Corporate Presentation
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Corporate Presentation
Corporate Presentation 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 2 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 • Relationships with outsourced R&D suppliers established • Partnering outreach launched 3 Value drivers and competitive advantage Leading allosteric z drug discovery • Proprietary 85,000 knowledge-based HTS library • Proprietary HTS high-fidelity pharmacology systems • Deep allosteric know-how & expertise Validated therapeutic z class • Proven mechanism, that has led to marketed products • Significant investment from all major pharma • Growing pipeline of allosteric modulators in the clinic Robust pipeline with z orphan drug potential • 3 Phase 2 programs • 1 Phase 1 ready program • Multiple preclinical & discovery programs z Partnership with leading pharma • Janssen Pharmaceuticals Inc. (JPI) for mGlu2 PAM z Extensive IP portfolio • 12 issued patents • 43 pending patents Financials • 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 z 4 Addex clinical pipeline, preclinical & discovery programs 5 Clinical stage pipeline Target R&D stage Indication Additional Information ADX71149 mGlu2PAM Phase IIa PoC in schizophrenia Completed. Signal in negative symptoms in schizophrenia Partnered with Janssen Pharmaceuticals Inc. Phase IIa POC in anxious depression - Completed Primary endpoint not met; however signal seen in some anxiety scores and all depression scores 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 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 * Data generated with compound 6 Pre-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): breast, ovarian, prostate cancer Preclinical PoC of in vivo modulation of FSH induced estradiol production* . Opportunity to develop an orally bioavailable non competitive FSHR antagonists 7 * Data generated with compound Discovery programs 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 antiinflammatory 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 antiinflammatory 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 8 * Data generated with compound Pipeline program: Dipraglurant in PD-LID and Dystonia (subject to securing resources) 9 Dipraglurant (ADX48621) overview • 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 Lewy body dementia Addiction 10 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. 11 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 data • Michael J. Fox Foundation supported the trial with a $900,000 grant 12 ADX48621-201 trial design EU and US Phase 2a dipraglurant trial for PD-LID • Primary objective: safety & tolerability • Dipraglurant taken with levodopa • Randomized, 76 patients • Dipraglurant titration double-blind, placebo-controlled, multi-center trial from 50mg q.d. to 100mg t.i.d over 4 weeks • Moderate to severe • Individual levodopa LID patients regimens remain constant for duration of study (300 -1500mg/day) • 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) • Patient and clinician global impression of change (PGIC & CGIC) • Evaluation of mood using Hospital Anxiety & Depression Scale (HADS) Positive Top-line results reported 1Q 2012 13 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 14 Dipraglurant reduces LID severity • Dipraglurant reduced peak dose mAIMS (90 min after dosing) dipra placebo * 35% % reduction 30% 25% ‒ Day 1 (50mg): * 19.9% vs 4.1% (p=0.042) 20% ‒ Day 14 (100mg): 32.3% vs 12.6% (p=0.034) 15% ‒ Day 28 (100mg): 31.4% vs 21.5% 10% Placebo response likely due to trial design 5% 0% Day 1 Day 14 Day 28 • 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 ‒ e.g. one patient was able to hold & read a newspaper for the first time in years ‒ e.g. another patient had improved speech and became more easily intelligible NB: Dipraglurant was as effective in patients who had undergone deep brain stimulation as in non DBS patients 15 Good correlations between Dipraglurant effect in reducing PD-LID and plasma concentration: IC50 = 1317 ng/mL 0 Mean change in mAIMs from baseline mean plasma conc ( ng/mL) 1400 1200 1000 800 600 400 200 0 0 1 2 3 4 -1 -2 visit 3 -3 visit 4 -4 visit 5 -5 -6 0 time (h) 500 1000 1500 Mean dipraglurant plasma conc (ng/mL) 14 mean mAIMS 12 10 Visit 3 (Day 1) 50 mg Visit 4 (Day 14) 100 mg Visit 5 (Day 28) 100 mg 8 Cmax (ng/mL) 793 ± 438 1683 ± 1107 1844 ± 1117 6 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 4 2 16 0 0 1 2 time (h) 3 4 Receptor occupancy PET study in non human primates: dipraglurant is brain penetrant and occupies the mGluR5 in a dose-dependent manner: EC50 = 510 ng/mL 17 Patient-reported measurable clinical effects “On” time with no dyskinesia - change from week -1 50 mg dose level 100mg dose level 18 Measurable clinical effects Modified AIMS Dipraglurant efficacy Patient Diary CGIC & PGIC subjective observations (patient diaries & PGIC/CGIC) consistent with objective measurements (mAIMS) 19 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. 20 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 Dipraglurant could qualify for orphan drug designation in dystonia – fasted path to market Human POC clinical testing of dipraglurant in dystonia could benefit from dystonia foundation funding 21 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) Tottering mouse model (paroxysmal dystonia) 22 Preclinical and clinical efficacy of dipraglurant in dystonia 23 Dipraglurant - conclusions and perspectives • • • • • There is a strong rationale for developing mGlu5 NAMs for treatment in PDLID (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). 24 pipeline program: ADX71441 – GABABR positive allosteric modulator (subject to securing resources) 25 Oral GABAB receptor PAM (ADX71441) • • ADX71441 is a novel, first-in-class, oral, small molecule activator of gammaaminobutyric 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 validation for GABABR activation MS Spasticity • • • • Visceral Pain Osteoarthritis and other pain Fragile X Syndrome / Autism Overactive Bladder (OAB) Anxiety Alcohol and nicotine dependence Epilepsy Charcot-Marie-Tooth (CMT1a) 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 26 ADX71441 pharmacology and tolerability PoC in models of anxiety, pain, OAB and addiction • 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 CNS related clinical signs attenuate and disappear after repeated dosing 27 ADX71441: pharmacokinetics & non clinical safety package Pharmacokinetics: • 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 nonrodent • 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 28 ADX71441 has improved dosing regimen and PK/tolerability profile over baclofen - simulation: profiles around efficacious plasma concentration and 3-times above Steady state plasma profiles in humans ADX71441: ADX71441: simulation of steady state plasma profile in humans (simulated with: HL 30 h; Vss 2.2 L/kg; F 70%) Plasma Conc. (ng/mL) 90 mg Q.D. 1000 30 mg Q.D. separated profiles 500 Habituation following multiple dosing improves tolerability in monkeys and rodents 0 0 8 16 ADX71441 (human prediction) - 1X daily oral (~30 mg) - low peak-trough ratio - flat plasma and CNS PK profile - no Cmax driven side effects expected 24 Time (h) ADX71441: predicted Improved PK and tolerability profile Baclofen: state plasmain profiles in humans Baclofen: steady stateSteady plasma profile humans Plasma Conc. (ng/mL) (simulated with: HL 2 h; Vss 0.9 L/kg; F 70%) 1000 overlapping profiles 75 mg T.I.D. 25 mg T.I.D. Baclofen (max. dose ~25 mg t.i.d.) -3X daily oral (or i.t. pump) -high peak-trough ratio -fluctuating PK profile -Cmax driven side effects reported 500 0 0 8 16 24 Time (h) Baclofen: Cmax driven side effects reported 29 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 30 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: Treatment • CMT rats showed an overexpression of PMP22 mRNA, axonal loss and reduced grip strength reflecting typical of CMT rats with CMT1A features ADX71441 ameliorates • In a comparative study with baclofen in CMT1A rats, axonal survival which ADX71441 significantly reduced Pmp22 mRNA at 3mg/kg should be the primary and 6 mg/kg p.o. (0.98-fold±0.49 and 0.93–fold±0.35, respectively). Baclofen reduced PMP22 mRNA expression aim of any CMT1A at 3mg/kg BID (0.91-fold±0.25) therapy Hypomyelinated axons • ADX71441 therapy (9 weeks) in CMT rats down regulated • • • PMP22 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 electrophysiological 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 and potentially delay the progression of the disease and therefore offer a unique therapeutic opportunity for CMT1A patients 31 Janssen partnership ADX71149: mGlu2 PAM • significant potential in treating of CNS disorders 32 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 ‒ Top-line results missed the primary end point but signals were seen on some anxiety measures (HDRS17 anxiety somatization factor, IDS-C30 anxiety subscale) and on all depression measures (HDRS17, HAM-D6 and IDS-C30) • Janssen reviewing future development in other indications 33 ADX71149 Janssen partnership economics • • • • 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 Janssen funds all development, launch and commercialization activities 34 Financial review & Summary 35 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) − Wedbush: Chris Marai & Greg Wade (San Francisco) 36 Summary • Key strategic objectives − Secure resources to advance clinical pipeline − Collaborate with Industry / academia / patient groups to advance clinical/preclinical/discovery programs • Starting 2014 with sufficient financial resources & team to execute key strategy objectives • Dipraglurant - first in class mGlu5NAM for PD-LID with robust Phase 2a data • ADX71441 - first in class GABA B PAM ready for Phase 1, with potential in several major indications as well as orphan indication • Extensive IP portfolio on allosteric modulator preclinical and discovery programs 37 allosteric modulators for human health www.addextherapeutics.com