Neuren Pharmaceuticals Limited · ASX:NEU
Neuren Pharmaceuticals — Non-Deal Roadshow (December 2006)
52 slides from Neuren Pharmaceuticals's roadshow presentation, Dec 5, 2006
Slide 1: Neuren's Partnering Update
Neuren’s Partnering Update 5 December 2006: Mr Larry Glass, Executive Vice President of Neuren Pharmaceuticals Ltd (ASX:NEU) will this week be meeting with a variety of biotechnology companies in Europe to increase the awareness of the Company and to explore potential partnering opportunities for it
Slide 2: Neuren Pharmaceuticals
neuren Pharmaceuticals
Slide 3: Disclaimer
Disclaimer This presentation includes forward-looking statements that are subject to risks and uncertainties. Such statements involve known and unknown risks and important factors that may cause the actual results, performance or achievements of Neuren to be materially different from the statements
Slide 4: Neuren Pharmaceuticals Ltd
Neuren Pharmaceuticals Ltd • Spun off from the University of Auckland • Listed on the ASX Feb 2005 • Excellent pipeline – 2 molecules in the clinic – 2 molecules in preclinical development – 3 families of compounds in discovery • Discovery programs: neurology, growth and metabolism • Clinical develo
Slide 5: Product Pipeline
Product Pipeline n 1 2 3 ati o g is al ad rin n al se se se al ry ic il n y Le ct u io ic il n ogy ha ha ha rci ve ed fa at al P al P al P e o C c e- ica at u ul C l e- ico ic ic ic m sc Pr Eff d an rm r n n n m Di li M Fo P ox l i l i l i C o Va T C C C Glypromate® NNZ-2566 (IV) NNZ-2566 (Oral) CNS
Slide 6: Glypromate
Glypromate®
Slide 7: Glypromate
Glypromate® • Drug-like molecule – Small molecule (MW=301.3 g/mol) – Highly neuroprotective at nM concentrations – Readily crosses the blood brain barrier – Rapidly cleared from circulation – Simple and inexpensive to synthesize – Simple and inexpensive formulation • Preclinical efficacy – Global hy
Slide 8: Multiple Modes of Action
Multiple Modes of Action • Inhibition of caspase-3 dependent apoptosis • Inhibition of microglial activation • Prevention of delayed or secondary necrosis • Protection of astrocytes and oligodendrocytes • Protection of neurons and neuronal function
Slide 9: Preclinical Safety and Toxicology
Preclinical Safety and Toxicology • Safety studies – No selectivity issues or unwanted secondary pharmacology predicted by wide binding – No inhibition of CYP-450 enzymes: low risk of drug- drug interactions – No in vivo effect on cardiovascular system observed with high i.v. doses – Clean result in
Slide 10: Glypromate is Neuroprotective After Acute Brain Injury
Glypromate is Neuroprotective After Acute Brain Injury Glypromate treatment 7 - 11 h post HI injury (3 mg/kg/h i.v. infusion) Vehicle (n = 17) 4 Glypromate (n = 19) Tissue Damage Score P < 0.001 3 2 1 0 Striatum CA1/2 CA3 CA4 DG Cortex Brain Region
Slide 11: Effect of Glypromate in MCAO Model of Acute Brain Injury
Effect of Glypromate in MCAO Model of Acute Brain Injury 4 Control (n = 15) 50 Control (n = 15) Size of infarct (mm 2) % Body weight gain (3/18 rats died) 2 Glypromate (n = 16) 40 Glypromate (n = 16) 0 (0/16 rats died) 30 -2 (P = 0.004) (P = 0.02) -4 20 -6 10 -8 0 -10 Control Glypromate 3 mg/kg/h i.
Slide 12: Long Term Improvements in Functional Recovery
Long Term Improvements in Functional Recovery • Improved behavioral outcome • Improved neurological outcome • Improved histological outcome 6 Glypromate® 5 Left/Right ratio of time take to contact patch Neurological score 5 Saline control 4 Glypromate® Normal Saline 4 3 3 P < 0.01 2 *P < 0.05 2 1 1
Slide 13: Glypromate Clinical Program
Glypromate® Clinical Program • Phase I – Single dose, double-blind, randomized, placebo-controlled, dose escalation – 30 healthy subjects – No SAEs; no drug-related AEs • Phase IIa (CABG +/- valves) – Randomized, ouble-blind, placebo-controlled, multiple dose – 32 patients >60 years old (22 treatmen
Slide 14: NNZ-2566
NNZ-2566 N CO>H 0 0 CO3H neuren
Slide 15: NNZ-2566 (IV) Development
NNZ-2566 (IV) Development • GMP manufacturing process validated • GLP acute toxicology program – Acute rat and dog and 14-day rat completed – 28-day dog scheduled for Q4 2006 (24-hr infusion) • Phase Ia initiated April 2006 (bolus, dose-escalation) • Phase 1b to be initiated Q4 2006 (continuous infu
Slide 16: NNZ-2566 is highly neuroprotective
NNZ-2566 is highly neuroprotective Control (Seizure rats, n = 9) Control (Non-Seizure rats, n = 19) NNZ-2566 (0.3 mg/kg/h, i.v., n = 25) 4 ** P < 0.01 *P = 0.004 Neuronal Damage Score 3 Tissue damage scores Vehicle 3 NNZ-2566 2 2 1 1 0 0 Striatum CA1-2 CA3 CA4 DG Cortex Striatum CA1-2 CA3 CA4 DG Cor
Slide 17: NNZ-2566 in a Penetrating Brain Injury Model
NNZ-2566 in a Penetrating Brain Injury Model Balance Beam Test (Foot Fault Deficits) 100% 80% 24 h % Im provem ent 60% 72 h 40% 20% 0% -20% Vehicle 1 mg 3 mg 10 mg -40% WRAIR TBI Model (12-hour infusion)
Slide 18: Microglial Cell Count
Microglial Cell Count (Ipsilateral minus Contralateral) (ipsalateral--contralateral) 50 Δ Activated Glia 40 30 47% 20 10 0 h h h kg kg kg kg h Ve Ve Ve Ve g/ g/ g/ g/ 3m 3m 3m 3m Area-t1 Area-t2 Area-b1 Area-b2
Slide 19: Balance Beam Performance
Balance Beam Performance 100 0.5 h delayed treatment 70% * 62% * 80 46% * 60 40 21% * 20 0% 3% 0 % Improvement V 0.01 0.1 1 3 10 NNZ-2566 (mg/kg, i.v.) 2 h delayed treatment 3mg/kg/h x 12h 10 mg/kg + 3mg/kg/h x 12h 100 70% * 3mg/kg/h x 12h 10 mg/kg + 3mg/kg/h x 24h 80 58% * 45% * 60 40 18% 20 0% 0 V
Slide 20: Injury Volume (H & E)
Injury Volume (H & E) vehicle 3mg/kg/h x 12h 120 10 mg/kg + 3mg/kg/h x 12h 10 mg/kg + 3mg/kg/h x 24h 100 23% % Change 80 37% * 34% * 60 40 20 0 2 h post PBBI
Slide 21: Attenuation of Non-Convulsive Seizures
Attenuation of Non-Convulsive Seizures Incidence Total Time Mean Time Latency (sec) (sec) (min) Vehicle 92% 1277 80.2 75.4 NNZ-2566 60% 555 48.7 208.7 Percent -35% -56% -39% +133% Change WRAIR MCAO Model (bolus + 12-hour infusion)
Slide 22: NCS Incidence
100 NCS Incidence % Rat with NCS 80 60 40 (12/13) (7/11) (9/12) * 20 (4/11) 0 Vehicle 3 10 100 Dose (mg/kg) followed by 3mg/kg/h x 12h infusion
Slide 23: Total NCS activity
Total NCS activity 1800 Total Time in NCS (sec)/rat 1600 1400 1200 1000 800 600 * * 400 200 0 Vehicle 3 10 100 Dose (mg/kg) followed by 3mg/kg/h x 12h infusion
Slide 24: NCS frequency
NCS frequency 30 25 20 # of NCS/rat 15 10 * * 5 0 Vehicle 3 10 100 Dose (mg/kg) followed by 3mg/kg/h x 12h infusion
Slide 25: NCS time course
NCS time course 5 Vehicle 4 3mg/kg bolus 10mg/kg bolus # of NCS/rat/hour 100mg/kg bolus 3 2 1 0 1 2 3 4 5 6 7 8 9 Time post pMCAo (hours)
Slide 26: Total seizure time among all rats with seizures
Total seizure time among all rats with seizures 1800 Total Time in NCS (sec)/rat 1600 1400 1200 1000 800 * 600 400 200 0 Vehicle NNZ-2566 (All group Combined)
Slide 27: Inhibition of Gene Up-regulation
Inhibition of Gene Up-regulation Gene 4 hours post-injury 24 hours post-injury Apoptotic/Pro-apoptotic genes Bax ● Caspase-8 ● Fadd ● Inflammatory cytokines IL-1β ● IL-6 ● TNFα ● ● = p < .05 Wei et al. NNZ-2566 treatment inhibits inflammatory and apoptotic gene up-regulation induced by experimental
Slide 28: Study 1: Phase IIa (severe)
Study 1: Phase IIa (severe) • Open-label, observational study in TBI patients with GCS 4-8 to evaluate… – Safety – Penetration of drug to injured brain – Preliminary evidence of efficacy in modifying acute disease/injury processes • Within-subjects and cohort comparison analyses • Drug administered
Slide 29: Study 1 (severe): Within-subjects comparisons
Study 1 (severe): Within-subjects comparisons • Incidence of non-convulsive seizures and epileptiform activity • Mean global EEG percent alpha variability (PAV) score • Biomarkers (measured in CSF at 24, 36, 72, 96 hrs) – Alpha II-spectrin breakdown product SBDP145 (calpain- mediated acute cell deat
Slide 30: Study 1 (severe): Cohort Comparisons
Study 1 (severe): Cohort Comparisons • Historical cohorts – Maas et al. Lancet Neurology 2006 – Vespa et al. J Neurosurgery 2002 – Vespa et al. J Neurosurgery 1999 – Hebb et al. J Neurotrauma (submitted) 2006 • Mortality at 30 days • GOSE at 6 months • Percent time of elevated intracranial pressure
Slide 31: Study 2: Phase IIa (mild-moderate)
Study 2: Phase IIa (mild-moderate) • Randomized, double-blind, placebo controlled, dose-escalation study in patients with GCS 9-15 to evaluate safety and efficacy • Intended enrollment = 200 (3:2 active : placebo randomization) • Interim analysis of efficacy and safety with ~50 completed patients •
Slide 32: NNZ-2566 Oral: Bioavailability
NNZ-2566 Oral: Bioavailability 6000 4500 NNZ-2566 (ng/ml) Saline 3000 Microemulsion Nanocapsule 1500 0 0 30 60 120 240 Time (min)
Slide 33: NNZ-2566 Oral (single dose)
NNZ-2566 Oral (single dose) MCAO-Induced Ischaemic Brain Damage: Effect of Oral NNZ-2566 120 100 80 Damage (mm2) 60 40 ** 20 ** 0 Veh 15 30 60 NNZ-2566 (m g/kg p.o.; 3 h post-stroke) ** P < 0.01, ANOVA with Dunnett’s post-hoc test. Group sizes: Veh (9), 15 mg/kg (8), 30 mg/kg (8), 60 mg/kg (7)
Slide 34: NNZ-2566 Oral (2 doses) Infarct Area
NNZ-2566 Oral (2 doses) Infarct Area 125 Mean Infarct Area ± SEM Unpaired t test 100 P value P<0.0001 P value summary *** 75 Are means signif. different? (P < 0.05) Yes (mm2) One- or two-tailed P value? Two-tailed t, df t=6.621 df=21 50 25 0 Vehicle NNZ2566 Effect of microemulsion NNZ2566 given oral
Slide 35: NNZ-2566 Oral (2 doses) Percentage Body Weight Change
NNZ-2566 Oral (2 doses) Percentage Body Weight Change 0.0 Post-pre MCAO value ± SEM (%) -2.5 Unpaired t test -5.0 P value 0.0035 P value summary ** Are means signif. different? (P < 0.05) Yes One- or two-tailed P value? Two-tailed -7.5 t, df t=3.286 df=21 -10.0 Vehicle NNZ 2566 Effect of microemulsi
Slide 36: NNZ-2566 Protects Striatum and Cortex
NNZ-2566 Protects Striatum and Cortex Single Dose Oral Administration of NNZ-2566 to Stroke Injured Rats 3 hours following endothelin-induced stroke injury 140 Total Infarct Area 120 Cortical Infarct Area Infarct Area (mm ) 2 100 Striatal Infarct Area 80 60 40 *** 20 *** *** *** *** *** 0 eh g g g h
Slide 37: Chronic NNZ-2566 treatment improves memory retention
Chronic NNZ-2566 treatment improves memory retention 60 4 month Control 12 Month Contol Mean Swim Time to Platform (s) 50 3 weeks (s.c.) 12 Month NNZ-2566 treatment 40 30 20 10 Aquisition Retention Re-aquisition 0 1 2 3 4 1 2 3 4 1 2 3 4 Test Day • Morris water-maze study; NNZ-2566 administered s.c.
Slide 38: Neuroprotection retained in rats after chronic oral treatment
Neuroprotection retained in rats after chronic oral treatment 100 Post-stroke Vehicle 90 Post-stroke NNZ-2566 80 Infarct Area (mm2) 70 60 50 40 * 30 20 10 ** 0 Chronic Vehicle Chronic NNZ-2566 • Oral NNZ-2566 (30 mg/kg) retains efficacy in rat neurodegeneration model • No statistical difference in e
Slide 39: NNZ-2591 (Lead Diketopiperazine)
NNZ-2591 (Lead Diketopiperazine)
Slide 40: Oral bioavailability of NNZ-2591
Oral bioavailability of NNZ-2591 50 30 mg/kg IV NNZ-2591 (µg/ml) 40 30 mg/kg Oral 30 20 10 0 2 15 30 60 90 120 Time (min) • Oral bioavailability of aqueous NNZ-2591: 100% • Plasma half-life in rats: 50 minutes • Excellent profile for chronic oral drug delivery
Slide 41: NNZ-2591: Chronic effects in Parkinson's disease
NNZ-2591: Chronic effects in Parkinson’s disease 100 7 Days Treatment adjusted steps (%) 75 with NNZ-2591(i.p.) shown by blue bar Vehicle L/R ratio 0.2 mg/day 50 1 mg/day 5 mg/day 25 0 0 2 4 6 8 10 12 Weeks post 6-OHDA lesion • NNZ-2591 given 2 weeks after striatal lesion • 1 week treatment - prolon
Slide 42: NNZ-2591 anti-Parkinsonian effect is centrally-mediated
NNZ-2591 anti-Parkinsonian effect is centrally-mediated 100 Vehicle (n=8) 90 ANOVA p = 0.05 NNZ 2591 (n=8) adjusting steps (%) L/R ratio 30 20 10 0 0 2 4 6 8 10 12 14 Weeks post 6-OHDA lesion • Parkinsonian disorder induced by intra-striatal 6-OHDA injection • NNZ-2591 (20 ng) injected directly into
Slide 43: NNZ-2591 Oral Administration: Histopathology
NNZ-2591 Oral Administration: Histopathology Infarct area Infarct area 140 Mean infarct area ± SEM One-way analysis of variance 120 P value 0.0011 P value summary ** 100 Are means signif. different? (P < 0.05) Yes (mm2) Number of groups 3 80 F 8.498 60 R squared 0.3541 40 ** 20 0 Vehicle 3mg/kg 30mg
Slide 44: NNZ-2591 Protects Cortex and Striatum
NNZ-2591 Protects Cortex and Striatum Single Dose Oral Administration of NNZ-2591 to Stroke Injured Rats 3 hours following endothelin-induced stroke injury 140 120 2) 100 INFARCT AREA (mm 80 Total Infarct Cortex Only 60 Striatum Only 40 ** ** 20 * 0 f f f tx tx tx r r r In In In St St St C C C h g g
Slide 45: Oral Administration: Body Weight
Oral Administration: Body Weight Percentage body weight change at 3 days post MCAO 2.5 ** Post-pre MCAO value ± 0.0 Wt change SEM (%) -2.5 One-way analysis of variance P value 0.0060 P value summary ** -5.0 Are means signif. different? (P < 0.05) Yes Number of groups 3 -7.5 F 6.073 R squared 0.2815
Slide 46: Oral Administration: Cognitive Performance
Oral Administration: Cognitive Performance Probe trial: Acquisition Latency to Platform Quadrant 80 10 Saline / water Time to platform (seconds) 7 Time (s) 70 Scopolamine Saline / NNZ-2591 60 Scopolamine / water 5 Scopolamine + NNZ-2591 Scopolamine / NNZ-2591 2 50 0 40 Time to Platform 30 20 20 15 T
Slide 47: Neural Regeneration Peptides
Neural Regeneration Peptides
Slide 48: Neural Regeneration Peptides – NRPs
Neural Regeneration Peptides – NRPs • Neuren scientist discovered a novel mouse Nrp gene encoding a Neural Regeneration Protein • Potent chemoattractive, neuronal survival-promoting factor • Short peptide analogues (NRPs) synthesised (12-24 amino acids) • Lead NRP: NNZ-4921 • Extremely potent – High
Slide 49: Positive Results in a Peripheral Neuropathy Model
Positive Results in a Peripheral Neuropathy Model Beam-Walking in Neuropathic Rats % Pre-PDX Body Weight 110.0 35.00 PDX Vehicle Saline or NRP Beam Walk Score (7 Steps) NNZ-4921 105.0 30.00 * 25.00 * ** 100.0 * 20.00 95.0 Vehicle 15.00 90.0 NNZ-4921 10.00 85.0 Day 0 Day 13 Day 17 Day 24 1 2 3 4 5 6
Slide 50: NNZ-8000
NNZ-8000
Slide 51: NNZ-8000
NNZ-8000 • Growth hormone produced by cancer cells (autocrine GH) drives malignant phenotype, drug resistance • NNZ-8000 inhibits extracellular signaling pathway (Trefoil Factors) • In vitro and in vivo proof of principle with RNAi, peptidomimetic, polyclonal and monoclonal antibodies • Antibodies t
Slide 52: Pipeline Development Strategy
Pipeline Development Strategy • Develop through registration – Glypromate®: cognitive decline post-CPB – Glypromate®: cardiac arrest – NNZ-2566 IV: • survival and neurological function in severe TBI • depression and memory in mild-moderate TBI • Out-license – NNZ-2566 IV: acute stroke – NNZ-2566 ora
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