Download - Addex Pharmaceuticals
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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
CHF63.8 (US$68/€50) million in cash as of Dec 31, 20102011 burn guidance CHF28-32 million
• Market cap (08 Apr): CHF81 (US$89/€61) million
• Traded on SIX Swiss Exchange: ADXN (ISIN:CH0029850754)
• 7,835,878 shares outstandingBiotechnology Value Fund holds 30%
• Five analysts covering:Jefferies Peter Welford & Philippa GardnerHelvea Olav Zilian Bank Vontobel Andrew C. Weiss Bank am Bellevue Bob Pooler Edison Robin Davison
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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!
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Allosteric Advantages
• Better specificity/selectivity for target– e.g. mGluRs
• Can target receptors considered intractable for small molecules
– e.g. GLP-1 and TNF
• Acts like a dimmer not “on/off” switch– better control = better drugs
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
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Platform
• 70,000+ compound allostery-biased library
• Proprietary high throughput screening tools
Structural Comparison
Intellectual property is
un-exploited!
Physicochemical Comparison
Addex LibraryMarketed Drugs
drug-like
ProxyLite for GPCRs ProxyLite for non GPCRsPhoenyx
APRAAddeLite
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Platform Performance
Summary of Partnerships
Partner Product Indication(s)Status
at signingUpfront Cash
Fees and milestones receiveda
Total Potential
MilestonesRoyalty
Ortho-McNeil-Janssen
mGluR2 PAM (ADX71149)
Anxiety & schizophreniab Hit-to-Lead
€3
(Dec 2004)€5.2 €112
low
double-digit
Merck & Co., Inc. mGluR4 PAMParkinson’s
diseaseb Hit-to-Lead$3
(Dec 2007)$3.3 $167.5 ND
Merck & Co., Inc. mGluR5 PAM Schizophreniab
Clinical Candidate
(ADX63365)
$22
(Jan 2008)- $680 ND
• Addex has received partnering revenue every year since 2004
• Cash inflows generated to date: CHF44 (US$45) million
• All three 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
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CNS
Molecule / Mechanism Phase IIPreclinical Phase I MilestoneLead
OptimizationHit-to-Lead
Assay Development & Screening
Partner
Pipeline
Merck & Co.
Ph II data 1H12
Start Ph I
2H11
Ortho-McNeil-Janssen
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
Parkinson’s Disease Levodopa Induced Dyskinesia (PD-LID)
Dystonia
Schizophrenia
Anxiety
Osteoarthritic Pain
Schizophrenia ‡
Endometriosis
partially funded by The Michael J. Fox Foundation
Dipraglurant-IR (ADX48621)
mGluR5 NAM
ADX71149 mGluR2 PAM
GABA-BR PAM
ADX68692 FSHR NAM
ADX63365 mGluR5 PAM
Alzheimer’s / DepressionmGluR2 NAM
Parkinson’s Disease ‡mGluR4 PAM
DepressionPost Traumatic Stress Disorder
mGluR7 NAM
Type II Diabetes
Rheumatoid Arthritis, Psoriasis, Inflammatory Bowel Disease
Alzheimer’s, Multiple Sclerosis
Psoriasis, Osteoarthritis
Gout, Type II Diabetes
TNFR1 (CD120a) NAM
GLP-1R PAM
A2A PAM
IL-1R1 (CD121a) NAM
Dipraglurant-ER (ADX48621)
mGluR5 NAM
funded & developed by Merck
Metabolism &
Inflammation
Merck & Co.
funded & developed by OMJPI*
funded & developed by Merck
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Selected development milestones
Product Indication(s) Milestone When
mGluR2 PAM
ADX71149 Schizophrenia Ph IIa start March 28th, 2011
mGluR5 NAM
Dipraglurant-IRPD-LID Ph IIa start March 31st, 2011
mGluR5 NAM
Dipraglurant-ERDystonia Ph I start 2H11
mGluR2 PAM
ADX71149Schizophrenia Ph IIa data ND
mGluR5 NAM
Dipraglurant-IRPD-LID Ph IIa data 1H12
mGluR5 NAM
Dipraglurant-ERDystonia 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• Post traumatic stress syndrome• 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• Schizophrenia
• Anxiety
• Addiction
– mGluR5 PAM• Schizophrenia
• Cognitive impairment
– mGluR4 PAM• 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 Study
A 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 – Subjects with residual positive symptoms or predominant
negative symptoms or insufficient response to clozapine– 50mg ADX71149 bid increasing to up to 150mg bid for 10 weeks– Patients continue on their currently prescribed antipsychotic
• Undisclosed endpoints will examine safety, tolerability and efficacy
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Dipraglurant (ADX48621) Overview
• Dipraglurant inhibits metabotropic glutamate receptor mGluR5 via negative allosteric modulation
• 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 completed sucessfully– 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
• Dystonia (abnormal sustained muscle contractions)– Third most common movement disorder (following PD and essential
tremor)– Dipraglurant is the first drug-candidate to report efficacy for dystonia in
LID models– Potential Orphan Drug and Fast Track status opportunities
• 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*for data: http://bit.ly/dgEVbH
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Dystonia (sustained muscle contractions)
Chorea (rapid uncontrolled movements)
Dipraglurant (ADX48621) in the MPTP model
• Parkinsonian 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 (ADX48621) 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 for 50mg o.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
• FSH 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
• FSH 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 is 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
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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
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0
36
9
12
15 *** *** ***
Exploration of novel vs familiar objects
veh veh veh veh 0
3
6
9
12
15
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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 are in development and clinically validated 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 GLP-1R PAM in ogtt test in diabetic db/db mouse model
• db/db knockout mice have 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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Management & Boards
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.
Mark A. Geyer, Ph.D.
Barbara J. Mason, Ph.D.
Jean-Philippe Rocher, Head of Core Chemistry Robert Lütjens, Head of Core Biology Tatiana Carteret, Head of Human Resources
Chris Maggos, Business Development & Communication
Executive Management
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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.