Slide 1: Pontus Forsell AAT-ADPD 2-5 April, 2020
Pontus Forsell AAT-ADPD 2-5 April, 2020
Slide 2: Disclosures
Disclosures X Company Honoraria/ Funded Patent Stock Ownership Employee Affiliation Name Expenses Research Options Equity AlzeCure X X X Foundation AlzeCure X X X X Pharma AB Karolinska X Institutet 2
Slide 3: Background to NGF & BDNF signaling in AD or PD
Background to NGF & BDNF signaling in AD or PD • Nerve growth factor (NGF) was discovered in the early 1950s due to its Human DRGs trophic effects on neurons (Levi-Montalcini and Hamburger, 1951) - NGF • Brain-derived neurotrophic factor (BDNF) was initially purified from pig brain (Barde et al., 19
Slide 4: BDNF signaling is a genetically validated pathway in AD and PD
BDNF signaling is a genetically validated pathway in AD and PD BDNF Val66Met heterozygotes Met allele - 30% reduction in BDNF secretion Prevalence: 37% of Caucasians, up to 70% of Asians Familial AD Sporadic AD Cognition in PD § Impaired memory performance, § Increased rates of decline § Conflicting
Slide 5: ACD856, study outline
ACD856, study outline q Objectives • There are numerous studies demonstrating that neurotrophins such as NGF and BDNF are important for cognitive function. The genetic linkage between BDNF and cognitive dysfunction in AD and PD also strongly support the development of positive modulators of neurotro
Slide 6: Discovery of ACD855 and ACD856
Discovery of ACD855 and ACD856 27,000 cmpds of 150,000 HTS completed in 2013 at KHTC Cell-based PathHunter • Screen at @10 uM in ”PAM-mode” NGF/ TrkA – SHC1 • Rescreen 3 concentrations on 0, 1 and 10 ng/mL NGF Reiterative chemistry Cell-based PathHunter • Screen hits at @10 uM in ”PAM-mode” BDNF / T
Slide 7: Chemical series originating from hit-identification
Chemical series originating from hit- HTS identification CTA Q2 2013 Q4 2019 HTS/Hit Lead generation Lead opt. CD Preclinical dev. Clinical dev Series A 330 cmpds EC50, 10 nM EC50, in vivo efficacy on hold Series B 140 cmpds EC50 Discontinued Series C ACD855 230 cmpds EC50 , enters CNS, in vivo effi
Slide 8: Different mechanisms of action of three selected hits
Category 1 Different mechanisms of action of three selected hits Ø Category 1: Positive modulators of neurotrophin signaling with no agonistic properties Category 2 (ACD856) Ø Category 2: Positive modulators of neurotrophin signaling with low agonistic properties, includes ACD856 Ø Category 3: Parti
Slide 9: ACD855 and ACD856 In vitro pharmacology
ACD855 and ACD856 In vitro pharmacology Potentiation of LTP Ø ACD855 and ACD856 are potent enhancers of human and rodent Trk signaling § Increases phosphorylation of Trk-receptors (phospho-Trk ELISA) § Increases phosphorylation of ERK1/2 in primary cortical neurons Ø Potentiates the induction and ma
Slide 10: Peripheral administration of ACD856 leads to increased levels of neurotransmitters in the hippocampus
Peripheral administration of ACD856 leads to increased levels of neurotransmitters in the hippocampus Ø Microdialysis was performed by placing the dialysis probe in the ventral hippocampus Ø ACD856 (10 mg/kg) was administered subcutaneously at t=0 min to freely moving rats Ø The levels of noradrenal
Slide 11: ACD855 and ACD856 attenuates memory impairment in a fear conditioning model
ACD855 and ACD856 attenuates memory impairment in a fear conditioning model in a TrkB-dependent manner Ø ACD855 and ACD856 reverses scopolamine or MK-801 induced memory impairment Ø No effect of the compounds itself on motor activity or on cognition in young naïve mice Ø Lowest dose of ACD856 with s
Slide 12: ACD856 affects different phases of memory formation
ACD856 affects different phases of memory formation ACD856 improves both acquisition, consolidation and retrieval of long-term memories Copy right AlzeCure Pharma AB, Sweden; All rights reserved. 12
Slide 13: ACD856 improves long-term memory in old mice
ACD856 improves long-term memory in old mice Ø Young animals retained a good memory up to 11-days post-training, addressed using a fear conditioning model Ø Old animals displayed impaired memory 24 hours after training which was statistically significant 11-days post-training Ø ACD856 could fully re
Slide 14: ACD856 is efficacious in a model of depression, forced swim test/Porsolt test
ACD856 is efficacious in a model of depression, forced swim test/Porsolt test Ø BDNF signaling has been implicated in depression Ø ACD856 was compared to Fluoxetine (SSRI) using the Forced Swim Test Ø ACD856 at 1 mg/kg demonstrates similar effect as Fluoxetine 20 mg/kg in both FSL-rats and in mice A
Slide 15: ACD856 shows favorable pharmacokinetic profile in multiple species
ACD856 shows favorable pharmacokinetic profile in multiple species Ø ACD855 demonstrated unexpectedly long-half life in man Ø ACD856 shows significantly shorter half-life than ACD855 in mice, rats and mini-pigs Oral administration of ACD855 in rats Oral administration of ACD856 in rats The half-life
Slide 16: ACD856 – DMPK, Safety pharmacology and Toxicology evaluation
ACD856 – DMPK, Safety pharmacology and Toxicology evaluation • Pharmacokinetic properties • ACD 856 demonstrates favourable pharmacokinetic properties (mice, rats and minipigs), high bioavailability,, high brain/plasma ratio with high enough exposure in brain • Safety pharmacology • ACD856 demonstra
Slide 17: Plans forward for ACD856
Plans forward for ACD856 ■ Clinical phase 1 studies will be initiated at the end of 2020 § Regular single ascending dose (SAD) study § Multiple ascending dose (MAD) study • The MAD-study will include an extension/cohort to look for pharmacodynamic effects in healthy volunteers with scopolamine-induc
Slide 18: Summary
Summary ■ ACD856 is more potent in vitro and in vivo than its predecessor ACD855 ■ ACd856 is a positive modulator of neurotrophin signaling ■ ACD856 significantly increases the levels of serotonin in the hippocampus ■ ACD856 attenuates scopolamine-induced cognitive impairment ■ ACD856 fully reverses
Slide 19: Acknowledgements
Acknowledgements Märta Dahlström, in vitro/ in vivo Department of Neurobiology, Care Nather Madjid, in vivo Sciences and Society Cristina Parrado, in vitro Prof Bengt Winblad Maria Backlund, ADME Assoc. Prof Maria Lindskog Veronica Lindell, in vivo Erika Vazquez-Juarez, Ph.D. Johan Sandin, in vivo M
Slide 20: Thank you!
Thank you! Questions? You can find us on LinkedIn Pontus Forsell or Martin Jonsson You can also e-mail any questions directly to: Pontus.Forsell@alzecurepharma.com Martin.Jonsson@alzecurepharma.com Copy right AlzeCure Pharma AB, Sweden; All rights reserved. 20