Denali Therapeutics Inc. · NASDAQ:DNLI
Denali Therapeutics — Technical Presentation (October 2021)
89 slides from Denali Therapeutics's technical presentation, Oct 6, 2021
Slide 1: ALS/FTD Webinar
ALS/FTD Webinar October 6, 2021
Slide 2: Disclaimers: Forward Looking Statements
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
Slide 3: Agenda
AGENDA TIME (PT) TOPIC SPEAKER 1:30 – 1:40pm Introduction Ryan Watts, PhD Chief Executive Officer Gene Yeo, PhD 1:40 – 2:00pm Stress Granules in Neurological Disease Professor of Cellular and Molecular Medicine University of California San Diego (UCSD) Ryan Watts, PhD Chief Executive Officer 2:00 –
Slide 4: Introduction
Introduction
Slide 5: Our Purpose: Defeat Degeneration
OUR PURPOSE: DEFEAT DEGENERATION Degeneration creates significant unmet medical need, with few disease-modifying medicines Amyotrophic Lateral Lysosomal Storage Parkinson’s Alzheimer’s Sclerosis & Disease Disease Disease Frontotemporal Dementia 5 ©2021 Denali Therapeutics. All rights reserved.
Slide 6: Our Approach: Apply Discovery and Development Principles
OUR APPROACH: APPLY DISCOVERY AND DEVELOPMENT PRINCIPLES LIFE-THREATENING DISEASES WITH OUR PRINCIPLES LIMITED OR NO TREATMENT OPTIONS DEGENOGENES ENGINEERING BIOMARKER Worldwide Prevalence Non-symptomatic GENETIC PATHWAY BRAIN DRIVEN Treatment Options POTENTIAL DELIVERY DEVELOPMENT ALZHEIMER’S DISE
Slide 7: Our Progress: Recent Achievements Create Momentum
OUR PROGRESS: RECENT ACHIEVEMENTS CREATE MOMENTUM ü DNL151 (Parkinson’s): Positive Ph1/1b; advancing to late-stage development ü DNL310 (Hunter syndrome): Positive six-month data; advancing to late stage 5 ü DNL343 (ALS): Positive interim Ph1 data; Ph1b ongoing in ALS clinical CLINICAL ü DNL788 (ALS
Slide 8: Our Development Portfolio
OUR DEVELOPMENT PORTFOLIO Small Molecules Biotherapeutics DRUG DEVELOPMENT PROGRAM TARGET DRUG CANDIDATE* DISEASE INDICATION PARTNER Drug IND-Enabling Early Clinical Late Clinical Approved Discovery LYSOSOMAL FUNCTION PATHWAY 50/50 US LRRK2 DNL151 Parkinson’s commercial Iduronate 2-sulfatase DNL310
Slide 9: Targeting Multiple Steps in Neurodegeneration
TARGETING MULTIPLE STEPS IN NEURODEGENERATION Direct genetic Mechanisms that link to disease speed up disease progression (e.g., inflammation) 9 ©2021 Denali Therapeutics. All rights reserved.
Slide 10: Broad Therapeutic Potential
BROAD THERAPEUTIC POTENTIAL POTENTIAL INDICATIONS KEY TAKEAWAYS Ot es These 3 programs address he as M) Alz fundamental pathways rD (33 ise he eIF2B ’s RIPK1 ise rD within neurodegeneration im er ) as 1K he eim er ’ Regulates Regulates (< MS es Ot D s stress microglial zh M (33 Broad therapeutic pot
Slide 11: The Blood-Brain Barrier (BBB) Challenge
THE BLOOD-BRAIN BARRIER (BBB) CHALLENGE • The blood-brain barrier evolved to protect the central nervous system and maintain a homeostatic environment in the brain • Tight junctions, efflux pumps, and transporters regulate access of substances to the brain • Achieving therapeutically relevant drug c
Slide 12: Engineering Small Molecules to Cross the BBB
ENGINEERING SMALL MOLECULES TO CROSS THE BBB THE BBB CHALLENGE PRINCIPLES & APPROACH Rigorous assessment of chemical starting points with BBB delivery potential Disciplined application of CNS- amenable physicochemical properties Systematic in vitro and in vivo workflow: de-risk early, rapidly progre
Slide 13: Small Molecules in Development for the Treatment of ALS
SMALL MOLECULES IN DEVELOPMENT FOR THE TREATMENT OF ALS High unmet medical need in ALS DNL343 eIF2B Activator • Designed to address hallmark TDP-43 pathology • Phase 1 study achieved biomarker goals at doses that were generally well tolerated • Phase 1b study in ALS initiated in Q3’21 Getty Images S
Slide 14: Solving the BBB Challenge for Brain Delivery of Biotherapeutics
SOLVING THE BBB CHALLENGE FOR BRAIN DELIVERY OF BIOTHERAPEUTICS THE BBB CHALLENGE OUR SOLUTION BLOOD Cargo : IDS TfR binding Brain Endothelial Transport Cell (BBB) TfR Vehicle (TV) Tf Tf The blood-brain barrier (BBB) is a major obstacle for brain Target delivery of biotherapeutics Brain Cell BRAIN T
Slide 15: DNL593 (PTV:PGRN) – Novel Therapeutic Approach
DNL593 (PTV:PGRN) – NOVEL THERAPEUTIC APPROACH DNL593 PTV:PGRN High unmet need in FTD • Protein Transport Vehicle: Progranulin (PTV:PGRN) • Deterioration of the frontal and temporal • TV enhanced brain uptake: most direct way to cortical areas of the brain increase progranulin in the brain • Disturb
Slide 16: Stress granules: composition and models for therapeutic interventions
Stress granules: composition and models for therapeutic interventions
Slide 17: Disclosure Statement of Financial Interest
Disclosure Statement of Financial Interest • Consultant: Locana, Eclipse Bioinnovations, Ribometrix, LGC, Sardona Therapeutics, Ladder, Nooma, Insitro • Founder: Locana, Eclipse Bioinnovations, ProteoNA*, Enzerna, Medea, Trotana • Shareholder: Locana, Eclipse Bioinnovations, ProteoNA, Aquinnah, Enze
Slide 18: RNA binding proteins modulate the RNA life cycle
RNA binding proteins modulate the RNA life cycle DNA Transcription RNA RNA processing Translation Protein 18
Slide 19: RNA binding proteins are mutated in ALS
RNA binding proteins are mutated in ALS Laferrière, A. and Polymenidou, M., 2015 ~95% of ALS patients display TDP-43 inclusions Cytoplasmic aggregates of TDP-43 Lagier-Tourenne et al., Cell 2009 19
Slide 20: RNA binding proteins linked to ALS contain intrinsically disordered regions
RNA binding proteins linked to ALS contain intrinsically disordered regions (IDRs) Kapeli & Yeo, Human Genet, 2017 20
Slide 21: Disordered regions affect RNA granule dynamics
Disordered regions affect RNA granule dynamics Li et al, JCB( 2013) Liquid phase transitions from Brangwynne et al., Nat Phys 2015 unstressed arsenite Cellular stress G3BP1 Stress granules are positive for G3BP1 Dynamics, size and composition of these granules are important 21 Parker, McKnight, Shor
Slide 22: ALS-linked mutations in disordered regions affect SG dynamics
ALS-linked mutations in disordered regions affect SG dynamics dynamic RNP stress granule Pathological inclusion (transient) (permanent, insoluble) wildtype ALS mutant 22
Slide 23: Stress granule dysfunction in age-related decline and neurodegeneration
Stress granule dysfunction is a shared feature in normal age-related cognitive decline and pathological neurodegeneration ALS and frontotemporal degeneration Persistent stress granules and TDP-43 inclusions Alzheimer’s disease Stress granule formation stimulates tau pathophysiology, mediated by the
Slide 24: Roadmap
Roadmap How does stress impact disease-relevant phenotypes? What is the composition of human stress granules? Can we identify small molecule regulators of stress granules? Can we identify genetic regulators of RNA granule biology? 24
Slide 25: Interplay between stress, genetics and aging using iPSC-derived neurons
Understanding the interplay between stress, genetics and aging using IPSC- derived neurons Genetic risk factors Aging Environmental stresses * * * * ? 🤷 ? 🤔 ? 🧐 q What are their relative contributions? q What are the molecular effectors? q How can we intervene? 25
Slide 26: Stress granules are defined as G3BP1-positive foci/puncta
Stress granules are defined as G3BP1-positive foci/puncta 26
Slide 27: Stress recapitulates disease-relevant phenotypes in iPSC-motor neurons
Stress recapitulates disease-relevant phenotypes in IPSC-motor neurons Stress drives TDP-43 into SGs in cytoplasm Stress reveals altered TDP43 binding to genes and STMN2 exon Stress reveals intransigent recovery of mRNA localization Stress exacerbates delayed-onset cell death in ALS mutant lines 27
Slide 28: Proximity labeling of proteins in Stress Granules
Proximity labeling of proteins in Stress Granules • Endogenous expression of G3BP1 • in vivo labeling of proteins in proximity • No post-lysis reassociation • No proteins that sediment by centrifugation 28 Markmiller & Yeo, Cell, 2018
Slide 29: Comprehensive identification of human SG composition
Comprehensive identification of human SG composition ~300 proteins identified in human SGs Majority of these are RBPs Neuronal cells contain similar SG components But there are cell-type differences Depletion of SG proteins reduces SG formation 29 Markmiller & Yeo, Cell, 2018
Slide 30: SG proteins modify toxicity in fly models of ALS
Known and novel SG proteins modify toxicity in fly models of ALS Rough eye neurodegenerative phenotype caused by overexpression Wing degeneration caused by overexpression Of human mutant versions of TDP-43 or FUS of C9ORF72-derived poly(GR) dipeptide repeat Mark Kankel & Anindya Sen, Biogen Dejun Ya
Slide 31: Small molecules that act on aggregates and enhance survival of ALS motor neurons
Small molecules that act directly on aggregates in vitro and enhance survival of ALS motor neurons in culture DMSO TT-1 TT-2 TT-3 TT-4 TT-1 Incubation of purified SG-like aggregates with small molecule compounds disrupts existing granules in vitro while known inhibitors of upstream signaling have no
Slide 32: Pooled CRISPR screens identify genes that control SG abundance
Pooled CRISPR screens identify genes that control SG abundance stress selection stress Pooled CRISPR library Cells transduced 1078 RBPs (10 sgRNAs/RBP) Bulk infected cells • at low MOI • 628 Postitive control sgRNAs • 1058 Non-targeting sgRNAs • >12,000 sgRNAs Images filtered through Cells plated an
Slide 33: Pooled CRISPR screens identify genes that control SG abundance
Pooled CRISPR screens identify genes that control SG abundance MicroRaft arrays enable pooled screens of SGs Example, snRNP200 depletion reduces SGs RBPs at multiple RNA life cycle steps affect SGs Vande Velde’s lab showed snrRNP200 inclusions in ALS Vu & Vande Velde, J Proteome Res, 2021 33 Wheeler
Slide 34: Strategies to understand and manipulate Stress Granules
Strategies to understand and manipulate Stress Granules Target proteins involved in granule formation Markmiller & Yeo, Cell 2018 Genetic regulators Identify of genetic targets Target RNA-protein interface to: granule formation that impact - prevent recruitment of disease-associated RBPs granule for
Slide 35: Thank you!
Thank you! Sebastian Markmiller Shashank Sathe Steve Finkbeiner Kari Server Ashkan Javaherian Thai Nguyen Sara Broski Mark Fang Anthony Vu Eric Bennett Shashank Sathe Amit Fulzele Joshua Schwartz Mark Perelis Eric Lécuyer Archana Shankar Sahar Soltanieh Kathryn Morelli Julie Bergalet Neal Cody Ionis
Slide 36: DNL343 (eIF2B) Development Program
DNL343 (eIF2B) Development Program
Slide 37: eIF2B - Broad Therapeutic Potential
eIF2B - BROAD THERAPEUTIC POTENTIAL POTENTIAL INDICATIONS eIF2B PROGRAM STATUS • DNL343 is a CNS penetrant small molecule activator of eIF2B Ot es he as M) Alz rD (33 • Pre-clinical data showed ise he eIF2B ’s RIPK1 ise rD robust rescue of pathology im er ) as 1K he eim er ’ Regulates Regulates (< M
Slide 38: The Integrated Stress Response in Health & Disease
THE INTEGRATED STRESS RESPONSE (ISR) IN HEALTH & DISEASE Healthy Cell Acute Stress Chronic Stress Neurodegeneration Normal Stalled Impaired Cell Death Protein Synthesis Protein Synthesis Protein Synthesis No Reversible Persistent Stress Granules Stress Granule Stress Granule Formation Formation Home
Slide 39: Evidence for ISR Pathway Modulation Across Neurodegenerative Diseases
EXTENSIVE EVIDENCE FOR ISR PATHWAY MODULATION ACROSS VARIOUS NEURODEGENERATIVE DISEASES 39 ©2021 Denali Therapeutics. All rights reserved.
Slide 40: Targeting Eukaryotic Translation Initiation Factor 2B (eIF2B)
TARGETING EUKARYOTIC TRANSLATION INITIATION FACTOR 2B (eIF2B) eIF2B activation has potential to halt neurodegeneration eIF2B Neurodegeneration DNL343 Treatment Inactive conformation Active conformation eIF2B activator • Intracellular protein complex that regulates protein synthesis • eIF2B activator
Slide 41: ALS Degenogenes Are Associated with Stress Granule Biology
ALS DEGENOGENES ARE ASSOCIATED WITH STRESS GRANULE BIOLOGY • ~50% of ALS degenogenes are associated with stress granules or RNA homeostasis C21ORF2 NEK1 DNAJC7 HNRNPA1 MOBP NEFH C9ORF72 FGD4 SQSTM1 HNRNPA2B1 SCFD1 ANXA11 50 CCNF KIF5A • ALS mutations have been shown to alter stress SS18L1 CHCHD10 TI
Slide 42: DNL343 Dissolves TDP-43 Inclusions In Vitro
DNL343 DISSOLVES TDP-43 INCLUSIONS IN VITRO ALS patient neurons with TDP-43 pathology Stress Granules TDP-43 expressing Neuman et al. Science 2006 cells TDP-43 inclusions TDP-43 inclusions are found in >95% of ALS patients and ~50% of FTD patients1 Stress DNL343 eIF2B activator DNL343 reverses pre-f
Slide 43: Stress Granule Dynamics Corrected by DNL343 in C9orf72 iPSC Neurons
STRESS GRANULE DYNAMICS ARE ALTERED IN C9ORF72 IPSC NEURONS AND ARE CORRECTED BY DNL343 C9orf72 ALS patient C9orf72 Isogenic iPSC-derived neuron DNL343 inhibits the increased stress Thapsigargin granules in C9orf72 neurons 3 Number of Stress Granules/Cell 2 1 Thapsigargin + CRISPR edited 0 DNL343 is
Slide 44: ISR Activation in ALS Patient Tissue
ISR ACTIVATION IN ALS PATIENT TISSUE ISR gene set is upregulated in ALS patient Top ISR upregulated genes spinal cord (Target ALS database) CEBPA MTHFD2 SLC1A5 TRIB3 Gene set enrichment analyses of the Target ALS transcriptomic database indication upregulation of a subset of ISR genes Expression dat
Slide 45: Role of eIF2B in Controlling ISR Signaling
ROLE OF eIF2B IN CONTROLLING ISR SIGNALING 45 ©2021 Denali Therapeutics. All rights reserved.
Slide 46: DNL343 Activates eIF2B and Can Reduce Cellular Stress
DNL343 ACTIVATES eIF2B AND CAN REDUCE CELLULAR STRESS DNL343 activates eIF2B halting stress response and restoring protein synthesis 46 ©2021 Denali Therapeutics. All rights reserved.
Slide 47: DNL343 Increases eIF2B Protein Stability In Vitro
DNL343 INCREASES eIF2B PROTEIN STABILITY IN VITRO eIF2B∂ subunit protein stability 40000 EIF2B4 Protein 30000 Protein (Raw MSD values) 20000 eIF2B∂ 10000 0 -12 -10 -8 -6 -4 DNL343 [log M] DNL343 activates eIF2B by directly interacting with the eIF2B protein complex 47 ©2021 Denali Therapeutics. All
Slide 48: DNL343 Inhibits ISR-Induced Signaling In Vitro
DNL343 INHIBITS ISR-INDUCED SIGNALING IN VITRO ATF4 protein 100 % Inhibition of 80 ATF4 Protein 60 40 20 0 -11 -10 -9 -8 -7 -6 -5 Log [DNL343] (M) CHAC1 transcript 100 CHAC1 Transcript % Inhibition of 80 60 40 20 0 -11 -10 -9 -8 -7 -6 -5 Log [DNL343] (M) DNL343 robustly inhibits ATF4 protein and CHA
Slide 49: DNL343 Inhibits Formation of Stress Granules In Vitro
DNL343 INHIBITS FORMATION OF STRESS GRANULES IN VITRO Stress granule assay 120 100 Stress Granules % inhibition of 80 60 40 20 0 -10 -8 -6 -4 Log [DNL343] (M) DNL343 dose-dependently reverses stress granule formation DAPI G3BP1 49 ©2021 Denali Therapeutics. All rights reserved.
Slide 50: In Vivo Pharmacokinetic Studies in Eif2b5 R191H Mouse Model
IN VIVO PHARMACOKINETIC STUDIES IN Eif2b5 R191H MOUSE MODEL • Eif2b5 R191H mutation causes chronic ISR activation and Vanishing White Matter (VWM) disease • Ideal in vivo model for DNL343 proof of concept Eif2b5 R191H DNL343 Exposure 100 Plasma Brain Drug Dosing WT 0 Paradigm Exposure 3 mg/kg 10 (un
Slide 51: DNL343 Achieved Target and Pathway Modulation In Vivo
DNL343 ACHIEVED TARGET AND PATHWAY MODULATION IN VIVO TARGET ENGAGEMENT PATHWAY ENGAGEMENT Target Pathw Chac1 Brain Gene Expression Eif2b5 5 Spleen Brain (relative to WT+Vehicle control) R191H 4 ng/mg] eIF2Bδ Protein 2 ng/mg) 3 d protein 2 (Log Log2 [eIF2B 1 0 0 3 0 0.3 1 3 10 mg/kg WT R191H Dose-de
Slide 52: DNL343 Broadly Regulates the ISR Pathway In Vivo
DNL343 BROADLY REGULATES THE ISR PATHWAY IN VIVO Increasing dose of DNL343 Eif2b5 R191H DNL343 (mg/kg) PATHWAY Reduction in ISR gene expression DNL343 robustly reduces ISR gene expression in the brain of Eif2b5 R191H mice 52 ©2021 Denali Therapeutics. All rights reserved.
Slide 53: DNL343 Rescues Body Weight and Motor Function Deficits
DNL343 RESCUES BODY WEIGHT AND MOTOR FUNCTION DEFICITS RESTORATION OF NORMAL BODY WEIGHT RESTORATION OF BALANCE AND MOTOR FUNCTION Falls 100 * ** Grade # of slips # of falls Top: 0-10 0 Percent of Mice Good: 11-30 1 (per Category) Eif2b5 R191H Poor: 31-50 2 50 51-60 3 10 Worst: Time to cross beam me
Slide 54: DNL343 Preclinical Summary
DNL343 PRECLINICAL SUMMARY Therapeutic Hypothesis DNL343 Key Preclinical Results In vitro ü Increases eIF2B protein stability ü Inhibits and reverses stress granules formation Eif2b5 R191H mouse model (chronic ISR) ü Dose-dependent target and pathway engagement Chronic ISR is eIF2B activation implic
Slide 55: DNL343 Phase 1 Study in Healthy Volunteers
DNL343 PHASE 1 STUDY IN HEALTHY VOLUNTEERS Single center, double-blind, placebo-controlled first-in-human safety, tolerability, pharmacokinetic and pharmacodynamic study of DNL343 in healthy volunteers STUDY OVERVIEW STUDY SCHEMA * Cohorts with CSF collection Type Phase 1 study in healthy volunteers
Slide 56: DNL343 Phase 1 Healthy Volunteer Safety Summary
DNL343 PHASE 1 HEALTHY VOLUNTEER SAFETY SUMMARY • DNL343 was generally safe and well tolerated across all dose levels studied • There were no serious adverse events (SAEs) or discontinuations due to study drug • Of those participants receiving DNL343 that experienced treatment emergent adverse event
Slide 57: DNL343 Multiple Ascending Doses: Most Common TEAEs
DNL343 MULTIPLE ASCENDING DOSES: MOST COMMON TEAEs PBO Total DNL343 MD1 MD2 MD3 MD4 MD5 N=13 N=34 N=6 N=7 N=7 N=7 N=7 Participants with TEAEs, N (%) 12 (92.3%) 31 (91.2%) 6 (100%) 7 (100%) 7 (100%) 5 (71.4%) 6 (85.7%) Participants with TEAEs reported in >2 PBO or DNL343 treated participants, N (%) H
Slide 58: DNL343 Phase 1 Healthy Volunteer Study: Pharmacokinetics
DNL343 PHASE 1 HEALTHY VOLUNTEER STUDY: PHARMACOKINETICS Steady-State STEADY-STATEPharmacokinetics PHARMACOKINETICS(Day 14)14) (DAY CSF / UNBOUND PLASMA CONCENTRATION RATIO (DAY 12) 1.5 Plasma Ratio Concentration (μM) Ratio (μM) 30 Concentration CSF:UnboundPlasma 10 1.0 Dose Level MD1 CSF:Unbound MD
Slide 59: DNL343 Phase 1 Healthy Volunteer Study: Pharmacodynamics
DNL343 PHASE 1 HEALTHY VOLUNTEER STUDY: PHARMACODYNAMICS CHAC1 Gene Expression in Stimulated PBMCs ATF4 PROTEIN 75 End of dosing CHAC 1 GENE EXPRESSION %Change From Baseline Median (IQR) in Stimulated PBMCs Expression in Stimulated PBMCs 75 End of End of dosing dosing End of of dosing 50 (IQR) 75 En
Slide 60: DNL343 Exposure and Pharmacodynamic Translatability
DNL343 EXPOSURE AND PHARMACODYNAMIC TRANSLATABILITY Brain PK- Brain PD Model Fit (% Change from Baseline) Plasma PK – Brain PD Model Fit Mutant Brain Chac1 Human PBMC CHAC1 (vs WT controls) Plasma PK- PBMC PD Model Fit Phase 1 HV Eif2b5 R191H Unbound DNL343 (nM) • Eif2b5 R191H mouse data provides ra
Slide 61: DNL343 Phase 1b Study in ALS
DNL343 PHASE 1B STUDY IN ALS Multi center, double-blind, placebo-controlled safety, tolerability, pharmacokinetic and pharmacodynamic study followed by open label extension of DNL343 in participants with ALS STUDY OVERVIEW STUDY SCHEMA Phase 1b study in Participants Type with ALS Randomization (1:1:
Slide 62: DNL343 Has First in Class Potential
DNL343 HAS FIRST IN CLASS POTENTIAL KEY RESULTS • Positive Phase 1 data in healthy volunteers Validation of DNL343 – DNL343 is generally well tolerated with extensive activity on the Integrated Stress CNS distribution Response Pathway (ISR) – PK data support once daily dosing – Robust dose-dependent
Slide 63: SAR443820/DNL788 (RIPK1) Development Program
SAR443820/DNL788 (RIPK1) Development Program
Slide 64: RIPK1 - Broad Therapeutic Potential
RIPK1 - BROAD THERAPEUTIC POTENTIAL POTENTIAL INDICATIONS RIPK1 PROGRAM STATUS • SAR443820/DNL788 is a CNS penetrant small Ot es molecule inhibitor of RIPK1 he as M) Alz rD (33 ise he eIF2B ’s RIPK1 • Robust target engagement & ise rD im er ) as 1K he eim safety goals achieved in Ph 1 er ’ Regulates
Slide 65: RIPK1 Regulates Inflammation and Necroptosis
RIPK1 REGULATES INFLAMMATION AND NECROPTOSIS GENETICS PATHWAY PATHOLOGY ALS and Alzheimer’s degenogenes RIPK1 activation can lead to Microglial dysfunction can lead to point to microglial dysfunction as a microglial dysfunction Inflammation and necroptosis of brain cells driver of disease BMP ↑ Micr
Slide 66: Evaluation of RIPK1 in ALS Spinal Cords
EVALUATION OF RIPK1 IN ALS SPINAL CORDS RIPK1 pRIPK1 Insoluble RIPK1 Insoluble pRIPK1 80000 300 pRIPK1 MSD signal (A.U.) ** RIPK1 MSD signal (A.U.) *** 60000 200 40000 100 20000 0 0 Control ALS Control ALS Sanofi Genzyme data from Target ALS, Mass General Hospital and University of Pittsburgh sample
Slide 67: SAR443820/DNL788 Phase 2 Study in ALS - HIMALAYA
SAR443820/DNL788 PHASE 2 STUDY IN ALS - HIMALAYA Multi center, double-blind, placebo-controlled safety, tolerability, and efficacy study followed by long-term extension of SAR443820 in participants with ALS Study Overview Dosing and Detailed Design Type Phase 2 study in Participants with ALS Randomi
Slide 68: RIPK1 Path Forward
RIPK1 PATH FORWARD KEY RESULTS • Robust target engagement & safety goals Validation of DNL788 achieved in Phase 1 on target engagement goals to advance to patient studies • Sanofi leading Ph2 HIMALAYA ALS study; planning in progress – 261 patient study in 50-60 global sites planning in Advancing Dev
Slide 69: DNL593 (PTV:PGRN) Development Program
DNL593 (PTV:PGRN) Development Program
Slide 70: Progranulin - Broad Therapeutic Potential
PROGRANULIN - BROAD THERAPEUTIC POTENTIAL POTENTIAL INDICATIONS PGRN PROGAM STATUS • DNL593 is recombinant PGRN protein fused to Denali's Transport Vehicle (TV) Ot es he as M) Alz • CNS-penetrant PGRN rD (33 ise he eIF2B ’s RIPK1 ise replacement therapy rD im er ) as 1K he eim er ’ Regulates Regulat
Slide 71: TV Platform Modularity Creates Multiple Opportunities
TV PLATFORM MODULARITY CREATES MULTIPLE OPPORTUNITES MODULAR TECHNOLOGY ENABLES OPTIMAL MODALITY FOR EACH TARGET Antibody Enzyme Transport ATV ETV Transport Vehicle Vehicle PTV OTV Protein Oligonucleotide Transport Transport Vehicle Vehicle 71 ©2021 Denali Therapeutics. All rights reserved.
Slide 72: Progranulin Deficiency Results in Lysosomal Dysfunction
PROGRANULIN DEFICIENCY RESULTS IN LYSOSOMAL DYSFUNCTION GENETICS PATHWAY PATHOLOGY Mutations in GRN lead to decreased PGRN deficiency dysregulates Lysosomal dysfunction leads to inflammation, PGRN levels in GRN-FTD lysosomal function lipofuscinosis, TDP-43 pathology and neuronal loss PGRN (human CSF
Slide 73: Model of PGRN Deficiency-Driven Lysosomal Dysfunction
MODEL OF PGRN DEFICIENCY-DRIVEN LYSOSOMAL DYSFUNCTION PGRN stabilizes BMP Lack of PGRN and GCase on destabilizes BMP and lysosomal membranes, GCase on lysosomal allowing for GlcSph membranes, causing metabolism GlcSph accumulation LYSOSOMAL LYSOSOMAL NORMAL FUNCTION DYSFUNCTION 73 ©2021 Denali Thera
Slide 74: PTV:PGRN (DNL593) Rescues BMP in GRN KO In Vitro
PTV:PGRN (DNL593) RESCUES BMP IN GRN KO IN VITRO Super-resolution microscopy DNL593 Protein (Progranulin ) TfR- binding site PTV:PGRN rescues PGRN and BMP levels in Grn KO macrophages and microglia 74 ©2021 Denali Therapeutics. All rights reserved.
Slide 75: DNL593 Rescues Lysosomal Defects in GRN KO In Vitro
DNL593 RESCUES LYSOSOMAL DEFECTS IN GRN KO IN VITRO Relative Lysosomal Protein Turnover PTV:PGRN restores normal lysosomal function in Grn KOs 75 ©2021 Denali Therapeutics. All rights reserved.
Slide 76: TfR Binding of DNL593 Confers Brain Uptake and CNS Distribution In Vivo
TFR BINDING OF DNL593 CONFERS BRAIN UPTAKE AND BROAD CNS PARENCHYMAL DISTRIBUTION IN VIVO Fc:PGRN PTV:PGRN Constructs Fc:PGRN PTV:PGRN NeuN (Neurons) Iba1 (Microglia) podocalyxin + CD31 (Vasculature) huIgG (Fc/PTV) PTV:PGRN is efficiently taken up by both neurons and microglia following systemic adm
Slide 77: DNL593 Rescues Lipid Abnormalities in Neurons, Microglia and Astrocytes
DNL593 RESCUES LIPID ABNORMALITIES IN NEURONS, MICROGLIA AND ASTROCYTES FROM GRN KO MICE • Strongest lipid phenotypes observed in Grn KO microglia • PTV:PGRN rescues deficits in all cell types 77 ©2021 Denali Therapeutics. All rights reserved.
Slide 78: DNL593 Rescues Function of Lysosomal Enzymes in Mouse Brain
DNL593 RESCUES FUNCTION OF LYSOSOMAL ENZYMES IN MOUSE BRAIN Mouse Brain GCase activity Mouse Brain GlcSph FTD-GRN Brain GlcSph Example: PTV:PGRN rescues brain GCase activity and FTD-GRN patient brains display reduces accumulation of its substrate GlcSph in Grn KO mice increase consistent with mouse
Slide 79: Chronic Dosing of DNL593 Rescues CNS Lipofuscinosis in Mice
CHRONIC DOSING OF DNL593 RESCUES CNS LIPOFUSCINOSIS IN MICE Saline Treatment Saline Treatment PTV:PGRN Treatment Grn +/+; TfR KI Grn –/–; TfR KI Grn –/–; TfR KI Relative Lipofuscin Lipofuscin accumulation similar to pathology present in FTD-GRN patients occurs in neurons of Grn KO mice and is attenu
Slide 80: Chronic Dosing of DNL593 Rescues Gliosis in Mice
CHRONIC DOSING OF DNL593 RESCUES GLIOSIS IN MICE Saline Treatment - Grn +/+; TfR KI Saline Treatment - Grn –/–; TfR KI PTV:PGRN Treatment Grn –/–; TfR KI IBA1 GFAP CD68 IBA1 CD68 GFAP Microgliosis and astrogliosis in Grn KO resembles FTD-Grn patient brain and is rescued by PTV:PGRN 80 ©2021 Denali T
Slide 81: PTV:PGRN Expands TV Platform with Potential in FTD-GRN
PTV:PGRN EXPANDS TV PLATFORM WITH POTENTIAL IN FTD-GRN Healthy FTD-GRN FTD-GRN + Sortillin block FTD-GRN + PTV:PGRN 81
Slide 82: PTV:PGRN Expands TV Platform with Potential in FTD-GRN
PTV:PGRN EXPANDS TV PLATFORM WITH POTENTIAL IN FTD-GRN Healthy FTD-GRN FTD-GRN + Sortillin block FTD-GRN + PTV:PGRN 81
Slide 83: PTV:PGRN Expands TV Platform with Potential in FTD-GRN
PTV:PGRN EXPANDS TV PLATFORM WITH POTENTIAL IN FTD-GRN Healthy FTD-GRN FTD-GRN + Sortillin block FTD-GRN + PTV:PGRN 81
Slide 84: PTV:PGRN (DNL593) Expands TV Platform with Potential in FTD-GRN
PTV:PGRN (DNL593) EXPANDS TV PLATFORM WITH POTENTIAL IN FTD-GRN KEY PRECLINICAL RESULTS • Protein Transport Vehicle (PTV) enhances brain TV Enhanced Brain Uptake uptake of peripherally administered progranulin Most direct way to increase PGRN • PTV:PGRN rescues a range of lysosomal defects Advance D
Slide 85: Milestones
% \ MILESTONES
Slide 86: Our Plans: Key Milestones
OUR PLANS: KEY MILESTONES EXPECTED TIMING ETV:IDS ü DNL310: 24-week data from Cohort A of Phase 1/2 study ▪ Mid 2021 Hunter Syndrome • DNL310: 24-week data from Cohort A+B of Phase 1/2 study ▪ Early 2022 LRRK2 • DNL151: Initiate late-stage clinical development in collaboration with Biogen ▪ Late 202
Slide 87: Our Future: Fully Integrated Global Organization to Serve Patients
OUR FUTURE: FULLY INTEGRATED GLOBAL ORGANIZATION TO SERVE PATIENTS ORGANIZATIONAL GROWTH PATH • Deep focus on science and commitment to discovery • Comprehensive global clinical development capabilities • Internal manufacturing capabilities 3 LARGE NEURODEGENERATIVE • Staged buildout of commercial i
Slide 88: Q&A
Q&A
Slide 89: Thank You
THANK YOU
Denali Therapeutics — Technical Presentation (October 2021) on 6ix