Alzecure Pharma Ab · OMXSTO:ALZCUR
Alzecure Pharma Ab — Investor Day (May 2023)
69 slides from Alzecure Pharma Ab's investor day presentation, May 17, 2023
Slide 1: Market Update on Alzheimer's & AlzeCure's Alzheimer's projects
May 17, 2023 V SS e= Market Update - On Alzheimer’s & AlzeCure’s Alzheimer's proje cts
Slide 2: Speakers' experiences
EXPERIENCES Bengt › Professor in Geriatrics and Aging at Karolinska Institute (KI) Winblad › Education: MD, PhDs from Umeå University MD, Ph.D, Professor at KI › Research focus on treatment & care of dementia with focus on Alzheimer's Johan Sandin › Expert in in vivo Pharmacology with 16 years exper
Slide 3: Agenda
• 10:00 Welcome address & agenda – Martin Jönsson, CEO, AlzeCure • 10:02 AlzeCure Pharma: Overview, vision & update – Martin Jönsson, CEO, AlzeCure • 10:10 Alzheimer’s disease; Challenges & Opportunities – Professor Bengt Winblad, M.D., PhD, Karolinska Institute • 10:25 Alzstatin: Background & evolu
Slide 4: AlzeCure Pharma overview
➢ Working in Alzheimer’s Disease (AD) and Pain – Hugh unmet medical need & multi-billion sales potential ➢ Spin-out from AstraZeneca – as a result of their exit from the CNS area ➢ Founded in 2016, out of a research foundation sponsored by Alzheimerfonden ➢ Experienced team with extensive background
Slide 5: R&D company with out-license or partner model
• We are a Research & Development company • Research & develop through early clinical phase and then to out-license or partner on our projects • Gain incomes through: − Upfront payments − Milestone payments − Royalties on sold products 5
Slide 6: Small molecules vs large biologics
DIFFERENCES BETWEEN SMALL MOLECULES & BIOLOGICS* SMALL MOLECULE LARGE BIOLOGIC DRUG Additional benefits: - Oral medications - Low production costs - … AlzeCure focus Monoclonal antibody Small molecule drug c. 25,000 atoms Smaller molecules can have increased likelihood of penetrating the Blood Brain
Slide 7: Pipeline: multiple candidates increase chance of success
– Multiple candidates increase chance of success Platform Candidate MoA Indication Research Preclinical Phase I Phase II Phase III NeuroRestore® Alzheimer’s Disease, Positive read-out Phase I trial Positive allosteric Sleep disorders, TBI ACD856 modulator (PAM) Parkinson’s disease, Safety, Tolerabil
Slide 8: Developments in the Alzheimer's field
• Validation of the amyloid hypothesis • Positive out-comes in clinical trials, incl in phase III • New products being approved • Vastly improved biomarkers & diagnostics • Additional Big Pharma companies entering the field • More funds and private equity investment in companies and projects • …
Slide 9: Meeting needs of AD patients: Alzstatin and NeuroRestore
MEETING NEEDS OF AD PATIENTS – ADRESSING SHORT TERM NEEDS WITH LONG-TERM BENEFITS Disease-modifying therapy Symptomatic & pot. Disease-modifying therapy Alzstatin® NeuroRestore® MoA: Gamma-secretase modulator MoA: Trk-PAM Targeting Amyloid Production Improving Cognitive Function - Novel Oral Small M
Slide 10: Karolinska Institutet Novum Science Park
Karolinska Institutet Novum Science Park Hälsovägen 7, 141 57 Stockholm SWEDEN www.alzecurepharma.com
Slide 11: Alzheimer's disease; Challenges & Opportunities
Alzheimer’s disease; Challenges & Opportunities Bengt Winblad, Professor Karolinska Institutet Dept NVS Center for Alzheimer Research Div of Neurogeriatrics AlzeCure, Solna, Sweden May 17, 2023
Slide 12: Dementia prevalence globally and in Sweden
Dementia prevalence globally and in Sweden Globally, more than 55 million people have dementia, of which Alzheimer disease may contribute to 60–70% of cases. - Every year, there are nearly 10 million new cases. Sweden: ▪ 150 000 persons with dementia, out of which -120 000 with Alzheimer disease, (9
Slide 13: Alzheimer's disease: genetic and environmental factors
Alzheimer’s disease Genetic factors Environmental /life style factors Mutations Genetic risk factors • APP (Chr 21) • ApoE4 (Chr 19) • Diet • Presenilin 1 (Chr 14) • Cholesterolemi • Presenilin 2 (Chr 1) • Hypertoni • Physical inactivity Amyloid beta plaques Sporadic AD Familial AD • 95-99 % of all
Slide 14: Therapy in AD: The first hundred years
Therapy in AD: The first hundred years and looking forward………. Memantine NMDA Uncompetitive Receptor Antagonist 1906 1910 1974 1982 1997 2004 2010 2015 2021-2023 The Acetylcholinesterase cholinergic inhibitors hypothesis First Disease Modifying Rx aducanumab & lecanemab approved by FDA in US. Donane
Slide 15: 2021 Alzheimer drug development pipeline
2021 Alzheimer drug development pipeline ➢ “Biologics” are generally derived from living organisms and include antibodies, vaccines, antisense oligonucleotides, and therapeutic proteins. ➢ “Small molecules” refers to drugs taken orally that are typically <500 daltons in size and can regulate a biolo
Slide 16: Important with early diagnosis
Important with early diagnosis! ▪ For the patient; → Explanation of symptoms → Practical future planning (eg economy, travels, retirement) → Access to treatment before too much damage, take part in clinical trials ▪ For the relatives; → Same as above → Increased understanding ▪ For society; → Patien
Slide 17: AD progress and biomarkers enables early diagnosis
AD progress and biomarkers enables early diagnosis Abnormal CSF Aβ42 Amyloid imaging FDG-PET MRI hippocampal FDG-PET volume MRI hippocampal CSF Tau volume Cognitive performance Function (ADL) CSF Aβ42 Amyloid Cognitive performance imaging Function (ADL) CSF Tau Normal Time Presymptomatic eMCI LMCI D
Slide 18: Addition of blood/plasma biomarkers
Addition of blood/plasma biomarkers C Teunissen, 2022, rev S Schedin-Weiss Bengt Winblad 18
Slide 19: Lecanemab reduced amyloid burden
Lecanemab phase 2 study showed reduced amyloid burden over 18 months (developed by BioArctic, Sweden) Global cortical average vs whole cerebellum reference PET SUVr 0.05 0.01 increase in PET Adjusted mean change from baseline (±SE) 0.00 –0.05 SUVr –0.10 IMPROVEMENT –0.15 –0.20 0.22 reduction in PET
Slide 20: Clarity AD treatment effect: CDR-SB
Clarity AD (phase 3)Treatment Effect: CDR-SB (Global Measure of Cognition and Function) Adjusted Clarity AD No. of Participants Mean % P (placebo, lecanemab) Difference Improvement Slowing Value CDR-SB Domains Favors lecanemab Memory 875, 859 -0.077 27.5 0.00117 CDR-SB Orientation 875, 859 -0.081 28
Slide 21: Donanemab: last reported positive immunotherapy study
Donanemab – last reported positive immunotherapy study ▪ Eli-Lilly, US reported in a press release May 3, 2023 positive top-line results of donanemab, from the phase 3 TRAILBLAZER-ALZ2 study ▪ Antibody treatment during 18 months targeting amyloid beta aggregates (plaques) in the brain ▪ 1,736 person
Slide 22: Lecanemab vs Donanemab
Lecanemab vs Donanemab ▪ Difference in study populations ▪ Different cognitive and ADL scales ▪ The only common scale is CDR-SB, but the outcome from this scale is also influenced by the different study populations In summary: ▪ These differences makes it difficult to properly compare the results fr
Slide 23: AlzeCure Pharma's two Alzheimer platforms
AlzeCure Pharma’s two Alzheimer platforms - 1st-in-class properties & potential game-changers Disease-modifying therapy Symptomatic therapy Alzstatin® NeuroRestore® Gamma-Secretase-Modulators Trk-PAMs Targeting Toxic Amyloid Production Improving Neuronal Function & Cognition - Novel Oral Small Molec
Slide 24: Research still needed for new treatment
Research – still needed & the only way forward to new treatment Neuroprotection Risk inhibition Other molecules (growth factors, APOE, (life style, cholesterol, (ACD856, gene therapy, autophagy, inflammation) BRICHOS etc) Beta-amyloid Tau Neprilysin activation) All patients? Treatment of New finding
Slide 25: Acknowledgement
Acknowledgement ▪ Angel Cedazo-Minguez ▪ Vesna Jelic ▪ Lars Lannfelt ▪ Anders Wimo ▪ Gunilla Johansson Bengt Winblad 2023-05-17 25
Slide 26: Alzstatin: Background & Evolution
May 17, 2023 Alzstatin® b A preventive treatment against Alzhe | / - Background & Evolution Johan Sandin, PhD, CSO, AlzeCure Pharma
Slide 27: Healthy brain vs Alzheimer's brain
Healthy brain Alzheimer’s brain 27
Slide 28: Amyloid in Alzheimer's brain
Ab amyloid Healthy brain Alzheimer’s brain 28
Slide 29: Alzheimer's disease progression
Alzstatin® – Gamma-Secretase Modulator b ALZHEIMER'S DISEASE PROGRESSION Pre-symptomatic Alzheimer Symptomatic Alzheimer 10-20 years 7-10 years Abnormal Area where the highest societal gains can be achieved, and which AlzeCure can cater to Aβ Amyloid Memory Tau Mediated Brain Injury & Structure Clin
Slide 30: Alzstatin gamma-secretase modulator
Alzstatin® – gamma-secretase modulator b Alzstatin® modulates the enzyme, alter its cleaving pattern and thereby limits the aggregation Aggregation X X Ab42 - main culprit in Alzheimer progression Alzstatin® targets the gamma- secretase as a modulator - does not block enzyme activity 30
Slide 31: Antibodies bind and clear aggregated Ab peptides
Alzstatin® – Gamma-Secretase Modulator Ab Antibodies bind and clear aggregated Ab peptides. 31
Slide 32: GSMs inhibit formation of Ab aggregates
Alzstatin® – Gamma-Secretase Modulator Aβ X GSM’s inhibits the formation of all Ab aggregates 32 32 *) GSM = Gamma Secretase Modulator
Slide 33: GSMs increase shorter protective Ab fragments
Alzstatin® – Gamma-Secretase Modulator Aβ X GSM’s increase formation of shorter protective Ab fragments 33 33 *) GSM = Gamma Secretase Modulator
Slide 34: Alzstatin: Gamma-Secretase Modulator
Alzstatin® – Gamma-Secretase Modulator b 34
Slide 35: Alzstatin reduces toxic Ab42 and Ab40
Alzstatin® – Gamma-Secretase Modulator b Alzstatin reduces toxic Ab42 and Ab40, while No effect on total Ab increasing protective Ab38 and Ab37 peptides Consistent with a GSM 35
Slide 36: Alzstatin reduces brain Ab42 in mice
Alzstatin® – Gamma-Secretase Modulator 120 100 Control Control 80 GSI Semagacestat ( 1 uM) 60 40 GSM cmpd ACD678 (3 uM) 20 0 C99-GVP Notch1DE- EphB2-GVP EphA4-GVP GVP Other proteins that are cleaved by gamma-secretase 0 30 100 200 µmol/kg Alzstatin potently reduces the Alzstatin compounds do not aff
Slide 37: Small molecule therapy benefits
Alzstatin® – Gamma-Secretase Modulator Small molecule therapy Oral formulation => Home treatment • Small molecules generally pass much more readily • Don’t need to go to the hospital once or twice a across the BBB to its target site - the brain month for an infusion of the drug • Provides a more cos
Slide 38: Clinical PoM and target engagement in Phase I
Alzstatin® – Gamma-Secretase Modulator • Clinical PoM and central target engagement already in Phase I − SAD/MAD studies conducted in healthy volunteers − Evaluation of safety and tolerability after single and repeated administration − Possibility to explore biomarker effects showing central target
Slide 39: Preventive and maintenance therapy
Alzstatin® – Gamma-Secretase Modulator Preventive therapy based on genetic risk factors* and biomarkers • Early stand-alone treatment before onset of symptoms and any major neurodegeneration occurs • Prevents build-up of amyloid – an early pathological feature of AD • Suitable for preventive therapy
Slide 40: Preventive and maintenance therapy
Alzstatin® – Gamma-Secretase Modulator Preventive therapy based on genetic risk factors* and biomarkers • Early stand-alone treatment before onset of symptoms and any major neurodegeneration occurs • Prevents build-up of amyloid – an early pathological feature of AD • Suitable for preventive therapy
Slide 41: Main known competitors
Alzstatin® – Gamma-Secretase Modulator Main known competitors: − UCSD-776890 (Steven Wagner)/NIH – Phase 1 − Roche RG6289 – Phase 1 Published data on Pfizer’s PF-06648671 show that GSM’s can display both potent efficacy and good safety in man. → Development stage of Alzstatin in line with competitor
Slide 42: Advantages with Alzstatin
Alzstatin® – Gamma-Secretase Modulator Advantages with Alzstatin ✓ Reduces amyloidogenic Aβ42 production ✓ Increase the shorter peptides Aβ37 and Aβ38 - suggested to have protective properties ✓ Do not affect the total amount of Aβ – thus any physiological function likely not affected ✓ Mode of acti
Slide 43: Team and collaborators
• Team at Alzecure Pharma • Karolinska Institutet − Gunnar Nordvall − Prof. Bengt Winblad − Boel Nilsson − Assoc. Prof. Lars Tjernberg − Maria Backlund − Azita Rasti • Göteborgs Universitet − Märta Dahlström − Prof. Henrik Zetterberg − Magnus Halldin − Lotta Agholme, PhD − Veronica Lidell − Stefanie
Slide 44: Karolinska Institutet Novum Science Park
Karolinska Institutet Novum Science Park Hälsovägen 7, 141 57 Stockholm SWEDEN www.alzecurepharma.com
Slide 45: NeuroRestore ACD856: Background & data supporting disease modification
May 17, 2023 NeuroRestore ACD856 jo SS Background & data supporting disedse modi
Slide 46: 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 47: ACD856 enhances neurotrophin signaling
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 48: In vitro and in vivo effects
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 49: Symptomatic and disease-modifying therapy
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 50: The life and death of a neuron
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 51: ACD856 protective against Ab1-42 neurotoxicity
NeuroRestore® – positive allosteric modulator of Trk-receptors • Vehicle (DMSO) or Ab1-42 was added to neurons, with or without ACD856 • The neuronal content of a synaptic protein (SNAP25) was quantified by microscopy ACD856 + Ab1-42 Ab1-42 51 ACD856 is protective against Ab1-42-induced neurotoxicit
Slide 52: In vitro and in vivo effects
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 53: ACD856 increases 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 54: In vitro and in vivo effects
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 55: BDNF and Alzheimer's disease
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 56: ACD856 increases BDNF levels
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 BDNF levelsincrease ACD856 in corticalBDNF neurons ACD856 increase BDNF Mean of individual experiment (n=4 +/- SD) le
Slide 57: In vitro and in vivo effects
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 58: 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 59: In vitro and in vivo effects
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 60: Sustained antidepressant-like effect
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 k
Slide 61: ACD856 effects summary
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 62: 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 63: Team and collaborators
• 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 64: AlzeCure Pharma AB
AlzeCure Pharma AB Karolinska Institutet Novum Science Park Hälsovägen 7, 141 57 Stockholm Sweden www.alzecurepharma.com info@alzecurepharma.com
Slide 65: Q&A session
Slide 66: Panel participants
EXPERIENCES Bengt › Professor in Geriatrics and Aging at Karolinska Institute (KI) Winblad › Education: MD, PhDs from Umeå University MD, Ph.D. Professor at KI › Research focus on treatment & care of dementia with focus on Alzheimer's Johan Sandin › Expert in in vivo Pharmacology with 16 years exper
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Slide 68: Concluding remarks
• Increased interest and activity level in the Alzheimer’s field - both with regard to investors and new pharma companies entering the area • Anti-bodies are very promising, slowing the disease progression, - but not curing the disease or increasing patient’s cognition • => Huge need for new more ef
Slide 69: AlzeCure Pharma AB
AlzeCure Pharma AB Karolinska Institutet Novum Science Park Hälsovägen 7, 141 57 Stockholm Sweden www.alzecurepharma.com info@alzecurepharma.com