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| Item 7.01 | Regulation FD Disclosure. |
On September 13, 2023, Vigil Neuroscience, Inc. (the “Company”) held a webcast highlighting its small molecule TREM2 agonist program for Alzheimer’s disease. A copy of the presentation that accompanied the webcast is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
The information set forth under Item 7.01 and in Exhibit 99.1 attached hereto is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934 (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, except as expressly set forth by specific reference in such filing.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Slide Presentation dated September 13, 2023 (Furnished herewith) | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Vigil Neuroscience, Inc. | ||||||
| Date: September 13, 2023 | By: | /s/ Ivana Magovčević-Liebisch | ||||
| Ivana Magovčević-Liebisch | ||||||
| President and Chief Executive Officer | ||||||
Exhibit 99.1 Vigil Neuroscience Small Molecule KOL Event September 13, 2023 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Today’s Agenda 7:30 – 7:35 AM (5 min) 8:30 – 8:45 AM (15 min) Opening Remarks & Corporate Overview Alzheimer’s Disease Treatment & Unmet Need Ivana Magovčević-Liebisch, PhD, JD Samuel E. Gandy, PhD, MD Chief Executive Officer, Vigil Neuroscience, Inc. Mount Sinai Professor of Alzheimer’s Disease Research, Professor of Neurology & Psychiatry Associate Director of Mount Sinai Alzheimer’s Disease Research Center, NYC 7:35 – 7:50 AM (15 min) Past Chairman, National Medical & Scientific Advisory Council of the TREM2 Concept in Alzheimer’s Disease Alzheimer’s Association Marco Colonna, MD Robert Rock Belliveau Professor of Pathology & Immunology 8:45 - 8:50 AM (5 min) Washington University School of Medicine, St. Louis, MO Clinical Development of VG-3297, Vigil’s Small Molecule TREM2 Vigil Neuroscience, Inc. Scientific Advisory Chairman Agonist 7:50 – 8:30 AM (40 min) David Gray, PhD Chief Science Officer, Vigil Neuroscience, Inc. Overview of Vigil’s Small Molecule TREM2 Agonist Program David Gray, PhD Chief Science Officer, Vigil Neuroscience, Inc. 8:50 – 9:00 AM (10 min) Closing Remarks and Q&A Session Christian Mirescu, PhD Vice President, Head of Neuroimmunology, Vigil Neuroscience, Inc. 2 © Vigil Neuroscience, Inc. 2023. All rights reserved. © Vigil Neuroscience, Inc. 2023. All rights reserved.
Reminders § Webcast scheduled to end at 9:00am U.S. ET § Presentation is available in investors section under Events & Presentations at www.vigilneuro.com § Moderated Q&A session following prepared remarks § To submit a written question, fill out form on webcast home page § Webcast replay available later today on Vigil website under Events & Presentations 3 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Forward-Looking Statements This presentation contains “forward-looking statements,” which are made pursuant to the safe harbor provisions of the federal securities laws, including the Private Securities Litigation Reform Act of 1995. Any statements that are not statements of historical fact may be deemed to be forward-looking statements. Such statements may contain words such as “may,” “might,” “will,” “could,” “should,” “would,” “expect,” “intend,” “plan,” “prepare,” “look,” “seek,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “possible,” “continue,” “ongoing” or the negative of these terms, or other comparable words. These forward-looking statements include, among others, statements relating to: the Company’s strategy, business plans, focus and value of future milestones; the progress and timing of the preclinical development, clinical development and regulatory development of Vigil’s programs, including VGL-101 and VG-3927 and the availability of data from our clinical trials involving our product candidates and expected timing of first dosing for VG-3927; our ability to discover and build a platform of precision medicine based therapies targeting the microglia; and the patient burden of Alzheimer’s disease and potential therapeutic benefit of our product candidates. These forward-looking statements, which are only predictions, involve risks and uncertainties, many of which are beyond our control and are based on our current beliefs, expectations and assumptions regarding our business. As such, you should not place undue reliance on any forward-looking statements because such risks and uncertainties could cause actual results, performance or achievement to differ materially and adversely from those anticipated or implied in the forward-looking statements. Factors that could cause actual results to differ from those predicted in our forward-looking statements include, among others, risks and uncertainties related to conducting and reporting data analyses; product development, including delays or challenges that may arise in the development and regulatory approval of our current and future product candidates or programs; uncertainties as to the availability, analyses and timing of results and data from preclinical and clinical studies and whether results from preclinical studies and early interim data will be predictive of the results of later preclinical studies and data readouts, and other clinical trials; the timing of our ability to submit and obtain regulatory clearance for investigational new drug applications and initiate additional clinical trials; our ability to work with the FDA to successfully remove the partial clinical hold on VG-3927; our ability to initiate and complete our current and expected clinical trials; whether our cash resources will be sufficient to fund our foreseeable and unforeseeable operating expenses and capital expenditure requirements; our ability to raise additional funding on favorable terms, or at all; the rate and degree of market acceptance and clinical utility of our product candidates; the accuracy of our data analyses or estimates for the potential and market for our products; our ability, and the ability of our collaborators, to protect our intellectual property and to conduct activities for the development and commercialization of our candidates in view of third party intellectual property positions; our financial performance; our ability to retain and recruit key personnel, as well as the potential contribution of our employees and board to our growth and success as a Company; developments and projections relating to our competitors or our industry; changes in general economic conditions and global instability, in particular economic conditions in the markets on which we or our suppliers operate; changes in laws and regulations; and those risks and uncertainties identified in our filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in Quarterly Report on Form 10-Q for the quarter ended June 30, 2023, and such other risks and uncertainties that may be described in other filings we make with the SEC. You should not rely upon forward-looking statements as predictions of future events or performance, or as a representation or warranty (express or implied) by us or any other person that we will achieve our objectives and plans in any specified time frame, on such specified terms, or at all. Although our management believes that the expectations reflected in our statements are reasonable, we cannot guarantee that the future results, performance or events and circumstances described in the forward-looking statements will be achieved or occur. These forward-looking statements speak only as of the date such statements are made. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. 4 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Corporate Overview Ivana Magovčević-Liebisch, PhD, JD Chief Executive Officer Vigil Neuroscience, Inc. © Vigil Neuroscience, Inc. 2023. All rights reserved.
Vigil Neuroscience Vigil Neuroscience is a clinical-stage microglia- focused therapeutics company § Founded ~3 years ago in July 2020 § Our purpose: to treat rare and common neurodegenerative diseases by restoring the vigilance of microglia, the brain’s sentinel immune cells § Precision-based strategy for developing microglia therapeutics § Only company known to have 2 modalities for TREM2 agonism – monoclonal an body and small molecule § Highly experienced, execution-focused management team and Board of Directors § >60 highly dedicated team members 6 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Vigil’s Precision Medicine Strategy to Target Broad Range of Neurodegenerative Diseases Pipeline Candidates for Genetically Defined Subpopulations in First Indication Common Indications Rare (AD) Microgliopathy Further Expansion (ALSP) into Broader Populations in Data Driven Common Indications Expansion in Other Rare Microgliopathies Apply learnings from genetically defined subpopulations to larger indications 7 ALSP: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; AD: Alzheimer’s Disease © Vigil Neuroscience, Inc. 2023. All rights reserved.
Vigil TREM2 Agonists: Differentiated Strategy & Multiple Modalities Vigil Neuroscience Small Molecule TREM2 mAb in TREM2 Agonist in Development for Development for ALSP: VGL101 AD: VG-3927 st The 1 & ONLY TREM2 small The ONLY targeted drug candidate molecule agonist entering clinical in development for ALSP development 8 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: Small Molecule TREM2 Agonist Well-Positioned for AD § First & only small molecule TREM2 agonist entering clinical development § Excellent profile as potential treatment for Alzheimer’s Disease (AD): – Oral dosing – Superior brain penetration & differentiated pharmacokinetics & MoA vs antibody-based therapeutics > Novel MoA potentiates TREM2 response to natural damage ligands may enable • Improved potency & specificity in active disease state • Potentially more favorable safety profile – Absence of Fc effector domain may limit observations of ARIA § Investigational New Drug (IND) is now open – Phase 1 clinical trial in healthy volunteers allowed to proceed with partial clinical hold related to maximum exposure limit § Dosing in Phase 1 clinical trial in healthy volunteers to commence in Oct 2023 9 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Featured Key Opinion Leaders (KOLs) Marco Colonna, MD Robert Rock Belliveau Professor of Pathology & Immunology Washington University School of Medicine, St. Louis, MO Vigil Neuroscience, Inc. Scientific Advisory Board Chairman Samuel E. Gandy, MD, PhD Mount Sinai Professor of Alzheimer’s Disease Research, Professor of Neurology & Psychiatry Associate Director of Mount Sinai Alzheimer’s Disease Research Center, NYC Past Chairman, National Medical & Scientific Advisory Council of the Alzheimer’s Association 10 © Vigil Neuroscience, Inc. 2023. All rights reserved.
TREM2 Concept in Alzheimer’s Disease (AD) Marco Colonna, MD Robert Rock Belliveau Professor of Pathology & Immunology Washington University School of Medicine, St. Louis, MO Vigil Neuroscience, Inc. Scientific Advisory Board Chairman
Unique Developmental Origin of the Brain Resident Immune System Microglial-specific Markers: CD11b low CD45 high Cx3cr1 Tmem119 FCRLS P2RY12 Sall1 https://www.mdpi.com/1422-0067/22/18/9706 12
Microglia in Healthy & Disease States Microglia are Brain-resident First Microglia are Key to Maintaining Normal Brain Responders to Acute Brain Injury Homeostasis and Neuronal Function Microglia surveillance of healthy brain to maintain Microglia processes quickly and precisely orient to Microglia surveillance of healthy brain to Microglia processes quickly and precisely orient maintain tissue homeostasis to damage niche following focal photo-injury tissue homeostasis damage niche following focal photo-injury Nimmerjahn, A et al. (2005) Science 13
Microglia Migration into AD's Neuropathological Amyloid Plaque Microenvironment Healthy Control Brain Alzheimer’s Disease Brain Amyloid plaque Microglia Microglia Insoluble ApoE Microglia marker Amyloid plaque Aggregated ApoE Colonna Lab, unpublished data 14
Genetics of AD Inspire the Next Generation of Microglia-Targeted Therapeutics Expansion of AD Sequenced Genomes Identifies AD Genetics-identified Genes Rare And Novel Causal Genetic Risk Factors Enriched in Microglia Astrocytes Oligos ABCA7 PTK2B RIN3 SORL1 SPI1 ZCWPW1 CR1 NME8 BIN1 CD33 MS4A6A IL1RAP INPP5D PLCG2 PICALM HLA-DRB1 TREM2 ABI3 CASS4 CD2AP EPHA1 MEF2C FERMT2 CLU APOE z-score -2 0 2 Cuyvers, E and Sleegers, K (2016) Lancet Neurology; Hansen, DV et al. (2018) J Biol Chem 15 Endo cells Microglia Neurons
Targeting Neuroimmunology Specifically for Alzheimer’s Disease Distinct Genetic Links vs Inflammation Disease States Human Genetic Underpinnings of Alzheimer’s Disease Biological Substrates of Multiple Point Directly to TREM2 with Further Validation by Sclerosis Points to a Distinct Multiple Pathway Interactors Signature Adapted from Kunkle, BW et al (2019) Nature Genetics; International Multiple Sclerosis Genetics Consortium (2013) Nature Genetics 16
Why All the Focus on TREM2? Overwhelming Human Data Point to AD-risk Associated Gene, Protein & Cellular Dysfunction Association of TREM2 Variants TREM2 Mutations in AD Gene Expression in Sporadic AD with AD Risk is Robust and Suggest Loss of Ligand Binding Further Validates Involvement of Highly Replicated and Loss of Microglia Function the TREM2 Pathway Cd33 MS4a6a MS4a4a DAP12 Central Hub for Microglial GWAS Condello, C et al. (2018) Biol Psychiatry; Kober, D et al. (2016) eLife; Zhang, B et al. (2013) Cell 17
Microglial Loss-of-Signaling Hypothesis for TREM2 TREM2-DAP12 Pathway & Its Importance Beyond AD TREM2-DAP12 Signaling Transduction and TREM2 and DAP12 Mutations Cause Rare Early-onset Familial Cellular Function in Microglia Microgliopathy Called Nasu-Hakola Disease (NHD) Low avidity ligand state High avidity ligand state MRI manifestations of NHD Neuropathology in NHD patient TREM2 Ligand Organized TREM2 Clustering DAP12 pSYK Phosphorylated Signaling Complex SYK Microglia Function intracellular intracellular Satoh et al. (2010) Neuropathology; Kilic et al. (2012) Clinical Imaging 18
TREM2's Role in Microglial Activation Disease State Molecular Evidence AD Mouse Models Human AD Validation TREM2 promotes non-inflammatory, TREM2 is required for neuroprotection within Plaque-associated microglia protect neuroprotective microglia state the amyloid plaque niche neighboring neurons Key activated processes Microglia chemotaxis Immune metabolism Amyloid plaque Microglia Amyloid plaque Neuronal damage Phagocytosis Microglia Keren-Shaul, H et al. (2017) Cell ; Wang, Y et al. (2015) Cell; Yuan, P et al. (2016) Neuron 19
Preclinical Proof-of-Principle via TREM2 Agonist Antibodies Target Validation via Pharmacological Modulation TREM2 Agonist Antibody Reduces Neuronal Damage Enhanced Brain Penetration Leads to Increased Locally Around Aβ Plaques Amyloid Reduction Control tvAb TREM2 tvAb TREM2/TfR bsAb Control TREM2 AL002c Ctrl antibody Antibody* Amyloid plaque TREM2 tvAb: TREM2 tetravalent antibody *AL002 TREM2/TfR bsAb: TREM2 tetravalent antibody engineered for enhanced brain penetration TfR: transferrin receptor epitope Amyloid plaque Neuronal damage Wang, S et al. (2020) J Exp Med 20
Leveraging Microglia to Restore Tissue Homeostasis in AD Evidence from Recent Anti-Aβ Therapeutics Antibody full effector function drives microglial Aβ Anti-Aβ dual binding to AD substrate and microglia clearance Microglia Recruitment Microglia and Aβ Clearance AD Pathological Forms of Aβ Effector inactivated mAbs fail to engage microglia and lack efficacy Chauraslya, A et al. (2023) Nanomedicine-Based Approaches for the Treatment of Dementia 21
Breakthroughs in Neuroimmunology Seed a Promising New Outlook for AD Therapeutics Summary of Key Concepts § Genetics of AD point to microglia as the next generation therapeutics § TREM2 is both directly implicated as a causal gene as well as indirectly as a genetic hub § Extensive research points to their protective role in the amyloid plaque microenvironment § Preclinical genetic and pharmacological studies validate the TREM2 agonism for AD concept § Recently approved anti-Aβ therapeutics provide clinical precedent that leveraging microglia can restore tissue homeostasis in AD 22
Acknowledgements Washington Univ. Weizmann Institute University of Brescia Vigil Neuroscience Alector Marina Cella Ido Amit Luigi Poliani David Gray Tina Schwabe Susan Gilfillan Hadas Keren-Shaul William Vermi Christian Mirescu Meer Moustafa Mattia Bugatti Borislav Dejanovic Ilaria Tassi Jonathan Kipnis Brain research Institute Andrea S Omodei Kelley Larson Herve` Rhinn Niigata, Japan Igor Smirnov Adiljan Ibrahim Akiyoshi Kakita Arnon Rosenthal David M. Holtzman Mari Tada Jason Ulrich Masaki Takao Mayo Clinic Rochester Aivi Nguyen CST, Boston Amgen Rachel Larsen Tyler Levy Daniel C. Ellwanger Eleni Costantopoulos Sean Beausoleil Samuel A. Hasson Richard Cho Menno van Lookeren Campagne 23
VG-3927: First & Only Small Molecule TREM2 Agonist Entering Clinical Development for Alzheimer’s Disease David Gray, PhD Chief Science Officer, Vigil Neuroscience, Inc. © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: First & Only Clinical Oral Small Molecule TREM2 Agonist We Are Microglia Experts O Ou ut ts st ta an nd di in ng g & & P Po ot te en nt t T TR RE EM M2 2 a ag go on ni is sm m B Br ro oa ad d a an nd d f fa av vo or ra ab bl le e d di if ff fe er re en nt ti ia at te ed d c cl li in ni ic ca al l s sy yn ne er rg gi iz ze es s w wi it th h n na at tu ur ra al l m mo od du ul la at ti io on n o of f c ca an nd di id da at te e f fr ro om m d da am ma ag ge e l li ig ga an nd ds s n ne eu ur ro op pa at th ho ol lo og gy y w wo or rl ld d- -c cl la as ss s R R& &D D 25 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927 Selected from High Quality Chemical Matter Deep Understanding of MoA with Multiple Excellent Back-up Compounds Highly Efficient and Structurally Diverse Target Coverage in CNS via Oral Dosing Strong Development Path § Consistent PK across preclinical species § CNS drug properties fully optimized § Scalable and versatile synthetic route pEC50 = log [pSYK EC50] measured in HEK293T–hTREM2 cells , LogD(7.4) = Measured water/octanol partition coefficient at pH 7.4, Rat%F = percentage oral bioavailability in Wistar-Han Rats , Rat Cl = Estimated metabolic clearance rate measured in Wistar Han rats, Rat Kp = Brain to plasma partition coefficient measures in Wistar Han rats 26 © Vigil Neuroscience, Inc. 2023. All rights reserved. pEC50
VG-3927: Entering Phase 1 with Excellent Product Profile § TREM2 EC : < 0.003 µM 50 § TREM1 selectivity: > 50,000-fold § Clean profile (evaluated in ~350 § PK consistent with QD dosing Highly Potent & off-target assays) § CSF exposure ≈ free plasma Selective for TREM2 § No CYP inhibition liability § No TDI risk Compelling VG-3927 PK profile § SIF solubility: 83 µM -6 Good § MDCK Papp: >10 cm /s Permeability and § MDCK PGP ER: ~0.5 Solubility § Well tolerated with sufficient safety margins to support Ph1 § hERG margin: > 3,500-fold Favorable Safety Profile EC : half maximal effective concentration; PK: pharmacokinetics; QD: once-daily; CSF: cerebrospinal fluid; CYP: cytochrome P450 enzymes; TDI: time-dependent inhibition; hERG: human ether-a-go-go-related 27 50 gene; SIF: stimulated intestinal fluids; MDCK Papp: Madin-Darby canine kidney apparent permeability; PGP ER: P-glycoprotein efflux ration © Vigil Neuroscience, Inc. 2023. All rights reserved.
Establishing VG-3927 for Development in AD Pharmacological & Clinical Translation VG-3927 Pharmacological Profile VG-3927 Functional & Model System Profile TREM2 Human iPSC Human CNS Mouse Nonhuman engineered microglia tri-culture neurodegenerative primate profiling systems monocultures platform disease models High-throughput Therapeutically relevant Biologically diverse human Established preclinical ID and validation of profiling target cells CNS model system AD transgenic mice translational biomarkers 28 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: Potent & Selective TREM2 Agonist VG-3927 – Highly Selective Agonist for VG-3927 Signaling in Human Microglia is Fully TREM2 Over TREM1 Dependent on TREM2 125 DMSO Control 300 100 VG-3927 TREM2 EC <1nM 50 75 200 50 TREM1 EC >50,000 nM 50 100 25 0 0 TREM2 Wild-type TREM2 Knockout Microglia Microglia VG-3927 (nM) 29 DMSO: dimethyl sulfoxide © Vigil Neuroscience, Inc. 2023. All rights reserved. pSYK Tyr525/526 Induction (% of Maximal Response) TREM2 Activation WT (% pSYK Induction vs TREM2 DMSO)
VG-3927: Potent TREM2 Agonist in Neurodegenerative Disease- Associated TREM2 Variants Supports Precision-based Clinical Development Vigil Precision AD Strategy VG-3927 Potency Across Notable AD-risk Variants of TREM2 TREM2 R47H TREM2 R62H TREM2 H157Y TREM2 Highly Variant Potent 125 Common 100 Variant 75 R47H 50 R62H 25 H157Y Accelerated Path to 0 Successful Clinical POC T96K -11 -10 -9 -8 -7 -6 -11 -10 -9 -8 -7 -6 -11 -10 -9 -8 -7 -6 Log [VG-3927, M] Log [VG-3927, M] Log [VG-3927, M] 30 © Vigil Neuroscience, Inc. 2023. All rights reserved. pSYK Tyr525/526 Induction (% of Maximal Response)
VG-3927 Potentiates Signaling of Damage-associated Ligands Damage-associated Ligand: Sulfatide Potentiation of TREM2 Focusing Efficacy in Pathological TREM2 Signaling Activation Activation Microenvironments VG-3927 800 High 600 VG-3927 Low VG-3927 400 + Sulfatide Plaque- 200 burdened CTL 100 AD State 0 VG-3927 32 100 320 1000 Sulfatide Alone Sulfatide Level Alone (Concentration, nM) 31 CTL: control; Low: VG-3927 at 2 nM; High: VG-3927 at 125 nM © Vigil Neuroscience, Inc. 2023. All rights reserved. TREM2 Signaling Activation (% Max pSYK of Natural Ligand) TREM2 Activation
TREM2 AD-risk Variants Are Loss of Function & Impact Signaling Example: R47H Leads to Defective Sensing of Sulfatide Mutation Impact: R47H TREM2 § Missense in ligand binding domain Variant § Loss of TREM2 response to sulfatide (damage-associated ligand) Damage- TREM2 Activation (CV vs R47H Variants) Genotype Impact on TREM2 Activation associated Based on pSYK Activation ligand R47H 32 TM: transmembrane domain; ICD: intracellular domain; CV: common variant; LoF: loss of function © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927 Restores TREM2 Response to Damage-associated Ligand in R47H Rescues Signaling Impairment in AD-risk Variant § TREM2-R47H defective response to damage-associated ligand (sulfatide) VG-3927 § VG-3927 rescues signaling and response to sulfatide TREM2 SM for AD § Similar effects observed in TREM2 R62H AD-risk variant VG-3927 Fully Restores Compromised VG-3927 Fully Restores TREM2 R47H Defect Signaling in AD-risk Variant R47H : R47H TREM2 400 VG-3927 343% 322% 334% High 334 300 VG-3927 VG-3927 VG-3927 Sulfatide Sulfatide Sulfatide 200 Synergy Synergy Synergy Low 100 100% CTL 56% <10% 0 -10 -9 -8 -7 -6 -5 CV:CV CV:R47H R47H:R47H Log [Sulfatide] (M) TREM2 Sulfatide Response (% CV:CV control) CTL: control; Low: VG-3927 at 1 nM; High: VG-3927 at 100 nM 33 © Vigil Neuroscience, Inc. 2023. All rights reserved. Relative pSYK Induction CV (% Max induction of TREM2 TREM2 Activation
VG-3927 Acts as a Molecular Glue to Stabilize TREM2 Complex Novel Mechanism of Action Higher molecular weight band reveals novel receptor ligand complex Non-denatured states (Native PAGE) in iMGLs TREM2 immunoprecipitation in HEK system 34 Neg CTL: negative control; DMSO: dimethyl sulfoxide; KO: knock-out; PAGE: polyacrylamide gel electrophoresis; iMGLs: induced pluripotent stem cell-derived microglia; HEK: human embryonic kidney © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927 Orchestrates Multi-Protein Interaction to Trigger Signaling Unique Molecular Glue Mechanism of Action Unassembled Inactive VG-3927 Minimal TREM2 and DAP12 VG-3927 Brings Together Quantification of TREM2- TREM2 Receptor Complex TREM2 SM for AD Interaction at Baseline Both Signaling Partners DAP12 Interaction extracellular Proximity-induced CTL VG-3927 80 fluorescence 60 40 TREM2 TREM2 20 0 p pD DA AP P1 12 2 CTL VG-3927 DAP12 pSYK Fluorescence signal § TREM2 clusters and utilizes DAP12 to initiate downstream signaling generated by TREM2- DAP12 proximity § VG-3927 coordinates these protein-protein interactions SYK SYK intracellular 35 © Vigil Neuroscience, Inc. 2023. All rights reserved. TREM2-DAP12 Proximity (Sum Spot Area per Well) >3x Induction
Establishing VG-3927 for Development in AD Pharmacological & Clinical Translation VG-3927 Pharmacological Profile VG-3927 Functional & Model System Profile TREM2 Human iPSC Human CNS Mouse Nonhuman engineered microglia tri-culture neurodegenerative primate profiling systems monocultures platform disease models High-throughput Therapeutically relevant Biologically diverse human Established preclinical ID and validation of profiling target cells CNS model system AD transgenic mice translational biomarkers 36 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: First & Only Small Molecule TREM2 Agonist Entering Clinical Development for Alzheimer’s Disease Christian Mirescu, PhD Vice President, Head of Neuroimmunology, Vigil Neuroscience, Inc. © Vigil Neuroscience, Inc. 2023. All rights reserved.
Establishing VG-3927 for Development in AD Pharmacological & Clinical Translation VG-3927 Pharmacological Profile VG-3927 Functional & Model System Profile TREM2 Human iPSC Human CNS Mouse Nonhuman engineered microglia tri-culture neurodegenerative primate profiling systems monocultures platform disease models High-throughput Therapeutically relevant Biologically diverse human Established preclinical ID and validation of profiling target cells CNS model system AD transgenic mice translational biomarkers 38 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Vigil Human CNS Platform Combines Neurons, Astrocytes & Microglia Human iMGL Monoculture Platform Human CNS Tri-culture Platform Pharmacology in disease-relevant human cells Bridge to a predictive human translational system § Microglial pharmacology§ Vigil’s fully human translational cell model § Target selectivity§ Understand interactions between diverse CNS cells § Fine mapping agonism§ Complementary with mono-culture applications Microglia Neurons Astrocytes Microglia 39 iMGL: induced pluripotent stem cell (iPSC)-derived microglia © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927 Functional Profiling in CNS Tri-Culture Platform VG-3927 Modulates Established VG-3927 Target Engagement Biomarker Platform Application: Understand 2,000 Mobilizing microglia response with a VG-3927 Downstream Biology & favorable, non-inflammatory profile Human Neuroprotective Actions 1,800 § Boosting of neuroprotective markers 1,600 § Plus countering inflammation- Neurons 1,400 induced neurodegeneration Astrocytes Microglia 1,200 1,000 40 © Vigil Neuroscience, Inc. 2023. All rights reserved. sTREM2 (pg/mL)
VG-3927: Enhances Signals of Microglia Mobilization Favorable, Non-inflammatory Profile Enhancement of Microglia Suppression of Migration Signal Pro-inflammatory Cytokines IL-1b Reduction IP-10 Increase VG-3927 Tunes Microglial Secreted Factors 4 0.25 * ** Chemotaxis * Signals 3 0.20 2 0.15 Baseline 1 0.10 Inflammation VG-3927 Cytokines * denotes p<0.05 * denotes p=0.01; ** denotes p=0.001 41 © Vigil Neuroscience, Inc. 2023. All rights reserved. IP-10 (pg/mL) IL-1b (pg/mL)
VG-3927 Reduces Established Neurodegeneration Biomarkers Reduction of Extracellular NfL & Tau VG-3927’s Impact on Key VG-3927 Reduces Extracellular NfL VG-3927 Reduces Extracellular Tau Neurodegeneration Biomarkers Accumulation in Human Tri-cultures Accumulation in Human Tri-cultures in Humans Vehicle VG-3927 Vehicle VG-3927 Extracellular 250 400 NfL & Tau Damage state 200 300 150 200 100 100 50 Intracellular NfL & Tau Healthy state 0 0 1 2 3 4 1 2 3 4 Days Post-Treatment Days Post-Treatment NfL: neurofilament ANOVA , p<0.0001 ANOVA , p<0.0001 Treatment Treatment 42 © Vigil Neuroscience, Inc. 2023. All rights reserved. Extracellular NfL (% Baseline) Extracellular Tau (% Baseline)
VG-3927 Protects Against Inflammation-Induced Astrogliosis VG-3927 Reduces Astrogliosis TREM2 Agonism Activates Anti- GFAP: Marker of Astrogliosis Biomarker (GFAP) in Human CNS inflammatory Benefit Tri-cultures CTL VG-3927 Neurodeg Stimulus Extracellular GFAP LPS/IFNy Damage state 150 125 VG-3927 100 Neuro- inflammation 75 Intracellular GFAP 50 Healthy state Neurodegeneration Astrogliosis 1 2 3 4 Extracellular NfL and Tau Extracellular GFAP Days Post-neurodegeneration Human iPSC Astrocyte Stimulus LPS: lipopolysaccharide; IFNƳ: interferon-gamma; GFAP: glial fibrillary acidic protein 43 © Vigil Neuroscience, Inc. 2023. All rights reserved. Extracellular GFAP (% Baseline)
VG-3927 Protects Against Biomarkers of Inflammation-Induced Neurodegeneration TREM2 Agonism Activates Anti- VG-3927 Suppresses Extracellular NfL & Tau Accumulation in LPS Model inflammatory Benefit CTL VG-3927 CTL VG-3927 Neurodeg Stimulus LPS/IFNy 200 400 150 300 VG-3927 100 200 Neuro- inflammation 50 100 0 0 Neurodegeneration Astrogliosis 1 2 3 4 1 2 3 4 Extracellular GFAP Extracellular NfL and Tau Days Post-neurodegeneration Days Post-neurodegeneration Stimulus Stimulus ANOVA , p<0.05 ANOVA , p<0.05 Treatment Treatment 44 © Vigil Neuroscience, Inc. 2023. All rights reserved. Extracellular NfL (% Baseline) Extracellular Tau (% Baseline)
Establishing VG-3927 for Development in AD Pharmacological & Clinical Translation VG-3927 Pharmacological Profile VG-3927 Functional and Model System Profile TREM2 Human iPSC Human CNS Mouse Nonhuman neurodegenerative engineered microglia tri-culture primate profiling disease models systems monocultures platform Established preclinical High-throughput Therapeutically relevant Biologically diverse human ID and validation of AD transgenic mice profiling target cells CNS model system translational CSF biomarkers 45 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: Functionally Active in AD State VG-3927 & VGL101 mAb Activate Neuroprotective Genes Similarly Mouse Amyloidosis Model VG-3927 Recapitulates TREM2 VG-3927 Activates Protective VG-3927 Oral Dosing Antibody Gene Signatures Microglia Gene Signatures Amyloid-beta (Aβ) Microglia (Iba1) Model: 5xFAD AD (mut APP/PS1) + hTREM2 46 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Exploring VG-3927 Therapeutic Effects in Aβ Plaque-bearing Mice Initial Pilot Study VG-3927 Effects in Humanized TREM2 Disease-modifying Effects of VG-3927 on Aβ Pathology & AD-related AD Mouse Model Hallmarks Intervention: Post-plaque deposition Vehicle VG-3927 vs Initial age: 4.5 month-old 5xFAD-hTREM2 mice Daily Dosing for 6 Weeks VG-3927 10mpk QD Amyloid plaques Microglia 47 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927 Reduces Aβ Pathology in Plaque-bearing Mice Preliminary Effects Following 6 Weeks of Oral Dosing VG-3927 Effects on VG-3927 Effects on VG-3927 Aβ Plaque Area Insoluble Aβ 1-42 Immunohistology from Brain Slices Biochemistry of Brain Homogenates § Trend toward reducing plaque 125 125 area and insoluble Aβ 100 100 § Additional potential to reduce 75 75 plaque-associated ApoE 50 50 25 25 0 0 48 © Vigil Neuroscience, Inc. 2023. All rights reserved. Aβ Plaque Area (Percent of Vehicle) Insoluble Aβ 1-42 (Percent of Vehicle)
VG-3927 Reduces Neuropathology-associated Aggregated ApoE Preliminary Effects Following 6 Weeks of Oral Dosing Working Model of VG-3927 Modulation No Change in Soluble ApoE Reduced Aggregated ApoE Functional Form Pathological Form of AD-related Pathology Aβ-ApoE Complexes 125 125 100 100 VG-3927 Extracellular Synergy 75 75 neuropathological microenvironment 50 50 VG-3927 25 25 Intracellular space of non inflammatory TREM2 TREM2 activated uptake 0 0 microglia VG-3927 microglia clearance 49 © Vigil Neuroscience, Inc. 2023. All rights reserved. Soluble ApoE (Percent of Vehicle) Insoluble ApoE (Percent of Vehicle)
Confirmation of Oral Bioavailability, Brain Penetrance & CNS Target Engagement Favorable PK & PD Demonstrated in Non-Human Primates (NHPs) Translation Biomarker Path to Clinic CSF Biomarker of TREM2 Target Engagement VG-3927 CNS Exposures Reduction of sTREM2 in NHP CSF PK Following Single Oral Dose Relative Change from Pre-dose Levels 30 CSF 20 sTREM2 10 iMGL pSYK EC 50 0 0 4 8 12 16 20 24 PK Timecourse (hours) Cynomolgus Monkey po: “per os” or oral dosing 50 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Establishing VG-3927 for Development in AD Pharmacological & Clinical Translation VG-3927 Pharmacological Profile VG-3927 Functional and Model System Profile TREM2 Human iPSC Human CNS Mouse Nonhuman engineered microglia tri-culture neurodegenerative primate profiling systems monocultures platform disease models High-throughput Therapeutically relevant Biologically diverse human Established preclinical ID and validation of profiling target cells CNS model system AD transgenic mice translational CSF biomarkers 51 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: First & Only Clinical Small Molecule TREM2 Agonist for AD Broad modulation of neuropathology by harnessing microglia VG-3927, TREM2 SM for AD § Phase 1 dosing in healthy volunteers to commence in Oct 2023 § Differentiated TREM2 agonist – Highly potent and selective – Orally bioavailable and brain penetrant § TREM2 natural ligand boosting § Broad modulation of neuropathology 52 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Alzheimer’s Disease Treatment & Unmet Need Samuel E. Gandy, PhD, MD Mount Sinai Professor of Alzheimer’s Disease Research, Professor of Neurology & Psychiatry Associate Director of Mount Sinai Alzheimer’s Disease Research Center, NYC Past Chairman, National Medical & Scientific Advisory Council of the Alzheimer’s Association
Alzheimer’s Disease (AD) β-amyloid Tau § Progressive degenerative disease § Most common cause of dementia in elderly § Progressive memory loss, impaired thinking, disorientation, language problems, mood disturbances § Complete dependence in advanced stages Inflammation Neurodegeneration Multiple Pathophysiological Mechanisms Underly Alzheimer’s Disease β-amyloid Plaques Tau Tangles Clinical Decline Inflammation Neurodegeneration Plowey E et al, Acta Neuropathol (2022); https://www.nlm.nih.gov/medlineplus/magazine/issues/fall10/articles/fall10pg20-21.html https://step1.medbullets.com/neurology/113089/alzheimer-disease; https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.027315 54
AD Presents a Significant Unmet Medical Need 1 § An estimated 6.7 million Americans are living with Alzheimer’s disease – 1 in 9 people, age 65 and older has AD – Accounts for 60-80% of all dementia cases – Increasing incidence due to an aging population – 7th leading cause of death § Enormous societal and economic burden – Long duration of illness and time spent in a state of severe disability & dependence – >11 million Americans provide unpaid care for a family member or friend with AD & other dementia § Delaying the onset and progression of AD by 1 year may result in 9.2 million fewer cases in global 2 burden by the year 2050 1. Alzheimer’s Disease Facts & Figures 2023 Alzheimer’s Association; 2. Brookmeyer R, et al. Alzheimer's Dement. 2007;3(3):186-19 55
Current Treatment Options for AD Symptomatic Treatment Anti-Aβ Monoclonal Antibodies § Cholinesterase inhibitors and NMDA antagonists § Aβ lowering immunotherapies to improve symptoms § 22-30% slowing in clinical decline § Does not impact brain pathology or modify the § Administered by intravenous infusion once or disease course twice a month § Offers modest clinical benefit but effects wane § Can cause ARIA (brain edema, microbleeds), a over time due to disease progression common side effect that requires MRI monitoring Unmet need remains for therapeutics with improved safety and efficacy that address broader AD disease pathophysiology ARIA - Amyloid-Related Imaging Abnormalities 56
Anti-Aβ mAbs with Efficacy Are Associated with ARIA § Transient radiographic finding, occurs early in the treatment course § Monitorable by MRI surveillance § Managed by dose titration and dose suspension Anti-Aβ mAbs Efficacy on CDR-SB Aβ plaque removal ARIA Effective at Lowering ~22-30% slowing ✓✓ 1-3 Aβ Plaques 4-5 Do Not Lower Aβ Plaques X X X Small Molecule Modality Offers the Potential to Mitigate ARIA Liability CDR-SB: Clinical Dementia Score Sum-of-Boxes; ARIA - Amyloid-Related Imaging Abnormalities 1. van Dyck et al. NEJM (2023); 2. Haeberlein et al. JPAD (2022); 3. Sims et al. JAMA (2023); 4. Honig et al. NEJM (2018); 5. Ostrowitzki et al. JAMA Neurol (2022) 57
Unmet Needs & Key Opportunities in AD Therapeutics § ARIA a common side effect, § Efficacy limited to ~30% requires MRI monitoring slowing in clinical decline Greater Improved § Immunogenicity Efficacy Safety Combination Access § Intravenous infusions § Address broader biology of Therapy once/twice monthly the disease beyond Aβ 58
Human Genetics Motivates Targeting Microglia for Next-gen AD Therapeutics >30% of AD-risk Genes Are Expressed by Microglia APP AAP Metabolism Causes AD PSEN2 PSEN1 Tau Metabolism Cholesterol metabolism Rare alleles causing Immune Response Mendelian inheritance Endocytosis High Cytoskeleton Development APOE4/ APOE4 Low frequency Epigenetics variants with Unknown intermediate effects APOE 4 Medium ADAM 10 UNC5C PLD3 TREM2 Common variants conferring small increased risk ZCWP PTK2 B BIN 3 FERMT 2 INPP5 W1 ADBA7 CR1 DSG2 SORL1 NME 8 BIN 1 CD33 PICALM CASS4 D Low HLA- SLC24 CD2AP MS4A CELF 1 MEF2C EPHA1 CLU DRB1 A4 Rare Low Frequency Common Allele Frequency Lane et al European Journal of Neurology (2017) 59 Risk of Alzheimer’s
Human Genetics & Disease Models Suggest Optimizing Microglia Function May Be Beneficial § AD-related TREM2 variants exhibit impaired ligand binding & partial loss-of- microglia function § Genetic mutations associated with reduced microglia function also implicated in other genetic forms of neurodegeneration Gene Condition Associated with Gene Mutation NHD/PLOSL TREM2 Increase risk for AD TYROBP/DAP12 NHD/PLOSL CSF1R ALSP TREM2 Agonism Enhanced Barrier Function and Phagocytosis Resulting in Reduced Neuronal Loss in in vitro and Animal Models of AD NHD – Nasu Hakola; PLOSL - Polycystic Lipomembranous Osteodysplasia; FTD – Frontotemporal Dementia; ALSP - Adult-onset Leukoencephalopathy with Axonal Spheroids Pigmented Glia Golde T. Neuron (2019); Lewcock JW et al. Neuron (2020); Wang S et al JEM 2020 60
TREM2-R47H Variant Carriers Exhibit Faster Decline & Worse Cognition Compared to Non-Carriers Individuals with AD Cognitively Normal Elderly Carriers 20 Noncarriers Worsening 15 More impairment 1.67 CDR-SB/year 10 1.37 CDR-SB/year 5 23% faster decline in carriers p=0.02 0 2 4 6 8 10 Years Jonsson T et al. NEJM (2013); Del-Aguila JL et al. J Alzheimer's Dis. (2018) 61 Model predicted CDR-SB
VG-3927: Well-Positioned for Clinical Development in AD § Orally bioavailable brain penetrant small molecule § Potent and highly TREM2-specific § Potentiates TREM2 response to natural damage ligands across different AD-associated genetic TREM2 variants § Optimal balance of promoting neuroprotective function and suppressing proinflammatory activity of microglia § Preliminary data showing impact on AD pathophysiology in an animal model of AD § Clear target engagement in non-human primates 62
VG-3927 Has Potential to Address Unmet Needs & Opportunities in AD Mitigate ARIA Drive greater efficacy • No Fc-mediated interactions • Boosting microglial repair functions • Specificity of response to • Impact broader disease disease microenvironment pathophysiology Greater Improved • Favorable kinetic profile vs Efficacy Safety mAbs Combination • Convenient oral option vs i.v. • Small molecule optimal for Access Therapy infusion of immunotherapies combination therapy and AD prevention paradigms 63
Clinical Development of VG-3297, Vigil’s Small Molecule TREM2 Agonist David Gray, PhD Chief Science Officer Vigil Neuroscience, Inc. 64 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927 Phase 1 Trial in Healthy Volunteers Trial Population§ Healthy volunteers (HVs) including an elderly cohort § Double-blind, placebo-controlled Trial Design § Single (SAD) & multiple (MAD) ascending dose cohorts § VG-3927 or placebo (oral dosing) Treatment Duration§ SAD – single dose § MAD – once daily for 14 days § Safety and tolerability Treatment Duration § Pharmacokinetics (PK) § Pharmacodynamics (PD) based on CSF biomarkers (sTREM2, sCSF1R, osteopontin) 65 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: Early-stage Clinical Strategy to De-risk Development for AD § Safety, tolerability, PK & PD § SAD/MAD in healthy volunteers includes an elderly cohort in MAD Phase 1 § Target engagement: based on CSF levels of sTREM2; downstream PD: based on sCSF1R and osteopontin in CSF Healthy Volunteers § Dosing to commence in Oct 2023 § Interim data on SAD/MAD cohorts in mid-2024 § Safety and proof-of-pharmacology in symptomatic AD patients Phase 1b § Characterize pharmacology in genetic subpopulations including disease associated TREM2 variant carriers to AD Patients inform patient population for future clinical development § Phase 1b to inform on target AD population and study design to assess safety and proof-of-concept in Phase 2/PoC AD Patients symptomatic AD patients 66 HIGHLY CONFIDENTIAL © Vigil Neuroscience, Inc. 2023. All rights reserved.
Closing Remarks Ivana Magovčević-Liebisch, PhD, JD Chief Executive Officer Vigil Neuroscience, Inc. © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927: Differentiated Oral TREM2 Agonist with De-risked Precision-based Clinical Strategy for AD § First & only small molecule TREM2 agonist entering clinical development § Harnesses neuroprotective activity of microglia via highly-potent & specific TREM2 agonism § Differentiated profile to potentially address AD therapeutic needs: – Unique MoA (potentiation of TREM2 response to natural damage ligands) for improved efficacy & safety – Activates microglia with broad non-inflammatory profile – Absence of Fc-effector domain & favorable PK for ARIA mitigation/management – Amenable to future combination treatment regimens – Convenient & patient-friendly oral dosing § Genetically guided precision-based clinical strategy to de-risk drug development 68 © Vigil Neuroscience, Inc. 2023. All rights reserved.
VG-3927 Small Molecule TREM2 Agonist Milestones Q3 2023 Submit IND for VG-3927, oral small molecule TREM2 agonist ü Begin Phase 1 dosing of VG-3927 in healthy volunteers Oct 2023 Report interim Phase 1 SAD/MAD data of VG-3927 in healthy volunteers Mid-2024 69 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Vigil is Well-positioned to Execute on Our Mission We are an experienced and Microglial biology is Our vision is a passionate team rapidly becoming a brighter tomorrow of innovators new frontier for for people with TREM2 deficiency CNS drug discovery devastating leads to microglial neurodegenerative dysfunction and drives diseases neurodegeneration 70 © Vigil Neuroscience, Inc. 2023. All rights reserved.
Q&A 71 © Vigil Neuroscience, Inc. 2023. All rights reserved.