Slide 1: NeuroRestore ACD856: Background & data supporting disease modifying effects
May 17, 2023 NeuroRestore ACD856 i SS Background & data supporting disease modifying Pontus Forsell, PhD, Head of Discovery & Research at AlzeCure Pharma \Z
Slide 2: NeuroRestore – positive allosteric modulator of Trk-receptors
NeuroRestore® – positive allosteric modulator of Trk-receptors • ACD856 is a novel small molecule positive modulator of Trk receptors enhancing the signaling of neurotrophins, such as Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) • The neurotrophins has been known for decade
Slide 3: NeuroRestore – positive allosteric modulator of Trk-receptors
NeuroRestore® – positive allosteric modulator of Trk-receptors • ACD856 is a novel small molecule positive modulator of Trk- receptors enhancing the signaling of neurotrophins such as NGF and BDNF • The enhanced signaling leads to short term symptomatic effects with long term benefits • The long-ter
Slide 4: In vitro / In vivo
NeuroRestore® – positive allosteric modulator of Trk-receptors • In vitro − Protection against amyloid-beta induced neurotoxicity − Potentiation of neuronal growth and neurite outgrowth − Increased levels of BDNF • In vivo − Improved memory possibly through increased neuroplasticity − Long term anti
Slide 5: Key pathological features of the Alzheimer's disease brain
NeuroRestore® – positive allosteric modulator of Trk-receptors • Key pathological features of the Alzheimer’s disease brain: - Amyloid plaque - Synapse dysfunction - Axon withdrawal Symptomatic & disease- modifying therapy - Mitochondrial dysfunction • These events are closely correlated with the co
Slide 6: Neuroprotective effects of ACD856
The life and death of a neuron Healthy Spine Synaptic Neurite Neuronal cell neuron degeneration dysfunction degeneration death Amyloid-beta aggregates Amyloid- plaque Dendrites Spines Axon Neurites Synaptic dysfunction Neuroprotective effects of ACD856 Neurite degeneration Neuronal function Neuronal
Slide 7: ACD856 is protective against Aβ1-42-induced neurotoxicity
NeuroRestore® – positive allosteric modulator of Trk-receptors • Vehicle (DMSO) or A 1-42 was added to neurons, with or without ACD856 • The neuronal content of a synaptic protein (SNAP25) was quantified by microscopy ACD856 + A 1-42 A 1-42 51 ACD856 is protective against A 1-42-induced neurotox
Slide 8: In vitro / In vivo
NeuroRestore® – positive allosteric modulator of Trk-receptors • In vitro − Protection against amyloid-beta induced neurotoxicity − Potentiation of neuronal growth and neurite outgrowth − Increased levels of BDNF • In vivo − Improved memory possibly through increased neuroplasticity − Long term anti
Slide 9: ACD856 increase neuronal growth and neurite formation
NeuroRestore® – positive allosteric modulator of Trk-receptors • Neurotrophins like NGF and BDNF are important for neurite outgrowth and neuronal proliferation • Effects of ACD856 on cell number and neurite outgrowth was studied in immature neuronal-like cells 40 Neurite total length per neuron ✱ ✱✱
Slide 10: In vitro / In vivo
NeuroRestore® – positive allosteric modulator of Trk-receptors • In vitro − Protection against amyloid-beta induced neurotoxicity − Potentiation of neuronal growth and neurite outgrowth − Increased levels of BDNF • In vivo − Improved memory possibly through increased neuroplasticity − Long term anti
Slide 11: BDNF stimulates neuroplasticity and synaptic function
NeuroRestore® – positive allosteric modulator of Trk-receptors • BDNF stimulates neuroplasticity and synaptic function • BDNF levels are increased in an activity-dependent manner. Exercise increase BDNF levels and it is believed to be one of the reasons for well-being after training • Several lines
Slide 12: ACD856 significantly increase the levels of BDNF
NeuroRestore® – positive allosteric modulator of Trk-receptors • Cortical neurons were incubated with ACD856 for 6 hours • Old animals were administered ACD856 once daily for 4 weeks ACD856 increase BDNF ACD856 increase BDNF levels in cortical neurons in brains of old mice ✱✱ ✱ ✱✱ ✱ % BDNF of DMSO t
Slide 13: In vitro / In vivo
NeuroRestore® – positive allosteric modulator of Trk-receptors • In vitro − Protection against amyloid-beta induced neurotoxicity − Potentiation of neuronal growth and neurite outgrowth − Increased levels of BDNF • In vivo − Improved memory possibly through increased neuroplasticity − Long term anti
Slide 14: ACD856 improves age-induced memory impairment
NeuroRestore® – positive allosteric modulator of Trk-receptors • Old animals were used to study effects of ACD856 on age-induced memory impairment • Two memory tests were performed at one or eleven days after a learning task Single dose ACD856 Learning Test 1 Test 2 Day 0 Day 1 Day 11 Memory test #1
Slide 15: In vitro / In vivo
NeuroRestore® – positive allosteric modulator of Trk-receptors • In vitro − Protection against amyloid-beta induced neurotoxicity − Potentiation of neuronal growth and neurite outgrowth − Increased levels of BDNF • In vivo − Improved memory possibly through increased neuroplasticity − Long term anti
Slide 16: Sustained antidepressant-like effect of ACD856
NeuroRestore® – positive allosteric modulator of Trk-receptors • Mice were treated with ACD856 once daily for 5 days • ACD856 was tested for antidepression-like effect 3, 5 or 7 days after the last dose 360 Depression-like model using mice 320 Immobility time (s) 280 *** ** 240 200 160 120 80 40 0 V
Slide 17: Summary of ACD856 effects
NeuroRestore® – positive allosteric modulator of Trk-receptors ACD856: ✓ Protects against amyloid-beta induced neurotoxicity ✓ Enhance neurite outgrowth and neuronal proliferation ✓ Increase the levels of BDNF in cortical neurons and in brains of aged mice ✓ Improves memory impairment, presumably vi
Slide 18: The preclinical data suggest a new potential use of ACD856
NeuroRestore® – positive allosteric modulator of Trk-receptors • The preclinical data suggest a new potential use of ACD856 • The effect of ACD856 on BDNF levels are very encouraging and supports that ACD856 can improve learning and memory in multiple ways • Neuroprotective and neurorestorative effe
Slide 19: Team at AlzeCure Pharma and Karolinska Institutet
• Team at Alzecure Pharma • Karolinska Institutet − Cristina Parrado − Prof. Bengt Winblad − Gunnar Nordvall − Prof. Maria Eriksdotter − Maria Backlund − Assoc. Prof. Sumonto Mitra − Veronica Lidell − Azita Rasti − Sanja Juric − Märta Dahlström − Magnus Halldin − Johan Sandin Some of the artwork wer
Slide 20: AlzeCure Pharma AB contact details
AlzeCure Pharma AB Karolinska Institutet Novum Science Park Hälsovägen 7, 141 57 Stockholm Sweden www.alzecurepharma.com info@alzecurepharma.com