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Alector Corporate Overview August 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; our plans, timelines and expectations related to our product candidates and our other clinical and pre-clinical programs, 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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3 Alector is Positioned to Drive Near- and Long-Term Value in Treating Brain Disorders Property of Alector *Assuming positive Phase 3 data and regulatory approval Well Resourced & Global Partnership o Experienced leadership and strong financial means with runway into 2H 2027 o Profit-sharing collaboration with commercial rights for PGRN product candidates o Continuing to pursue brain-penetrant anti-Aβ antibody o Continuing to pursue brain-penetrant GCase ERT o Positioned to develop multiple therapeutic candidates in Alzheimer’s and Parkinson’s disease Late-Stage Clinical Programs: o Pivotal Phase 3 data readout in FTD-GRN by mid-Q4 2025 o Completed enrollment of Phase 2 clinical trial in AD with trial completion expected in 2026 o Potential for commercialization* Innovative Science with 3R Strategy and Advanced Technologies: Remove- Misfolded Proteins Replace- Dysfunctional Proteins Restore- Dysfunctional Immune Cells and Neurons
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TARGET & MODALITY CANDIDATE RESEARCH PRECLINICAL PHASE 1 PHASE 2 PHASE 3 ALECTOR’S COMMERCIAL OWNERSHIP RIGHTS PGRN-Abs Latozinemab 4 FTD-GRN IP portfolio across all programs contains 60+ patent families, which include 177 issued patents directed to more than 25 targets and/or technologies U.S. 50-50 profit share with co-promote. Tiered double-digit royalties ex-U.S.AL101 AD Development Portfolio: Advancing Late-Stage Programs with Established Partner, Supported by Genetically Validated Research Portfolio and Proprietary ABC Platform FTD-GRN = frontotemporal dementia with a GRN gene mutation, AD = Alzheimer’s disease, PD= Parkinson’s disease, GD = Gaucher Disease, LBD = Lewy body dementia, Aβ = amyloid beta, Abs = antibodies, ERT = enzyme replacement therapy, UD = Undisclosed, siRNA = small interference RNA Property of Alector Wholly-Owned Proprietary Preclinical Pipeline ADP037-ABCAβ-Abs ADP050-ABC GCase-ERT $307.3 MILLION 1 IN CASH PROVIDES RUNWAY INTO SECOND HALF OF 2027 1. Cash, cash equivalents, and marketable securities as of June 30, 2025, were $307.3 million. ABC = Alector Brain Carrier Wholly-Owned Proprietary Research Pipeline AD, FTDADP064-ABCTau-siRNA ADP056 Reelin-UD AD ADP063-ABCTau-Abs AD AD PD, GD, LBD
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5 Clinical Programs: Replace Progranulin to Address FTD-GRN and AD AL101 in Alzheimer’s Disease (AD) • Ph 2 enrollment completed in April 2025 with 76-week treatment period ongoing • Phase 2 expected to complete in 2026 • Modest reductions in PGRN constitute a genetic risk of developing AD1 • Elevation of PGRN has been shown to be protective in animal models of AD3 1. Rhinn H, Tatton N, McCaughey S, Kurnellas M, Rosenthal A. Progranulin as a therapeutic target in neurodegenerative diseases. Trends Pharmacol Sci. 2022 Aug;43(8):641-652. 2. ARTFL Diagnoses. The breakdown of clinical diagnoses among ARTFL FTD mutations carriers. [Courtesy of Adam Boxer.] https://www.alzforum.org/print-series/1093496 3.Mendsaikhan A, Tooyama I, Bellier JP, Serrano GE, Sue LI, Lue LF, Beach TG, Walker DG. 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. Latozinemab (AL001) in Frontotemporal Dementia with a Granulin Mutation (FTD-GRN) • Ph 3 pivotal study results expected by mid-Q4 2025 • Breakthrough Therapy, FastTrack, and Orphan Drug designations • Open-label Ph 2, with encouraging trends in clinical outcome measure and biomarkers • Haploinsufficiency mutations in PGRN cause FTD-GRN1,2 Property of Alector
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6 Research and Preclinical Programs: Remove toxic proteins, Replace deficient proteins using advanced technology Antibody + ABC ADP037-ABC Removing A Enzyme + ABC ADP050-ABC Replacing GCase Antibody + ABC / siRNA + ABC ADP063-ABC / ADP064-ABC Removing Tau Applying our versatile ABC platform with potentially high value targets and multiple drug modalities • Targeting AD and PD with the potential for multiple successful products • Leveraging recent advances in the field of neurodegeneration to streamline drug development and optimize product profiles Establish Alector Brain Carrier (ABC) Technology Across Modalities 6Property of Alector
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• Versatile: ABCs as Fab and scFv that bind transferrin receptor (TfR) in multi-specific formats • Adaptable Fc: Optimizing effector function and half-life • Tailored for Cargo: Wide range of affinities and TfR-binding epitopes facilitating optimization to multiple cargo modalities • Tailored for Development: Designed for testing in non-human primates and manufacturability Versatile Features Alector Brain Carrier (ABC): Designed for Lower Dosing, Improved Efficacy and Safety, and SubQ Delivery Across Multiple Cargo Types and Configurations 7 Nucleic Acid Cargo Versatile Configurations Adaptable Fc Therapeutic arm Therapeutic arm Brain Carrier Adaptable linker Antibody Cargo Enzyme Cargo Enzyme cargo Brain Carrier Adaptable Fc Adaptable linker Property of Alector Adaptable Fc Nucleic Acid Cargo Brain Carrier Adaptable linker
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Alector Brain Carrier enables brain tissue concentration of ~18nM in NHP and compares favorably with other blood brain barrier technologies (e.g., Kariolis et al, STM 2020; Edavettal et al, MED 2022; Grimm et al., MABS, 2023; Freskgård, PEGS Europe 2024) Deep Brain Penetration in Vessel-depleted NHP Brain Fraction Up to 40X Brain Uptake (18nM concentration) Compared to Naked Antibody Alector Brain Carrier Naked Antibody Alector Brain Carrier Tool Compound Demonstrates Deep Brain Penetration 8 Fold change over naked antibody Fold change over naked antibody Fold change over naked antibody Deep Brain Penetration with Alector Brain Carrier in Rodents Naked Antibody Alector Brain Carrier antibodies visualized 72h post 2X weekly iv dosing of 50 mg/kg antibody visualized 48hrs post 2 monthly doses (n=3, 20mg/kg dose, +/-SEM) Property of AlectorAlector data on file
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Proprietary and Confidential Property of Alector Alector ABC Shows Superior Serum Half-Life, Safety, and Brain Penetration in Rodents *Reference TfR binder binds TfR at the same affinity as a lead Alector TfR but at a different epitope Antibody levels in serum were measured after 2 IV doses of 3 mg/kg, 14 days apart into mice that express the human TfR receptor. Antibody levels in the brain were measured 24 hours after the second injection. Abs ng/ml ng/mg total protein % Reticulocytes in whole blood Alector TfR shows rapid recovery of reticulocytes Reference TfR binder shows prolonged reticulocyte reduction Alector TfR binder is associated with rapid recovery of reticulocytes compared to reference TfR binder with the same affinity Property of Alector 9 Vehicle Naked reference anti-Aβ Ab Reference Anti-Aβ Ab with Alector TfR binder Reference Anti-Aβ Ab with reference* TfR binder PBS 3 mg/kg 10 mg/kg 30 mg/kg Serum Half-Life of Tested Abs Brain Uptake of Tested Abs Reticulocyte Levels 7 Days Post-Injection Alector data on file
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Property of Alector 10 Partnered Portfolio: Alector's Progranulin-Elevating Franchise For Frontotemporal Dementia and Alzheimer's Disease
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11 Latozinemab and AL101: Pioneering Approach to Elevating Progranulin Levels with Potential to Enhance Microglial and Neuronal Function and Treat FTD and AD Property of AlectorSource: 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. Latozinemab and AL101: PGRN Elevating Program PGRNDegradation Pathway (Sort1) PGRN degradation Degradation Pathway (SORT1) AL001/AL101PGRN PGRN PGRN PGRN PGRN PGRN Latozinemab (AL001) and AL101 elevate PGRN levels by blocking sortilin (SORT1), a degradation receptor for PGRN • Genetics: Mutations in GRN, which encodes PGRN, are deleterious. - Homozygous (100% LOF): Neuronal ceroid lipofuscinosis with onset <25 years of age, 100% penetrance. - Heterozygous (50% LOF): Reduce progranulin levels to 50% of normal; Frontotemporal dementia with onset ~58 years of age, >90% penetrance. - Non-coding mutations (~10-20% LOF): Increase risk for ALS, FTD, AD, PD. • Biology: PGRN is a critical immune regulator, neuronal survival factor and a lysosomal chaperone. PGRN: Genetic and Biologic Rationale
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12 Frontotemporal Dementia (FTD): A Rapidly Progressive Form of Dementia, with No Approved Treatment P R E V A L E N C E : • 50,000 to 60,000 people in the U.S. and approximately 110,000 people in the EU with FTD.2,3 FTD-GRN accounts for an estimated 5% to 10% of all individuals living with the condition.4 S Y M P T O M S & P R O G R E S S I O N : • Compulsive behavior, lack of restraint, apathy, aphasia, motor symptoms5 • Symptoms typically begin between the ages of 45-64 years old7 • Life expectancy after diagnosis is 7-10 years6 D I A G N O S I S : • Frequently misdiagnosed as AD, depression, PD, or psychiatric condition7 • 50% of behavioral-variant FTD cases are misdiagnosed8 • Average time to an accurate diagnosis is 3.6 years7 • Approximately 41 million cases of dementia are undiagnosed worldwide9, underscoring broader diagnostic challenges that also affect FTD T R E AT M E N T : • No approved treatments to cure or slow progression of FTD7 F O R M S : • Sporadic FTD occurs without a clear familial or inherited pattern4 • Majority of genetic FTD occurs due to mutations in one of three genes: GRN, C9orf72 or MAPT4 • 1. With permission from Tommy Nash Jr. and Alyssa Nash, May 2023. • Tommy Nash Jr., with his daughter, Alyssa Nash. Tommy was diagnosed with FTD at 38 years old.1 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. UCSF Memory and Aging Center. Frontotemporal dementia. University of California, San Francisco. 6. Taylor, R., & Finger, E. (2019, June). Frontotemporal dementias. Practical Neurology. 7. The Association for Frontotemporal Dementia. 8. Woolley et al., J Clin Psychiatry, 2011 9..Alzheimer’s Disease International. World Alzheimer Report 2021. Property of Alector
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ACHIEVED PGRN RESTORATION IN FTD -GRN PARTICIPANTS 13 INFRONT-2: Latozinemab Restores PGRN to Levels Seen in Healthy Volunteer Controls Property of Alector Symptomatic 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. Symptomatic FTD-GRN1 N = 12 INFRONT -2: OPEN -LABEL PHASE 2 TRIAL Symptomatic FTD -GRN (N=12), Latozinemab 60 mg /kg q4w for 49 weeks PGRN Plasma Concentration PGRN CSF Concentration Property of Alector Data cut-off June 15, 2021 Mean +/- SEM Source: AAIC 2021.
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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. 14 INFRONT-2: Latozinemab Treatment Decreases Glial Fibrillary Acidic Protein (GFAP) Levels Towards Range Seen in Asymptomatic Carriers of FTD-GRN Mutation Property of Alector GFAP Plasma Concentration GFAP CSF Concentration Symptomatic 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.
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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) 15 INFRONT-2: Preliminary Data Suggests Latozinemab May Slow Disease Progression in FTD-GRN Participants Compared to Matched Historical Controls Property of Alector Estimated to slow annual disease progression by ~48% (3.1 point change) 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.
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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. * In the U.S. only. Does not apply to the EU. 16 CO-PRIMARY ENDPOINTS CDR® plus NACC FTLD-SB Plasma Progranulin* SECONDARY CLINICAL OUTCOMES ASSESSMENTS: CGI-S, CGI-I, FRS, RBANS INFRONT-3: Ongoing Pivotal Phase 3 Study with Latozinemab 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) Property of Alector EXPLORATORY ENDPOINTS vMRI, Plasma Biomarkers
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INFRONT-3 Baseline Age 17 CDR® plus NACC FTLD-GS, Clinical Dementia Rating scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Global Score; CDR® plus NACC FTLD-SB, Clinical Dementia Rating scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Sum of Boxes; NfL, neurofilament light chain; SD, standard deviation INFRONT-3 Baseline Clinical Characteristicsa At-Risk (n=16) Symptomatic (n=103) Total (N=119) Age, mean (min, max), years 59.2 (37, 79) 62.5 (48, 85) 62.1 (37, 85) At-Risk (n=16) Symptomatic (n=103) Total (N=119) CDR® plus NACC FTLD-GS, n (%) 0 15 (93.8) 0 15 (12.6) 0.5 1 (6.3) 23 (22.3) 24 (20.2) 1 0 49 (47.6) 49 (41.2) 2 0 31 (30.1) 31 (26.1) CDR® plus NACC FTLD-SB, n 16 103 119 Mean (SD) 0.0 (0.1) 6.9 (4.1) 6.0 (4.4) NfL concentration (pg/mL), n 12 87 99 Mean (SD) 16.0 (9.7) 73.0 (41.5) 66.1 (43.3) Median (min, max) 14.4 (7.8, 42.9) 66.9 (6.5, 190.0) 61.7 (6.5, 190.0) Symptomatic FTD-GRN participants from ALLFTD and GENFI Registry Studies (n=84):1 Mean age of 63.7 years (SD: 8.8) Mean CDR® plus NACC FTLD-SB score of 9.19 (SD: 6.53) Mean plasma NfL geometric mean: 56.8 pg/mL INFRONT-3 Baseline Characteristics: Data Suggest a Representative Study Population for Testing Effects of Latozinemab in FTD-GRN Compared Against Registry Data Property of Alectora. As of July 2024. 1. Staffaroni AM, et al. Nat Med. 2022;28:2194-2206.
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18 FTD-GRN Market Opportunity Property of Alector Strong Regulatory Momentum Targeted, Genetically Defined Patient Population • FTD mutation identification, age of onset, and familial association allow for targeted engagement • Latozinemab, an investigational candidate being studied in a pivotal Phase 3 trial, was granted Breakthrough, Fast Track, and Orphan Drug Designations • Support for expedited development and review High Unmet Need in FTD • Rapid progression beginning in mid-life, with significant impact on patients, families, and healthcare systems – with costs nearly 2X higher than for AD1 • Strong advocacy and family-driven efforts raising awareness No Approved Therapies • Latozinemab is the most advanced therapy in development for FTD-GRN2 FTD-GRN is a rare disease with high unmet need and no approved therapies 1. Galvin JE, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Nov 14;89(20):2049-2056. 2. Alector is not aware of any candidates in a Phase 3 for FTD-GRN as of August 2025.
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AL101/GSK4527226: Developed to Align with Needs of Larger Indications (AD) 19 • Genetics: PGRN deficiency is a risk for AD. • Biology: Modulation of PGRN in AD disease models. - PGRN ablation exacerbates AD in disease models. - PGRN overexpression is protective in AD disease models. PGRN: Genetic and Biologic Rationale for AD AL101/GSK4527226 AD Program • Phase 1: Completed in healthy volunteers. • Phase 2: Received IND clearance from FDA in AD. • Phase 2: Completed enrollment in the 76-week trial in April 2025, with trial completion expected in 2026. Property of Alector 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 7, 215 (2019). The breakdown of clinical diagnoses among ARTFL FTD mutations carriers. [Courtesy of Adam Boxer.] https://www.alzforum.org/print-series/1093496; Bellenguez C, Küçükali F, Jansen I, et al. New insights on the genetic etiology of Alzheimer’s and related dementia. medRxiv; 2020.
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Proprietary and Confidential Property of Alector 20Property of Alector AL101/GSK4527226: 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 A Plaques2 PGRN overexpression decreases Aβ plaque load in the dentate gyrus of AD mice PGRN is Protective in AD Model2
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21 76 weeks Treatment Period Up to 12 weeks Screening & Baseline AL101/GSK4527226 Dose 1 IV Placebo IV AL101/GSK4527226 Dose 2 IV 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) PHASE 2, RANDOMIZED, DOUBLE -BLIND, PLACEBO -CONTROLLED STUDY TO E VALUATE THE EFFICACY AND SAFETY OF AL101/GSK4527226 IN PATIENTS WITH EAR LY ALZHEIMER’S DISEASE AL101/GSK4527226: PROGRESS-AD Study Design Property of Alector
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22 Latozinemab and AL101 • $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. • $160 million for first commercial sale in the U.S. • $90 million for first commercial sale in at least two of the following countries: France, Germany, Italy, Spain, or the UK Latozinemab and AL101: Currently Partnered in a Collaboration Agreement with GSK Property of Alector Latozinemab INFRONT-3 pivotal Phase 3 data anticipated by mid-Q4 2025. AL101 PROGRESS-AD Phase 2 completion expected in 2026.
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Property of Alector 23 Proprietary Fully Owned Portfolio: Alector's Brain-Penetrant Anti-Aβ Antibody ADP037-ABC For Alzheimer's Disease
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Anti-Aβ Antibodies with BBB Technology Poised to Transform Treatment of AD 24 Ideal Aβ Targeted Therapy Profile • Robust efficacy • SubQ administration • Good safety profile - Low/no anemia - Low/no ARIA - No MRI monitoring - No APOE genotyping • Prevention therapy potential 1st Generation Aβ 2nd Generation Aβ 4th Generation Aβ + BBB• No approval • No efficacy • Safety risk CAA (ARIA) • Accelerated approval • Limited uptake • Safety risk / ARIA • Discontinuation • Full approvals • Modest efficacy • Slow uptake • Payer restrictions • IV infusion • Safety risk/ARIA • No approvals yet • Efficacy in testing • Rapid Aβ clearance • Low doses • Low ARIA • Anemia risk 1st Generation Aβ 2nd Generation Aβ 3rd Generation Aβ 4th Generation Aβ + BBB Alector Goals for ADP037-ABC Property of Alector Early 2000’s Today Source: ALZFORUM, Therapeutics, Amyloid-Related
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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 A plaques Safety • Proprietary ABC with tuned affinity and binding epitope seeks to facilitate effective brain penetration while minimizing hematologic adverse effects Convenience • ABC enables potential for low dosing regimen and subcutaneous delivery Optimal Engineered Anti- PyroGlu3 A Binding Epitope 1 Optimal TfR-Binding Epitope and Affinity to Maximize Brain Penetration and Avoid Hematologic Adverse Effects 3 Fully Active Constant Region 2 25 Optimal Linker4 Targeted Design Features Combines Alector’s proprietary anti-Aβ antibody with our proprietary ABC with the goal of facilitating rapid clearance of Aβ plaques with minimal ARIA and anemia and the potential for subcutaneous delivery Optimized Design of ADP037-ABC: Alector Brain Carrier-Enabled Anti-Aβ Antibody Property of Alector
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Selective Uptake of ADP037-ABC in Human Brain Endothelial Cell Line 26 ADP037-1 No-ABC ADP037-2 No-ABC ADP037-2 ABC ADP037-1 ABC Isotype Control Property of Alector Antibodies at a concentration of 500nM were incubated on the cells for 2 hours and then detected with an anti-hu IgG antibody. Alector ABC facilitated robust internalization of the anti-Aβ antibody. Alector data on file
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ADP037-ABC Facilitates Rapid Removal of A In-Vitro and In-Vivo 27 Antibody-Dependent Phagocytosis of PyroGlu3 A by Human IPSC Microglia in Culture Reduction in Brain A42 After Up to 4 Weekly IV Injections in 9-Month-Old 5XFAD Mice Reference clinical stage antibodies synthesized by Alector Property of Alector ADP037-ABC Reference anti-A-TfR Reference anti-A Isotype control A only +/-SEM, n=16-17 per group; assessed 24-168h post last dose in whole brain lysates Alector data on file
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Property of Alector 28 Proprietary Fully Owned Portfolio: Alector's Brain-Penetrant GCase Enzyme Replacement Drug ADP050-ABC For Parkinson's Disease
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GBA1 Gene Mutations Are a Major Risk Factor for Neurodegenerative Diseases 29Property of Alector Toxic when accumulated Toxic when accumulated Mutant GBA1 GCase Deficiency = Α-synuclein Aggregation Altered Lipid Homeostasis Autophagy-Lysosomal Dysfunction Mitochondrial Dysfunction • Parkinson’s Disease (PD) ▪ ~10 million patients worldwide1 ▪ 5-15% are GBA1 mutation carriers2 ▪ Activity is reduced in non-carriers2 • Gaucher’s Disease (GD) ▪ ~125,000 patients worldwide5 ▪ GBA1 mutations are causal ▪ GD type 1 have increased risk of PD6 ▪ GD type 2 and 3 are neuronopathic7 • Lewy Body Dementia (LBD) ▪ ~5-8 million patients worldwide3 ▪ 3-30% 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
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Potency • Using machine learning, ~1,400 mutations were engineered, and screened • Engineered enzyme that is >10-fold more active and stable than the WT enzyme and can enter the brain Safety • Alector Brain Carrier with tuned affinity and binding epitope and a silenced FcgR binding domain seeks to facilitate effective brain penetration while minimizing hematologic adverse effects Convenience • Alector Brain Carrier enables potential for: low dose regimen, subcutaneous delivery, and monthly dosing Engineered GCase with Improved Activity and Stability 1 Optimal TfR Epitope and Binding Affinity 3 Silenced Constant Region 2 30 Optimal Drug Format 4 Optimized Design of ADP050-ABC: Alector Brain Carrier-Enabled GCase Enzyme Combines Alector-engineered GCase enzyme with our proprietary ABC for brain-penetrant enzyme replacement for GBA1 mutation carriers with PD, GD, and LBD Targeted Design Features Property of Alector 2
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Recombinant wild-type and ADP050 GCases were tested for their ability to process 4-MUG in a cell-free in vitro assay and their stability after incubation at 37C at pH7.4. ADP050-ABC Demonstrates Greater in Vitro Activity Than WT GCase and Enhances GCase Activity in NHP CSF 31 ADP050-ABC Dependent ~10 to 100-Fold Elevation in GCase Activity in NHP CSF ADP050-ABC Activity and Stability Exceed that of the Wild-type GCase in Cell-free Assays Property of Alector Three NHP / group were injected intravenously every 7 days with ADP050-ABC, and GCase activity in CSF was analyzed following the protocol by Oftedal et al. (Sci Rep 2020). Assessment of GCase activity in brain tissue is ongoing. Enzyme Mutations Tm ℃ Half-life in PBS at 37℃ Wild-type n/a 57.5 ~ 6.0 hrs ADP050 3AA 64.2 < 4-days Alector data on file
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32 No Changes in Hemoglobin Levels After 4 Injections of up to 50mg/kg ADP050-ABC No Reduction in RBC After 4 Injections of up to 50mg/kg ADP050-ABC No Change in Red Blood Cells or Hemoglobin Following Multiple Injections of ADP050-ABC in NHP Property of Alector 3 NHP/group injected intravenously4 times at weekly intervals (black arrows) with different doses of ADP050-ABC and blood samples were analyzed for hemoglobin levels and red blood cell number at the indicated times -14 -7 0 7 14 21 0 2 4 6 8 Day RBC Count (10^6/uL) Vehicle Control ADP050 10mg/kg ADP050 50mg/kg -14 -7 0 7 14 21 0 50 100 Day Normalized Hemoglobin (%) Vehicle Control ADP050 10mg/kg ADP050 50mg/kg Alector data on file
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Alector is Focused on Opportunities to Drive Near- and Long-Term Value 33Property of Alector Alector Brain Carrier applied to: • Antibodies: Aβ, Tau • Enzymes: GCase • siRNA: Tau Novel 3R (Replace, Remove, Restore) drugs for degenerative brain disorders Advance Programs to Clinic •Latozinemab Phase 3 data by mid-Q4 2025 •AL101 Phase 2 study completion in 2026 Deliver Late-Stage Clinical Programs Future Potential to Expand Portfolio Alector’s Current Focus & Priority Goals
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Thank You