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Addex Pharmaceuticals

Addex Pharmaceuticals. Corporate Presentation August 2011. Disclaimer

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Addex Pharmaceuticals

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  1. Addex Pharmaceuticals Corporate Presentation August 2011

  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. Vision Goal: allosteric modulators for human health How: proprietary discovery platform Focus: CNS, metabolic disorders & inflammation

  4. Financials & Stock • Cash through early 2013 • CHF50.2 (US$63 / €44) million in cash as of June 30, 2011 • 2011 burn guidance CHF28-32 million • Market cap (29 Jul ): CHF82 (US$104/€72) • Traded on SIX Swiss Exchange: ADXN (ISIN:CH0029850754) • 7,835,878 shares outstanding • Biotechnology Value Fund holds 30% • Four analysts covering:

  5. 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, Business Development & Communication André J. Mueller,Executive Chairman Tim Dyer, Chief Financial Officer Charlotte Keywood, Chief Medical Officer Sonia Poli, Head of Non-Clinical Development & Interim Head of CNS Laurent Galibert, Head of Inflammation & Metabolic Disorders Board of Directors André J. Mueller,Executive Chairman Andrew Galazka, SVP Scientific Affairs, Merck-Serono Ray Hill,former Head of EU Licensing, Merck & Co., Inc. Hoyoung Huh, BiPar Sciences Inc. and Geron Corp. Vincent Lawton,former MD of Merck Sharp & Dohme U.K. Oleg Nodelman, Biotechnology Value Fund Antoine Papiernik,Sofinnova Partners Scientific Advisory Board George F. Koob,Chairman Bernhard Bettler Mark A. Geyer Barbara J. Mason Jean-Philippe Pin

  6. 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 • Allostericdiscovery 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

  7. Allosteric modulators (AM) are an emerging new therapeutic class • 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! Allosteric Modulation Explained

  8. 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 • AM have better specificity/selectivity • e.g. mGluRs • AM can target receptors considered intractable for small molecules • e.g. GLP-1 and TNF • AM act like dimmer (not “on/off”) switch • better control = better drugs

  9. Physicochemical Comparison Physicochemical Comparison Structural Comparison Structural Comparison drug-like drug-like Intellectual property is un-exploited! Intellectual property is un-exploited! Platform: Unique Library + Proprietary HTS • 70,000+ compound allostery-biased library

  10. Platform Performance • Addex has received partnering revenue every year since 2004 • Cash inflows generated to date: CHF46.5 (US$53/€37) million • Both partnerships are fully funded by our partners • Addex is eligible for up to about $1 billion in milestones plus royalties anot including upfront payment band undisclosed indications

  11. Pipeline Preclinical Clinical Partner Molecule / Mechanism Assay Development & Screening Hit-to-Lead Lead Optimization Clinical Candidate Phase I Phase IIa Milestone Ph II data 1H12 Dipraglurant-IR (ADX48621) mGluR5 NAM Parkinson’s Disease Levodopa Induced Dyskinesia (PD-LID) partially funded by The Michael J. Fox Foundation Dipraglurant-ER (ADX48621) mGluR5 NAM Dystonia Schizophrenia Janssen Pharmaceuticals, Inc. ADX71149 mGluR2 PAM funded & developed by JPI* Anxiety Endometriosis FSHR/LHR NAM GABA-BR PAM Pain CNS mGluR2 NAM Alzheimer’s / Depression Merck & Co., Inc. mGluR4 PAM Parkinson’s Disease ‡ DepressionGeneralized Anxiety Disorder mGluR7 NAM mGluR5 PAM Schizophrenia ‡ Neurodegenerative & other diseases Receptor tyrosine kinase superfamily (TrkB) Metabolism & Inflammation GLP1R PAM Type II Diabetes TNF receptor superfamily(TNFR1 NAM) Rheumatoid Arthritis, Psoriasis, Inflammatory Bowel Disease Alzheimer’s, Multiple Sclerosis A2A PAM Psoriasis, Osteoarthritis Interleukin receptor family(IL-1R1 NAM) NAM = negative allosteric modulator (an inhibitor) ‡ and undisclosed additional indications PAM = positive allosteric modulator (an activator) *Janssen Pharmaceuticals, Inc., formerly Ortho-McNeil-Janssen Pharmaceuticals, Inc.

  12. Selected development milestones

  13. 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 NAM • Alzheimer’s disease • Depression • mGluR5 NAM(dipraglurant/ADX48621 & backups) • PD-LID / dystonia • Fragile X syndrome / autism • Anxiety / depression / addiction • GERD • Pain • mGluR7 NAM • Generalized Anxiety Disorder • Depression • Addiction • mGluR2 PAM (JPI) • Schizophrenia • Anxiety • Addiction • mGluR5 PAM • Schizophrenia • Cognitive impairment • mGluR4 PAM (Merck) • Parkinson’s disease • Anxiety

  14. 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)

  15. 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)

  16. 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) Source: http://1.usa.gov/dOAMIi

  17. 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

  18. 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

  19. Dipraglurant (ADX48621) in PD-LID model Chorea (rapid uncontrolled movements) 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 • 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 Dystonia (sustained muscle contractions) Dystonia (sustained muscle contractions)

  20. 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

  21. FSHR NAM 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 GnRH 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

  22. FSHR NAM efficacy in rats4 weeks treatment - effect on estrus cycle duration ADX68692 disrupts the estrus cycle leading to complete blockade at high dose

  23. 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

  24. Locomotor activity during the test Rat novel object recognition (NOR) test β- Amyloid* 120 sham Exploration of novel vs familiar objects sham β-Amyloid* 18 90 15 *** 12 Line crosses 9 6 60 3 Exploration time (sec) 0 veh veh veh veh *** *** 15 30 *** 18 12 9 6 0 t1 t2 t1 t2 t1 t2 t1 t2 3 Veh 10 30 Donepezil 0 veh 10 30 Donepezil (1 mg/kg, ip) ADX92639 (mg/kg, p.o.) (1 mg/kg, ip) ADX92639(mg/kg, p.o.) Familiar object Novel object ADX92639 reverses β amyloid-induced deficit *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

  25. 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

  26. 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 -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. ADX71943 demonstrated antihyperalgesic effects in a model of osteoarthritis Days post-monosodium iodocate (MIA)

  27. 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

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

  29. allosteric modulators for human health www.addexpharma.com tell us which targets interest you!

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