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Addex Pharmaceuticals

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Presentation on theme: "Addex Pharmaceuticals"— Presentation transcript:

1 Addex Pharmaceuticals
Corporate Presentation June 2011

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

3 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:CH ) 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

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

5 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

6 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

7 Allosteric Advantages
Time Natural ligand Agonist Antagonist Biological response Orthosterics are steady state 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 Natural ligand Time PAM + natural ligand NAM + natural ligand Biological response Allostery preserves natural rhythm

8 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 EP ProxyLite for GPCRs EP ProxylLite for non GPCRs EP AddeLite EP

9 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 Partner Product Indication(s) Status at signing Upfront Cash Fees and milestones receiveda Total Potential Milestones Royalty Ortho-McNeil-Janssen mGluR2 PAM (ADX71149) Anxiety & schizophreniab Hit-to-Lead €3 M (Dec 2004) €7.2 M €112 M low double-digit Merck & Co., Inc. mGluR4 PAM Parkinson’s diseaseb $3 M (Dec 2007) $3.3 M $167.5 M ND mGluR5 PAM Schizophreniab Clinical Candidate (ADX63365) $22 M (Jan 2008) - $680 M anot including upfront payment band undisclosed indications

10 Assay Development & Screening Ortho-McNeil-Janssen
Pipeline Preclinical Clinical Partner Molecule / Mechanism Assay Development & Screening Hit-to-Lead Lead Optimization Clinical Candidate Phase I Phase IIa Milestone Dipraglurant-IR (ADX48621) mGluR5 NAM Parkinson’s Disease Levodopa Induced Dyskinesia (PD-LID) Ph II data 1H12 partially funded by The Michael J. Fox Foundation Dipraglurant-ER (ADX48621) mGluR5 NAM Dystonia Start Ph I 2H11 Ortho-McNeil-Janssen ADX71149 mGluR2 PAM Schizophrenia funded & developed by OMJPI* Anxiety Merck & Co. ADX63365 mGluR5 PAM Schizophrenia ‡ funded & developed by Merck FSHR/LHR NAM Endometriosis GABA-BR PAM CNS Pain / Anxiety mGluR2 NAM Alzheimer’s / Depression Merck & Co. mGluR4 PAM Parkinson’s Disease ‡ mGluR7 NAM Depression Generalized Anxiety Disorder Receptor tyrosine kinase superfamily Neurodegenerative & other diseases Metabolism & Inflammation GLP1R PAM Type II Diabetes TNF receptor superfamily Rheumatoid Arthritis, Psoriasis, Inflammatory Bowel Disease Alzheimer’s, Multiple Sclerosis A2A PAM Psoriasis, Osteoarthritis 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

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

12 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) Schizophrenia Anxiety Addiction mGluR5 PAM (Merck) Cognitive impairment mGluR4 PAM (Merck) Parkinson’s disease 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 Addiction

13 Schizophrenia Prevalence
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, (2008)

14 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, (2008)

15 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 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:

16 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

17 Why PD-LID & Dystonia? PD-LID Dystonia
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:

18 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 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)

19 Dipraglurant Phase IIa PD-LID Trial
Study ADX (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

20 GnRH, FSH & Endometriosis
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

21 FSHR NAM efficacy in rats 4 weeks treatment - effect on estrus cycle duration
ADX68692 disrupts the estrus cycle leading to complete blockade at high dose

22 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): **Bioorganic & Medicinal Chemistry Letters, Dec 1, 2010; 20(23):

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

24 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

25 Maximum response bewteen 1 and 2 hr Withdrawal threshold (g)
ADX71943 demonstrated antihyperalgesic effects in a model of osteoarthritis 50 100 150 200 250 300 350 Pre-MIA Post-MIA Day 1 Day 8 Maximum response bewteen 1 and 2 hr Withdrawal threshold (g) Vehicle 1 mg/kg ADX71943 3 mg/kg ADX71943 10 mg/kg ADX71943 30 mg/kg ADX71943 Celecoxib (30 mg/kg) * ** *** Pre-treatment Treatment -1 14 21 ###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. ### Days post-monosodium iodocate (MIA)

26 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

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

28 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.

29 allosteric modulators for human health
tell us which targets interest you!

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