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Addex Pharmaceuticals Investor Relations Slides January 2010.

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Presentation on theme: "Addex Pharmaceuticals Investor Relations Slides January 2010."— Presentation transcript:

1 Addex Pharmaceuticals Investor Relations Slides January 2010

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 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 The Company

4 4 Financials Cash: about CHF75m* (€62m / US$89m) at end /11 cash burn guidance: CHF35-40m Market cap (6 Jan 10): CHF82m (€55m / US$80m) SIX Swiss Exchange: ADXN (ISIN:CH ) 5,862,492 shares outstanding as of June 30, 2009 Five analysts covering: Piper JaffraySam Fazeli & Michael Aitkenhead JefferiesPeter Welford & Philippa Gardner HelveaOlav Zilian Bank VontobelAndrew C. Weiss & Silvia Schanz Bank am BellevueBob Pooler *assuming midpoint of cash burn guidance for CHF43-47m was achieved

5 5 Inflammation CNS Metabolic Disorders MechanismPartner Assay Dev & Screening Hit-to-Lead Lead Optimization PreclinicalPhase IPhase IIMilestone mGluR5 NAM Start Ph II 4Q10 mGluR2 PAM J&J * not disclosed mGluR5 PAM Merck & Co.not disclosed GABA B PAM Start Ph I 4Q10 FSH NAM Start Ph I 1Q11 mGluR2 NAM mGluR4 PAM Merck & Co. mGluR7 NAM Orexin 2R NAM GLP-1 PAM GIPR PAM TNF-R1 NAM A2A PAM IL-1R1 NAM Type II diabetes Rheumatoid Arthritis, Psoriasis, Alzheimer’s, Multiple Sclerosis Pipeline ADX71943 Pain / Urinary Incontinence / GERD ADX68692 Endometriosis / Prostate Cancer Alzheimer’s / Depression Depression / Post Traumatic Stress Disorder Psoriasis, Osteoarthritis Gout, Type II diabetes NAM = negative allosteric modulator (an inhibitor) * Ortho-McNeil-Janssen Pharmaceuticals Inc., a Johnson & Johnson company PAM = positive allosteric modulator (an activator) ‡ undisclosed additional indications ADX71149 Anxiety / Schizophrenia funded & developed by J&J ADX63365 Schizophrenia ‡ funded & developed by Merck ADX48621 Parkinson’s disease levodopa induced dyskinesia (PD-LID) Parkinsons’s disease ‡ with Merck funding Sleep disorders

6 6 Deals to Date Partner ProductIndication(s) Status at signing Upfront Cash (Date) Milestones Ortho-McNeil-Janssen (a J&J company) ADX71149 mGluR2 PAM Anxiety & schizophrenia Hit-to-Lead €3 million 1 (Dec 2004) not disclosed 2 Merck & Co., Inc.mGluR4 PAM Parkinson’s disease 3 Hit-to-Lead $3 million 4 (Dec 2007) $167.5 million 2 Merck & Co., Inc. ADX63365 mGluR5 PAM Schizophrenia 3 Clinical Candidate $22 million (Jan 2008) $680 million 2 1 €4.2 million in research funding were paid to Addex during the research collaboration, which completed in 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

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 Levodopa induced dyskinesia (LID) develops in 40% of PD patients receiving levodopa The two main components of LID are chorea and dystonia – Chorea is manifest as abnormal involuntary movements – Dystonia is characterized by sustained muscle contractions that frequently cause twisting/repetitive movements & abnormal, painful, postures/positions – Occurrence of LID is associated with a significant up-regulation of mGluR5 binding in the striatum and globus pallidus of Parkinsonian monkeys and humans Three mGluR5 NAM have been shown to alleviate PD-LID to date –ADX48621 reduced chorea and dystonia in the MPTP model –ADX10059 (Addex) reduced chorea and dystonia in the MPTP model –AFQ056 (Novartis) Reduced LID in MPTP model of PD Ph IIa clinical validation achieved in patients with PD-LID

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 **p<0.01, ***p<0.001 versus vehicle group

10 10 ADX48621 works in MPTP model Significant effects on ChoreaSignificant effects on Dystonia ADX48621 is the first product to reduce both Chorea & Dystonia in this model

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

12 12 Study ADX (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 ADX48621 PD–LID Phase II Plan

13 13 ADX71149 mGluR2 PAM ADX71149 is a positive allosteric modulator of mGluR2 – mGluR2 activation is clinically validated in anxiety 1 & schizophrenia 2anxietyschizophrenia – 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

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

15 15 ADX71943 GABA B PAM GABA B receptor is a clinically validated target – Baclofen, GABA B agonist, is marketed to treat spasticity off-label use in pain and other indications experimental GABA B 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)

16 16 ADX71943 analgesic-like effects in preclinical models Analgesic-like effect of ADX71943 in the CFA* model in rats after oral administration ADX71943 caused a dose-dependent increase in the withdrawal threshold in the CFA induced mechanical hypersensitivity test in rats, with a minimum effective dose of 10 mg/kg p.o. non-CFACFA1 hr2 hr * ** * * Time post-dose (hr) Withdrawal Threshold Vehicle 1 mg/kg ADX mg/kg ADX mg/kg ADX mg/kg ADX mg/kg Naproxen Analgesic-like effect in the writhing test of oral ADX71943 in mice ADX71943 caused a dose-dependent reduction of acetic acid-induced writhing in mice with a minimum effective dose between 3 and 10 mg/kg p.o. *p<0.05, **p<0.01, ***p<0.001 vs. JQ-02 vehicle; +++p<0.001 vs. 1%CMC vehicle Experiment 1 Experiment 2 Experiment 3 Experiment 4 vehicle Number of writhes *** * ** * * * mg/kg ADX71943 Baclofen ADX71943Baclofen *CFA = Complete Freund's Adjuvant

17 17 ADX68692 FSH NAM FSH in females – 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 S.F. Betz, J.Med.Chem., 2008 Potential applications include: Contraception Osteoporosis Endometriosis Uterine fibroids Precocious puberty Polycystic ovarian disease Dysfunctional uterine bleeding Hormone-dependent cancer (add-on therapies) Prostate cancer Breast cancer Ovarian cancer Hormone-dependent benign diseases Benign prostate hyperplasia

18 18 ADX68692 stops ovulation in female rats Treatment with ADX68692 at pharmacological and multiple of pharmacological doses for 4 weeks was well tolerated Treatment for 4 weeks with the FSH NAM ADX68692 reduced the number of female rats in the estrus/proestrus phase (ovulatory phase), and increased the number of female rats in the diestrus phase, indicating disruption of menstrual cycle. Eventually at the highest dose, animals were found in persistent diestrus Histopathological examination showed follicular atresia which is the consequence of the FSH function blockade (blockade of ovulation) Estradiol levels were lowered, even in the proestrus phase Synchronisation Treatment start Total number of animals in Proestrus/Estrus stage

19 19 Summary / Prospectives In vivo & in vitro data show ADX68692 is a potent NAM with dual action on FSH and LH receptors ADX68692 is a small molecule with a good develop-ability & drug-like profile ADX68692 is able to block FSH action in vivo after oral administration Good rational for – women’s health indications like endometriosis – hormone refractory prostate cancer ADX68692 Treatment for 4 weeks with the FSH/LH NAM ADX68692 lowered circulating testosterone levels but did not have any other significant effects on the male rat reproductive system ADX68692 effects on testosterone in male rats

20 20 Addex Pharmaceuticals ~~~~~~~~ Allosteric Discovery & Optimization Platform

21 21 Unlike orthosteric drugs, allosteric modulators are non-competitive. Therefore, their effects on signal transduction are observed primarily when endogenous ligands bind the active site. Allosteric Modulation Explained NB: Most marketed drugs are orthosteric. Endogenous ligands are natural activators in the body. orthosteric drugs compete with endogenous ligands for the active site on a receptor allosteric drugs bind another site on same receptor NB: Most marketed drugs are orthosteric. Endogenous ligands are natural activators in the body. orthosteric drugs compete with endogenous ligands for the active site on a receptor allosteric drugs bind another site on same receptor

22 22 Orthosteric ≠ Allosteric Advantages include: Greater specificity than orthosteric molecules Less toxicities from “off-target” interactions compared to more promiscuous orthosteric molecules Greater specificity leads to greater productivity Non-competitive mechanism Intellectual property space relatively un-exploited Lower doses required – less dose related toxicity – lower COGs Acts like a dimmer not an “on/off” switch Body maintains control – physiological rhythm preserved Less tolerance/desensitization Potentially fewer side effects vs orthosteric drugs at same target Can target receptors considered “intractable” or only addressable with peptide/protein drugs Lower COGs and lower administration cost (beats biosmilars!) Better compliance with oral drugs Potential safety, tolerability and efficacy advantages with allosteric mechanism Natural ligand Time PAM + natural ligand NAM + natural ligand Biological response Allostery preserves natural rhythm Time Natural ligand Agonist Antagonist Biological response Orthosterics are steady state

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)

24 24 Marketed Drugs Addex Library Addex corporate library occupies a unique structural space while sharing many other drug-like properties with marketed drugs Addex AM focused library: Comparative Structural Analysis

25 25 Building of an Allosteric Fragment Database Establish virtual AM fragment database: from literature and in-house data Generate signature fragments (identification of privileged structural motifs by machine learning) examples of privileged motifs B A C D F E G H F E G H B A C D

26 26 Addex targets allosteric sites in GPCR families 1, 2 & 3 From P.J. Conn, A. Christopoulos and C. Lindsley, Nature Reviews Drug Discovery, 2009, 8, Family 1 (e.g. Orexin & FSH) Family 2 (e.g. GLP-1R, GIPR) Family 3 (e.g. mGluR 1-8, GABA B R)

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)

28 28 Addex targets allosteric sites in type 1 single-pass transmembrane proteinsIL1R1 AcP IL-1  /IL-1  ST2 AcP IL-33 RP2 AcP IL-1F6/8/9 IL18R1 IL18R2 IL-18 IL-33 Toll-likereceptors Pathogens TIRdomains TNFR family IL-1R family

29 29 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) Proprietary Novel Assays type 1 single-pass transmembrane proteins

30 30 The Addex Platform Inflammation CNS Metabolic Disorders Core Chemistry Non-Clinical Development Clinical Development Core Biology


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