Addex Pharmaceuticals

Investor Relations SlidesJanuary 2010

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

•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

Financials• Cash: about CHF75m* (€62m / US$89m) at end 2009

• 2010/11 cash burn guidance: CHF35-40m

• Market cap (6 Jan 10): CHF82m (€55m / US$80m)

• SIX Swiss Exchange: ADXN (ISIN:CH0029850754)

• 5,862,492 shares outstanding as of June 30, 2009

• Five analysts covering:

Piper Jaffray Sam Fazeli & Michael AitkenheadJefferies Peter Welford & Philippa GardnerHelvea Olav Zilian Bank Vontobel Andrew C. Weiss  & Silvia SchanzBank am Bellevue Bob Pooler      

*assuming midpoint of cash burn guidance for CHF43-47m was achieved

5

Inflammation

CNS

Metabolic Disorders

Mechanism PartnerAssay Dev &

ScreeningHit-to-Lead

Lead Optimization

Preclinical Phase I Phase II Milestone

mGluR5 NAM Start Ph II 4Q10

mGluR2 PAM J&J* not disclosed

mGluR5 PAM Merck & Co. not disclosed

GABAB 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

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 companyPAM = positive allosteric modulator (an activator) ‡ undisclosed additional indications

ADX71149 Anxiety / Schizophreniafunded & 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

Deals to Date

Partner Product Indication(s)Status

at signing

Upfront Cash

(Date)Milestones

Ortho-McNeil-Janssen

(a J&J company)ADX71149

mGluR2 PAMAnxiety &

schizophreniaHit-to-Lead

€3 million1

(Dec 2004)not

disclosed2

Merck & Co., Inc. mGluR4 PAMParkinson’s

disease3 Hit-to-Lead$3 million4

(Dec 2007)$167.5 million2

Merck & Co., Inc.ADX63365

mGluR5 PAMSchizophrenia3 Clinical

Candidate$22 million

(Jan 2008)

$680

million2

1€4.2 million in research funding were paid to Addex during the research collaboration, which completed in 2007. Addex received an additional €1 million milestone when ADX71149 started Ph I testing. 2 plus royalties on sales3 & other undisclosed indications4 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

ADX48621 for Parkinson’s Disease

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

0

10

20

30

40

50

60

70

80

90

Vehicle ADX48621, 1mg/kg

ADX48621, 3mg/kg

ADX48621, 10mg/kg

ADX48621, 30mg/kg

MTEP, 30mg/kg

Lat

ency

(se

c)

1st experiment2nd experiment3rd experiment

***

*********

****

***

**

***

+ 1 mg/kg haloperidol

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

ADX48621 works in MPTP model

0

5

10

15

L-DOPA (100%)

vehicle

ADX48621 (mg/kg)

3 10 30

**

chor

ea (

0-2

hr)

Significant effects on Chorea

0

5

10

15

L-DOPA (100%)

vehicle

ADX48621 (mg/kg)

3 10 30

*

dys

ton

ia (

0-2

hr)

Significant effects on Dystonia

ADX48621 is the first product to reduce both Chorea & Dystonia in this model

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

• Study ADX48621-201 (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

ADX71149 mGluR2 PAM

• ADX71149 is a positive allosteric modulator of mGluR2– mGluR2 activation is clinically validated in anxiety1 & schizophrenia2

– 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

1http://bit.ly/JOtTb 2http://bit.ly/54lKd

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

ADX71943 GABAB PAM

• GABAB receptor is a clinically validated target– Baclofen, GABAB agonist, is marketed to treat spasticity

• off-label use in pain and other indications

• experimental GABAB 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

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-CFA CFA 1 hr 2 hr0

5

10

15

20

25

*****

Time post-dose (hr)

Wit

hd

raw

al T

hre

sho

ld

Vehicle

1 mg/kg ADX-71943

3 mg/kg ADX-71943

10 mg/kg ADX-71943

30 mg/kg ADX-71943

30 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 1Experiment 2Experiment 3Experiment 4

vehicle

Nu

mb

er

of

wri

the

s

0

24

6

810

1214

16

1820

22

0.3 1 3 10 30 100 3

+++****** ***

***

*

** ***

*

mg/kgmg/kg

AD

X71

943

Bac

lofe

n

ADX71943 Baclofen

*CFA = Complete Freund's Adjuvant

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

. B

etz

, J.

Me

d.C

he

m.,

20

08

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

Control group

02468

1012141618

-14 -11 -8 -5 -2 2 5 8 11 14 17 20 23 26 29

Day of treatment

ADX68692: 20 mg/kg/day

02468

1012141618

-14 -11 -8 -5 -2 2 5 8 11 14 17 20 23 26 29

Day of treatment

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

SynchronisationTreatment start

To

tal n

um

ber

of

anim

als

in P

roes

tru

s/E

stru

s st

age

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

0.0

5.0

10.0

15.0

20.0

25.0

After 3-week treatment with ADX68692

Te

sto

ste

ron

e (

nn

mo

l/L

)

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)

******

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

Addex Pharmaceuticals~~~~~~~~

Allosteric Discovery & Optimization Platform

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

Orthosteric ≠ Allosteric

Advantages include: • Greater specificity than orthosteric molecules

Less toxicities from “off-target” interactions compared to more promiscuous orthosteric moleculesGreater specificity leads to greater productivity

• Non-competitive mechanismIntellectual property space relatively un-exploited Lower doses required

–less dose related toxicity–lower COGs

• Acts like a dimmer not an “on/off” switchBody maintains control – physiological rhythm preservedLess tolerance/desensitizationPotentially 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 drugsPotential safety, tolerability and efficacy advantages with allosteric mechanism

Natural 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

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

Marketed Drugs

Addex Library

Addex corporate library occupies a unique structural space while sharing many other drug-like properties with marketed drugs

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

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

BAC

D

FE

G

HF

E

GHBA

CD

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, 41-54.

Family 1(e.g. Orexin & FSH)

Family 2(e.g. GLP-1R, GIPR)

Family 3(e.g. mGluR1-8, GABABR)

27

Proprietary Novel AssaysG-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

Addex targets allosteric sites in type 1 single-pass transmembrane proteins

IL1R

1IL

1R1

AcP

AcP

IL-1IL-1/IL-1/IL-1

ST

2S

T2

AcP

AcP

IL-33IL-33R

P2

RP

2A

cPA

cPIL-1F6/8/9IL-1F6/8/9

IL18

R1

IL18

R1

IL18

R2

IL18

R2

IL-18IL-18IL-33IL-33

Toll-like Toll-like receptorsreceptors

PathogensPathogens

TIR TIR domainsdomains

TNFR family

IL-1R family

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 Assaystype 1 single-pass transmembrane proteins

30

The Addex Platform

Inflammation CNSMetabolicDisorders

Core Chemistry

Non-Clinical Development

Clinical Development

Core Biology