Addex Pharmaceuticals

Corporate Presentation

September 2011

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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.

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Vision

Goal: allosteric modulators for human health

How: proprietary discovery platform

Focus: CNS, metabolic disorders & inflammation

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Financials & Stock• Cash through early 2013

CHF50.2 (US$63 / €44) million in cash as of June 30, 20112011 burn guidance CHF28-32 million

• Market cap (05 Sep ): CHF54 (US$68/€48)

• Traded on SIX Swiss Exchange: ADXN (ISIN:CH0029850754)

• 7,835,878 shares outstandingBiotechnology Value Fund holds 30%

• Five analysts covering:Jefferies Peter Welford & Philippa GardnerLadenberg Thalmann Juan SanchezHelvea Olav Zilian Bank am Bellevue Bruno EschliEdison Robin Davison

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Management & Board

Bharatt Chowrira, Chief Executive Officer Tim Dyer, Chief Financial Officer Charlotte Keywood, Chief Medical Officer Laurent Galibert, Head of Inflammation & Metabolism

Sonia Poli, Head of Non-Clinical Development & Interim Head of CNS

Chris Maggos, Business Development & Communication

Jean-Philippe Rocher, Head of Core Chemistry Robert Lütjens, Head of Core Biology Tatiana Carteret, Head of Human Resources

Executive Management

Board of Directors

André J. Mueller (Chairman), former CFO of Actelion

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 (vice-chairman), former MD of Merck Sharp & Dohme U.K.

Oleg Nodelman, Biotechnology Value Fund

Antoine Papiernik, Sofinnova Partners

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• 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

Small molecule drug discovery is an important bottleneck

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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

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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 drugsNatural ligand

Time

PAM + natural ligand

NAM + natural ligand

Bio

log

ical

res

po

nse

Allostery preserves natural rhythm

Time

Natural ligand

Agonist

Antagonist

Bio

log

ical

res

po

nse

Orthosterics are steady state

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Platform: Unique Library + Proprietary HTS• 70,000+ compound allostery-biased library

Addex HTS Platform Assays - Patent PortfolioAssay Filing #

APRA WO 2010/082133Phoenyx EP09178233 ProxyLite for GPCRs EP10160519ProxylLite for non GPCRs EP10191973AddeLite EP10162068

Physicochemical Comparison Structural Comparison

drug-like

Intellectual property is

un-exploited!

Addex HTS Platform Assays - Patent PortfolioAssay Filing #

APRA WO 2010/082133Phoenyx EP09178233 ProxyLite for GPCRs EP10160519ProxylLite for non GPCRs EP10191973AddeLite EP10162068

Structural Comparison

drug-like

Intellectual property is

un-exploited!

Physicochemical Comparison

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Platform Performance

Summary of Partnerships

Partner Product Indication(s)Status

at signingUpfront Cash

Fees and milestones receiveda

Total Potential

MilestonesRoyalty

Janssen Pharmaceuticals,

Inc.

mGluR2 PAM (ADX71149)

Anxiety & schizophreniab Hit-to-Lead

€3 M

(Dec 2004)€7.2 M €112 M

low

double-digit

Merck & Co., Inc. mGluR4 PAMParkinson’s

diseaseb Hit-to-Lead$3 M

(Dec 2007)$3.3 M $167.5 M ND

• 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 $300 million in milestones plus royalties

anot including upfront payment band undisclosed indications

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CNS

Pipeline

Molecule / Mechanism Phase IIaClinical

CandidatePhase I Milestone

Lead

OptimizationHit-to-Lead

Assay Development & Screening

Partner

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.

Parkinson’s Disease Levodopa Induced Dyskinesia (PD-LID)

Dystonia

Schizophrenia

Anxiety

Schizophrenia ‡

Endometriosis

Janssen Pharmaceuticals,

Inc.

Dipraglurant-IR (ADX48621)

mGluR5 NAM

ADX71149 mGluR2 PAM

FSHR/LHR NAM

Dipraglurant-ER (ADX48621)

mGluR5 NAM

Ph II data 1H12partially funded by The Michael J. Fox Foundation

funded & developed by JPI*

PainGABA-BR PAM

Alzheimer’s / DepressionmGluR2 NAM

Parkinson’s Disease ‡mGluR4 PAM

DepressionGeneralized Anxiety Disorder

mGluR7 NAM

Neurodegenerative & other diseasesReceptor tyrosine kinase superfamily (TrkB)

Metabolism &

Inflammation

Type II Diabetes

Rheumatoid Arthritis, Psoriasis, Inflammatory Bowel Disease

Alzheimer’s, Multiple Sclerosis

Psoriasis, Osteoarthritis

TNF receptor superfamily(TNFR1 NAM)

GLP1R PAM

A2A PAM

Interleukin receptor family(IL-1R1 NAM)

Preclinical Clinical

mGluR5 PAM

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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 NAMPD-LID Ph IIa data 1H12

Dipraglurant-ER mGluR5 NAM

Dystonia Ph I data 1H12

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Metabotropic Glutamate Receptors (mGluR)

– 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

• 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 (JPI)

• Schizophrenia

• Anxiety

• Addiction

– mGluR5 PAM• Schizophrenia

• Cognitive impairment

– mGluR4 PAM (Merck)• Parkinson’s disease

• Anxiety

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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)

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ADX71149 mGluR2 PAM for Schizophrenia

Normal Neurotransmission

Disease State

glutamate

Treated

ADX71149

Marketed antipsychotic drugs exert efficacy predominantly via dopamine D2 receptors

Adapted from Nature Reviews Drug Discovery 7, 471-472 (2008)

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ADX71149 Schizophrenia StudyAn 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

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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

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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

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Dystonia (sustained muscle contractions)

Dystonia (sustained muscle contractions)

Chorea (rapid uncontrolled movements)

Chorea (rapid uncontrolled movements)

Dipraglurant (ADX48621) in PD-LID model

• 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

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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

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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

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

GnRH

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FSHR NAM efficacy in rats4 weeks treatment - effect on estrus cycle duration

0

2

4

6

8

10

12

14

16

18

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Number of Estrous cycles during treatment duration Mean duration of Estrous cycle (days)

0 mg/kg/day 2x10 mg/kg/day 2x30 mg/kg/day 2x100 mg/kg/day 2x300 mg/kg/day

***

***

***

***

ADX68692 disrupts the estrus cycle leading to complete blockade at high dose

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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

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Familiar object

Novel object

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

ADX92639 reverses β amyloid-induced deficit

*Single administration into the lateral ventricle of 8 μl solutionFinal concentration of amyloid = 2 mg/ml

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sham β- Amyloid*

0

30

60

90

t1 t2 t1 t2 t1 t2 t1 t2

Veh 10 30 Donepezil

ADX92639 (mg/kg, p.o.)

Lin

e c

ros

se

s

Locomotor activity during the test

(1 mg/kg, ip)ADX92639 (mg/kg, p.o.)

veh 10 30 Donepezil

18

0

36

9

12

15 *** *** ***

Exploration of novel vs familiar objects

veh veh veh veh 0

3

6

9

12

15

18

Exp

lora

tio

n t

ime

(se

c) ***sham β-Amyloid*

(1 mg/kg, ip)

Rat novel object recognition (NOR) test

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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

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ADX71943 demonstrated antihyperalgesic effects in a model of osteoarthritis

Days post-monosodium iodocate (MIA)

0

50

100

150

200

250

300

350

Pre-MIA Post-MIA Day 1 Day 8

With

draw

al th

resh

old

(g)

Max

imum

resp

onse

bew

teen

1 a

nd 2

hr

Vehicle 1 mg/kg ADX71943 3 mg/kg ADX7194310 mg/kg ADX71943 30 mg/kg ADX71943 Celecoxib (30 mg/kg)

* ***

***

*****

Pre-treatment Treatment

-1 14 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.

###

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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

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

allosteric modulators for human health

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