Neuren Pharmaceuticals Limited · ASX:NEU
Neuren Pharmaceuticals — Arrowhead TBI Conference 2012
28 slides from Neuren Pharmaceuticals's conference presentation, Mar 8, 2012
Slide 1: Development of NNZ-2566 for Mild TBI
Development of NNZ-2566 for Mild TBI Arrowhead TBI Conference March 2012
Slide 2: Acknowledgement and Forward Looking Statement
Acknowledgement and Forward Looking Statement Research described in this presentation has been partially funded by the U.S. Army Medical Research and Materiel Command (grant number W81XWH-09-1-0496). The opinions expressed are not necessarily endorsed by the U.S. Army. This presentation contains for
Slide 3: NNZ-2566 in mild TBI: an "addressable" indication
NNZ-2566 in mild TBI: an “addressable” indication • Unmet medical need • Biological rationale • Oral bioavailability and CNS penetration • Acceptable safety profile • Feasible clinical trial • Clear regulatory pathway 3
Slide 4: Unmet need
Unmet need • >1 million cases of mTBI in the US annually • >168,000 in the military from 2001 – 2011 (77.6% of total reported TBI) • Post-concussive symptoms affect up to 50% of mTBI patients at 1 month and 15-25% at 1 year • Symptoms can include impaired cognitive performance, memory and attention,
Slide 5: Biological rationale
Biological rationale • mTBI can result in a wide range of molecular and cellular effects • Up-regulation of inflammatory cytokine expression • Up-regulation of pro-apoptotic gene expression • Down-regulation of anti-apoptotic gene expression • Astrogliosis • Microglial activation • EEG abnormalities
Slide 6: NNZ-2566 attenuates expression of inflammatory cytokines and adhesion molecules
NNZ-2566 attenuates expression of inflammatory cytokines and adhesion molecules Wei, et. al., J Neuroinflammation (2009) 6
Slide 7: NNZ-2566 normalizes Bax and Bcl-2 expression
NNZ-2566 normalizes Bax (pro-apoptotic) and Bcl-2 (anti- apoptotic) expression; Bax co-localized with astrocytes Bax Bcl-2 Lu, et. al., J Neurotrauma (2009) 7
Slide 8: Caspase-3 activity is reduced by NNZ-2566
Caspase-3 activity is reduced by NNZ-2566 Lu, et. al., J Neurotrauma (2009) 8
Slide 9: NNZ-2566 inhibits reactive gliosis
NNZ-2566 inhibits reactive gliosis: IL-1β immunoreactivity localized to microglia Wei, et. al., J Neuroinflammation (2009) 9
Slide 10: NNZ-2566 inhibits microglial activation
NNZ-2566 inhibits microglial activation 200 * Cell Counts 150 100 50 0 Vehicle NNZ-2566 Treatment PBBI Model MCAO Model Lu, et. al., J Neurotrauma (2009) 10
Slide 11: NNZ-2566 inhibits leukocyte infiltration
NNZ-2566 inhibits leukocyte infiltration Lu, et. al., J Neurotrauma (2009) 11
Slide 12: Increased cellular proliferation in the subventricular zone of aged rat brains
Increased cellular proliferation in the subventricular zone of aged rat brains 18-month old rats 9-month old rats 12
Slide 13: Reduction of reactive astrocytes in the brains of aged rats
Reduction of reactive astrocytes in the brains of aged rats (CA4 sub-region of hippocampus) 200 *# GFAP-positive cells 100 0 4 months 9 months 18 months Lateral cortex 13
Slide 14: Effects on synaptic plasticity in the MeCP2 model
Effects on synaptic plasticity in the MeCP2 model 250 Saline 220 NNZ-2566 200 Dendritic Length (µm) 200 Saline (% of baseline) NNZ-2566 fEPSP slope 180 150 160 140 100 120 50 100 80 0 0 20 40 60 80 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 Time (min) Distance from Soma (µm) NNZ-
Slide 15: Increased dendritic branching in the MeCP2 model
Increased dendritic branching in the MeCP2 model 15
Slide 16: Dose-dependent reduction in brain injury with single oral dose at 3 hrs
Dose-dependent reduction in brain injury with single oral dose at 3 hrs Bickerdike, et. al., J Neurological Sciences (2009) 16
Slide 17: Reduction of brain injury and weight loss with two oral doses
Reduction of brain injury and weight loss with two oral doses at 2 and 4 hrs following injury (MCAO model) A B 120.0 12.0 100.0 10.0 Body Weight Loss (g) Infarct Area (mm2) 80.0 8.0 60.0 6.0 4.0 40.0 ** ** 20.0 2.0 0.0 0.0 Vehicle NNZ-2566 Vehicle NNZ-2566 Oral Drug Treatment Oral Drug Treatment 40
Slide 18: Dose-dependent improvement in neurofunction decrement (foot faults)
Dose-dependent improvement in neurofunction decrement (foot faults) Lu, et. al., J Neurotrauma (2009) 18
Slide 19: Dose-dependent attenuation of post-injury non-convulsive seizure activity
Dose-dependent attenuation of post-injury non- convulsive seizure activity Lu, et. al., JCBFM (2009) 19
Slide 20: Attenuation of post-injury non-convulsive seizures after onset
Attenuation of post-injury non-convulsive seizures after onset Lu, et. al., JCBFM (2009) 20
Slide 21: Improved working memory (Morris water maze) in a cortical impact model
Improved working memory (Morris water maze) in a cortical impact model at 28 days 100 90 Escape Latency (s) 80 Vehicle 70 3 mg/kg/h 10 mg/kg/h 60 30 mg/kg + 10 mgkg/h 50 Naive (non-injured) 40 * 30 20 1 2 3 4 5 Trial 30 25 Vehicle Path Length (m) 20 3 mg/kg/h 10 mg/kg/h 15 30 mg/kg + 10 mg/kg/h 10 N
Slide 22: Oral bioavailability and CNS penetration
Oral bioavailability and CNS penetration Fed Rats 14 12 [NNZ-2566] (µg/mL) 10 Water High Surfactant 8 High Oil 6 4 2 0 0 2 4 6 8 10 Time (h) Fasted Rats 14 12 [NNZ-2566] (µg/mL) Water 10 High Surfactant 8 High Oil 6 4 2 0 0 2 4 6 8 10 Time (h) Tmax at <2 hours with aqueous formulation Enzymatic stab
Slide 23: Safety profile: non-clinical
Safety profile: non-clinical • Safety pharmacology – no or insignificant effects on: • Genotoxicity (Ames, chromosome aberration, micronucleus) • hERG channel assays • Respiratory safety pharmacology • Irwin screen (rat neurobehavioral) • Reproductive toxicology (Segment I) – Mating fertility and fe
Slide 24: Safety profile: clinical
Safety profile: clinical • Four Phase I studies in healthy volunteers (intravenous formulation) • 3 studies in males, 1 study in females • 106 total volunteers (77 exposed to NNZ-2566) • Doses up to 20 mg/kg bolus followed by 6 mg/kg/hr x 72 hours • No SAEs • All AEs were mild or moderate; moderate
Slide 25: Feasibility of clinical trials: challenges
Feasibility of clinical trials: challenges • High placebo response rate (>50% of mTBI patients recover within 1 month) • Heterogeneous population (type and extent of injury, age, sex, previous history of mTBI, baseline neurocognitive performance, other risk factors) • Relying on normative data to de
Slide 26: Clinical trial feasibility: Phase II trial overview
Clinical trial feasibility: Phase II trial overview • Randomized, double-blind, placebo and true (musculoskeletal injury) control • Investigational product: 2 g or 3 g (based on weight) liquid dose TID for 5 days • Single site: University of Pittsburgh Sports Medicine Concussion Program • PI: A. Kon
Slide 27: Regulatory pathway: assumptions
Regulatory pathway: assumptions • Strong evidence of efficacy with acceptable safety in adequately powered Phase II will support progression to pivotal trial • Time to recovery is an approvable endpoint • ImPACT is acceptable as a primary outcome measure • No a priori standard for magnitude of effec
Slide 28: Larry Glass, CEO, Neuren Pharmaceuticals
Larry Glass, CEO Neuren Pharmaceuticals 3 Bethesda Metro Center, Suite 700 Bethesda, MD 20814 301-941-1830 lglass@neurenpharma.com 28
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