February 2014
Overview and background
•
History•
Addex was founded in 2002 in Geneva, Switzerland•
ADXN is traded on the SIX Swiss Stock Exchange since 2007•
Focus: pioneering oral small molecule allosteric modulation-based drug discovery and development•
Invested more than CHF300m in building allosteric modulator platform and pipeline•
Due to a recent shortfall in funding, Addex was forced to put the majority of its programs on hold and scale down operations•
Going forward, focus on:•
Maintaining mGlu2PAM collaboration with Janssen Pharmaceuticals Inc.•
Seek partners for clinical and preclinical programs – dipraglurant, ADX71441, etc•
Maintain and continue to establish risk sharing partnerships with industry and academia:• to advance early discovery programs; and • leverage allosteric modulator platform
Status of rebuild
• Restructuring completed
• IP portfolio and allosteric modulator technology platform secured
• Cash burn significantly reduced - runway through end 2014
• Current headcount – 6FTE
• Infrastructure reduced to 500m2 of lab & office space
• Majority of liabilities and commitments extinguished
• Rebuild plan in process of being executed
• Bridge financing of CHF3.2m raised in August 2013
• Restart team in place – know how protected
• Academic / patient group relationships and collaborations established to advance research at low cost
4 z zLeading allosteric drug discovery z zValidated therapeutic class
•Proven mechanism, that has led to marketed products
•Significant investment from all major pharma
•Growing pipeline of allosteric modulators in the clinic
z
zRobust pipeline with
orphan drug potential
•3 Phase 2 programs
•1 Phase 1 ready program
•Multiple preclinical & discovery programs
z
zPartnership with
leading pharma •Janssen Pharmaceuticals Inc. (JPI) for mGlu2 PAM
z
zExtensive IP portfolio •12 issued patents
•43 pending patents
z
zFinancials
•CHF4.5M (US$4.9M/ €3.7M) in cash as of June 30, 2013
•Capital increase 9 Aug 2013 of CHF3.2M
•No debt & Cash through to end of 2014
•Proprietary 85,000 knowledge-based HTS library
•Proprietary HTS high-fidelity pharmacology systems
•Deep allosteric know-how & expertise
Addex clinical pipeline, preclinical
& discovery programs
6
Target R&D stage Indication Additional Information
ADX71149 mGlu2PAM
Phase IIa PoC in schizophrenia Completed.
Phase IIa POC in anxious depression - Completed Signal in negative symptoms in schizophrenia Primary endpoint not met; however signal seen in some anxiety scores and all depression scores
Partnered with Janssen Pharmaceuticals Inc.
Following the lack of signal in the primary outcome measure in the anxious depression trial, Janssen has halted development in anxious depression and is reviewing future development of the program in other indications
Dipraglurant mGlu5NAM
Phase IIa PoC in PD-LID achieved Back-up series in LO L-DOPA induced dyskinesia DYT1 Dystonia (orphan indication) Potential in treatment resistant depression
Clinical PoC of mGlu5 NAMs in PD-LID*, migraine*, GERD*, generalised anxiety disorders and FXS
Preclinical PoC in PD-LID*, anxiety*, depression*, obsessive compulsive disorders*, PD*, PD-LID*, dystonia*, HD, addiction, and pain.
Other mGlu5NAMs are undergoing clinical tested in FXS, OCD, TRD ADX71441 GABABPAM Phase I ready 1 follow-up series in LO CMT1A (orphan indication) Addiction (nicotine and alcohol) OAB
Clinical PoC in several indication with baclofen
Preclinical PoC in CMT1A*, anxiety*, alcohol and nicotine addiction*, OA pain*, visceral pain*, overactive bladder*. Potential in FXS, autism and spasticity in MS or cerebral palsy Collaboration with NIDA to generate data in preclinical models of addiction
Clinical stage pipeline
Target R&D stage Indication Additional Information
mGlu4 PAM 1 main series in LO 2 back-up series
L-DOPA sparing in PD Anxiety
Multiple Sclerosis
Preclinical PoC in PD*, MS (EAE mice and early immune response*), anxiety*and OCD*.
Potential to address multiple aspect of MS including anti-inflammatory, disease modification and
neuroprotection
Collaboration with NIDA to generate data in preclinical models of addiction
mGlu2 NAM 1 main series in LO 3 back-up series
Depression (treatment resistant)
Cognitive deficits, AD
Preclinical PoC in cognition* and depression*. mGlu2NAMs ongoing clinical trials include TRD
mGlu2 PAM 1 chemical series in LO (outside of Janssen agreement) 1 lead identified
New indications currently explored
Preclinical PoC in anxiety*, schizophrenia*, addiction. Clinical PoC in negative symptoms in schizophrenia
mGlu7 NAM 2 chemical series in LO
1 lead identified
Psychosomatic disorders Preclinical PoC in anxiety*. Other proposed indications: pain, neuroprotection, schizophrenia, ADHD, GI tract disorders and retino-protection
FSH NAM 1 main series in LO 5 sub-series
Women’s health: endometriosis, uterine fibrosis, polycystic ovarian disease.
Hormone dependent cancer (add-on therapy):
Preclinical PoC of in vivo modulation of FSH induced estradiol production* . Opportunity to develop an orally bioavailable non competitive FSHR antagonists
8
Target R&D stage Indication Additional Information
mGlu3 PAM
HTS performed screening HITs
neuroprotection in PD Neuroprotection achieved through modulation of growth factors
mGlu8 PAM
HTS performed screening HITs
Exploratory target mGlu8 activation has been linked to
anxiety/GAD, neuroprotection/anticonvulsive activity, fear acquisition, PD, cognition, pain, addiction, ADHD and MS
M4 PAM HTS performed screening HITs Hit confirmation
Schizophrenia
cognitive deficits in AD
GLP1 PAM 1 main series in LO 2 additional chemical series
Type II Diabetes Clinically validated for type II diabetes Alternative to peptidic GLP1 agonists GLP1 PAM PoC in OGTT (achieved with Addex lead)*
TNFR1 NAM
HTS performed screening HITs
RA, psoriasis, osteoarthritis Huntington’s disease and sickle cell disease (rare disease)
Small molecule and broadly applicable anti-inflammatory approach
A2a PAM HTS performed screening HITs
RA, psoriasis, osteoarthritis, Huntington’s disease and sickle cell disease (rare disease)
PAM vs. agonist are expected to provide anti-inflammatory effects, devoid of cardiovascular side-effects
TrkB PAM HTS and hit validation performed 3 chemical series validated Disease-modification, neuroprotection in AD Potential in PD, AD and Huntington’s disease
Modulation of BDNF signalling pathways
Discovery programs
Pipeline program:
Dipraglurant in PD-LID and Dystonia
10 10
Dipraglurant (ADX48621) overview
10
•
Dipraglurant is a highly selective oral brain penetrant small molecule
metabotropic glutamate receptor 5 (mGlu5) inhibitor (negative
allosteric modulator-NAM) discovered at Addex
•
mGlu5 inhibition has been validated in multiple indications
Clinical validation for mGlu5 NAM
Parkinson’s disease levodopa-induced dyskinesia (PD-LID)
Generalized anxiety disorder (GAD) Gastroesophageal reflux disease (GERD)
Fragile X Syndrome / Autism Acute migraine pain
Preclinical validation for mGlu5 NAM
Dystonia Tardive dyskinesia
Huntington’s Disease Treatment-Resistant Depression
Dipraglurant - a compelling market opportunity
•
Dipraglurant is a novel and highly differentiated drug candidate within
the movement disorders market
•
Rare disease opportunities in dystonia could accelerate NDA filing
•
Market potential of dipraglurant is significant
–
Potential to be first in class after the decision of Novartis to pull out of PD-LID–
Datamonitor estimates dipraglurant sales over $1 billion/year for PD-LID and dystonia indications–
Label expansion to additional Parkinson’s and non-Parkinson’s indications could more than double sales opportunity•
Pursing partner with vision and capabilities to broadly develop
dipraglurant in PD-LID and other indications.
12
Summary of dipraglurant clinical development
•
Initial Phase I program of dipraglurant successful
−
Three studies: single & multiple ascending doses, gender/food effects−
132 subjects studied to date, including 30 older subjects−
Dipraglurant – IR formulation developed and tested−
Pharmacokinetics of IR is ideal for acute treatment of PD-LID−
Safety & tolerability support further clinical study•
Dipraglurant-IR Phase IIa trial in 76 PD-LID patients achieved key
objectives
−
Primary objectives: safety and tolerability in PD-LID patients−
Secondary objectives: clinical effect & dose characterization•
Top-line data showed statistically significant reduction in dyskinesia
−
50 min reduction in off-time in week 4−
2.3 hours more of on-time without dyskinesia (i.e. good quality on-time)−
Concordance of mAIMS with the diary and the PGIC and CGIC dataADX48621-201 trial design
EU and US Phase 2a dipraglurant trial for PD-LID
76 patients •Randomized, double-blind, placebo-controlled, multi-center trial •Moderate to severe LID patients •Dipraglurant taken with levodopa •Dipraglurant titration from 50mg q.d. to 100mg t.i.d over 4 weeks •Individual levodopa regimens remain constant for duration of study
(300 -1500mg/day)
•Primary objective:
safety & tolerability
•Secondary objective:
exploratory efficacy
•Objective evaluation in the clinic
on day 1 and 14 & 28
– Trained observer scores LID severity using mAIMS – modified Abnormal Involuntary Movement Scale
•Patient diaries of on & off time
•Unified Parkinson’s Disease Rating
Scale (UPDRS)
14
ADX48621-201 Phase 2a proof of concept study in
patients with PD-LID:
•
Dipraglurant-IR Phase 2a trial in 76 PD-LID patients was successful
– Achieved significant reduction in dyskinesia severity• Reduction in mAIMS (both at peak levodopa concentrations & area under the curve over the three hours post-dose period)
• 50 min reduction in “off-time” in week 4
• 2.3 hours more “on-time” without dyskinesia in week 4
• Concordance of mAIMS with the patient-reported diary and the PGIC and CGIC data
•
Achieved key objectives:
– Primary objectives: safety and tolerability in PD-LID patients
– Secondary objectives: clinical effect & dose characterization
•
Michael J. Fox Foundation for Parkinson’s disease supported the
trial with a $900,000 grant
• Dipraglurant reduced peak dose mAIMS (90 min after dosing)
‒ Day 1 (50mg): 19.9% vs 4.1% (p=0.042)
‒ Day 14 (100mg): 32.3% vs 12.6% (p=0.034)
‒ Day 28 (100mg): 31.4% vs 21.5%
• Dipraglurant reduced dyskinesia severity for the full 3 hour post-dosing period - mAIMS area under the curve (AUC0-3)
• A 30% reduction in mAIMS is clinically meaningful
0% 5% 10% 15% 20% 25% 30% 35%
Day 1 Day 14 Day 28
dipra placebo * * % r e d u ct io n
Dipraglurant reduces LID severity
Good correlations between Dipraglurant effect in reducing
PD-LID and plasma concentration: IC50 = 1317 ng/mL
16 -6 -5 -4 -3 -2 -1 0 0 500 1000 1500 M e a n c h a n g e i n m A IM s fr o m b a se li n e
Mean dipraglurant plasma conc (ng/mL)
visit 3 visit 4 visit 5 0 200 400 600 800 1000 1200 1400 0 1 2 3 4 m e a n p la sm a c o n c ( n g /m L) time (h) 0 2 4 6 8 10 12 14 0 1 2 3 4 m e a n m A IM S time (h) Visit 3 (Day 1) 50 mg Visit 4 (Day 14) 100 mg Visit 5 (Day 28) 100 mg Cmax (ng/mL) 793 ± 438 1683 ± 1107 1844 ± 1117 Tmax (hours) 1.14 ± 0.52 1.23 ± 0.66 1.08 ± 0.51 T1/2 (hours) 0.68 ± 0.81 0.75 ± 0.44 0.74 ± 0.44
Receptor occupancy PET study in non human primates: dipraglurant
is brain penetrant and occupies the mGluR5 in a dose-dependent
manner: EC
50= 510 ng/mL
18
“On” time with no dyskinesia - change from week -1
50 mg dose level 100mg dose level
Patient-reported measurable clinical effects
Dipraglurant efficacy Modified AIMS Patient Diary CGIC & PGIC
Measurable clinical effects
20
MGlu5 NAMs for the treatment of dystonia
• Dystonias are movement disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful,
movements and positions (postures)
• Dystonia etiologies and symptoms are heterogeneous – can affect a single part of the body (focal), multiple areas (segmental) or the whole body
(generalized). Further, dystonias are distinguished as either primary (idiopathic, genetic) or secondary (drugs, toxins or metabolic disorders)
• A number of types of dystonia are classified by NIH as “rare” (e.g., cervical dystonia, DYT1 familial generalized dystonia or X-linked dystonia
parkinsonism)
• An estimated 300,000 people in the United States have been diagnosed with a dystonia of some type
• Based on the literature and our own preclinical and clinical observations, the scientific rationale for an mGlu5 negative allosteric modulator (NAM) as a therapeutic agent in the treatment of dystonia is very strong.
Dipraglurant for the treatment of dystonia – a
compelling orphan drug opportunity
• Dystonias are a set of heterogeneic diseases with a huge unmet medical need and no viable treatment alternatives
• Dipraglurant, a highly selective, oral mGlu5 NAM, has been shown to be safe and effective in human clinical testing
• Dipraglurant has shown positive anti-dystonia effect in multiple animal models of dystonia as well as positive anti-dystonia effect in Parkinson’s patients
• Dipraglurant could be a first-in-class dystonia therapeutic with the potential to significantly change the treatment paradigm for a variety of dystonias
• Dipraglurant could establish a dominant position in the $500 MM+ dystonia market
22
Preclinical and clinical efficacy of dipraglurant in dystonia
Phase 2a studies in PD-LID Patients
PD-LID MPTP monkey (drug induced dyskinesia
with features of dystonia)
DYT-1 mouse model (genetic dystonia)
24
• There is a strong rationale for developing mGlu5 NAMs for treatment in PD-LID
• (IR) dipraglurant has shown an optimal PK and PD profile for the indication
• There are currently no other mGlu5 NAM in clinical development for this indication, therefore dipraglurant could become a first in class
• The recent decision of Novartis to terminate development of mavoglurant in PD-LID seems to be related to the properties of the compound or to a
potential unappreciated mechanistic which results in different pharmacological profile
• (IR) dipraglurant can also be developed in a number of other major disease areas where mGlu5 inhibition has been proven useful, and an acute and short blockade of the receptor would be beneficial (acute treatment of migraine, treatment resistant depression).
pipeline program:
ADX71441 – GABA
B
R positive
allosteric modulator
(subject to securing resources)
26
Oral GABA
Breceptor PAM (ADX71441)
• ADX71441 is a novel, first-in-class, oral, small molecule activator of
gamma-aminobutyric acid subtype B (GABAB) receptor function through positive allosteric modulation (PAM)
• Activation of GABAB receptor is preclinically, clinically & commercially validated in a number of indications
• Addex GABAB receptor PAMs have shown efficacy in multiple preclinical models
including: OAB, pain, osteoarthritis pain, anxiety, alcohol and nicotine dependency and CMT1a
• IND enabling studies complete
• CTA accepted for Phase 1 clinical testing in EU
• Phase 1 data expected 9 months from start
validation for GABABR activation
MS Spasticity
Visceral Pain Osteoarthritis and other pain
Fragile X Syndrome / Autism Overactive Bladder (OAB)
Anxiety Alcohol and nicotine dependence
• Efficacious in animal models:
• Anxiety - mouse marble burying and rat elevated plus maze
• Pain - mouse acetic-acid induced writhing test and rat MIA OA pain model
• Overactive bladder - Mouse and Guinea pig overactive bladder model
• Alcohol consumption – mouse
• Nicotine withdrawal - rat
• Genetic model of a rare neuropathy - CMT1A rat
• CNS profile: Rat EEG (with LMA; body temperature); Rat Irwin; Mouse rotarod; Mouse locomotor activity (acute and chronic administration); Mouse body temperature
• No sign of tolerance development on efficacy after repeated dosing while
ADX71441 pharmacology and tolerability
PoC in models of anxiety, pain, OAB and addictionPharmacokinetics:
• ADX71441 administered orally is slowly absorbed, has a good bioavailability and a long half-life
• ADX71441 administered IV shows: Low clearance, Large volume of distribution, Long half life
• ADX71441 is moderately protein bound
• ADX71441 crosses the blood brain barrier
• Very little ADX71441 is excreted unchanged in bile and urine (data not shown)
• ADX71441 undergoes extensive metabolism (data not shown)
• ADX71441 does not inhibit any of the major CYPs
Non Clinical Safety Package:
• In vitro (GLP) – hERG, Ames and micronucleus tests
• In vivo Safety Pharmacology (GLP) - CNS activity (Functional Observation Battery) in rat, respiratory Function in rat, and Cardiovascular Function by Telemetry in non-rodent
• General Toxicology Studies (GLP) - MTD & 4-week study in rat & non rodent
• Reprotoxicology studies: Preliminary study for effects on Embryo-Fetal development in rat and rabbit
ADX71441: pharmacokinetics & non clinical safety package
ADX71441: Steady state plasma profiles in humans (simulated with: HL 30 h; Vss 2.2 L/kg; F 70%) 0 500 1000 0 8 16 24 Time (h) P la s m a C o n c . (n g /m L ) 90 mg Q.D. 30 mg Q.D.
Baclofen (max. dose ~25 mg t.i.d.) -3X daily oral (or i.t. pump)
-high peak-trough ratio
separated profiles
ADX71441 has improved dosing regimen and PK/tolerability profile over
baclofen -
simulation: profiles around efficacious plasma concentration and 3-times aboveBaclofen: Steady state plasma profiles in humans (simulated with: HL 2 h; Vss 0.9 L/kg; F 70%) 500 1000 a C o n c . (n g /m L ) 75 mg T.I.D. 25 mg T.I.D. overlapping profiles
ADX71441: predicted Improved PK and tolerability profile
ADX71441 (human prediction) - 1X daily oral (~30 mg)
- low peak-trough ratio
- flat plasma and CNS PK profile - no Cmaxdriven side effects expected
Habituation following multiple dosing improves tolerability in monkeys and rodents
ADX71441: simulation of steady state plasma profile in humans
30
Charcot-Marie-Tooth (CMT1a) disease
• Charcot-Marie-Tooth (CMT) disease was first recognized independently in France and Great Britain (Charcot and Marie, 1886; Tooth, 1886).
• Orphan genetic peripheral polyneuropathies
‒ More recent nomenclature designated Charcot-Marie-Tooth disease as a hereditary motor and sensory neuropathy (HMSN) or CMT1a
• Prevalence of CMT1a: 3 in 10,000
‒ Upper limit of orphan classification
‒ Most common inherited neurological disease
‒ CMT1a involves duplication of the PMP22 gene
• Disease characterized by:
‒ Severe and uniformly reduced nerve conduction velocities and primary hypertrophic myelin
‒ CMT1a disease slowly gets worse with some parts of the body becoming numb, and pain can range from mild to severe. The disease is highly debilitating and
accompanied by severe cases of neurological pain and muscular disability
‒ There is no known cure for this incapacitating disease
• ADX71441 demonstrated POC in validated transgenic CMT rats
‒ Down regulated PMP22 mRNA, reduced the amount of hypo-myelinated axons and increased compound muscle action potentials in peripheral nerves in transgenic CMT rats. It also prevented grip strength loss in CMT rats compared to wild type rats
GABAB R Activation Therapy with ADX71441 in CMT Rats
Key results: Treatmentof CMT rats with
ADX71441 ameliorates axonal survival which should be the primary aim of any CMT1A therapy
•
CMT rats showed an overexpression of PMP22 mRNA,axonal loss and reduced grip strength reflecting typical CMT1A features
•
In a comparative study with baclofen in CMT1A rats, ADX71441 significantly reduced Pmp22 mRNA at 3mg/kg and 6 mg/kg p.o. (0.98-fold±0.49 and 0.93–fold±0.35, respectively). Baclofen reduced PMP22 mRNA expression at 3mg/kg BID (0.91-fold±0.25)•
ADX71441 therapy (9 weeks) in CMT rats down regulatedPMP22 mRNA, reduced the amount of hypomyelinated
axons and increased compound muscle action potentials in peripheral nerves
•
ADX71441 therapy (9 weeks) in wild-type rats did not affect PMP22 mRNA expression, axonal number and electro-physiological parameters, however caused a reduction in rat grip strength•
Since there is not a comparable loss of grip strength between CMT treated and untreated rats, the data suggests some benefit by ADX71441 on underlying pathophysiology•
ADX71441 could lower toxic PMP22 overexpression andH y p o m ye li n a te d a xo n s
32
Janssen partnership
ADX71149: mGlu2 PAM
• significant potential in treating of CNS
disorders
Overview of Janssen partnership (ADX71149)
•
ADX71149 is a highly selective oral brain penetrant small molecule
metabotropic glutamate receptor 2 (mGlu2) positive allosteric
modulator (PAM) discovered in collaboration with Janssen
Pharmaceuticals Inc.
•
mGlu2 PAM is validated in multiple indications: schizophrenia and
anxiety
•
Phase 1 complete (more than 8 studies conducted)
•
Phase 2 study of ADX71149 in schizophrenia as adjunctive therapy:
− Reported positive data in November 2012•
Phase 2 study of ADX71149 as adjunctive therapy for anxiety seen in
major depressive disorder patients reported in Q1 2014
34 34
ADX71149 Janssen partnership economics
34
• To date, Addex has received €10.2 million in upfront, research funding and milestones
• Eligible to receive €109 million in additional pre-launch milestones for 2 indications
• Eligible to receive low double-digit royalties on net sales
36
Financials and stock
•
Cash runway through Q4 2014−
CHF4.5M (US$4.9M / €3.7M) million in cash as of June 30, 2013−
Capital increase of 9 August 2013 increased cash reserves by CHF3.2M•
Traded on SIX Swiss Exchange: ADXN (ISIN:CH0029850754)•
10,173,576 shares outstanding (11 million fully diluted)−
Biotechnology Value Fund holds 27%−
Visium holds 4.8%•
Analysts coverage:−
Ladenburg Thalmann: Juan Sanchez (New York)Summary
•
Key strategic objectives−
Secure resources to advance clinical pipeline−
Collaborate with Industry / academia / patient groups to advanceclinical/preclinical/discovery programs
