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Alector R&D Briefing: A Review of Our Progranulin Franchise and Brain Carrier Programs September 2025
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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 - looking statements by terminology such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potentially,” “predict,” “should,” “will” or the negative of these terms or other similar expressions. Forward - looking statements contained in this presentation also include, but are not limited to, statements regarding: our future financial condition, including the sufficiency of cash to fund operations into the second half of 2027; results of operations; business strategy and plans; the beneficial characteristics, safety, efficacy, and therapeutic effects of our product candidates; the properties of our Alector Brain Carrier platform; our plans, timelines and expectations related to our Alector Brain Carrier platform, research and preclinical programs, and product candidates , including with respect to the availability of data, the initiation of future clinical trials and plans and expectations regarding planned regulatory filings with respect to such programs; expectations regarding the timing and financial benefit of our collaborations; and objectives of management for future operations, as well as statements regarding industry trends. We, Alector, Inc. (“Alector”), have based these forward - looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward - looking statements are subject to a number of risks, uncertainties and assumptions, including, among other things: Alector’s plans relating to its research programs, preclinical and clinical development programs and the development and manufacturing of its product candidates and blood - brain barrier technology platform; the ability of Alector’s clinical trials to demonstrate safety and efficacy of its product candidates, and other positive results; the timing and focus of Alector’s clinical trials, and the reporting of data from those trials, including the anticipated timing and detail regarding the release of data for INFRONT - 3 and PROGRESS - AD; Alector's plans relating to commercializing its product candidates, if approved, including the geographic areas of focus and sales strategy; the expected potential benefits of strategic collaborations with third parties and Alector's ability to attract collaborators with development, regulatory and commercialization expertise; Alector’s estimates of the number of patients in the United States, the European Union and world - wide who suffer from the diseases it is targeting and the number of patients that will enroll in its clinical trials; the anticipated timing of enrollment in its clinical trials; the size of the market opportunity for Alector’s product candidates in each of the diseases it is targeting; Alector’s ability to expand its product candidates into additional indications and patient populations; the success of competing therapies that are or may become available; the beneficial characteristics, safety, efficacy, and therapeutic effects of Alector’s product candidates; the timing or likelihood of regulatory filings and approvals, including Alector’s expectation to seek special designations, such as orphan drug designation, for its product candidates for various diseases; Alector’s ability to obtain and maintain regulatory approval of its product candidates; Alector's plans relating to the further development and manufacturing of its product candidates, including additional indications that it may pursue; existing and future regulations and regulatory developments in the United States and other jurisdictions; Alector’s reliance on third parties to conduct clinical trials of its product candidates, and for the manufacture of its product candidates for preclinical studies and clinical trials; the impact of worldwide economic conditions, including macroeconomic downturns stemming from increased inflation, supply chain and other economic impacts of the coronavirus (COVID - 19) pandemic and geopolitical events on our business; and the other risks, uncertainties and assumptions discussed in the public filings we have made and will make with the Securities and Exchange Commission (“SEC”). These risks are not exhaustive. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward - looking statements. You should not rely upon forward - looking statements as predictions of future events. Although we believe that the expectations reflected in the forward - looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. This presentation also contains results based on data from our clinical trials. These clinical trials are ongoing and this presentation does not speak to, and you should make no assumptions about, any additional data. In addition, the information we have chosen to publicly disclose regarding our product candidates has been selected from a more extensive amount of available information. You or others may not agree with what we determine is the material or otherwise appropriate information to include in our disclosure, and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions, conclusions, views, activities or otherwise. If the initial data that we report differ from updated, late, final or actual results, or if others, including regulatory authorities, disagree with the conclusions reached, our ability to obtain approval for, and commercialize our product candidates may be harmed, which could harm our business, financial condition, results of operations and prospects. This presentation discusses certain investigational therapeutic agents which have not yet been approved for marketing by the U.S. Food and Drug Administration. No representation is made as to the safety or effectiveness of our product candidate for the therapeutic use for which it is being studied. This presentation contains statistical data based on independent industry publications or other publicly available information, as well as other information based on our internal sources. We have not independently verified the accuracy or completeness of the data contained in these industry publications and other publicly available information. Accordingly, we make no representations as to the accuracy or completeness of that data. Except as required by law, we undertake no obligation to update any statements in this presentation for any reason after the date of this presentation. We have filed Current Reports on Form 8 - K, Quarterly Reports on Form 10 - Q, Annual Reports on Form 10 - K, and other documents with the SEC. You should read these documents for more complete information about us. You may obtain these documents for free by visiting EDGAR on the SEC website at www.sec.gov. 2 Forward-Looking Statement Property of Alector
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Today’s Agenda 3 01 Opening Remarks: Advancing a Multi-Stage Pipeline in Neurodegeneration Sara Kenkare-Mitra, Ph.D., President and Head of Research and Development 02 PGRN-Elevating Franchise for FTD-GRN and Alzheimer’s Disease Sara Kenkare-Mitra, Ph.D., President and Head of Research and Development 03 Progressing Our Wholly-Owned, Versatile Alector Brain Carrier Technology Platform Arnon Rosenthal, Ph.D., Chief Executive Officer 04 Alector Brain Carrier–Enabled Programs: Delivering Antibodies, Enzymes, and siRNA Across the BBB Arnon Rosenthal, Ph.D., Chief Executive Officer 9:00 - 9:05 am PT 9:05 - 9:25 am PT 9:25 - 9:40 am PT 9:40 - 10:00 am PT 05 Closing Remarks and Q&A Arnon Rosenthal, Ph.D., Chief Executive Officer 10:00 - 10:30 am PT Property of Alector
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Alector is Positioned to Drive Near- and Long- Term Value in Treating Brain Disorders Property of Alector Well Resourced & Global Partnership: o Experienced leadership o Profit-sharing collaboration with commercial rights for multiple programs o Over $300M in cash provides runway into 2H 2027 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 in 2026 o Selected lead candidates for brain-penetrant anti-Aβ antibody o Selected lead candidate for brain-penetrant GCase ERT o Advancing brain-penetrant siRNA programs targeting tau, α-Synuclein and NLRP3 Innovative Science with 3R Strategy and Advanced Technologies: Remove - Misfolded Proteins Replace - Dysfunctional Proteins Restore - Dysfunctional Immune Cells and Neurons 4
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Proprietary and Confidential Property of Alector 5 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; Targeting Initiation of First-in-Human Trial in 2026 GCase-ERT-ABC: In Parkinson’s Disease Tau-siRNA-ABC: In Alzheimer’s Disease αSyn-siRNA-ABC: In Parkinson’s Disease NLRP3-siRNA-ABC: In Multiple Neurodegenerative Diseases Property of Alector
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6Property of Alector Partnered Portfolio: Progranulin (PGRN)-Elevating Franchise for FTD-GRN and Alzheimer’s Disease
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7 T h e D i s e a s e : • Aggressive, early-onset, dementia with compulsive behavior, lack of restraint, apathy, anxiety, aphasia, and life expectancy < 10 years since diagnosis T h e C a u s e : • Heterozygous loss-of-function mutations in the GRN gene reduce progranulin levels by ~50% N o A v a i l a b l e T r e a t m e n t : • No approved symptomatic or disease modifying therapy UCSF Memory and Aging Center. Frontotemporal dementia. University of California, San Francisco. Taylor, R., & Finger, E. (2019, June). Frontotemporal dementias. Practical Neurology. The Association for Frontotemporal Dementia. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2019 Dec 3;19(2):145–156. doi: 10.1016/S1474 - 4422(19)30394 - 1 Property of Alector O u r T h e r a p e u t i c H y p o t h e s i s: • Elevating PGRN back to physiological levels by blocking sortilin to prevent its degradation FTD-GRN: Frontotemporal Dementia Caused by Mutations in the GRN Gene FTD-GRN
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8 FTD Treatment Centers Worldwide6 Property of Alector Estimated Prevalence and Treatment Centers for FTD 1.The Association for Frontotemporal Degeneration. 2. Patient estimates based on internal forecasting analysis using published literature sources. 3. E.U. estimates include EU5 countries only (Spain, Italy, France, U.K. and Germany). 4. FTD Disorders Registry. 5. Galvin JE, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Nov 14;89(20):2049 - 2056. 6. FPI | FTD Prevention Initiative FTD is the most common cause of dementia under the age of 60, and most cases occur 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 EU2,3 The FTD disease burden is estimated to be nearly 2X that of Alzheimer’s.5 FTD-GRN accounts for 5 to 10% of FTD4, representing ~8,000 to 17,000 symptomatic FTD-GRN across the U.S. and EU.2,3,4
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FTD-GRN Appears To Be Underdiagnosed: An Opportunity for Early, Genetically Based Improved Diagnosis ~30% of FTD-GRN is misdiagnosed as dementia not otherwise specified. 9Property of Alector Moore et al., 2019 Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 3;19(2):145–156. doi: 10.1016/S1474 - 4422(19)30394 - 1 Diagnosis of GRN Mutation Carriers GRN (N = 1179) ~8% of FTD-GRN is misdiagnosed as Alzheimer's disease. ~2.5% of FTD-GRN is misdiagnosed as Parkinson's disease, dementia with Lewy Bodies, or vascular dementia
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PGRN levels inversely correlate with sortilin expression in human Latozinemab and nivisnebart are human monoclonal antibodies that are designed to increase the levels of PGRN by blocking sortilin Hu et al, Neuron 2010 10Property of Alector PGRN expression levels inversely correlate with sortilin levels in mice Latozinemab (AL001) and Nivisnebart (AL101): Designed to Increase PGRN Levels by Blocking Sortilin, a Degradation Receptor Carasquillo et al, AJHG 2010 Nivisnebart latozinemab nivisnebart
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LOF = Loss - of - function 1. Sci Transl Med. 2017 Apr 12;9(385) 2. Dement Geriatr Cogn Disord Extra 2016;6:330 - 340; 3. Eur J Neurol. 2013 Dec;20(12):1571 - 3; Gene. 2014 Jun 1;542(2):141 - 5 Property of Alector 11 Heterozygous LOF Mutations in the GRN Gene Reduce PGRN and Directly Cause FTD Plasma2 Cerebrospinal fluid (CSF)2 Destruction of Brain Structures Cognitive and Behavioral Deficits Life Expectancy: 7-10 years Since Diagnosis PGRN Deficiency Neuronal Cell Death Microglia Dysfunction TDP - 43 Accumulation Lysosomal Dysfunction Complement Activation Inflammation Latozinemab: Rationale for PGRN-Elevating Drugs in FTD PGRN Deficiency Triggers a Multi-System Neurodegenerative Cascade
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Proprietary and Confidential Property of Alector 12 Nivisnebart: Rationale for PGRN-Elevating Drugs in Alzheimer’s Disease 1. https://doi.org/10.1101/2020.10.01.20200659 (Left); ARTFL Diagnoses. The breakdown of clinical diagnoses among ARTFL FTD mutations carriers. [Courtesy of Adam Boxer.] https://www.alzforum.org/print - series/1093496 (Right). 2. Mendsaikhan A, et al. Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer's disease and aged brains: increased levels correlate with neuropathology. Acta Neuropathol Commun. 2019 Dec 21;7(1):215. GRN Chromosome –log10(P) PGRN is a Risk Gene for AD1 Microglia (green) surround amyloid plaques (blue), which also contain high levels of PGRN (purple) PGRN is Embedded in Aβ Plaques2 PGRN overexpression decreases Aβ plaque load in the dentate gyrus of AD mice PGRN is Protective in AD Model2 Property of Alector
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13 Genetic and Biological Rationale for Blocking Sortilin to Elevate PGRN AL101 = Nivisnebart; Alz Res Therapy 4, 4 (2012); Sci Transl Med. 2017 Apr 12;9(385); Dement Geriatr Cogn Disord Extra 2016;6:330 - 34.; Eur J Neurol. 2013 Dec;20(12):1571 - 3; Gene. 2014 Jun 1;542(2):141 - 5.; Kashyap et al., bioRxiv 2025, https://www.biorxiv.org/content/10.1101/2024.09.15.613118v1 Genetics: Loss-of-function mutations in SORT1 • Lead to chronic elevation of PGRN in humans and mice with minimal/no discernible adverse effects Biology: PGRN that does not bind sortilin • Enters lysosomes where it remains active • Promotes neuronal survival • Restores lysosomal function of PGRN-deficient neurons and microglia in mice • Appears more potent than WT PGRN in rescuing microglial pathology, reducing NfL, and correcting lipid abnormalities in mice Experiments: Sortilin-blocking antibodies • Elevated PGRN and rescued phenotypes in an FTD- GRN mouse model • Elevated PGRN with encouraging trends in clinical outcomes and biomarkers in FTD-GRN patients in our open-label INFRONT-2 Phase 2 trial Property of Alector PGRN enters the lysosomes of SORT1-deficient cells through multiple alternative receptors Baseline AL101 Baseline AL101 Baseline AL101 Blocking sortilin, encoded by SORT1, increases PGRN in FTD mice Supporting evidence from genetics, biology, and experiments
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14 Differentiating Alector’s PGRN-Elevating Antibodies: Latozinemab and Nivisnebart Latozinemab and Nivisnebart Have a Distinct Binding Epitope on SORT1 3D CRYSTALLOGRAPHY STRUCTURE OF SORT1 Drug Candidate Profiles Alector data on file Latozinemab Binding Nivisnebart Binding PGRN Binding Property of Alector Latozinemab and nivisnebart are human anti- SORT1 antibodies. PK/PD profile distinguishes nivisnebart from latozinemab. Latozinemab and nivisnebart have demonstrated a 2- to 3-fold increase in PGRN levels and have been generally well-tolerated in clinical trial results to date. Nivisnebart is designed for more prevalent neurodegenerative diseases, including AD and PD.
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CTSD = cathepsin D; LAMP1 = lysosomal associated membrane protein 1; C1QB = complement C1q B chain; GFAP = glial fibrillary acidic protein CDR® plus NACC FTLD - SB = Clinical Dementia Rating (CDR) dementia staging instrument plus National Alzheimer’s Coordinating Center (NACC) behavior and language domains frontotemporal lobar degeneration (FTLD) sum of boxes (SB) PGRN e.g. CTSD, LAMP1 e.g. C1QB GFAP MRI CDR® plus NACC FTLD-SB CSF and plasma PGRN levels Dysfunctional lysosomes are hallmarks of FTD- GRN Elevation of complement proteins occurs in FTD-GRN Elevation of GFAP is a hallmark of FTD-GRN correlates with cognitive decline Accelerated brain tissue loss is a hallmark of FTD-GRN and correlates with cognitive decline A measure of clinical progression in FTD agreed upon by the FDA and EMA Key biomarkers and clinical outcome assessments reflect underlying disease activity in FTD-GRN patients BIOMARKERSTARGET ENGAGEMENT CLINICAL BENEFIT Clinical Outcome Assessments PGRN (Plasma and CSF) Lysosomal Dysfunction Inflammation Brain AtrophyAstrogliosis INFRONT-2 Open-Label Phase 2 Trial with Latozinemab 15 Symptomatic FTD -GRN (N=12), Latozinemab 60 mg/kg q4w for 49 weeks Property of Alector
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ACHIEVED PGRN RESTORATION IN FTD -GRN PARTICIPANTS 16 INFRONT-2: Latozinemab Restores PGRN in Plasma and CSF to Levels Seen in Healthy Volunteer Age - Matched Controls Property of Alector Data cut - off June 15, 2021 Mean +/ - SEM Source: AAIC 2021. PGRN Plasma Concentration PGRN CSF Concentration Correlation of PGRN CSF vs. Plasma Pearson R=0.79, p<0.0001 Samples collected post-treatment Concentrations in ng/ml (ng/ml) (ng/ml)
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BIOMARKERS OF DISEASE ACTIVITY – ASTROGLIOSIS Data cut - off June 15, 2021, Mean +/ - SEM,. 1. Range is of baseline GFAP levels in asymptomatic FTD - GRN patients enrolled in INFRONT – 2, Source: AAIC 2021. 17Symptomatic GRN mutation carriers were injected with AL001 60 mg/kg q4w for 49 weeks, and the levels of their PGRN in the Plasma and CSF was measured. Property of Alector GFAP Plasma Concentration GFAP CSF Concentration INFRONT-2: Latozinemab Treatment Decreases Glial Fibrillary Acidic Protein (GFAP) Levels Towards Range Seen in Asymptomatic Carriers of FTD-GRN Mutation
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Parameter Estimate1 95% CI Annual Change in GENFI2 (n=10) 6.4 [4.32,8.45] Parameter Estimate1 95% CI Annual Change in GENFI2 (n=10) 6.4 [4.35,8.42] Annual Change in Latozinemab (n=12) 3.3 [1.38,5.28] Difference in Annual Change (GENFI2 – Latozinemab) 3.1 [0.24,5.88] CLINICAL OUTCOME ASSESMENT CDR® plus NACC FTLD-SB2 CDR® plus NACC FTLD-SB Change from Baseline -3.0 0 2.5 5.0 7.5 10.0 12.5 Baseline 3 Months 6 Months 9 Months 12 Months GENFI2 clinical progression Latozinemab clinical progression Nominal Time (Months) 18 GENFI = The Genetic Frontotemporal Initiative GENFI2 refers to the longitudinal FTD registry dataset 1. Random Coefficient Model with Repeated Measurements including baseline & all available post - baseline measurements up to 12 months. Data cut - off Sep 8, 2021. 2. CDR® plus NACC FTLD - SB: Clinical Dementia Rating (CDR) dementia staging instrument plus National Alzheimer’s Coordinating Center (NACC) behavior and language domains frontotemporal lobar degeneration (FTLD) sum of boxes (SB). Phase 2 data presented at CTAD 2021 and ADPD 2022. NCT03987295. Estimated to slow annual disease progression by ~48% (3.1-point change) Property of Alector INFRONT-2: Preliminary Data Suggests Latozinemab May Slow Disease Progression in FTD-GRN Participants Compared to Matched Historical Controls
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“At risk” = GRN carriers who are pre - symptomatic and meet a pre - specified NfL threshold for enrollment in the Phase 3 trial; CDR® plus NACC FTLD - SB = Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains Sum of Boxes; CGI - S = Clinician’s Global Impression - Severity; CGI - I = Clinician’s Global Impression - Improvement; FRS = Frontotemporal Dementia Rating Scale; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status 1. Alector is not aware of any other candidates in a Phase 3 trial for FTD as of August 2025. *Plasma progranulin is a co-primary endpoint in the U.S. only and does not apply to the EU. 19 CO - PRIMARY ENDPOINTS CDR® plus NACC FTLD-SB Plasma Progranulin* SECONDARY CLINICAL OUTCOMES ASSESSMENTS: CGI-S, CGI-I, FRS, RBANS 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 Completion VisitRandomization Latozinemab 60 mg/kg (IV q4w for 96 weeks) Randomized, Double-Blinded, Placebo-Controlled Study 103 symptomatic and 16 at-risk FTD-GRN carriers Continuation study 10-week safety follow-up 96-week open-label extensionPlacebo (IV q4w for 96 weeks) EXPLORATORY ENDPOINTS e.g., NfL, GFAP , vMRI Property of Alector
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20 76-Week Treatment Period with an Independent Interim Analysis in 1H 2026 Up to 12 weeks Screening & Baseline Nivisnebart Dose 1 IV (n~141)* Placebo IV (n~94)* Nivisnebart Dose 2 IV (n~47)* Safety Follow - up 12 weeks after final dose Primary endpoint Change from Baseline in CDR - SB across Weeks 52, 64 and 76. Key secondary endpoints Change from Baseline across Weeks 52, 64 and 76 for iADRS, ADAS - Cog14, ADCS - iADL, ADCS - ADL - MCI, ADCOMS Biomarkers: Amyloid PET, Tau PET, CSF and Plasma Key inclusion criteria • Age 50 - 85 years, inclusive • Diagnosis of MCI due to AD up to mild AD dementia • Amyloid positivity (by PET or CSF) RANDOMIZED, DOUBLE -BLIND, PLACEBO -CONTROLLED STUDY TO EVALUATE T HE EFFICACY AND SAFETY NIVISNEBART IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE Nivisnebart: Phase 2 PROGRESS-AD Study Design Property of Alector Completed Enrollment in April 2025 *Planned sample size
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21 Latozinemab and Nivisnebart: Currently Partnered in a Collaboration Agreement $700M upfront (2021 and 2022) $1.5B in potential milestone payments U.S. 50/50 profit share and co - commercialization Tiered double - digit royalties (ex U.S.) $160M for first commercial sale in U.S. $90M for first commercial sale in at least two of the following countries: France, Germany, Italy, Spain or U.K. Property of Alector Latozinemab Pivotal Phase 3 INFRONT-3 data anticipated by mid-Q4 2025. Nivisnebart Phase 2 PROGRESS-AD enrollment completed in April 2025.
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22 Alector Brain Carrier (ABC) Platform Property of Alector
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Versatile Configurations, Orientations and Size of Linkers That Are Optimal for the Cargo 23 Nucleic Acid Cargo Adaptable Fc Therapeutic arm Therapeutic arm Brain Carrier Adaptable linker Antibody Cargo Enzyme Cargo Enzyme cargo Brain Carrier Adaptable Fc Adaptable linker • Designed to enable optimal brain penetration, drug activity, stability and manufacturability • Serum half-life compatible with monthly IV/SubQ dosing • Adaptable to cargos whose mechanism of action requires effector function • Ability to deliver into brain parenchyma and/or brain cells ABC Designed to Optimize Configuration, Orientation, Linker Size, Valency and Effector Function Alector’s Versatile Drug Configurations Are Tailored to the Cargo Property of Alector Brain Carrier Adaptable linker Adaptable Fc Nucleic Acid Cargo
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24Alector data on file TfR Binder KD (nM) Binder 1 5 Binder 2 19 Binder 3 126 Binder 4 127 Binder 5 176 Binder 6 182 Binder 7 274 Binder 8 390 Binder 9 639 Binder 10 1040 Binder 11 1210 Binder 12 4720 Adaptable TfR Binding Affinities and Effector Functions for a Variety of Cargos 500-Fold Affinity Range Tailored to Antibodies, Enzymes, and siRNA ABC Displays Affinity-Dependent Internalization Into Human Brain Endothelial Cells TfR Binding Affinities Tailored to Drug Modalities and Antibody Effector Function Facilitates transcytosis of drugs through the BBB Designed to reduce effect on drug half-life Reduces concurrent binding to TfR and FcγR Property of Alector Tailored to enter cell types of interest Binder 3 Binder 8 Binder 4 Binder 10 Binder 5 Isotype Control Anti-TfR binders at multiple affinities were incubated on hCMEC/D3, cells for 2 hours. Internalized antibodies detected with anti-huIgG in green; nuclei labeled in blue with DAPI. 500nM 100nM 500nM 100nM
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25 Alector’s TfR ABC Reduces TfR-Mediated ADCC: A Measure for Reticulocytes Depletion Property of Alector Structure of The Human Transferrin Receptor Bound to TfR and Binding Epitopes of Distinct BBB Approaches TfR and Antibody-Dependent Cell Cytotoxicity (ADCC) Are Determined by the TfR Binding Epitope and Affinity 0.01 0.1 1 10 100 1000 0 2000 4000 6000 8000 10000 Concentration [ug/ml] Luminescence ADCC on hTfR OE CHO ADP037-ABC Masked TfR High ADP037-ABC Masked TfR Med ADP037-ABC Exposed TfR Low ADP037 IgG AL037-Epitope B AL037-ABC ADCC signal on CHO cells Expressing hTfR AL037-Naked AL037 AL137 Alector data on file ATV1 Alector Epitope B8D34 Trontinemab3 BioArctic2 Alector Brain Carrier TfR Protease-like domain Transferrin N-Lobe Transferrin C-Lobe ABC TfR Apical domain AL037 = Alector ABC-enabled anti-Aβ-antibody. AL137 = second Alector ABC-enabled anti-Aβ antibody. AL037-Naked = AL037 without ABC platform. RBC = Red Blood Cells. Structure of human transferrin receptor-transferrin complex from 1SUV. (1)ATV epitope (Kariolis et al., 2000); (2) BioArctic epitope (International Patent Pub. No. WO2024200271); (3) Trontinemab epitope (Alector internal data) (4) 8D3 epitope (de la Rosa et al., 2025). Epitope B binds TfR at the same region as Denali’s ATV and Roche’s Trontinemab. ADCC activity, used here as a surrogate for TfR-dependent hematologic adverse effects, was assayed using Promega ADCC Reporter Bioassay kit with huTfR overexpressing Chinese Hamster Ovary (CHO) cells.
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26 Research and Preclinical Programs: Remove toxic proteins and Replace deficient proteins using advanced technology Antibodies + ABC Removing Aβ Enzymes + ABC Replacing GCase siRNAs + ABC Removing Tau Removing α-Synuclein Removing NLRP3 Applying our versatile ABC platform toward multiple drug modalities Targeting AD and PD with research and preclinical programs against validated drug targets Establish Alector Brain Carrier (ABC) Technology Across Modalities 26Property of Alector Removing Tau
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27 AL037: Alector Brain Carrier (ABC)—Enabled Anti-Aβ Antibody for Alzheimer's Disease Property of Alector
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28 Engineered Anti-PyroGlu3 Aβ Binding Epitope 1 Optimized TfR-Binding Epitope and Affinity to Maximize Brain Penetration and Reduce Hematologic Adverse Effects 3 Fully Active Constant Region 2 Optimized Linker4 Selectivity • Engineered high-affinity, fully human antibody that selectively binds toxic Aβ plaques Potency • Fully active constant region enabling effective recruitment of myeloid cells to remove Aβ plaques Safety • Proprietary ABC with tuned affinity and binding epitope seeks to facilitate effective brain penetration and plaque removal while minimizing hematologic adverse effects Convenience • ABC enables potential for low dosing regimen and subcutaneous delivery Targeted Design Features Design of AL037: ABC-Enabled Anti-Aβ Antibody Property of Alector
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29 ABC-Dependent Transcytosis of AL037 in Human Brain Endothelial Cells AL037-Naked AL037 2 Hour Pulse with Antibody 4 Hour Chase and Assessment of Antibody Levels AL037-Naked (without the ABC platform) or AL037 at various concentrations were incubated on hCMEC/D3 cells for 2 hours. Internalized antibodies detected with anti-huIgG in yellow; nuclei labeled in blue with DAPI. Levels of internalized, recycled or transcytosed antibody were assessed by MSD. Alector ABC facilitated robust uptake and transport of AL037. Property of Alector 500 nM 125 nM 31.25 nM Alector data on file
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AL037 Facilitates Phagocytosis of PyroGlu3 Aβ by Human Microglia 30Property of Alector AL037-Naked (without the ABC platform), Isotype huIgG, or AL037 and pyroGlu3 Aβ were incubated with IPSC-derived CNS triple cultures (containing iMicroglia, iNeurons, human fetal astrocytes) for 24h and imaged hourly for uptake of pHrodo-labeled pyroGlu3 Aβ in GFP-iMicroglia. (inset, iMicroglia in green, Aβ in orange) AL037-Dependent Phagocytosis of PyroGlu3 Aβ by Human IPSC Microglia in Culture PyroGlu3 Aβ only huIgG AL037 - Naked AL037 Fluorescent Imaging (red) of PyroGlu3 Aβ Phagocytosed by Microglia in 24h iMicroglia Aβ -naked Alector data on file
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31 AL037 Surrogate Binds To and Reduces Amyloid Plaque in the Mouse Brain Plaque specific binding of AL037 Surrogate in the mouse brain Reduction in Brain Aβ42 in AL037 Surrogate-dosed Mice Property of Alector MOUSE 50 mg/kg Q7Dx3 5 mg/kg Q7Dx3 p=0.035 One way ANOVA with Dunnett's multiple comparisons test Iso mTfR 5 mg/kg Iso Control 50 mg/kg AL037-mTfR 5 mg/kg Light sheet microscopy on 9-month-old 5xFAD mice dosed 3 times weekly at levels indicated. Aβ42 levels were assessed in total brain lysates by ELISA; means +/-SEM, n=16-17 per group; 24-168h post last dose. Naked antibody primarily labels the vasculature and ventricles while AL037 Surrogate with mouse TfR binding domain is on amyloid plaques distributed throughout the brain. AL037-mTfR 3D Reconstruction Alector data on file
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AL037 Displays Favorable Serum Pharmacokinetics in NHP NHP Day 1 Day 10 terminal Day 9 Three NHP per group were injected on days 1 and 9. Serum samples were analyzed for the levels of AL037- Naked (without the ABC platform) and AL037. AL037-Naked 30 mg/kg AL037 30 mg/kg AL037-Naked 3 mg/kg AL037 3mg/kg Timepoint (hours) Concentration (ug/mL) AL037 Displays an Estimated Serum Half-life of 106h Property of Alector 32 Half-Life AL037-Naked 192h AL037 106h Alector data on file
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33Property of Alector AL037 Impact on Reticulocytes RBC and Hemoglobin NHP Three NHP per group were injected on days 1 and 9 (red arrows). Blood samples were analyzed for reticulocytes, red blood cell counts and hemoglobin levels at the indicated times. AL037 caused a transient decrease in reticulocytes but did not negatively impact red blood cell count. AL037-Naked = AL037 without ABC platform. Hemoglobin Levels Were Not Affected Red Blood Cell Counts Were Not Affected Reticulocyte Counts Quickly Recover AL037-Naked 30 mg/kg AL037 30 mg/kg AL037 3 mg/kg AL037-Naked 3 mg/kg RBC % change from baseline Hemoglobin % change from baseline Alector data on file
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ABC Enhances Brain Uptake of AL037 NHP 34 Three NHP per group were dosed on days 1 and 9. Brain tissues were collected 24 hours after the second injection and drug levels were measured in the vessel-depleted fraction. *E.g. According to our calculations, trontinemab is reaching 2.1nM in the NHP vessel-containing cortex 24h following a single injection of 10mg/kg (Grimm et al., MABS, 2023). AL037-Naked = AL037 without ABC platform. Frontal Cortex Hippocampus 18x 14x 18x 8x AL037 at 3mg/kg reached 3.8nM in vessel containing frontal cortex, comparing favorably with other brain carriers (~5X higher)* AL037-Naked 30 mg/kg AL037 30 mg/kg AL037-Naked 3 mg/kg AL037 3 mg/kg AL037-Naked 30 mg/kg AL037 30 mg/kg AL037-Naked 3 mg/kg AL037 3 mg/kg Alector data on file Property of Alector
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ABC Enhances Brain Uptake of AL137: A Second Anti-Aβ Antibody Lead NHP Frontal Cortex Hippocampus 29x 15x 32x 8x Three NHP per group were dosed on days 1 and 9. Brain tissues were collected 24 hours after the second injection and drug lev els were measured in the vessel-depleted fraction. AL137 is associated with a reduction in reticulocytes and different PK than AL037 (Data not Shown) *E.g. According to our calculations trontinemab reaches levels of 2.1nM in the NHP vessel-containing cortex 24h following a single injection of 10mg/kg (Grimm et al., MABS, 2023) and estimated half-life of 31h. AL137-Naked = AL037 without ABC platform. Property of Alector 35 AL137 at 3mg/kg reached 8.4nM in vessel containing frontal cortex, comparing favorably with other brain carriers (~12X higher)* Estimated Half-Life ~65 h AL137-Naked 3 mg/kg AL137 30 mg/kg AL137 3 mg/kg AL137-Naked 3 mg/kg AL137 30mg/kg AL137-Naked 30mg/kg AL137 3 mg/kg AL137-Naked 30 mg/kg Alector data on file
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Summary and Conclusion 36Property of Alector 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 by BBB tech D e s i g n : • AL037/AL137 were designed to treat Alzheimer’s disease by delivering an ABC-enabled anti- Aβ antibody that targets PyroGlu3 Aβ with a fully active Fc region, to optimize for brain penetration safety and efficacy. D e m o n s t r a t e d : • Robust brain penetration (18-32-fold representing 3.8-8.4 nM with 3 mg/kg) • Plaque engagement, microglial activation, and reduction of amyloid burden in preclinical models • Adequate PK , transient effect on Reticulocytes and no apparent findings on RBC to date C l i n i c Ta r g e t : • Targeting first-in-human trial in 2026 1. Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012 Aug 1;2(8):a006239.
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37 AL050: Alector Brain Carrier (ABC)—Enabled GCase ERT for Parkinson's Disease Property of Alector
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GBA1 Gene Mutations Are a Major Risk Factor for Neurodegenerative Diseases 38 • Parkinson’s Disease (PD) ▪ ~10 million patients worldwide1 ▪ 0.5-1.5 millions are GBA1 mutation carriers2 ▪ Activity is reduced in non-carriers2 • Gaucher’s Disease (GD) ▪ ~125,000 patients with GBA1 mutation worldwide5 ▪ GD type 1 have increased risk of PD6 ▪ GD type 2 and 3 are neuronopathic7 • Lewy Body Dementia (LBD) ▪ ~5-8 million patients worldwide3 ▪ 0.15--2.4 millions are GBA1 mutation carriers4 ▪ Activity is reduced in non-carriers4 GBA1 mutations lead to reduced GCase enzyme activity and toxic substrate accumulation (GlcCer and GlcSph) in the brain. 1. Parkinson’s Foundation Statistics 2. Smith L, Schapira AHV. GBA Variants and Parkinson Disease: Mechanisms and Treatments. Cells. 2022 Apr 8;11(8):1261. 3. Alzheimer’s Disease International, Dementia with Lewy Bodies 4. Nalls MA, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 2013 Jun;70(6):727 - 35. 5. Meikle PJ, et al. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20;281(3):249 - 54. 6. Bultron G, et al. The risk of Parkinson's disease in type 1 Gaucher disease. J Inherit Metab Dis. 2010 Apr;33(2):167 - 73. 7. National Gaucher Foundation, Gaucher Disease Types 2 and 3 No therapy has effectively restored GCase activity in the brain: Current GCase enzyme replacement therapy does not enter the brain Property of Alector Toxic when accumulated Toxic when accumulated Mutant GBA1 GCase Deficiency = Α-synuclein Aggregation Altered Lipid Homeostasis Autophagy-Lysosomal Dysfunction Mitochondrial Dysfunction (GlcSph) (GlcCer)
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2021 Huh et al. NPJPD Glucosylceramide in cerebrospinal fluid of patients with GBA - associated and idiopathic Parkinson’s disease enrolled in PPMI 2023 Oftedal et al. Translational Neurodegeneration Early GCase activity is a predictor of long-term cognitive decline in Parkinson’s disease Parkinson’s Disease Patients with Higher CSF Toxic Substrate Levels at Diagnosis Progress Faster Parkinson’s Disease Patients with Lower CSF GCase Activity at Diagnosis Progress Faster Rationale for GCase ERT in Parkinson's Disease 39Property of Alector These Findings Support the Hypothesis that Brain Penetrant GCase ERT Could Slow Parkinson's Disease Progression
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Engineered GCase with Improved Activity and Stability Optimal TfR Epitope and Binding Affinity Silenced Constant Region 40 Optimal Drug Format Optimized Design of AL050: ABC-Enabled GCase Enzyme Replacement Therapy (ERT) Potency • Engineered enzyme that is more active and stable than the WT enzyme and effectively enters the brain Safety • ABC with tuned affinity and binding epitope and a silenced FcgR binding domain seeks to minimize hematologic adverse effects Convenience • ABC enables potential for low-dose regimen and monthly dosing Targeted Design Features 1 3 4 2 Property of Alector Enzyme Mutations Tm ℃ Half-life at 37℃ Wild-type n/a 57.5 ~ 6.0 hrs AL050 <5 AA 64.9 > 7-days AL050 ActivityAL050 Stability Determined in monovalent - Fc format Alector data on file
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41 AL050 Affinity Was Optimized for Cell Rescue and Lysosomal Uptake Alector data on file Property of Alector tGCase-ABC LAMP-1EEA-1 Overlay GCase-ABC Is Delivered to the Lysosomes of GBA1- / - Neuroblastoma Cells Ability of AL050 to Rescue GCase Activity in GBA1- / - Neuroblastoma Cells Is TfR-Affinity-Dependent TfR Affinity Low High Isotype Left: GBA1-/- SH-SY5Y cells were incubated with 100nM toolGCase-TfR for 2h. Cell uptake was determined by confocal microscopy with antibodies against EEA-1 (early endosomes), LAMP-1 (lysosomes), and anti-human Fc (tGCase-TfR). Nuclei: DAPI (blue). Right: GBA1-/- SH-SY5Y cells were incubated with increasing concentrations of AL050-ABC at different anti-TfR affinities for 2 hours. GCase activity was measured by flow cytometry using the GCase fluorescent substrate PFB-FDGlu (1h incubation).
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AL050 Displays ~10 Fold Longer Half-Life in NHP Plasma Compared to Current GCase ERTs 42 Displays terminal t½ up to for ~20–30 min in human patients • European Medicines Agency (EMA), Cerezyme EPAR – Scientific discussion. European Medicines Agency (EMA) • Therapeutic Goods Administration (TGA, Australia), AusPAR: Velaglucerase alfa (VPRIV). Therapeutic Goods Administration (TGA) • EMA, VPRIV EPAR – Public assessment report European Medicines Agency (EMA) • TGA, AusPAR: Taliglucerase alfa (Elelyso) Current GCase ERTs Display Protein Half-Life of 5 to 30 Minutes in Plasma AL050 Displays Plasma Half-Life of ~5 hours in NHPs Property of Alector Imiglucerase: Displays terminal t½ of ~25min in human patients Taliglucerase alfa: Displays terminal t½ of 5-12 min in NHP Velaglucerase alfa: NHP Alector data on file
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AL050 Displays ~40 Fold Longer Enzymatic Activity in NHP Plasma Compared to Current GCase ERTs 43 T½ Enzymatic Activity 3.6 – 10.4 min. in human patients • European Medicines Agency (EMA), Cerezyme EPAR – Scientific discussion. European Medicines Agency (EMA) • Therapeutic Goods Administration (TGA, Australia), AusPAR: Velaglucerase alfa (VPRIV). Therapeutic Goods Administration (TGA) • EMA, VPRIV EPAR – Public assessment report European Medicines Agency (EMA) Current GCase ERTs Display Enzymatic Activity Half-Life of 4 to 10 Minutes in Plasma AL050 Displays GCase Enzymatic Activity Half-Life of ~6.6 hours in NHP Plasma Property of Alector Imiglucerase: T½ Enzymatic Activity 4.0 – 4.7min. in NHP Velaglucerase alfa: NHP Alector data on file
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44 Three NHP per group were injected on days 1 and 8 (vertical lines). Blood samples were analyzed for reticulocytes, red blood cell counts and hemoglobin levels at the indicated times. Increase in reticulocytes was observed in all groups due to frequent blood collections. AL050-Naked = AL050 without ABC platform. Property of Alector AL050 Did Not Negatively Impact Reticulocytes, RBC Count or Hemoglobin Levels NHP Reticulocyte Counts in Normal Range Hemoglobin Levels Were Not Affected Red Blood Cell Counts Were Not Affected Alector data on file
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*Samples below lower limit of detection graphed at LLOD. ABC Enhances Brain Delivery of Engineered GCase Cargo by 5- to 19-Fold 45Property of Alector NHP 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 the vessel-depleted fraction. AL050-Naked = AL050 without ABC platform. HippocampusFrontal Cortex PutamenSubstantia Nigra X10X5 X6 X19 * * * * Alector data on file *
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One way ANOVA with Dunnett’s multiple comparison test AL050 Increases GCase Activity in the Brain of NHPs by >2-Fold 46Property of Alector NHP Three NHP per group were injected on days 1 and 8 and brain tissues were collected 24 hours after the second injections. GCase enzymatic activity was determined using a 4-MUG kinetic assay (graphs represent the combination of endogenous NHP GCase and AL050. AL050-Naked = AL050 without ABC platform. Hippocampus PutamenSubstantia Nigra 132% Increase 112% Increase 63% Increase 124% Increase Frontal Cortex Alector data on file
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AL050 Surrogate Rescues GCase Activity and Reduces Toxic Substrate Accumulation in Peripheral Tissues of Gba1-Mutant Mice 47Alector data on file Liver GlcSph Levels are Reduced by 87% 24h After a Single Dose of AL050-TfR-Surrogate Property of Alector Wild-type or Gba1-mutant mice were injected once with PBS or 10mg/kg toolGCase-anti-mouse-TfR. Liver samples were collected 24h after injection. GCase activity was determined using a 4-MUG kinetic assay on liver lysates and GlcSph was quantified by LC-MS/MS. MOUSE - 87% Liver GCase Activity is Rescued 24h After Injection
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AL050 Surrogate Rescues Brain GCase Activity and Reduces Toxic Substrate Accumulation in the Brain of Gba1-Mutant Mice Alector data on file Durable Reduction in Brain GlcSph 48Property of Alector +95% MOUSE GCase-ABC Increases Brain GCase GCase-ABC Reduces GlcSph by ~80% 8dpi Wild-type or Gba1-mutant mice were injected once (left, right) or twice (middle) with PBS, or 10mg/kg toolGCase-Iso, AL050-TfR Surrogate (left), or toolGCase-anti-mouse-TfR (middle, right). GCase activity (left) was determined by 4-MUG kinetic assay in vessel-depleted brain lysates. Brain GlcSph concentration (middle, right) was determined by LC-MS/MS. - 78%
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Summary and Conclusion 49Property of Alector G B A 1 G e n e M u t a t i o n I m p a c t : • 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 gene mutations A L 0 5 0 D e s i g n : • AL050 was designed to address GCase deficiencies in PD, LBD, and GD by enhancing GCase, encoded by the GBA1 gene, delivery to the brain A L 0 5 0 D e m o n s t r a t e d : • Superior activity and stability in vitro and in NHP compared to current GCase ERT • Superior PK in the NHP plasma compared to current GCase ERT • Good brain penetration and doubling of enzymatic activity in the NHP C l i n i c Ta r g e t : • Targeting first-in-human trial in 2027
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50 Alector Brain Carrier (ABC)—Enabled siRNA Programs Property of Alector
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51 P H A R M A C O K I N E T I C S PA R A M E T E R S T E S T E D F O L D B R A I N P E N E T R AT I O N * *The control represents a less effective drug configuration TAs 4 IV or 1 ICV (5 mg/kg siRNA Dose equivalent dose) Day 0 1 8 15 22 25 Plasma collection at 1h, 4h, 24h post dose 1st and 4th dose E X P E R I M E N T A L P R O T O C O L P O T E N T I A L A D V A N TA G E S SiRNA-ABC: Designed to Support Effective Brain Distribution with Peripheral Delivery Safer than IT, ICV delivery Better efficacy due to homogeneous brain distribution Ease and convenience of use Scalable to a large patient population Applicable for brain and peripheral tissue delivery ~1,000-fold range of TfR affinities Multiple drug configurations Multiple siRNA linkers (cleavable, e.g., Val-Cit and non-cleavable, e.g., SMCC) Multiple siRNA modifications (e.g., 2′-OMe, PS, etc) Property of Alector SOD1- Superoxide dismutase Long Plasma half-life Alector data on file
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52 Peripheral Delivery of SOD1 siRNA-ABC: 50-80% Knockdown Across Multiple Brain Structures Property of AlectorSOD1 - Superoxide dismutase 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 mRNA was measured at day 25. Naked siRNA (without ABC). Alector data on file
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Proprietary and Confidential Property of Alector 53 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 Property of Alector
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Alector is Focused on Opportunities to Drive Near- and Long- Term Value • Latozinemab Ph 3 data in FTD-GRN by mid-Q4 2025 • AL101 Ph 2 study in AD, with enrollment completed in April 2025 D E L I V E R L A T E - S T A G E C L I N I C A L P R O G R A M S Alector Brain Carrier applied to: • Antibodies: Anti-Aβ-ABC For AD • Enzymes: GCase-ABC For PD, LBD, GD • siRNA: Tau-siRNA-ABC for AD, FTD; a-Syn-siRNA-ABC for PD, LBD; NLRP3- siRNA-ABC for AD, PD, ALS, MS, HD A D V A N C E P R O G R A M S T O C L I N I C • Novel 3R (Replace, Remove, Restore) drugs for degenerative brain disorders • Well-resourced to continue advancement of our ABC pipeline • Clear, value-creating catalysts through 2026–2027 F U T U R E P O T E N T I A L T O E X P A N D P O R T F O L I O Alector’s Current Focus & Priority Goals 54Property of Alector
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Thank You