Addex Pharmaceuticals
  Investor Relations Slides
       January 2010
Disclaimer

These materials do not constitute or form part, or all, of any offer or invitation to sell or issue,
neither i...
The Company
• Goal: allosteric modulators for human health
• Focus: CNS, inflammation, metabolic disorders
• Proprietary a...
Financials
 •   Cash: about CHF75m* (€62m / US$89m) at end 2009
 •   2010/11 cash burn guidance: CHF35-40m
 •   Market cap...
Pipeline
                                Assay Dev &                Lead
Mechanism         Partner                   Hit-t...
Deals to Date
                                                                  Status      Upfront Cash
        Partner  ...
ADX48621 for
Parkinson’s Disease
Why PD with mGluR5 NAM?
• Loss of dopamine producing cells leads to
 excess glutamatergic stimulation

• Inhibition of mGl...
ADX48621 efficacy in HIC
• Haloperidol induced catalepsy (HIC) is a model of PD
                    ADX48621 dose-dependen...
ADX48621
                                        works in MPTP model
                       ADX48621 is the first product ...
ADX48621 Perspectives
•   ADX48621 has the potential to be a best-in-class for PD/PD-LID
     – Potential effects on PD sy...
ADX48621 PD–LID
                    Phase II Plan
•   Study ADX48621-201 (about 150 to 200 patients)
•   Goal: dose escala...
ADX71149 mGluR2 PAM
   • ADX71149 is a positive allosteric modulator of mGluR2
          – mGluR2 activation is clinically...
ADX63365 mGluR5 PAM
•   Merck & Co., Inc. is performing preclinical development of ADX63365 and
    multiple mGluR5 PAM ba...
ADX71943 GABAB PAM

•   GABAB receptor is a clinically validated target
    –   Baclofen, GABAB agonist, is marketed to tr...
ADX71943 analgesic-like effects
                      in preclinical models
       Analgesic-like effect of ADX71943 in th...
ADX68692 FSH NAM
                                                   •   FSH in females
S.F. Betz, J.Med.Chem., 2008




  ...
ADX68692
             stops ovulation in female rats
•   Treatment with ADX68692 at                                       ...
ADX68692
    Summary / Prospectives
•   In vivo & in vitro data show                                     ADX68692 effects ...
Addex Pharmaceuticals
       ~~~~~~~~
 Allosteric Discovery &
 Optimization Platform


                          20
Allosteric Modulation Explained
                                                                                arketed
  ...
Orthosteric ≠ Allosteric
                                   Orthosterics are steady state
                                ...
Industrializing Allostery

Addex is pioneering the industrialization of allosteric
 drug discovery and optimization
• Adde...
Addex AM focused library:
     Comparative Structural Analysis
  Marketed Drugs




Addex Library




                   A...
Building of an Allosteric
             Fragment Database
 • Establish virtual AM fragment database: from literature and in...
Addex targets allosteric sites in
     GPCR families 1, 2 & 3
   Family 1                         Family 2                ...
Proprietary Novel Assays
         G-Protein Coupled Receptors

• Phoenyx: a cAMP dynamic non stop assay

• FBBA: Fluoresce...
Addex targets allosteric sites in
type 1 single-pass transmembrane proteins



 TNFR family




                          ...
Proprietary Novel Assays
     type 1 single-pass transmembrane proteins

•   APRA: Accessory Protein Relocalization Assays...
The Addex Platform
                 Clinical Development
               Non-Clinical Development




                     ...
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Addex Jan 2010 Presentation

  1. 1. Addex Pharmaceuticals Investor Relations Slides January 2010
  2. 2. 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.
  3. 3. The Company • Goal: allosteric modulators for human health • Focus: CNS, inflammation, metabolic disorders • Proprietary allosteric modulator discovery platform - Unique chemical library (~70,000 compounds) - Proprietary biological screening tools • Pipeline - ADX48621 starts Phase II in PD-LID in 4Q10 (Ph I completed in 2009) - ADX71149 Phase I program (initiated June 2009) by Ortho-McNeil-Janssen - 13 preclinical/discovery programs • Pharma validation - Drug development deals with Merck & Co., Inc. and Ortho-McNeil-Janssen - Equity investments by GlaxoSmithKline (5%) and Roche • 145 staff / founded 2002 in Geneva, Switzerland 3
  4. 4. Financials • Cash: about CHF75m* (€62m / US$89m) at end 2009 • 2010/11 cash burn guidance: CHF35-40m • Market cap (6 Jan 10): CHF82m (€55m / US$80m) • SIX Swiss Exchange: ADXN (ISIN:CH0029850754) • 5,862,492 shares outstanding as of June 30, 2009 • Five analysts covering: Piper Jaffray Sam Fazeli & Michael Aitkenhead Jefferies Peter Welford & Philippa Gardner Helvea Olav Zilian Bank Vontobel Andrew C. Weiss & Silvia Schanz Bank am Bellevue Bob Pooler *assuming midpoint of cash burn guidance for CHF43-47m was achieved 4
  5. 5. Pipeline Assay Dev & Lead Mechanism Partner Hit-to-Lead Preclinical Phase I Phase II Milestone Screening Optimization mGluR5 NAM ADX48621 Parkinson’s disease levodopa induced dyskinesia (PD-LID) Start Ph II 4Q10 mGluR2 PAM J&J* ADX71149 Anxiety / Schizophrenia funded & developed by J&J not disclosed mGluR5 PAM Merck & Co. ADX63365 Schizophrenia‡funded & developed by Merck not disclosed GABAB PAM ADX71943 Pain / Urinary Incontinence / GERD Start Ph I 4Q10 FSH NAM ADX68692 Endometriosis / Prostate Cancer Start Ph I 1Q11 mGluR2 NAM Alzheimer’s / Depression mGluR4 PAM Merck & Co. Parkinsons’s disease‡ mGluR7 NAM with Merck funding Depression / Post Traumatic Stress Disorder CNS Orexin 2R NAM Sleep disorders GLP-1 PAM Type II diabetes GIPR PAM Type II diabetes Metabolic Disorders TNF-R1 NAM Rheumatoid Arthritis, Psoriasis, Alzheimer’s, Multiple Sclerosis A2A PAM Psoriasis, Osteoarthritis Inflammation IL-1R1 NAM Gout, Type II diabetes NAM = negative allosteric modulator (an inhibitor) PAM = positive allosteric modulator (an activator) *Ortho-McNeil-Janssen Pharmaceuticals Inc., a Johnson & Johnson company 5 ‡ undisclosed additional indications
  6. 6. Deals to Date Status Upfront Cash Partner Product Indication(s) Milestones at signing (Date) Ortho-McNeil-Janssen ADX71149 Anxiety & €3 million1 not Hit-to-Lead (a J&J company) mGluR2 PAM schizophrenia (Dec 2004) disclosed2 Parkinson’s $3 million4 $167.5 Merck & Co., Inc. mGluR4 PAM Hit-to-Lead disease3 (Dec 2007) million2 ADX63365 Clinical $22 million $680 Merck & Co., Inc. Schizophrenia3 mGluR5 PAM Candidate (Jan 2008) million2 1€4.2 million in research funding were paid to Addex during the research collaboration, which completed in 2007. Addex received an additional €1 million milestone when ADX71149 started Ph I testing. 2 plus royalties on sales 3 & other undisclosed indications 4 After the first two preclinical milestones were achieved (totaling $750k) the collaboration was extended in late 2009 and Merck agreed to add $1.8 million in research funding in addition to original terms 6
  7. 7. ADX48621 for Parkinson’s Disease
  8. 8. Why PD with mGluR5 NAM? • Loss of dopamine producing cells leads to excess glutamatergic stimulation • Inhibition of mGluR5 has been shown to reduce glutamatergic stimulation and have anti-Parkinsonian effects in animal models Conclusion: mGluR5 inhibition may be a levodopa sparing strategy 8
  9. 9. ADX48621 efficacy in HIC • Haloperidol induced catalepsy (HIC) is a model of PD ADX48621 dose-dependently reversed HIC in 3 independent experiments This effect was statistically significant and comparable to MTEP • ADX48621 effects in HIC suggest that it should be tested further as a potential drug for PD has potential to be a dopamine sparing agent 1st experiment **p<0.01, ***p<0.001 versus vehicle group 2nd experiment 90 3rd experiment 80 70 60 Latency (sec) 50 ** 40 ** *** ** 30 *** *** *** *** *** 20 10 0 Vehicle ADX48621, 1 ADX48621, 3 ADX48621, 10 ADX48621, 30 M TEP, 30 mg/kg mg/kg mg/kg mg/kg mg/kg + 1 mg/kg haloperidol 9
  10. 10. ADX48621 works in MPTP model ADX48621 is the first product to reduce both Chorea & Dystonia in this model Significant effects on Chorea Significant effects on Dystonia 15 15 dystonia (0-2 hr) chorea (0-2 hr) 10 10 ** 5 5 * 0 0 vehicle 3 10 30 vehicle 3 10 30 ADX48621 (mg/kg) ADX48621 (mg/kg) L-DOPA (100%) L-DOPA (100%) 10
  11. 11. ADX48621 Perspectives • ADX48621 has the potential to be a best-in-class for PD/PD-LID – Potential effects on PD symptoms – Potential levodopa sparing agent – Potential effects on dystonia & chorea in PD-LID • Evidence supporting mGluR5 inhibition for PD as well as PD-LID – Our rodent HIC data suggest ADX48621 potentiates the anti-parkinsonian effect of levodopa – mGluR5 blockade reverses PD symptoms/deficits in rodents (Breysse et al 2003, Armetero et al 2006) – mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion (De Leonibus et al 2009) – mGluR5 effects on central pain processing may reduce pain symptoms in PD / PD-LID / dystonia – Gastrointestinal dysfunction is a frequent and occasionally dominating symptom of PD, and mGluR5 blockade, might also address these symptoms – mGluR5 blockade may also be interesting for the treatment of co-morbid anxiety • Potential first treatment for dystonia – Parkinson’s disease – Generalized dystonia – Tardive dyskinesia – Levodopa non-responsive PD syndrome – Multiple system atrophy 11
  12. 12. ADX48621 PD–LID Phase II Plan • Study ADX48621-201 (about 150 to 200 patients) • Goal: dose escalation study to find median effective dose • Placebo-controlled, randomised, multi-center study in EU and U.S. • One to two week run in baseline dyskinesia and PD symptom evaluation period • 12 weeks dosing with study medication • Dose escalation over the first 4 weeks • Symptoms evaluated on a stable dose regimen over the subsequent weeks 5-12 • Outcome measures would include – UPDRS subscales 32 and 33 movement rating – Abnormal Involuntary Movement Score (AIMS) – Levodopa Induced Dyskinesia rating scale (LIDS – still undergoing validation) – Patient reported outcome of “good on time” – Evaluation of other anti-Parkinsonian effects – Overall UPDRS – Activities of Daily Living – Global Clinical Impression – Safety and tolerability • Scheduled start: 4Q10 • Data: 1H12 12
  13. 13. ADX71149 mGluR2 PAM • ADX71149 is a positive allosteric modulator of mGluR2 – mGluR2 activation is clinically validated in anxiety1 & schizophrenia2 – Our mGluR2 PAM will be differentiated from mGluR2/3 agonists in development at Eli Lilly • ADX71149 Phase I testing started in June ’09 by our partner Ortho-McNeil-Janssen (a J&J company) • ADX71149 is a high priority for J&J – It is one of the most exciting products for schizophrenia today – J&J markets Risperdal – Eli Lilly markets Zyprexa and has an mGluR2/3 agonist in Ph II testing • ADX71149 is the first PAM of an mGluR to enter humans 13 1http://bit.ly/JOtTb 2http://bit.ly/54lKd
  14. 14. ADX63365 mGluR5 PAM • Merck & Co., Inc. is performing preclinical development of ADX63365 and multiple mGluR5 PAM backups • mGluR5 PAM have demonstrated efficacy in animal models of schizophrenia – mGluR5 PAM reversed schizophrenia-like brain activity induced in animals by NMDA receptor antagonists – mGluR5 PAM reverse both the effects of excess dopamine and NMDA receptor hypofunction in schizophrenia models – mGluR5 PAM reversed psychosis in preclinical testing – mGluR5 PAM reversed cognitive dysfunction in preclinical testing • mGluR5 PAM will be highly differentiated if they address cognitive deficit in schizophrenia clinical testing – Many schizophrenia patients are unable to learn skills or support themselves – Marketed drugs and most drugs in development can reduce psychosis BUT have not been shown to improve cognitive function – FDA has recognized that cognitive deficit is an unmet medical need in schizophrenia 14
  15. 15. ADX71943 GABAB PAM • GABAB receptor is a clinically validated target – Baclofen, GABAB agonist, is marketed to treat spasticity • off-label use in pain and other indications • experimental GABAB agonists efficacious in Phase II clinical GERD trials(XP19986/Xenoport & AZD3355/AstraZeneca) • ADX71943 is differentiated – Allosteric mechanism may avoid dose dependent CNS side effects (somnolence/dizziness) seen with orthosteric agonists – Allosteric mechanism may avoid desensitization and open the possibility of oral chronic use thus allowing potential to treat pain (i.e. osteoarthritis) 15
  16. 16. ADX71943 analgesic-like effects in preclinical models Analgesic-like effect of ADX71943 in the Analgesic-like effect in the writhing CFA* model in rats after oral administration test of oral ADX71943 in mice Vehicle 22 vehicle ADX71943 Baclofen 25 Withdrawal Threshold 1 mg/kg ADX-71943 20 Experiment 1 3 mg/kg ADX-71943 18 Number of writhes Experiment 2 10 mg/kg ADX-71943 Experiment 3 20 16 * Experiment 4 30 mg/kg ADX-71943 14 *** ** 15 30 mg/kg Naproxen * 12 * ** Baclofen ADX71943 10 *** *** * *** 8 ** ** +++ 10 6 4 5 2 0 0.3 1 3 10 30 100 3 0 non-CFA CFA 1 hr 2 hr mg/kg mg/kg Time post-dose (hr) *p<0.05, **p<0.01, ***p<0.001 vs. JQ-02 vehicle; +++p<0.001 vs. 1%CMC vehicle ADX71943 caused a dose-dependent increase in the withdrawal ADX71943 caused a dose-dependent reduction of threshold in the CFA induced mechanical hypersensitivity test in acetic acid-induced writhing in mice with a minimum rats, with a minimum effective dose of 10 mg/kg p.o. effective dose between 3 and 10 mg/kg p.o. 16 *CFA = Complete Freund's Adjuvant 16
  17. 17. ADX68692 FSH NAM • FSH in females S.F. Betz, J.Med.Chem., 2008 – involved in folliculogenesis – induces maturation of ovarian follicles – & production of estrogen and progesterone • FSH in males – stimulates Sertoli cell proliferation – supports spermatogenesis – LH stimulates testosterone production Potential applications include: • Contraception • Hormone-dependent cancer (add-on therapies) • Osteoporosis • Prostate cancer • Endometriosis • Breast cancer • Uterine fibroids • Ovarian cancer • Precocious puberty • Hormone-dependent benign diseases • Polycystic ovarian disease • Benign prostate hyperplasia • Dysfunctional uterine bleeding 17
  18. 18. ADX68692 stops ovulation in female rats • Treatment with ADX68692 at Control group Total number of animals in Proestrus/Estrus stage pharmacological and multiple of 18 16 pharmacological doses for 4 weeks 14 was well tolerated 12 10 • Treatment for 4 weeks with the FSH 8 6 NAM ADX68692 reduced the 4 number of female rats in the 2 0 estrus/proestrus phase (ovulatory -14 -11 -8 -5 -2 2 5 8 11 14 17 20 23 26 29 phase), and increased the number of Day of treatment female rats in the diestrus phase, indicating disruption of menstrual ADX68692: 20 mg/kg/day cycle. 18 • Eventually at the highest dose, 16 14 animals were found in persistent 12 10 diestrus 8 6 • Histopathological examination 4 2 showed follicular atresia which is the 0 consequence of the FSH function -14 -11 -8 -5 -2 2 5 8 11 14 17 20 23 26 29 blockade (blockade of ovulation) Day of treatment • Estradiol levels were lowered, even in Treatment start 18 the proestrus phase Synchronisation
  19. 19. ADX68692 Summary / Prospectives • In vivo & in vitro data show ADX68692 effects on testosterone in male rats ADX68692 is a potent NAM with Treatment for 4 weeks with the FSH/LH NAM ADX68692 lowered circulating testosterone levels but did not have any other dual action on FSH and LH 25.0 significant effects on the male rat reproductive system receptors Testosterone (nnmol/L) 20.0 • ADX68692 is a small molecule with a good develop-ability & 15.0 drug-like profile *** 10.0 *** • ADX68692 is able to block FSH 5.0 action in vivo after oral administration 0.0 After 3-week treatment with ADX68692 • Good rational for Group 1 (0 mg/kg/day) Group 2 (2 x 10 mg/kg/day) – women’s health indications Group 3 (2 x 30 mg/kg/day) Group 4 (2 x 100 mg/kg/day) like endometriosis – hormone refractory prostate cancer 19
  20. 20. Addex Pharmaceuticals ~~~~~~~~ Allosteric Discovery & Optimization Platform 20
  21. 21. Allosteric Modulation Explained arketed NB: Most m hosteric. drugs are ort s ligands Endogenou ctivators orthosteric drugs compete orthosteric drugs compete are natural a with endogenous ligands for with endogenous ligands for in the body. the active site on a receptor the active site on a receptor allosteric drugs allosteric drugs bind another site bind another site on same receptor on same receptor Unlike orthosteric drugs, allosteric modulators are non-competitive. Therefore, their effects on signal transduction are observed primarily when endogenous ligands bind the active site. 21
  22. 22. Orthosteric ≠ Allosteric Orthosterics are steady state Advantages include: • Greater specificity than orthosteric molecules Biological response Agonist Less toxicities from “off-target” interactions compared to more promiscuous orthosteric molecules Natural ligand Greater specificity leads to greater productivity • Non-competitive mechanism Antagonist Intellectual property space relatively un-exploited Lower doses required –less dose related toxicity Time –lower COGs • Acts like a dimmer not an “on/off” switch Allostery preserves natural rhythm Body maintains control – physiological rhythm preserved Less tolerance/desensitization Potentially fewer side effects vs orthosteric drugs at same target Biological response PAM + natural ligand • Can target receptors considered “intractable” or only Natural ligand addressable with peptide/protein drugs Lower COGs and lower administration cost (beats biosmilars!) Better compliance with oral drugs NAM + natural ligand Potential safety, tolerability and efficacy advantages with allosteric mechanism Time 22
  23. 23. Industrializing Allostery Addex is pioneering the industrialization of allosteric drug discovery and optimization • Addex has built a unique allosteric modulator focused library (70k compounds & growing) • Addex has built tailored proprietary screening tools capable of direct detection of allosteric modulators (facilitates discovery and medicinal chemistry) • Allosteric modulators have broad potential as therapeutics targeting GPCRs & other types of receptors, including type I single pass transmembrane proteins (i.e. cytokine receptors) 23
  24. 24. Addex AM focused library: Comparative Structural Analysis Marketed Drugs Addex Library Addex corporate library occupies a unique Addex corporate library occupies a unique structural space while sharing many other structural space while sharing many other drug-like properties with marketed drugs drug-like properties with marketed drugs 24
  25. 25. Building of an Allosteric Fragment Database • Establish virtual AM fragment database: from literature and in-house data D D C G C A B H G F A B F H E E • Generate signature fragments (identification of privileged structural motifs by machine learning) examples of privileged motifs 25
  26. 26. Addex targets allosteric sites in GPCR families 1, 2 & 3 Family 1 Family 2 Family 3 (e.g. Orexin & FSH) (e.g. GLP-1R, GIPR) (e.g. mGluR1-8, GABABR) From P.J. Conn, A. Christopoulos and C. Lindsley, Nature Reviews Drug Discovery, 2009, 8, 41-54. 26
  27. 27. Proprietary Novel Assays G-Protein Coupled Receptors • Phoenyx: a cAMP dynamic non stop assay • FBBA: Fluorescence-Based Binding Assay measuring bi-molecular interactions (GLP1) • ADX-tags series 1: Proximal & dynamic assays for functional measurements of all types of GPCRs (GLP1, GIP) 27
  28. 28. Addex targets allosteric sites in type 1 single-pass transmembrane proteins TNFR family Pathogens IL-1α/IL-1β IL- /IL- IL-33 IL- IL-1F6/8/9 IL- IL-18 IL- IL-1R family TIR domains IL18R1 IL18R2 IL1R1 AcP AcP RP2 AcP ST2 Toll-like Toll- receptors 28
  29. 29. Proprietary Novel Assays type 1 single-pass transmembrane proteins • APRA: Accessory Protein Relocalization Assays (TNF R1) • ADX-tags series 1: Proximal & dynamic assays for functional measurements. – Measures activation-dependent association or dissociation of binding partners (IL-1R) • ADX-tags series 2: measures conformational changes or multimerization changes that lead to an activation signal (TNF R1, IL-1R) 29
  30. 30. The Addex Platform Clinical Development Non-Clinical Development Metabolic Inflammation CNS Disorders Core Biology Core Chemistry 30

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