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Transporting Biotherapeutics Across the Blood-Brain Barrier

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Transporting Biotherapeutics Across the Blood-Brain Barrier Transporting Biotherapeutics Across the Blood-Brain Barrier October 15, 2020 Disclaimers Forward Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this presentation, including, without limitation, statements regarding future results of operations and financial position of Denali Therapeutics Inc. (“Denali” or the “Company”); Denali’s business strategy, business plans, product candidates, planned preclinical studies and clinical trials; expectations regarding the timing of results of such studies and trials; plans, timelines and expectations related to DNL310, Denali’s TV technology platform and TV programs; the ability of the TV technology to effectively deliver large therapeutic molecules across the blood-brain barrier (“BBB”); plans, timelines and expectations related to DNL151 and other LRRK2 inhibitor molecules; plans, timelines and expectations related to DNL788, DNL758 and DNL343; expectations related to clinical trials to address Hunter Syndrome and the ability to establish biomarker proof-of-concept in patients by end of 2020; the potential benefits and results of the collaborations with Denali’s partners, including Biogen, Sanofi and Takeda; plans and expectations regarding patient recruitment, planned regulatory filings, long-term development plans and near-term pipeline milestones; and Denali’s priorities, regulatory approvals, timing and likelihood of success and expectations regarding collaborations, are forward-looking statements. Denali has based these forward-looking statements largely on its current expectations and projections about future events. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including but not limited to, risks related to: any and all risks to Denali’s business and operations caused directly or indirectly by the evolving COVID-19 pandemic; the risk of the occurrence of any event, change or other circumstance that could give rise to the termination of Denali’s collaboration agreements, including those with Biogen, Sanofi and Takeda; Denali’s early stages of clinical drug development; Denali’s ability to complete the development of, and if approved, commercialization of its product candidates; Denali’s dependence on successful development of its BBB platform technology, product candidates currently in its core program and biomarker strategy; expectations and potential benefits of strategic collaboration agreements may not be met and Denali may not be able to attract collaborators with development, regulatory and commercialization expertise; Denali’s ability to conduct or complete clinical trials on expected timelines; the risk that preclinical profiles of Denali’s product candidates, such as DNL 151 and DNL788, may not translate in clinical studies, and the uncertainty that any of Denali’s product candidates will receive regulatory approval necessary to be commercialized; Denali’s ability to obtain and maintain regulatory approval of its product candidates, and any related restrictions, limitations and/or warnings in the label of any approved product candidate; Denali’s ability to continue to create a pipeline of product candidates and develop commercially successful products; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates and BBB platform technology; implementation of Denali’s strategic plans for its business, product candidates and BBB platform technology; Denali’s ability to obtain funding for its operations, including funding necessary to develop and commercialize its product candidates; and other risks. In light of these risks, uncertainties and assumptions, the forward-looking statements and events discussed in this presentation are inherently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward- looking statements. Accordingly, you should not rely upon forward-looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali’s Annual Report on Form 10-K filed with the SEC on March 12, 2019, Denali’s Quarterly Report on Form 10-Q filed with the SEC on August 7, 2020 and Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward-looking statements, to conform these statements to actual results or to make changes in Denali’s expectations, except as required by law. Accuracy of Data This presentation contains statistical data based on independent industry publications or other publicly available information, as well as other information based on Denali’s internal sources. Denali has not independently verified the accuracy or completeness of the data contained in these industry publications and other publicly available information. Accordingly, Denali makes no representations as to the accuracy or completeness of that data. 2 AGENDA TIME (ET) TOPIC SPEAKER 1:00 – 1:30 p.m. Introduction and Blood-Brain Barrier Transport Vehicle (TV) Overview Ryan Watts, PhD CEO, Denali Simon Jones, MRCPCH, MBChB 1:30 – 1:50 p.m. Hunter Syndrome: Overview Willink Unit, Manchester Centre for Genomic Medicine 1:50 – 2:20 p.m. TV Flagship Program: ETV:IDS (DNL310) Carole Ho, MD CMO and Head of Development, Denali 2:20 – 2:40 p.m. Q&A 2:40 – 2:50 p.m. Break 2:50 – 3:20 p.m. TV Portfolio Programs Joe Lewcock, PhD CSO and Head of Discovery, Denali 3:20 – 3:35 p.m. UnlocKing the TV Platform Potential Alex Schuth, MD COO, Denali 3:35 – 4:00 p.m. Q&A 3 Introduction Ryan Watts, PhD, CEO OUR PURPOSE: DEFEAT DEGENERATION RARE NEURODEGENERATIVE AMYOTROPHIC DISEASES LATERAL SCLEROSIS PARKINSON’S ALZHEIMER’S Orphan 20,000+ (US) 1,000,000+ (US) 5,800,000+ (US) >30 lysosomal storage diseases >45 known genetic associations >95 known genetic associations >35 known genetic associations D n i o s i t e a a l s u e p P o o P p y u h l t a l t a i o e n H Normal PD Normal AD Significant unmet medical need with few disease-modifying medicines 5 OUR PRINCIPLES SCIENTIFIC Genetic Pathway Potential Engineering Brain Delivery Biomarker-Driven Development BUSINESS Broad Portfolio Parallel Investments Strategic Partnering 6 DEGENOGENES DEFINE NEURODEGENERATION BIOLOGY Glial Biology-related Degenogenes PILRA Lysosomal Function-related Degenogenes Cellular Homeostasis-related Degenogenes Other Degenogenes Number of Genetic Associations and Implicated Genes Implicated and Associations of Genetic Number Disease Alzheimer’s Alzheimer’s APOE4 Disease Parkinson’s Parkinson’s ALS / FTD / ALS 7 OUR PORTFOLIO APPROACH DIVERSE DIFFERENTIATED DATA-DRIVEN Therapeutic Pipeline Brain Delivery Technology Drug Development D n i o s i t e a a l s u e p P o o P p y u h l t a l t a i o e n H Multiple therapeutic targets, Two Platforms: Focus on target engagement, modalities and indications in Degenogene Biology & pathway engagement, and neurodegeneration BBB Technologies patient phenotyping for clinical decisions 8 OUR PROGRESS: PAST TWO YEARS • RIPK1 decision to advance 3Q DNL788; pause DNL747 3Q 1Q • Biomarker PoC LRRK2 inhibitors • Initiated P1/2 in Hunter syndrome (HV & PD for DNL201; HV for (ETV:IDS/DNL310) DNL151) • Sanofi initiated Ph1b COVID-19 of • IND accepted for ETV:IDS/DNL310 • Sanofi initiated Ph1 HV peripheral inhibitor for MPSII 1Q with peripheral inhibitor (RIPK1:DNL758) (RIPK1: DNL758) • First in human dosing of EIF2B • Selected DNL151 for late-stage • Initiated Ph1b in ALS activator (DNL343) testing in PD (LRRK2) (RIPK:DNL747) • Added PTV:PRGN & ETV:SGSH to • Initiated Ph1b in PD • Biogen partnership portfolio • Initiated Ph1b in AD (LRRK2: DNL151) $560M upfront, $465M equity (RIPK:DNL747) • $207M follow-on offering ($23/share) investment 2019 2020 • PoC data expected for • Orphan Drug & Rare Pediatric Disease ETV:IDS/DNL310 in Designation for ETV:IDS/DNL310 Back-to-back publications on 2Q 2Q TV Platform Technology in 4Q Hunter syndrome Science Translational Medicine Clinical RegUlatory Portfolio Corporate Milestones Milestones Transitions Strategy 9 OUR PORTFOLIO Large Molecule (TV Platform) Small Molecule AAV DRUG DEVELOPMENT PROGRAM TARGET DRUG CANDIDATE DISEASE INDICATION PARTNER Drug Discovery IND-Enabling Early Clinical Late Clinical Approved LYSOSOMAL FUNCTION PATHWAY LRRK2 DNL151 Parkinson’s Biogen Iduronate 2-sulfatase DNL310 MPS II (Hunter Syndrome) PGRN DNL593 Frontotemporal Dementia Takeda Alpha-Synuclein ATV:aSyn Parkinson’s, DLB, MSA Sulfamidase ETV:SGSH MPS IIIA (Sanfilippo Syndrome) Undisclosed ETV:LF1 LSD with Neurodegeneration Undisclosed AAV:LF2 Parkinson’s GLIAL BIOLOGY PATHWAY RIPK1 (CNS) DNL788 Alzheimer’s, ALS, MS Sanofi TREM2 DNL919 Alzheimer’s Takeda Undisclosed GB1 ALS CELLULAR HOMEOSTASIS EIF2B DNL343 ALS, FTD Tau ATV:Tau Alzheimer’s Takeda Abeta ATV:Abeta Alzheimer’s Biogen Undisclosed CH1 ALS, Parkinson’s OTHER COVID-19, Peripheral RIPK1 (Peripheral) DNL758 Sanofi Inflammatory Diseases LRRK2 (Peripheral) DNL975 Crohn’s Disease Biogen 10 HER2 ATV:HER2 Oncology 2020 CLINICAL PROGRESS AND PLANS LRRK2 § Entered strategic collaboration with Biogen Parkinson’s § Advancing DNL151 into late-stage clinical trials in 2021 EIF2B § DNL343 Phase 1 in HV results to enable patient study – end of 2020 / early 2021 ALS RIPK1 § IND submitted for DNL788 (Sanofi) CNS § First in human dosing
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