Denali Therapeutics Inc. · NASDAQ:DNLI
Denali Therapeutics — Investor Presentation (July 2023)
44 slides from Denali Therapeutics's investor presentation, July 2023
Slide 1: Corporate Overview
Corporate Overview July 2023
Slide 2: Disclaimers
Disclaimers Forward-Looking Statements. This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements do not relate strictly to historical or current facts and they may be accompanied by such words a
Slide 3: Our Focus and Strategic Principles
OUR FOCUS AND STRATEGIC PRINCIPLES OUR FOCUS OUR SCIENTIFIC PRINCIPLES OUR BUSINESS PRINCIPLES Defeat Degeneration Increase Likelihood of Success Create Value Lysosomal Storage Degenogene Broad Diseases Pathways Portfolio Rare Neurodegenerative Diseases (ALS, FTD) Integrated Brain Delivery Global Ca
Slide 4: Our Science: BBB Platforms and Degenogene Pathways
OUR SCIENCE: BBB PLATFORMS AND DEGENOGENE PATHWAYS Published May 27, 2020 Published Sept 2, 2021 Published March 4, 2020 Published May 27, 2020 Published July 22, 2020 Published October 22, 2020 Published April 8, 2020 Published July 30, 2020 Published June 8, 2020 Published Sept 4, 2019 Published J
Slide 5: Our Development Portfolio
OUR DEVELOPMENT PORTFOLIO DEVELOPMENT STAGE IND- MODALITY TARGET BIOLOGY DRUG CANDIDATE* DISEASE INDICATION Enabling Early Mid Late PARTNER Iduronate Lysosomal DNL310 MPS II (Hunter) 2-Sulfatase Function (ETV:IDS) Lysosomal TAK-594/DNL593 Frontotemporal Dementia- PGRN Function (PTV:PGRN) Granulin (F
Slide 6: Our Strategic Partnerships
OUR STRATEGIC PARTNERSHIPS CO-DEVELOPMENT & CO-COMMERCIALIZATION PARTNERSHIPS $1.3B Total upfront payments1 § LRRK2 inhibitor for Parkinson’s and two TV-Platform programs, including ATV:Abeta § $1.025B upfront (cash/equity) and $2B in milestones Total earned & potential LRRK2: 50/50 profit share in
Slide 7: Our Vision: Commercial Organization to Serve Patients
OUR VISION: COMMERCIAL ORGANIZATION TO SERVE PATIENTS >50M patients WW* >$5B per indication >500,000 patients WW* $1-5B per indication >30,000 patients WW* COMMON NEURODEGENERATIVE DISEASES $500M-1B+ per indication RARE NEURODEGENERATIVE DISEASES LYSOSOMAL STORAGE DISEASES (e.g., MPS II, MPS IIIA) (
Slide 8: Our TV Platform for Brain Delivery of Biotherapeutics
OUR TV PLATFORM FOR BRAIN DELIVERY OF BIOTHERAPEUTICS
Slide 9: Addressing the Challenge of Delivering Therapy to the Brain
ADDRESSING THE CHALLENGE OF DELIVERING THERAPY TO THE BRAIN The Transport Vehicle (TV) is engineered to deliver efficacious concentrations of biotherapeutics (large molecules) to brain cells via receptor mediated transcytosis Blood Vessel Enzyme + Transport Vehicle Blood-Brain Barrier Transferrin Re
Slide 10: Transport Vehicle Enables Modality-Optimized Brain Delivery
TRANSPORT VEHICLE ENABLES MODALITY-OPTIMIZED BRAIN DELIVERY Enzyme Transport Vehicle Antibody Transport Vehicle Deliver enzymes to the brain to replace Deliver antibodies in bivalent deficient or missing enzyme activity ETV or bispecific format to the brain ATV Protein Transport Vehicle PTV Oligonuc
Slide 11: TV Platform Opportunities Drive Sustainable Value Creation
TV PLATFORM OPPORTUNITIES DRIVE SUSTAINABLE VALUE CREATION Each TV modality is a platform opportunity FUTURE PROGRAM ETV:GCase TV PLATFORM ETV:ARSA FUTURE DEVELOPMENT PROGRAM PROGRAMS ETV:NAGLU OTV:Epilepsy FUTURE ETV:GAA PROGRAM OTV:UBE3A-ATS ETV:IDUA ATV:HER2 OTV:DMPK FUTURE FUTURE ETV:SGSH ATV:Ab
Slide 12: DNL310 (ETV:IDS): Lead ETV Program Targeting MPS II
DNL310 (ETV:IDS): LEAD ETV PROGRAM TARGETING MPS II Addressing behavioral, cognitive & physical Rapid and durable normalization of CSF HS in manifestations of MPS II (Hunter syndrome) ongoing Phase 1/2 study • ~2,000 MPS II patients, mainly boys, worldwide • Delivery of IDS enzyme to the brain is a
Slide 13: DNL310 Phase 1/2 Study Design and Interim Analysis Population
DNL310 PHASE 1/2 STUDY DESIGN AND INTERIM ANALYSIS POPULATION • Open-label, 24-week study followed by an open-label extension (NCT04251026) • Approximately 45 participants ≤18 years of age with MPS II • Participants receiving IDS at baseline switch to DNL310 without a washout period COHORTS Primary
Slide 14: Overview of DNL310 Phase 1/2 Study Interim Safety
OVERVIEW OF DNL310 PHASE 1/2 STUDY INTERIM SAFETY Cumulative information, including previously reported1,2 • All participants reported treatment-emergent adverse events (TEAEs), which were mostly mild or moderate • There were no dose-related safety findings • Infusion-related reactions (IRRs) were t
Slide 15: Safety: Infusion Related Reactions (IRRs)
SAFETY: INFUSION RELATED REACTIONS (IRRs) Total No. of Infusions During Study: 1792 100 Severe Moderate Associated With IRRs (%) Proportion of Infusions 75 Mild 50 25 0 1-12 13-24 25-36 37-48 49-60 61-72 72-109 Study Week Period Tolerance to DNL310 occurred with longer-term dosing Source: Muenzer, J
Slide 16: Biomarkers: CSF HS
2023 WORLDSymposiumTM BIOMARKERS: CSF HSa Mean HS reduction Week n from BL, % 24 25 90.6 49 19 90.0 104b 3 91.4 ADA Titer at BL ● Negative ● Positive/low-medium (<1×106) ● Positive/high (> 1×106) Rapid and sustained normalization of CSF HS achieved with DNL310 treatment ADA, anti-drug antibodies. aP
Slide 17: Clinical Phenotype of MPS and GAG Accumulation
CLINICAL PHENOTYPE OF MPS AND GAG ACCUMULATION TYPE NAME ENZYME DEFICIENCY GAG MPS I Hurler / Scheie α-L-iduronidase HS, DS MPS II Hunter Iduronate-2-sulfatase HS, DS MPS IIIA Sanfilippo A Heparan sulfamidase HS MPS IIIB Sanfilippo B N-acetyl-α-D-glucosaminidase HS MPS IIIC Sanfilippo C Acetyl-CoA:α
Slide 18: Lysosomal Lipid Gangliosides and Glucosylsphingosine
LYSOSOMAL LIPID GANGLIOSIDES AND GLUCOSYLSPHINGOSINE Near normalization or complete normalization of lysosomal biomarker was observed in most participants, and the effect was sustained a a a ADA, anti-drug antibody; BL, baseline; CSF, cerebrospinal fluid; GM, ganglioside; GlcSph, glucosylsphingosine
Slide 19: DNL310: Serum NfL in Ph1/2 Participants
DNL310: SERUM NfL IN PH1/2 PARTICIPANTS Week n Mean serum NfL change from BL, % 24 27 +11.9 49 23 -13.5 104 13 -63.8 (**p<0.001) 53.5% mean reduction (p=0.011) in CSF NfL at Week 104 (n=11) Spearman Correlation coefficient is 0.76 for the change from baseline at week 104 between serum NfL & CSF NfL
Slide 20: Neurofilament (NfL): A Marker of Neuroaxonal Damage
NEUROFILAMENT (NfL): A MARKER OF NEUROAXONAL DAMAGE NfL elevation NfL reduction Indication disease vs. non-disease control Therapeutic on treatment FDA approval CLN2a ~50-fold (plasma) cerliponase alfa ~85% (plasma @ 3 yrs) SMA Type 1b ~30-fold (CSF) nusinersen 75% (CSF @ ~ Wk 12) SOD1 ALSc,d ~4-fol
Slide 21: DNL310 (ETV:IDS): Summary of Clinical Assessments in Phase 1/2 Study
DNL310 (ETV:IDS): SUMMARY OF CLINICAL ASSESSMENTS IN PHASE 1/2 STUDY VABS-II Raw Score Mean Change From Baseline BSD-III Raw Score Mean Change From Baseline Week 49 BSID Cognitive Raw Score (age equivalent <=42 months, n=11) BSID Cognitive Raw Score (with imputation of KABC)a (n=15) aImputed KABC sc
Slide 22: Summary of Interim Results
SUMMARY OF INTERIM RESULTS • Interim safety profile was consistent with those of other enzyme replacement therapies Clinical safety • IRRs accounted for the most frequent TEAEs and decreased in frequency and severity with continued dosing • Rapid normalization or near normalization of CSF HS was obs
Slide 23: DNL310 Phase 2/3 Study Design in Pediatric MPS II Patients
DNL310 PHASE 2/3 STUDY DESIGN IN PEDIATRIC MPS II PATIENTS DNLI-E-0007 STUDY OVERVIEW (NCT05371613) DOSING SCHEMA Double-Blind, Randomized Study of DNL310 vs Idursulfase in children with neuronopathic (96-week study) or non- Study neuronopathic (48-week study) MPSII followed by OLE Design • DNL310 i
Slide 24: Summary & Conclusions
SUMMARY & CONCLUSIONS DNL310 (ETV:IDS) DEVELOPMENT • Biochemical: Rapid and sustained normalization of CSF heparan sulfate to normal healthy levels Further Validation of • Cellular: Improvement in lysosomal function TV Platform biomarkers • Neuronal: Robust reduction in NfL • Clinical: Positive chan
Slide 25: DNL126 (ETV:SGSH): Expands ETV Platform for MPS IIIA
DNL126 (ETV:SGSH): EXPANDS ETV PLATFORM FOR MPS IIIA Addressing cognitive, behavioral & physical IV DNL126 treatment reduces HS in a manifestations of Sanfilippo syndrome Type A dose-dependent manner in brain and CSF • Rare lysosomal storage disease (LSD) that causes neurodegeneration; no treatments
Slide 26: DNL593 (PTV:PGRN): PGRN Brain Delivery for FTD-GRN
DNL593 (PTV:PGRN): PGRN BRAIN DELIVERY FOR FTD-GRN Brain delivery of progranulin (PGRN) Dose-dependent increase in CSF PGRN in HV with designed to treat FTD-GRN IV DNL593 further validates TV for BBB crossing • FTD is the most common dementia in people under 60; no approved therapies • FTD-GRN is as
Slide 27: ATV:Abeta for Alzheimer's Disease (AD)
ATV:ABETA FOR ALZHEIMER’S DISEASE (AD) ATV:Abeta shows broad parenchymal plaque binding with minimal perivascular distribution Anti-Abeta ATV:Abeta 5xFAD;TfR KI Abeta Abeta Perivascular amyloid hIgG Parenchymal plaque hIgG iDISCO whole brain image 24h post 10mg/kg single dose in AD mouse model Bioge
Slide 28: DNL919 (ATV:TREM2) for Alzheimer's Disease (AD)
DNL919 (ATV:TREM2) FOR ALZHEIMER’S DISEASE (AD) ATV:TREM2 shifts most microglia to responsive states compared to standard anti-TREM2 in mice APP KI;TfR KI TREM2 TREM2 Single cell RNAseq UMAP plots of brain microglia 24h post 10 mg/kg dose van Lengerich et al. 2023 Nature Neuroscience 28 ©2023 Denali
Slide 29: OTV Is Designed to Enhance CNS Delivery of Oligonucleotides
OTV IS DESIGNED TO ENHANCE CNS DELIVERY OF OLIGONUCLEOTIDES Therapeutic oligonucleotides have the potential OTV has potential to revolutionize to address challenging targets ASOs/oligos for treating CNS disease • Oligonucleotide Transport Vehicle (OTV) is designed to: - Enable superior biodistributi
Slide 30: OTV Provides Uniform ASO Deposition Across the CNS with IV Delivery
OTV PROVIDES UNIFORM ASO DEPOSITION ACROSS THE CNS WITH IV DELIVERY NAKED ASO INTRATHECAL (IT) DELIVERY OTV INTRAVENOUS (IV) DELIVERY Limited ASO Biodistribution Widespread ASO Biodistribution BRAIN BRAIN ANTERIOR POSTERIOR ANTERIOR POSTERIOR SPINAL CORD SPINAL CORD 30 anti-ASO ©2023 Denali Therapeu
Slide 31: OTV Provides Uniform ASO Deposition Across the CNS with IV Delivery
OTV PROVIDES UNIFORM ASO DEPOSITION ACROSS THE CNS WITH IV DELIVERY NAKED ASO INTRATHECAL (IT) DELIVERY OTV INTRAVENOUS (IV) DELIVERY Limited ASO Biodistribution Widespread ASO Biodistribution CORTEX STRIATUM CORTEX STRIATUM CEREBELLUM WHITE MATTER CEREBELLUM WHITE MATTER 31 anti-ASO ©2023 Denali Th
Slide 32: OTV Enables More Uniform Knockdown of Target Gene Expression
OTV ENABLES MORE UNIFORM KNOCKDOWN OF TARGET GENE EXPRESSION NAKED ASO INTRATHECAL (IT) DELIVERY OTV INTRAVENOUS (IV) DELIVERY Data represented as mean +/- SEM; n=3 IV OTV shows uniform knockdown across the CNS compared to IT ASO 32 ©2023 Denali Therapeutics Inc. All rights reserved.
Slide 33: OTV Target Selection
OTV TARGET SELECTION TARGET INDICATION PREVALENCE DIFFERENTIATION STRATEGY COMMON NEURODEGENERATIVE DISEASES MAPT Alzheimer’s Disease 6-10M cases US Uniform knockdown of MAPT across the CNS to effectively reduce all forms of Tau protein & decrease aggregates SNCA Parkinson’s Disease 1M cases US Unif
Slide 34: Our Brain-Penetrant Small Molecule Programs
OUR BRAIN-PENETRANT SMALL MOLECULE PROGRAMS
Slide 35: BIIB122 (LRRK2 Inhibitor): Targeting the Lysosome in PD
BIIB122 (LRRK2 INHIBITOR): TARGETING THE LYSOSOME IN PD Targeting LRRK2 may impact the underlying Phase 2b LUMA Study of BIIB122 in PD patients biology and slow the progression of PD with and without LRRK2 mutations • 10M+ people with Parkinson’s disease (PD) WW Phase 2b LUMA Study • Mutations in LR
Slide 36: BIIB122 Clinical Development Program (CDP) Modifications
BIIB122 CLINICAL DEVELOPMENT PROGRAM (CDP) MODIFICATIONS • On June 5, 2023, Denali and Biogen announced planned modifications to the BIIB122 CDP • Planned CDP modifications are based on review of portfolio timelines and resource prioritization • The planned revisions are not based on any safety or e
Slide 37: eIF2B Activation Has Potential to Slow Neurodegeneration in ALS
EIF2B ACTIVATION HAS POTENTIAL TO SLOW NEURODEGENERATION IN ALS In ALS, TDP-43 pathology is linked to cellular dyshomeostasis resulting from chronic activation of the Integrated Stress Response (ISR) via inactivation of the eukaryotic initiation factor 2b (eIF2B) DNL343 is an eIF2B agonist designed
Slide 38: DNL343 Effects in Neurons and iPSC-Derived Neurons
DNL343 EFFECTS IN NEURONS AND IPSC-DERIVED NEURONS DNL343 EFFECTS IN NEURONS DNL343 EFFECTS IN iPSC-DERIVED NEURONS Stress Stress + DNL343 CRISPR edited isogenic Stress Stress + DNL343 control (ISO) Stress Granules 3 Number of Stress Granules/Cell 2 0 min 20 min 95 min C9orf72 ALS patient iPSC- 1 de
Slide 39: DNL343 Effects in Neurons and iPSC-Derived Neurons
DNL343 EFFECTS IN NEURONS AND IPSC-DERIVED NEURONS DNL343 is BBB penetrant and achieved CNS pathway modulation in association with functional correction in an in vivo model IN VIVO STUDY DESIGN Wild-type and R191H mice self-administered chow-formulated DNL343 (ad libitum) for 13 weeks at doses rangi
Slide 40: DNL343 (eIF2B Activator): Inhibiting the ISR Pathway in ALS
DNL343 (eIF2B ACTIVATOR): INHIBITING THE ISR PATHWAY IN ALS By inhibiting the ISR pathway, DNL343 is 28-day dosing with DNL343 reduced ISR biomarkers intended to prevent or slow ALS progression in blood samples* from ALS patients (Phase 1b) • ALS is a fatal neurodegenerative disease with ATF4 protei
Slide 41: RIPK1 Inhibitors: Targeting Inflammation and Cell Death
RIPK1 INHIBITORS: TARGETING INFLAMMATION AND CELL DEATH RIPK1 is a critical signaling protein in a canonical 93% to 99% RIPK1 inhibition achieved in Phase 1 inflammatory and cell death pathway after multiple doses of SAR443820* • Increased RIPK1 activity drives neuroinflammation and cell necroptosis
Slide 42: Our Priorities
OUR PRIORITIES Commercial 1 Clinical Execution 2 TV Expansion 3 Readiness • 4 late-stage programs enrolling • Clinical data expected from 3 • Define go-to-market strategies in studies in MPS II, ALS, and PD TV-platform enabled programs the US and key global markets • Multiple earlier-stage trials •
Slide 43: Our Purpose: Defeat Degeneration
OUR PURPOSE: DEFEAT DEGENERATION Thank you to all those who are part of Denali’s purpose, especially our patients and their families LYSOSOMAL STORAGE RARE NEURODEGENERATIVE PARKINSON’S ALZHEIMER’S DISEASE DISEASES (ALS, FTD) DISEASE DISEASE Denali The name captures the formidable challenges in figh
Slide 44: Thank You
THANK YOU
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