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Addex Pharmaceuticals Investor Presentation September 2010

Addex Pharmaceuticals Investor Presentation September 2010. Disclaimer

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Addex Pharmaceuticals Investor Presentation September 2010

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  1. Addex PharmaceuticalsInvestor PresentationSeptember 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. The Company • Goal: allosteric modulators for human health • Focus: CNS, metabolic disorders, inflammation • Proprietary allosteric modulator discovery platform • 15 discovery/development programs • Pharma validation • Partners: Johnson & Johnson and Merck & Co., Inc. • Investors: SR-One (GSK) and Roche Venture Fund • 138 staff / founded 2002 in Geneva, Switzerland

  4. Financials • Cash for operations through end of 2011 • CHF56.7 (US$54/€42) million in cash as of June 30 • Market cap (6 Sep): CHF52m (€40m / US$51m) • SIX Swiss Exchange: ADXN (ISIN:CH0029850754) • 5,871,242 shares outstanding as of June 30, 2010 • Five analysts covering:

  5. PIPELINE Molecule / Mechanism Partner Assay Development & Screening Hit-to-Lead Lead Optimization Preclinical Phase I Phase II Milestone ADX48621mGluR5 NAM Parkinson’s Disease Levodopa Induced Dyskinesia (PD-LID) Start Ph II 4Q10 Dystonia Start Ph IIa 1Q11 Ortho-McNeil-Janssen Schizophrenia ADX71149mGluR2 PAM Start Ph IIa1Q11 funded & developed by OMJPI* Ortho-McNeil-Janssen Anxiety Start Ph IIa1Q11 funded & developed by OMJPI* Osteoarthritic Pain ADX71943GABA-B PAM Start Ph I2011 ADX63365mGluR5 PAM Merck & Co., Inc. Schizophrenia ‡ funded & developed by Merck Endometriosis / Benign Prostatic Hyperplasia ADX68692FSHR NAM 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

  6. DISCOVERY PROGRAMS Molecule / Mechanism Partner Assay Development & Screening Hit-to-Lead Lead Optimization Preclinical Phase I Phase II Milestone CNS Alzheimer’s / Depression mGluR2 NAM Merck & Co., Inc. Parkinson’s Disease ‡ mGluR4 PAM funded by Merck DepressionPost Traumatic Stress Disorder mGluR7 NAM Sleep Disorders Orexin 2R NAM Metabolic Disorders Type II Diabetes GLP1 PAM Type II Diabetes GIPR PAM Inflammation Rheumatoid Arthritis, Psoriasis, Alzheimer’s, Multiple Sclerosis TNFR1 NAM (CD120a) Psoriasis, Osteoarthritis A2A PAM Gout, Type II Diabetes IL1R1 NAM (CD121a) NAM = negative allosteric modulator (an inhibitor) ‡ and undisclosed additional indications PAM = positive allosteric modulator (an activator)

  7. Partnered Programs

  8. Agreement With Ortho-McNeil-Janssen Pharmaceuticals, Inc. (OMJPI) Utilize Addex platform to identify & develop orally available mGluR2 PAM for schizophrenia, anxiety and undisclosed indications OMJPI funds collaboration on discovery & lead optimization OMJPI funds & performs preclinical and clinical development Addex sits on oversight committees ADX71149 Terms • €3 million upfront • Research funding to Addex during discovery collaboration (2005-2007) • €112 in potential milestones upon completion of clinical and regulatory milestones • Low double-digit royalties

  9. ADX71149 Progress to Date • Collaboration generated clinical candidates • €4.2 million in R&D funding between 2005-2007 • Comprehensive Ph I program started in June 2009 • €1 million milestone paid upon initiation of Phase I • More than 5 Phase I trials in healthy volunteers • SAD, MAD • Food & gender • Ketamine challenge (schizophrenia model) • Anxiety challenge • Phase II program scheduled to start in 1Q11 • schizophrenia • anxiety • potentially other indications Note mGluR2 activation is clinically validated in anxiety & schizophrenia * Nature Medicine 2007: http://bit.ly/bbnsyQ

  10. ADX63365 Terms • $22 million upfront • $680 million in milestones • Undisclosed royalties Agreement • Merck & Co., Inc. licensed Addex mGluR5 PAMs in 2008 • mGluR5 PAM expected to be highly differentiated • Merck already had demonstrated mGluR5 PAM have efficacy in animal models of schizophrenia • Preclinical data show efficacy for cognitive deficit (& psychosis) • Despite efficacy of marketed drugs many schizophrenia patients remain unable to learn new skills to support themselves • FDA has recognized cognitive deficit as an unmet medical need in schizophrenia • Merck is responsible for development of ADX63365 & backups

  11. Agreement Discover and develop metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAM) with Merck & Co., Inc. The deal includes mGluR4 PAM leads already discovered by Addex Merck is responsible for preclinical and clinical development Addex will sit on oversight committees mGluR4 PAM Terms • $3 million upfront • $167.5 million in potential milestones • Annual tech access fee $250,000 • Research funding 2009/2010 • Undisclosed royalties • Option to co-promote in EU Progress • Deal signed (Dec 07) • 1st Preclinical milestone (Feb 08) • $250,000 • 2nd preclinical milestone (Jul 09) • $500,000 • Orally available mGluR4 PAM showed efficacy in model of PD • Collaboration extended (Dec 09) • Merck commits $1.8 million in research funding • Going forward all costs transferred to Merck

  12. Platform Revenues Proprietary Platform Revenues * and undisclosed indications • Addex has received partnering revenue every year since 2004 • Cash inflows generated to date: CHF43 million • All three partnerships are fully funded by our partners • Potential for up to about $1 billion in milestones plus royalties

  13. Wholly Owned Programs

  14. ADX48621 Overview • Phase I completed • Three studies: SAD, MAD, gender & food effects • 110 patients treated to date, including older volunteers • Safety & tolerability justify further clinical study • Ph II to start in 4Q10 for PD-LID and 1Q11 for dystonia • Differentiated • Only product shown to reduce dystonia in MPTP model • Chemical series unrelated to other mGluR5 NAM • Unique metabolic profile • NCE patents valid through 2025 in most territories • Unrelated series of backup molecules in clinical candidate selection

  15. **p<0.01, ***p<0.001 versus vehicle group ADX48621 efficacy in HIC model • Haloperidol induced catalepsy (HIC) is a preclinical model of PD • ADX48621 dose-dependently reversed HIC in 3 independent experiments • MTEP mGluR5 antagonist is well documented to work in the HIC model • ADX48621 effects in HIC model suggest • It should be tested further as a potential drug for PD • It has potential to be a dopamine sparing agent

  16. MPTP model of PD-LID What is the MPTP Model? • MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) • Neurotoxin destroys dopaminergic neurons • Symptoms similar to PD, treatable with levodopa • MPTP monkeys develop levodopa induced dyskinesia (LID), including both chorea (trembling) and dystonia (cramping) seen in humans • MPTP PD-LID model is predictive of efficacy in humans • KOLs consider it among the most translational models in the CNS space • AFQ056 (mGluR5/Novartis) showed efficacy in MPTP PD-LID model • AFQ056 showed efficacy in Phase IIa PD-LID trial

  17. ADX48621 MPTP Study Design • ADX48621 or vehicle administered 30 min prior to levodopa • Behavioral assessment began upon levodopa administration • trained observers performed video review • dyskinesia & PD disability scoring (10 min every 30 min for 2hrs) • lower scores (left axis) indicate fewer symptoms/disability • dyskinesia symptoms are side effects from levodopa • disability is a measure of Parkinson’s disease severity

  18. Dyskinesia + levodopa ADX48621 dose-dependently reduced dyskinesia (chorea + dystonia) ADX48621 efficacy in MPTP model Disability ADX48621 does not reduce levodopa efficacy ADX48621 reduced dyskinesia without compromising levodopa efficacy

  19. Chorea Dystonia Dystonia = sustained muscle contractions (e.g. cramps) Chorea = involuntary movements (e.g. trembling) ADX48621 efficacy in MPTP model ADX48621 is the first drug-candidate known to have efficacy on dystonia

  20. ADX48621Commercial Potential • Levodopa induced dyskinesia (LID) and dystonia are unmet medical needs • Most Parkinson’s disease (PD) patients develop LID • There are no drugs specifically approved for PD-LID • PD represents a growing unmet medical need • Dystonia is poorly addressed by existing drugs • Dystonia market could be significant • Occurrs in multiple conditions • Occurrs as a side effect of drugs • PD-LID/dystonia is a faster path to market than PD • Addex can retain co-promotion rights • PD, PD-LID & dystonia are treated by specialists • geographic split possible • mGluR4 PAM & mGluR2 NAM represent potential additions to future neurodegenerative disease franchise

  21. ADX71943 • ADX71943 is a gamma-aminobutyric acid subtype B (GABAB)receptor PAM • Clinically/commercially validated mechanism • generic GABAB agonist, baclofen, is marketed • other orthosteric GABAB agonists are clinically validated • ADX71943 is differentiated • ADX71943 is the only allosteric modulator of GABAB in development • Demonstrated analgesic effects in three preclinical pain models • Potential for chronic pain (e.g. osteoarthritis) and other indications • Phase I to start in 2011 • ADX71943 is available for partnering

  22. 100 PHASE I 1st experiment 2nd experiment 3rd experiment Nocifensive behaviour (s) . 80 * 60 ** *** * * ** * 40 *** +++ 20 0 0.3 1 3 10 30 100 Baclofen, Baclofen, ADX71943 vehicle vehicle 6 mg/kg ADX71943 (mg/kg) 200 1st experiment PHASE II 180 2nd experiment 3rd experiment 160 Nocifensive behaviour (s) . 140 ** 120 *** 100 *** *** 80 *** 60 40 ++ 20 0 Baclofen, ADX71943 0.3 1 3 10 30 100 Baclofen, vehicle vehicle 6 mg/kg ADX71943 (mg/kg) ADX71943 significantly reduces nocifensive behaviour in the formalin test in mice after single oral administration Phase I Dose-dependent reduction in nocifensive behaviour. Statistically significant from the dose of 3 mg/kg. Phase II Dose-dependent reduction in nocifensive behaviour. Statistically significant from between the doses of 3 and 10 mg/kg. *p<0.05, **p<0.01, ***p<0.001 vs. ADX71943 vehicle ++p<0.01, +++:p<0.001 vs baclofen vehicle

  23. ADX71943 significantly attenuates CFA-induced mechanical hyperalgesia after single oral administration • Single oral of administration ADX71943 caused a dose-dependent increase of the withdrawal threshold in CFA-inflamed rats. • The effect was statistically significant from the dose of 10 mg/kg.

  24. 22 Experiment 1 20 Experiment 2 18 Experiment 3 16 Experiment 4 14 * * * 12 Number of writhes ** *** *** 10 *** * ** ** +++ 8 6 4 2 0 ADX71943 vehicle Baclofen vehicle 0.3 1 3 10 30 100 3 mg/kg Baclofen ADX71943 (mg/kg) *p<0.05, **p<0.01, ***p<0.001 vs. JQ-02 vehicle; +++p<0.001 vs. 1%CMC vehicle ADX71943 significantly reduces nocifensive behaviour in the writhing test in mice after single oral administration • ADX71943 caused a dose-dependent reduction of acetic acid-induced writhing in mice. • The effect was statistically significant from the dose of 3 mg/kg.

  25. ADX71943 demonstrates antihyperalgesic effects in the MIA model of OA in rats Pre-treatment Treatment 350 *** 300 ** * * 250 *** 200 ### ** Withdrawal threshold (g) Maximum response bewteen 1 and 2 hr 150 100 50 0 Pre-MIA Post-MIA Day 1 Day 8 Day post-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 animals 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.

  26. Pre-treatment Treatment 15.0 12.5 10.0 Maximum Paw Withdrawal Threshold (g) 7.5 ## 5.0 2.5 0.0 Pre-MIA Pre-drug Day 1 Day 8 Days post-MIA-1 14 14 21 Vehicle 1 mg/kg ADX71943 3 mg/kg ADX71943 ##p<0.01 vs. Pre-MIA; paired t-test, 9≤n≤10 animals per group 10 mg/kg ADX71943 30 mg/kg ADX71943 Celecoxib (30 mg/kg) Mechanical allodynia in the MIA model of OA in rats • The effects of ADX71943 and celecoxib in the von Frey test did not reach statistical significance

  27. Roles of FSH/LH Females • FSH involved in folliculogenesis • maturation of follicles • estrogen production • LH triggers ovulation, progesterone Males • FSH supports spermatogenesis • LH stimulates testosterone production ADX68692 Status • ADX68692 is a follicle stimulating hormone receptor (FSHR) NAM • Orally available non-steroidal molecule with drug-like characteristics • In late preclinical development • ADX68692 is available for partnering Preclinical Data & Potential Indications • Statistically significant reduction in testosterone & prostate weight • Benign prostatic hyperplasia (BPH) • Statistically significant reduction in estradiol • Endometriosis

  28. In vivo target related efficacy in female rats: 4 week treatment • Treatment with ADX68692 at pharmacological and multiple of pharmacological doses for 4 weeks was well tolerated • Treatment for 4 weeks with 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 Total number of animals in Proestrus/Estrus stage Treatment start Synchronisation

  29. In vivo target related efficacy in female rats: 4 week treatment Effect on Estrous cycle duration‏ POC that ADX68692 disrupts the estrous cycle and increases its mean duration, eventually leading to complete blockade at high dose.

  30. 25.0 20.0 Testosterone (nnmol/L) 15.0 *** 10.0 *** 5.0 0.0 After 3-week treatment with ADX68692 Group 1 (0 mg/kg/day) Group 2 (2 x 10 mg/kg/day) Group 3 (2 x 30 mg/kg/day) Group 4 (2 x 100 mg/kg/day) In vivo target related efficacy in male rats: 4 weeks treatment Circulating testosterone levels were significantly lowered at the lowest and intermediate dose. Relative weight changes were observed for prostate (). These changes were dose dependent and became statistically significant at the highest dose

  31. GLP-1 PAM project • To develop a small molecule GLP-1 PAM for the treatment of Type II Diabetes • Orally available • Should increase insulin secretion and decrease blood glucose • No or reduced nausea/vomiting compared to competition • Should preferably induce weight loss • Could be used in combination with other therapies

  32. Oral GLP1R PAM in db/db mouse model • Leptin receptor–deficient db/db knockout mice are considered an established model • develop human Type II diabetes mellitus • hypertension and obesity • disrupted circadian blood pressure (BP) rhythm • We orally administered to db/db mice • ADX91886 GLP1R PAM • Januvia sitagliptin DPP IV inhibitor • or vehicle • 15 min later 2 g/kg glucose is given orally • Blood glucose + insulin levels were measured 10 ; 20 ; 30 ; 60 ; 90 min after glucose administration

  33. 30 * 25 20 Glucose AUCB (mM.hr) 15 10 *** 5 Glucose AUCB (0-90 min) 0 A: Vehicle po B: ADX91886 (220 mg/kg po) C: Sitagliptin 10 mg/kg po A B C Oral GPL1R PAM compared to sitagliptin in db/db mice

  34. mGluR2 NAM • Data from Addex and others show that mGluR2 inhibition can reverse cognitive deficit • 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* • mGluR2 NAM may also be disease modifying *The Journal of Neuroscience, March 17, 2010; 30(11):3870-3875

  35. Familiar object Novel object *** *** 15 *** 12 9 6 3 0 ADX92639 is effective against icv β amyloid-induced deficit in NOR in the rat Locomotor activity during the test Exploration of novel vs familiar objects sham β-Amyloid* 18 β- Amyloid* 120 sham 15 *** 12 9 90 6 3 Line crosses 0 Exploration time (sec) veh veh veh veh 60 18 30 0 t1 t2 t1 t2 t1 t2 t1 t2 veh 10 30 Donepezil Veh 10 30 Donepezil (1 mg/kg, ip) (1 mg/kg, ip) ADX92639(mg/kg, p.o.) ADX92639 (mg/kg, p.o.) *Single administration into the lateral ventricle of 8 μl solution Final concentration of b amyloid = 2 mg/ml • ADX92639 reverses cognitive impairment induced by intracebroventricular (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

  36. Allosteric Modulator Discovery & Optimization

  37. Because they bind a different site on the receptor, allosteric modulators do not turn receptors on or off the way the body’s natural activators and most drugs do. Instead, they act more like a dimmer switch, offering control over the ease & intensity of (de-)activation while allowing the body to retain its natural control over initiating receptor activation via the active site (e.g. the on/off switch). Allosteric Modulation

  38. Orthosterics are steady state Biological response Natural ligand PAM + natural ligand Agonist Time NAM + natural ligand Antagonist Allostery preserves natural rhythm Natural ligand Biological response Time Allosteric Advantages • Greater specificity than orthosteric molecules – e.g. mGluRs • Can target receptors considered “intractable” or only tractable by biologics, peptides or proteins • e.g. GLP-1 • Non-competitive mechanism • Un-exploited intellectual property • Less dose related toxicity • Acts like a dimmer not “on/off” switch • Body maintains control of receptor activation cycle

  39. Serendipity has yielded some marketed allosteric modulators. Most recent examples include: Sensipar/Mimpra cinacalcet (Amgen) Positive allosteric modulator (PAM) of calcium sensing receptor Approved 2004 treats secondary hyperparathyroidism Selzentry/Celsentri maraviroc (Pfizer) Negative allosteric modulator (NAM) of CCR5 Approved 2007 Treats CCR5-tropic HIV-1 Allosteric Modulators 101

  40. The Addex raison d'être • Allosteric modulators are hard to find • Industrial tools for orthosteric drugs are not appropriate • Pharma has been focused on tools for finding orthosteric drugs • Why didn’t pharma industrialize allosteric drug discovery? • Upfront investment to build allosteric drug discovery platform was high • Time to value creation was long & uncertain • Addex is industrializing allosteric modulation discovery • Proprietary assays • High throughput screening & optimization tools (384 well plates & robotics) • Direct detection systems • proximal to target • continuous real-time observation • works for molecules (i.e. allosteric modulators) that do not activate target receptor • Allostery biased library of over 70,000 compounds

  41. Proprietary Screening AssaysG-Protein Coupled Receptors • Phoenyx • a cAMP dynamic non stop assay • FBBA (GLP1R, mGluR7) • Fluorescence-Based Binding Assay • Measures bi-molecular interactions • Proxylite (GLP1R, GIP) • Proximal & dynamic assays for functional measurements of all types of GPCRs

  42. Proprietary Screening Assaystype 1 single-pass transmembrane proteins • APRA (TNFR1) • Accessory Protein Relocalization Assays • ADX-tags series 1 (IL1R) • Proximal & dynamic assays for functional measurements • Measures activation-dependent association or dissociation of binding partners • ADX-tags series 2 (TNFR1, IL1R) • measures conformational changes that lead to activation signal • measures multimerization changes that lead to activation signal

  43. Marketed Drugs Marketed Drugs Addex Compounds Addex Compounds Allostery Biased Library in-silico analysis StructuralComparison Physicochemical Comparison Addex library and marketed drugs share the same physicochemical property space BUT Addex library occupies a unique structural space

  44. Platform Validation • Addex identified selective orally available small molecules for • Challenging GPCRs (mGluRs, GABA-B & A2A) • Peptide receptors (GLP1R, GIPR) • Cytokine receptors (TNFR1 & IL1R1) • The proof is in the pudding • Merck & Co., Inc. licensed mGluR4 PAM & mGluR5 PAM • Johnson & Johnson licensed mGluR2 PAM

  45. Summary • 15 Programs for High Value Targets/Indications • Highly differentiated allosteric mechanism • Low target related risk (i.e. mostly clinically validated targets) • Allosteric Modulator Platform • Proprietary tools + tailored library • Platform + multi-disciplinary approach are scalable • 3 Validating Partnerships (MRK/J&J) • Top Tier Investors • Cash to end of 2011

  46. Management & Boards Executive Management Jean-Philippe Rocher, Head of Core Chemistry Robert Lütjens, Head of Core Biology Tatiana Carteret, Head of Human Resources Chris Maggos, Investor Relations & Communications Vincent Mutel,Chief Executive Officer Tim Dyer,Chief Financial Officer Charlotte Keywood,Chief Medical Officer Sonia Poli,Head of Non-Clinical Development Laurent Galibert, Head of Inflammation & Metabolic Disorders Board of Directors André J. Mueller,Chairman Vincent Mutel,Vice Chairman & CEO of Addex Andrew Galazka, SVP Scientific Affairs, Merck-Serono Ray Hill,former Head of EU Licensing, Merck & Co., Inc. Vincent Lawton,former MD of Merck Sharp & Dohme U.K. Beat E. Lüthi,CEO of CTC Analytics Antoine Papiernik,Sofinnova Partners Scientific Advisory Board George F. Koob,Ph.D., Chairman Bernhard Bettler,Ph.D. Arthur Christopoulos,Ph.D. Patrick M. Sexton,Ph.D. Mark A. Geyer,Ph.D. Barbara J. Mason,Ph.D.

  47. allosteric modulators for human health www.addexpharma.com

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