Alector, Inc. · NASDAQ:ALEC
Alector — Technical Presentation (September 2025)
55 slides from Alector's technical presentation, September 2025
Slide 1: Alector R&D Briefing: A Review of Our Progranulin Franchise and Brain Carrier Programs
Alector R&D Briefing: A Review of Our Progranulin Franchise and Brain Carrier Programs September 2025
Slide 2: Forward-Looking Statement
Forward-Looking Statement This presentation contains forward - looking statements that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this presentation are forward - looking statements. In some cases, you can identify forward - look
Slide 3: Today's Agenda
Opening Remarks: Advancing a Multi-Stage Pipeline in Neurodegeneration 01 Sara Kenkare-Mitra, Ph.D., President and Head of 9:00 - 9:05 am PT Research and Development PGRN-Elevating Franchise for FTD-GRN and Alzheimer’s Disease 02 Sara Kenkare-Mitra, Ph.D., President and Head of 9:05 - 9:25 am PT Res
Slide 4: Alector is Positioned to Drive Near- and Long-Term Value in Treating Brain Disorders
Alector is Positioned to Drive Near- and Long- Term Value in Treating Brain Disorders Clinical Programs: o Pivotal Phase 3 data readout in FTD-GRN by mid-Q4 2025 o Phase 2 clinical trial in AD with enrollment completed in April 2025 o First-in-human clinical trial with Alector Brain Carrier expected
Slide 5: Key Programs
Key Programs Latozinemab (AL001) Antibody: Pivotal Ph 3 in FTD-GRN; Breakthrough Therapy, Fast Track, Orphan Drug Designations; Data by Mid-Q4 2025 Nivisnebart (AL101/GSK4527226) Antibody: Phase 2 in Alzheimer’s Disease; Enrollment Completed in April 2025 Anti-Aβ-Antibody-ABC: In Alzheimer’s Disease
Slide 6: Partnered Portfolio: Progranulin (PGRN)-Elevating Franchise for FTD-GRN and Alzheimer's Disease
Partnered Portfolio: Progranulin (PGRN)-Elevating Franchise for FTD-GRN and Alzheimer’s Disease Property of Alector 6
Slide 7: FTD-GRN: Frontotemporal Dementia Caused by Mutations in the GRN Gene
FTD-GRN: Frontotemporal Dementia Caused by Mutations in the GRN Gene The Disease: • Aggressive, early-onset, dementia with compulsive behavior, lack of restraint, apathy, anxiety, aphasia, and life expectancy < 10 years since diagnosis The Cause: • Heterozygous loss-of-function mutations in the GRN
Slide 8: Estimated Prevalence and Treatment Centers for FTD
Estimated Prevalence and Treatment Centers for FTD FTD is the most common cause of dementia under the age of 60, and most cases occur FTD Treatment Centers Worldwide6 between the ages of 45 and 64.1 FTD affects ~50,000 to 60,000 individuals in the U.S. and ~110,000 in the EU.2,3 FTD-GRN accounts for
Slide 9: FTD-GRN Appears To Be Underdiagnosed
FTD-GRN Appears To Be Underdiagnosed: An Opportunity for Early, Genetically Based Improved Diagnosis Diagnosis of GRN Mutation Carriers GRN (N = 1179) ~30% of FTD-GRN is misdiagnosed as dementia not otherwise specified. ~8% of FTD-GRN is misdiagnosed as Alzheimer's disease. ~2.5% of FTD-GRN is misdi
Slide 10: Latozinemab and Nivisnebart: Designed to Increase PGRN Levels by Blocking Sortilin
Latozinemab (AL001) and Nivisnebart (AL101): Designed to Increase PGRN Levels by Blocking Sortilin, a Degradation Receptor PGRN levels inversely correlate Latozinemab and nivisnebart are human monoclonal antibodies that with sortilin expression in human are designed to increase the levels of PGRN by
Slide 11: Latozinemab: Rationale for PGRN-Elevating Drugs in FTD
Latozinemab: Rationale for PGRN-Elevating Drugs in FTD Heterozygous LOF Mutations in the GRN Gene PGRN Deficiency Triggers a Multi-System Reduce PGRN and Directly Cause FTD Neurodegenerative Cascade Plasma2 Cerebrospinal fluid (CSF)2 PGRN Deficiency TDP - 43 Lysosomal Complement Inflammation Accumul
Slide 12: Nivisnebart: Rationale for PGRN-Elevating Drugs in Alzheimer's Disease
Nivisnebart: Rationale for PGRN-Elevating Drugs in Alzheimer’s Disease PGRN is a Risk Gene for AD1 PGRN is Embedded in Aβ Plaques2 PGRN is Protective in AD Model2 GRN –log10(P) Microglia (green) surround PGRN overexpression decreases Aβ amyloid plaques (blue), which plaque load in the dentate gyrus
Slide 13: Genetic and Biological Rationale for Blocking Sortilin to Elevate PGRN
Genetic and Biological Rationale for Blocking Sortilin to Elevate PGRN PGRN enters the lysosomes of SORT1-deficient cells Supporting evidence through multiple alternative receptors from genetics, biology, and experiments Genetics: Loss-of-function mutations in SORT1 • Lead to chronic elevation of PG
Slide 14: Differentiating Alector's PGRN-Elevating Antibodies
Differentiating Alector’s PGRN-Elevating Antibodies: Latozinemab and Nivisnebart Latozinemab and Nivisnebart Have a Distinct Drug Candidate Profiles Binding Epitope on SORT1 3D CRYSTALLOGRAPHY STRUCTURE OF SORT1 Latozinemab and nivisnebart are human anti- SORT1 antibodies. PK/PD profile distinguishe
Slide 15: INFRONT-2 Open-Label Phase 2 Trial with Latozinemab
INFRONT-2 Open-Label Phase 2 Trial with Latozinemab Symptomatic FTD-GRN (N=12), Latozinemab 60 mg /kg q4w for 49 weeks Key biomarkers and clinical outcome assessments reflect underlying disease activity in FTD-GRN patients TARGET ENGAGEMENT BIOMARKERS CLINICAL BENEFIT PGRN Lysosomal Brain Clinical O
Slide 16: INFRONT-2: Latozinemab Restores PGRN in Plasma and CSF
INFRONT-2: Latozinemab Restores PGRN in Plasma and CSF to Levels Seen in Healthy Volunteer Age - Matched Controls ACHIEVED PGRN RESTORATION IN FTD -GRN PARTICIPANTS PGRN Plasma Concentration PGRN CSF Concentration Correlation of PGRN CSF vs. Plasma Pearson R=0.79, p<0.0001 Samples collected post-tre
Slide 17: INFRONT-2: Latozinemab Treatment Decreases GFAP Levels
INFRONT-2: Latozinemab Treatment Decreases Glial Fibrillary Acidic Protein (GFAP) Levels Towards Range Seen in Asymptomatic Carriers of FTD-GRN Mutation BIOMARKERS OF DISEASE ACTIVITY – ASTROGLIOSIS GFAP Plasma Concentration GFAP CSF Concentration Symptomatic GRN mutation carriers were injected with
Slide 18: INFRONT-2: Preliminary Data Suggests Latozinemab May Slow Disease Progression
INFRONT-2: Preliminary Data Suggests Latozinemab May Slow Disease Progression in FTD-GRN Participants Compared to Matched Historical Controls CLINICAL OUTCOME ASSESSMENT CDR® plus NACC FTLD-SB2 -3.0 Parameter Estimate1 95% CI Annual Change 6.4 [4.35,8.42] [4.32,8.45] CDR® plus NACC FTLD-SB 0 in GENF
Slide 19: Latozinemab: Pivotal Phase 3 INFRONT-3 Study Design
Latozinemab: Pivotal Phase 3 INFRONT-3 Study Design LATOZINEMAB IS THE MOST ADVANCED CANDIDATE IN DEVELOPMENT FOR FTD -GRN 1 , WITH PIVOTAL DATA EXPECTED BY MID -Q4 2025 Part 1 Study Randomization Completion Visit Randomized, Double-Blinded, Placebo-Controlled Study 103 symptomatic and 16 at-risk FT
Slide 20: Nivisnebart: Phase 2 PROGRESS-AD Study Design
Nivisnebart: Phase 2 PROGRESS-AD Study Design RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE T HE EFFICACY AND SAFETY NIVISNEBART IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE Completed Enrollment in April 2025 Up to 12 weeks 76-Week Treatment Period with an Independent Interim Analysis
Slide 21: Latozinemab and Nivisnebart: Currently Partnered in a Collaboration Agreement
Latozinemab and Nivisnebart: Currently Partnered in a Collaboration Agreement $700M upfront $1.5B in potential U.S. 50/50 profit Tiered double - $160M for first $90M for first (2021 and 2022) milestone payments share and co - digit royalties (ex commercial sale in commercial sale in commercializatio
Slide 22: Alector Brain Carrier (ABC) Platform
Alector Brain Carrier (ABC) Platform Property of Alector 22
Slide 23: Alector's Versatile Drug Configurations Are Tailored to the Cargo
Alector’s Versatile Drug Configurations Are Tailored to the Cargo Versatile Configurations, Orientations and Size of Linkers That Are Optimal for the Cargo Antibody Cargo Enzyme Cargo Nucleic Acid Cargo Therapeutic Therapeutic Enzyme Brain arm arm cargo Carrier Nucleic Acid Cargo Adaptable Adaptable
Slide 24: Adaptable TfR Binding Affinities and Effector Functions for a Variety of Cargos
Adaptable TfR Binding Affinities and Effector Functions for a Variety of Cargos ABC Displays Affinity-Dependent TfR Binding Affinities Tailored to Drug 500-Fold Affinity Range Tailored to Internalization Into Human Brain Modalities and Antibody Effector Antibodies, Enzymes, and siRNA Endothelial Cel
Slide 25: Alector's TfR ABC Reduces TfR-Mediated ADCC
Alector’s TfR ABC Reduces TfR-Mediated ADCC: A Measure for Reticulocytes Depletion Structure of The Human Transferrin Receptor Bound to TfR TfR and Antibody-Dependent Cell Cytotoxicity (ADCC) and Binding Epitopes of Distinct BBB Approaches Are Determined by the TfR Binding Epitope and Affinity Alect
Slide 26: Research and Preclinical Programs
Research and Preclinical Programs: Remove toxic proteins and Replace deficient proteins using advanced technology Establish Alector Brain Carrier (ABC) Technology Across Modalities Antibodies + ABC Removing Aβ Removing Tau Enzymes + ABC Replacing GCase siRNAs + ABC Removing Tau Removing α-Synuclein
Slide 27: AL037: ABC-Enabled Anti-Aβ Antibody for Alzheimer's Disease
AL037: Alector Brain Carrier (ABC)—Enabled Anti-Aβ Antibody for Alzheimer's Disease Property of Alector 27
Slide 28: Design of AL037: ABC-Enabled Anti-Aβ Antibody
Design of AL037: ABC-Enabled Anti-Aβ Antibody Targeted Design Features 1 Engineered Selectivity Anti-PyroGlu3 Aβ • Engineered high-affinity, fully human antibody that Binding Epitope selectively binds toxic Aβ plaques Potency • Fully active constant region enabling effective Fully Active recruitment
Slide 29: ABC-Dependent Transcytosis of AL037 in Human Brain Endothelial Cells
ABC-Dependent Transcytosis of AL037 in Human Brain Endothelial Cells AL037-Naked AL037 2 Hour Pulse with 4 Hour Chase and Assessment Antibody of Antibody Levels 500 nM 125 nM 31.25 nM AL037-Naked (without the ABC platform) or AL037 at various concentrations were incubated on hCMEC/D3 cells for 2 hou
Slide 30: AL037 Facilitates Phagocytosis of PyroGlu3 Aβ by Human Microglia
AL037 Facilitates Phagocytosis of PyroGlu3 Aβ by Human Microglia Fluorescent Imaging (red) of PyroGlu3 AL037-Dependent Phagocytosis of PyroGlu3 Aβ by Aβ Phagocytosed by Microglia in 24h Human IPSC Microglia in Culture PyroGlu3 Aβ only huIgG iMicroglia Aβ -naked AL037 - Naked AL037 AL037-Naked (witho
Slide 31: AL037 Surrogate Binds To and Reduces Amyloid Plaque in the Mouse Brain
AL037 Surrogate Binds To and Reduces Amyloid Plaque in the Mouse Brain MOUSE Iso Control Iso mTfR AL037-mTfR AL037-mTfR Reduction in Brain Aβ42 50 mg/kg 5 mg/kg 5 mg/kg 3D Reconstruction in AL037 Surrogate-dosed Mice p=0.035 50 mg/kg Q7Dx3 5 mg/kg Q7Dx3 Plaque specific binding of AL037 Light sheet m
Slide 32: AL037 Displays Favorable Serum Pharmacokinetics in NHP
AL037 Displays Favorable Serum Pharmacokinetics in NHP NHP AL037 Displays an Estimated Serum Half-life of 106h AL037-Naked 30 mg/kg AL037 30 mg/kg Concentration (ug/mL) AL037-Naked 3 mg/kg AL037 3mg/kg Half-Life AL037-Naked 192h Timepoint (hours) AL037 106h Three NHP per group were injected on days
Slide 33: AL037 Impact on Reticulocytes RBC and Hemoglobin
AL037 Impact on Reticulocytes RBC and Hemoglobin NHP Reticulocyte Counts Red Blood Cell Counts Were Hemoglobin Levels Were Quickly Recover Not Affected Not Affected RBC % change from baseline Hemoglobin % change from baseline AL037-Naked 3 mg/kg AL037 3 mg/kg AL037-Naked 30 mg/kg AL037 30 mg/kg Thr
Slide 34: ABC Enhances Brain Uptake of AL037
ABC Enhances Brain Uptake of AL037 NHP Frontal Cortex Hippocampus AL037 at 3mg/kg reached 3.8nM in vessel containing 8x 14x frontal cortex, comparing favorably with other brain carriers (~5X higher)* 18x 18x AL037-Naked AL037 AL037-Naked AL037 AL037-Naked AL037 AL037-Naked AL037 3 mg/kg 3 mg/kg 30
Slide 35: ABC Enhances Brain Uptake of AL137: A Second Anti-Aβ Antibody Lead
NHP ABC Enhances Brain Uptake of AL137: A Second Anti-Aβ Antibody Lead Frontal Cortex Hippocampus AL137 at 3mg/kg reached 15x 8.4nM in vessel containing frontal cortex, comparing favorably with other brain 8x carriers (~12X higher)* Estimated Half-Life ~65 h 29x 32x AL137-Naked AL137 AL137-Naked AL
Slide 36: Summary and Conclusion
Summary and Conclusion A l z h e i m e r ’s D i s e a s e I m p a c t : • Approximately 24 million people worldwide affected by Alzheimer’s disease1 • Aβ pathology remains a key driver of disease progression • Significant unmet need for safe, effective, and convenient anti-amyloid therapies enabled
Slide 37: AL050: ABC-Enabled GCase ERT for Parkinson's Disease
AL050: Alector Brain Carrier (ABC)—Enabled GCase ERT for Parkinson's Disease Property of Alector 37
Slide 38: GBA1 Gene Mutations Are a Major Risk Factor for Neurodegenerative Diseases
GBA1 Gene Mutations Are a Major Risk Factor for Neurodegenerative Diseases GBA1 mutations lead to reduced GCase enzyme activity and toxic substrate accumulation (GlcCer and GlcSph) in the brain. No therapy has effectively restored GCase activity in the brain: Current GCase enzyme replacement therapy
Slide 39: Rationale for GCase ERT in Parkinson's Disease
Rationale for GCase ERT in Parkinson's Disease Parkinson’s Disease Patients with Lower CSF Parkinson’s Disease Patients with Higher CSF Toxic GCase Activity at Diagnosis Progress Faster Substrate Levels at Diagnosis Progress Faster These Findings Support the Hypothesis that Brain Penetrant GCase ERT
Slide 40: Optimized Design of AL050: ABC-Enabled GCase ERT
Optimized Design of AL050: ABC-Enabled GCase Enzyme Replacement Therapy (ERT) Engineered GCase Targeted Design Features 1 with Improved Potency 3 Activity and Stability • Engineered enzyme that is more active and Optimal TfR stable than the WT enzyme and effectively Epitope and enters the brain Opti
Slide 41: AL050 Affinity Was Optimized for Cell Rescue and Lysosomal Uptake
AL050 Affinity Was Optimized for Cell Rescue and Lysosomal Uptake GCase-ABC Is Delivered to the Lysosomes Ability of AL050 to Rescue GCase Activity in GBA1- / - of GBA1- / - Neuroblastoma Cells Neuroblastoma Cells Is TfR-Affinity-Dependent Overlay tGCase-ABC TfR Affinity Isotype Low EEA-1 LAMP-1 Hig
Slide 42: AL050 Displays ~10 Fold Longer Half-Life in NHP Plasma
AL050 Displays ~10 Fold Longer Half-Life in NHP Plasma Compared to NHP Current GCase ERTs AL050 Displays Plasma Half-Life of ~5 hours Current GCase ERTs Display Protein Half-Life in NHPs of 5 to 30 Minutes in Plasma Imiglucerase: Displays terminal t½ up to for ~20–30 min in human patients Taliglucer
Slide 43: AL050 Displays ~40 Fold Longer Enzymatic Activity in NHP Plasma
AL050 Displays ~40 Fold Longer Enzymatic Activity in NHP Plasma NHP Compared to Current GCase ERTs AL050 Displays GCase Enzymatic Activity Current GCase ERTs Display Enzymatic Activity Half-Life of ~6.6 hours in NHP Plasma Half-Life of 4 to 10 Minutes in Plasma Imiglucerase: T½ Enzymatic Activity 3.
Slide 44: AL050 Did Not Negatively Impact Reticulocytes, RBC Count or Hemoglobin
AL050 Did Not Negatively Impact Reticulocytes, RBC Count or NHP Hemoglobin Levels Reticulocyte Counts in Red Blood Cell Counts Were Not Hemoglobin Levels Were Not Normal Range Affected Affected Three NHP per group were injected on days 1 and 8 (vertical lines). Blood samples were analyzed for reticu
Slide 45: ABC Enhances Brain Delivery of Engineered GCase Cargo by 5- to 19-Fold
NHP ABC Enhances Brain Delivery of Engineered GCase Cargo by 5- to 19-Fold Frontal Cortex Hippocampus Substantia Nigra Putamen X5 X10 X6 X19 ** * * * Three NHP per group were injected on days 1 and 8. Brain tissues were collected 24 hours after the second injection and drug levels were measured in t
Slide 46: AL050 Increases GCase Activity in the Brain of NHPs by >2-Fold
NHP AL050 Increases GCase Activity in the Brain of NHPs by >2-Fold Frontal Cortex Hippocampus Substantia Nigra Putamen 132% Increase 112% Increase 63% Increase 124% Increase Three NHP per group were injected on days 1 and 8 and brain tissues were collected 24 hours after the second injections. GCase
Slide 47: AL050 Surrogate Rescues GCase Activity in Peripheral Tissues of Gba1-Mutant Mice
MOUSE AL050 Surrogate Rescues GCase Activity and Reduces Toxic Substrate Accumulation in Peripheral Tissues of Gba1-Mutant Mice Liver GCase Activity is Rescued 24h Liver GlcSph Levels are Reduced by 87% 24h After Injection After a Single Dose of AL050-TfR-Surrogate - 87% Wild-type or Gba1-mutant mic
Slide 48: AL050 Surrogate Rescues Brain GCase Activity in Gba1-Mutant Mice
AL050 Surrogate Rescues Brain GCase Activity and Reduces Toxic MOUSE Substrate Accumulation in the Brain of Gba1-Mutant Mice GCase-ABC Increases Brain GCase GCase-ABC Reduces GlcSph by ~80% 8dpi Durable Reduction in Brain GlcSph +95% - 78% Wild-type or Gba1-mutant mice were injected once (left, righ
Slide 49: Summary and Conclusion
Summary and Conclusion GBA1 Gene Mutation Impact: • Up to 1 million Parkinson’s disease (PD) cases are associated with GBA1 gene mutations • Up to 2.4 million Lewy body dementia (LBD) cases are associated with GBA1 gene mutations • Approximately 125,000 Gaucher disease (GD) cases are caused by GBA1
Slide 50: Alector Brain Carrier (ABC)-Enabled siRNA Programs
Alector Brain Carrier (ABC)—Enabled siRNA Programs Property of Alector 50
Slide 51: SiRNA-ABC: Designed to Support Effective Brain Distribution with Peripheral Delivery
SiRNA-ABC: Designed to Support Effective Brain Distribution with Peripheral Delivery POTENTIAL FOLD BRAIN PA R A M E T E R S T E S T E D PHARMACOKINETICS A D V A N TA G E S P E N E T R AT I O N Long Plasma half-life Safer than IT, ICV ~1,000-fold range of TfR delivery affinities Multiple drug config
Slide 52: Peripheral Delivery of SOD1 siRNA-ABC: 50-80% Knockdown Across Multiple Brain Structures
Peripheral Delivery of SOD1 siRNA-ABC: 50-80% Knockdown Across Multiple Brain Structures Thalamus Cortex Hippocampus Brain Stem Cerebellum Spinal Cord Striatum 4 mice per group were injected either IV at days 1, 8, 15, 22 or one ICV at day 1 with 5 mg/kg siRNA-dose-equivalent and the level of Sod1 m
Slide 53: Developing a Platform of siRNA-ABC Drugs
Developing a Platform of siRNA-ABC Drugs Tau-siRNA-ABC: For Alzheimer’s Disease and Frontotemporal Dementia Syn-siRNA-ABC: For Parkinson’s Disease and Lewy Body Dementia NLRP3-siRNA-ABC: For Multiple Neurodegenerative Diseases Proprietary and Confidential Property of Alector 53
Slide 54: Alector is Focused on Opportunities to Drive Near- and Long-Term Value
Alector is Focused on Opportunities to Drive Near- and Long- Term Value Alector’s Current Focus & Priority Goals FUTURE POTENTIAL T O E X PA N D P O R T F O L I O A DVA N C E P R O G R A M S • Novel 3R (Replace, Remove, Restore) TO CLINIC drugs for degenerative brain disorders D E L I V E R L AT E -
Slide 55: Thank You
Wik Thank You