                                                               28
allosteric modulators for human health

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