Denali Therapeutics Inc. · NASDAQ:DNLI
Denali Therapeutics — Investor Presentation (March 2023)
41 slides from Denali Therapeutics's investor presentation, March 2023
Slide 1: Corporate Overview
Corporate Overview March 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: Building Denali to Defeat Degeneration
BUILDING DENALI TO DEFEAT DEGENERATION Accomplishments to Date Mid-Term Goals (2023-2025) Long-Term Goals Track Record of Invention & Creating Value & Defeating Execution Delivering Medicines Degeneration 10 INDs across 6 indications, Complete 3 - 4 late-stage clinical Commercial portfolio of 7 prog
Slide 4: 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 5: 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 6: 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 LARGE Function (PTV:PGRN) Granu
Slide 7: 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 50/50 profit share in US, 40/
Slide 8: Our Strategy: Broad Portfolio in Parallel Development
OUR STRATEGY: BROAD PORTFOLIO IN PARALLEL DEVELOPMENT COMMON NEURODEGENERATIVE DISEASES RARE NEURODEGENERATIVE DISEASES LYSOSOMAL STORAGE DISEASES (e.g., MPS II, MPS IIIA) (e.g., ALS, FTD) (e.g., Parkinson’s, Alzheimer’s) DRUG CANDIDATE PHASE IN 2023 DRUG CANDIDATE PHASE IN 2023 DRUG CANDIDATE PHASE
Slide 9: 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 10: Our TV Platform for Brain Delivery of Biotherapeutics
OUR TV PLATFORM FOR BRAIN DELIVERY OF BIOTHERAPEUTICS
Slide 11: 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 12: 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 13: 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 14: 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 15: DNL310 Phase 1/2 Study in Pediatric Patients with MPS II
DNL310 PHASE 1/2 STUDY IN PEDIATRIC PATIENTS WITH MPS II • Open-label, 24-week study followed by an open-label extension (NCT04251026) • Approximately 45 participants ≤18 years of age with MPS II are enrolling into 5 cohorts (A-E); treatment-naive and -experienced patients are eligible • Differences
Slide 16: 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 17: 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 18: Biomarkers: Urine Heparan Sulfate and Dermatan Sulfate
BIOMARKERS: URINE HEPARAN SULFATE AND DERMATAN SULFATE Heparan Sulfate (HS)a Dermatan Sulfate (DS)a Mean HS reduction Mean DS reduction Week n Week n from BL, % from BL, % 24 23 82.7 24 23 88.1 49 16 84.8 49 16 88.8 Cohort Dose 104b 2 67.5 104b 2 83.6 ● A 3 to 30 mg/kg ● B1 3 to 15 mg/kg ● B2 7.5 to
Slide 19: Biomarkers: CSF HS
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) Safety profile enabled achievement of healthy, normal levels of CSF HS, sustained over time, including in those with high pre-
Slide 20: Clinical Outcomes: VABS-II Raw Score
CLINICAL OUTCOMES: VABS-II RAW SCORE Individual Longitudinal Raw Scores in Selected Raw Score Mean Change From Baseline at Week 49a Subdomains Relevant to MPS IIb (n=16) Mean Change (95% CI) (n=22) Over 49 weeks, mean VABS-II raw scores increased across subdomains, including those most relevant to M
Slide 21: Clinical Outcomes: BSID-III Raw Score
CLINICAL OUTCOMES: BSID-III RAW SCORE Cognitive Raw Score Mean Change From Baseline at Individual Longitudinal BSID-III Cognitive Raw Scoreb Week 49a Transition to KABC: BSID Cognitive Participants Raw Score older than 36 (age equivalent months and <=42 months, cognitively n=11) capable of completin
Slide 22: Clinical Outcomes: Clinician and Caregiver Global Impression Scales of Change
CLINICAL OUTCOMES: CLINICIAN AND CAREGIVER GLOBAL IMPRESSION SCALES OF CHANGEa Week 49: CGI-C Week 49: CaGI-C Much worse A little worse No change Not assessed A little improved Much improved 16 16 14 14 No. of participants No. of participants 12 12 10 10 8 8 6 6 4 4 2 2 0 0 Overall Daily Communicati
Slide 23: Clinical Outcomes: Change in Estimated Hearing Loss (ABR Testing)
CLINICAL OUTCOMES: CHANGE IN ESTIMATED HEARING LOSS (ABR TESTING) ABR thresholds improved across all frequencies; improvements tended to be greater at higher frequencies Week 24 Week 49 Improved hearing Worsened hearing Improved hearing Worsened hearing 500 Hz −1.4 500 Hz −6.7 1000 Hz −2.5 1000 Hz −
Slide 24: 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 25: 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 26: 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 dose- manifestations of Sanfilippo syndrome Type A dependent manner in brain and CSF • Rare lysosomal storage disease (LSD) that causes MPS IIIa;TfR KI *** < 0.001 ***
Slide 27: DNL593 (PTV:PGRN): PGRN Brain Delivery for FTD-GRN
DNL593 (PTV:PGRN): PGRN BRAIN DELIVERY FOR FTD-GRN Brain delivery of progranulin (PGRN) designed to treat frontotemporal dementia-granulin (FTD-GRN) • FTD is the most common dementia in people under 60; no approved therapies • FTD-GRN is associated with progranulin (PGRN) deficiency; accounts for 5-
Slide 28: 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 Drug Mechanism Therapeutic single d
Slide 29: 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 Drug Mechanism
Slide 30: 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 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 BRAIN BRAIN ANTERIOR POSTERIOR ANTERIOR POSTERIOR SPINAL CORD SPINAL CORD 31 anti-ASO ©2023 Denali Therapeu
Slide 32: 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 32 anti-ASO ©2023 Denali Th
Slide 33: 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 33 ©2023 Denali Therapeutics Inc. All rights reserved.
Slide 34: 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 35: Our Brain-Penetrant Small Molecule Programs
OUR BRAIN-PENETRANT SMALL MOLECULE PROGRAMS
Slide 36: BIIB122 (LRRK2 Inhibitor): Targeting the Lysosome in PD
BIIB122 (LRRK2 INHIBITOR): TARGETING THE LYSOSOME IN PD Targeting LRRK2 may impact the underlying Rigorous development program to evaluate BIIB122 biology and slow the progression of PD in patients with and without LRRK2 mutations Phase 2b Phase 3 • 10M+ people with Parkinson’s disease (PD) WW LUMA
Slide 37: 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 intended to prevent or slow ALS progression biomarkers in blood samples* from ALS patients (interim Phase 1b data) • ~250,000 people with ALS WW ATF4 protein lev
Slide 38: 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 RIPK1 (Mean Percent
Slide 39: 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 40: 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 41: Thank You
THANK YOU
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