Corporate Overview

May 24, 2021

 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, future milestones, planned preclinical studies and clinical trials; expectations regarding the timing of results
of such studies and trials; plans, timelines and expectations related to DNL151 and other LRRK2 inhibitor molecules; plans, timelines, challenges, benefits and expectations related to
DNL310, the DNL310 program and Denali’s TV technology platform, other programs enabled by Denali’s TV platform, and the ongoing Phase 1/2 study, and planned future studies, of
DNL310; plans, timelines and expectations related to DNL343, including with respect to the availability of data and the initiation of future clinical trials; plans, timelines and expectations
related to DNL788 and DNL758 of both Denali and Sanofi, including with respect to the availability of data and the initiation of future clinical trials; Denali’s expectations regarding
DNL593 and DNL919 and plans and expectations regarding planned regulatory filings and milestone payments with respect to such programs; the potential benefits and results of the
collaborations with Denali’s partners, including Biogen, Sanofi and Takeda, and expected milestone payments; and Company 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; risk of the occurrence of any event, change or other
circumstance that could give rise to the termination of Denali’s agreements with its collaborators; Denali’s early stages of clinical drug development; Denali’s and its collaborators’ ability
to complete the development and, if approved, commercialization of its product candidates; Denali’s and its collaborators’ ability to enroll patients in its ongoing and future clinical trials;
Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; Denali’s dependence on successful development of its blood-brain barrier
platform technology and TV-enabled product candidates; Denali’s and its collaborators’ ability to conduct or complete clinical trials on expected timelines; the risk that preclinical
profiles of Denali’s product candidates may not translate in clinical trials; the potential for clinical trials of Denali’s product candidates to differ from preclinical, early clinical, preliminary
or expected results; the uncertainty that product candidates will receive regulatory approval necessary to be commercialized; Denali’s ability to continue to create a pipeline of product
candidates or develop commercially successful products; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates; implementation of
Denali’s strategic plans for its business, product candidates and blood-brain barrier platform technology; and other risks. In light of these risks, uncertainties and assumptions, the
forward-looking statements in this press release 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 and Quarterly Reports filed on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 26, 2021, and May 4,
2021, respectively, 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 ©2021 Denali Therapeutics. All rights reserved.

 OUR PURPOSE: DEFEAT DEGENERATION
RARE
NEURODEGENERATIVE AMYOTROPHIC
DISEASES LATERAL SCLEROSIS PARKINSON’S ALZHEIMER’S

Orphan 20,000+ (US) 1,000,000+ (US) 5,500,000+ (US)

>30 lysosomal storage diseases >45 known genetic associations >95 known genetic associations >35 known genetic associations
on

Di
sea
y Populati

se Popula
alth

tio
He

Normal PD Normal AD

3
Significant unmet medical need with few disease-modifying medicines
 OUR PRINCIPLES: DISCOVERY AND DEVELOPMENT

GENETIC PATHWAY PATIENT IMPACT

POTENTIAL

ENGINEERING BRAIN
DELIVERY

Increase the likelihood of success

BIOMARKER-DRIVEN to bring effective therapies to
DEVELOPMENT patients and families

4 ©2021 Denali Therapeutics. All rights reserved.

 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 MPS II (Hunter Syndrome)

50/50 US
PGRN DNL593 Frontotemporal Dementia commercial

GLIAL BIOLOGY PATHWAY

50/50 US
RIPK1 (CNS) DNL788 ALS, MS, Alzheimer’s commercial
50/50 US
TREM2 DNL919 Alzheimer’s commercial

CELLULAR HOMEOSTASIS

EIF2B DNL343 ALS, FTD

OTHER

Cutaneous lupus
RIPK1 (Peripheral) DNL758 Royalty
erythematosus

15+ programs in Discovery stage (including 6 ETVs, 4 ATVs, 2 OTVs, and 3 small molecules)
5 ©2021 Denali Therapeutics. All rights reserved. *Investigational – not approved for treatment
 OUR PROGRESS: RECENT ACHIEVEMENTS CREATE 2021 MOMENTUM

ü DNL151 (Parkinson’s): Positive Ph1/1b; advancing to late-stage development

ü DNL310 (Hunter syndrome): Expanded Ph1/2 based on positive interim data 5
ü DNL343 (ALS): Positive interim Ph1 data; planning Ph1b in ALS clinical
CLINICAL ü DNL788 (ALS, Alzheimer's, MS): Ph1 ongoing in healthy volunteers* programs
PORTFOLIO
ü DNL758 (Inflammation): Ph2 recruiting CLE patients*

ü 1st human biomarker Proof of Concept with ETV:IDS (DNL310)

ü PTV:PGRN (FTD): added to TV portfolio 15
ü Expanded Enzyme TV portfolio with ETV:SGSH and five other ETVs TV-enabled
TRANSPORT programs
VEHICLE (TV) ü TV-enabled ASOs (OTV) validated pre-clinically
PLATFORM

ü ~$1.45B in cash and investments (as of 3/31/21)

~$1.45B
Well-resourced
ü Biogen collaboration: $1.025B upfront**, up to $1.125B milestones
to build
ü Strong corporate partnerships (Biogen, Sanofi, Takeda) fully integrated
CORPORATE
STRATEGY ü Building manufacturing and commercial capabilities company and
deliver for patients
6 * Sanofi study ** Cash and equity ©2021 Denali Therapeutics. All rights reserved.
 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 3
• Internal manufacturing capabilities LARGE NEURODEGENERATIVE
• Staged buildout of commercial infrastructure DISORDERS
(e.g. Alzheimer's, Parkinson's)
2
RARE CNS DISEASES
(e.g. ALS, FTD)
1
LYSOSOMAL STORAGE
DISEASES
(e.g. MPS II, MPS IIIA, Gaucher)

>30,000 patients WW* >200,000 patients WW* >50M patients WW*

Commercial growth concurrent with development timelines of portfolio

* Approximate per each therapeutic area based
* Denali estimates on Denaliaggregate
of world-wide internal assessment
prevalence

7 ©2021 Denali Therapeutics. All rights reserved.

OUR TV PLATFORM 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

The Transport Vehicle (TV) is engineered to deliver efficacious concentrations of

biotherapeutics to brain cells via receptor mediated transcytosis
9 ©2021 Denali Therapeutics. All rights reserved.
 TV TECHNOLOGY DELIVERS BIOTHERAPEUTICS TO THE BRAIN

ATV ATV
TfR TfR

V:IDS
Antibody Enzyme
Transport Vehicle ETTransport Vehicle
(ATV) (ETV)
Tf Tf Tf Tf
endothelial cell membrane endothelial cell membrane

Cortex (cynomolgus monkey) IDS KO Mouse Brain

Published May 27, 2020

• TV achieves high concentrations and broad distribution of biotherapeutic in brain

• TV achieves dose-dependent reduction in brain substrate
10 ©2021 Denali Therapeutics. All rights reserved.
 WIDESPREAD BIODISTRIBUTION WITH BBB-CROSSING COMPARED TO LIMITED
INTRATHECAL BIODISTRIBUTION
INTRATHECAL BIOTHERAPEUTIC
Limited distribution with sharp gradients at brain
and spinal cord CSF-contacting surfaces
INTRAVENOUS BBB-CROSSING BIOTHERAPEUTIC
Widespread biodistribution dictated by capillary TfR
expression and CNS vascularity

Capillary TfR
Sharp gradient expression
limits brain facilitates
biodistribution widespread
biodistribution

CNS vascularity
facilitates
Sharp gradient widespread
limits biodistribution biodistribution
along the spinal
cord

IV IDS
Lumbar Region IT IDS

11 ©2021 Denali Therapeutics. All rights reserved.

 TV PLATFORM MODULARITY CREATES MULTIPLE OPPORTUNITES

MODULAR TECHNOLOGY ENABLES OPTIMAL BENEFITS OF TV PLATFORM

MODALITY FOR EACH TARGET Increase biodistribution (~10-30X) to brain

Antibody Enzyme Unlock Targets

Transport Transport • Brain delivery of biotherapeutics for previously
Vehicle Vehicle intractable targets

Enhance Efficacy
• Further enhance activity through synergistic TfR
and target biology

Protein Oligonucleotide FIRST HUMAN BIOMARKER PROOF OF

Transport Transport CONCEPT ACHIEVED WITH DNL310
Vehicle Vehicle (ETV:IDS) IN HUNTER SYNDROME

12 ©2021 Denali Therapeutics. All rights reserved.

 BRAIN DELIVERY IS A CRITICAL UNMET NEED OF HUNTER SYNDROME THERAPY

Monogenic lysosomal storage disorder caused by deficient iduronate-2-sulfatase

Enzyme replacement therapy

(ERT)* partially addresses 2/3 of patients with Hunter syndrome (MPS II)
physical manifestations have neuronopathic disease

DNL310
(ETV:IDS)

DNL310 is a brain-penetrant
ERT designed to treat both
physical and neurocognitive
manifestations of MPS II
(IV, once weekly)
*ERT (idursulfase ~$700M WW annual sales)
13 ©2021 Denali Therapeutics. All rights reserved.
HALLMARK & EXPLORATORY BIOMARKERS IN HUNTER SYNDROME
GAGs are a hallmark biomarker in MPS II Exploratory biomarkers in MPS II

• GAGs are elevated in

patients with MPS II,
particularly in the
CNS—despite current
treatment options1
• Patients with
neuronopathic MPS II
have elevated levels of
GAGs in the CSF1

GAGs: Glycosaminoglycans
Reference: 1. Bhalla A, et al, 2020.

Monitoring CSF levels of GAGs may indicate DNL310 activity in the CNS
©2021 Denali Therapeutics. All rights reserved.
 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-glucosaminidase HS
MPS IIID Sanfilippo D N-acetylglucosamine-6-sulfatase HS
MPS IVA Morquio A N-acetylgalactosamine-6-sulfatase KS, CS
MPS VI Maroteaux-Lamy N-acetylgalactosamine-4-sulfatase DS, CS
MPS VII Sly β-Glucuronidase HS, DS, CS
MPS IX Natowicz Hyaluronidase HA

HS= heparan sulfate

CNS involvement Kobayashi et al., Journal of Human Genetics 2019 DS= dermatan sulfate
CS= chondroitin sulfate
KS= keratin sulfate
HA= hyaluronic acid

Heparan sulfate is associated with MPS disorders with CNS involvement

15 ©2021 Denali Therapeutics. All rights reserved.
 DNL310 PHASE 1/2 COHORT A (N=5): POSITIVE 3-MONTH DATA
Summary of key results after 12 weekly IV doses Biomarker proof of concept achieved
for Denali’s TV technology
• Heparan sulfate (HS) levels were normalized in the CSF
of 4/5 patients at first analysis1
• HS reductions were sustained after 3 months of dosing
(mean 85% reduction, P<.001)1
• Total urine HS levels decreased after switching from
enzyme replacement therapy (ERT) to DNL3101
• Reductions in exploratory CSF biomarkers consistent
with improved lysosomal function1
• Generally well tolerated with safety profile consistent Sustained Normalization
*
with other ERTs; most frequently observed adverse
events of mild or moderate infusion-related reactions1
References: 1. Bakardjiev AI, 2021. 2. Hendriksz CJ, et al, 2015.
*Normal range determined using 30 adult CSF samples (range 10-90%ile); adult and child CSF GAG levels are similar.2

Phase 1/2 interim data support late-stage clinical development of DNL310 in MPS II
16 ©2021 Denali Therapeutics. All rights reserved.
 DNL310 PHASE 1/2 PROGRESS AND MPS II DEVELOPMENT PLANS

ü Achieved biomarker proof of concept for Denali’s TV technology

Cohort A
ü Triggered addition of Cohort C to Phase1/2 study
Ages 5-10 y.o.
ü Enabled “GO” decision on Phase 2/3 development plans
Neuronopathic
ü Ungated expansion of Enzyme TV portfolio with 5 additional programs

Cohort B
Ages 2-18 y.o.
Designed to inform dose selection for Phase 2/3 development
Neuronopathic &
Non-neuronopathic

Cohort C Designed to further explore clinical endpoints – including behavior and

cognition – in an age range for which treatment effects on developmental
Ages <4 y.o. milestones may have the highest likelihood to be observed
Neuronopathic
17 ©2021 Denali Therapeutics. All rights reserved.
ETV:IDS EFFECTS ON PERIPHERAL & CNS ABNORMALITIES IN MPS II
ETV:IDS rescues neurocognitive and skeletal phenotypes in a mouse model of MPS II1

In an assessment
of behavioral and
skeletal phenotypes
following systemic
delivery of ETV:IDS
in a mouse model of
Hunter syndrome…1
Reduced Corrected
cognitive deficits1 skeletal disease1
Normalizes spatial learning Corrects trabecular
and memory and cortical bone mass
Improved Improved auricular
motor function1 abnormalities1
Improves locomotor Improves outer and
performance and agility middle ear structure

Preclinical data highlight the potential of DNL310 to treat peripheral and CNS abnormalities in MPS II

Reference: 1. Arguello A, 2021.

©2021 Denali Therapeutics. All rights reserved.

TV PLATFORM DIFFERENTIATION &
BROAD POTENTIAL
 MILESTONES IN DEVELOPING TRANSFERRIN RECEPTOR (TfR) TECHNOLOGY

1980-1990 1990-2010 2010-2015 2015-2021

TfR binding transport vehicle (TV)

platform for brain delivery

Transport Vehicle

TfR MAb brain Reduced affinity Monovalent single TfR bispecific brain
TfR at the BBB delivery in rats TfR MAb bispecific chain Fab antibody delivery in mice
and mice brain delivery fusion brain and NHPs TfR
binding
in mice delivery in mice

1500

#CNS drug delivery 1000

papers per year in
Pubmed 500

1980 1990 2000 2010 2020

We have invented a TfR-based biotherapeutic platform with optimized BBB-crossing properties

20 ©2021 Denali Therapeutics. All rights reserved. NHPs = nonhuman primates
 DELIVERY OF BIOTHERAPEUTICS TO BRAIN: TfR-BASED PLATFORMS
JCR Pharma Genentech BLOOD Roche DENALI
Standard Protein Antibody Fusion Bispecific Single Chain Fusion Fc Fragment Transport Vehicle

Cargo : IDS
Cargo : IDS

IgG:IDS Traditional
MAb Monovalent Monovalent
TfR TfR binding
Bispecific Single chain
ETV:IDS Transport
Antibody Fab antibody
Vehicle (TV)

Tf Tf

BIVALENT BINDING MONOVALENT BINDING MONOVALENT BINDING MONOVALENT, MODERATE

HIGH AFFINITY HIGH & LOWER AFFINITIES HIGH & LOWER AFFINITIES AFFINITY FOR BRAIN UPTAKE
ENDOTHELIAL CELL

• Molecule architecture alters transferrin receptor (TfR) engagement, impacting brain delivery
• How do architectures differ in brain uptake, required biodistribution & GAG substrate reduction?
21 ©2021 Denali Therapeutics. All rights reserved.
 Brain Concentration [nM
DNL310 -
DNL310 -
10
ETV:IDS SHOWS IMPROVED BRAIN UPTAKE COMPARED
Brain TO IgG:IDS DNL310 -

100
DNLI-20-0265 DNL310
ETV:IDS IgG:IDS
IgG:IDS
TfRmu/hu IV1of 1, 3 or 10mg/kg

Brain Concentration [nM]

1mg/kg IgG:IDS 1
DNL310 - 1mg/kg
1mg/kg
Human TfR knockin mouse model n=3-5/group
IgG:IDS 3
DNL310 - 3mg/kg
3mg/kg 3mg/kg
10
0.1 10mg/kg IgG:IDS 1
DNL310 - 10mg/kg
10mg/kg
0.5 h 40 h 84h 8 12
24 16
h 20 24
Time (hours) IgG:IDS
Serum Liver
1 Brain
IgG:IDS 1mg/kg
10000 DNL310 DNL310
1000 15
Serum Concentration [nM]

IgG:IDS 3mg/kg

Brain Concentration [nM]

Liver Concentration [nM]
DNL310 - 1mg/kg DNL310 - 1mg/kg
1000 0.1 IgG:IDS 10mg/kg
DNL310 - 3mg/kg DNL310 - 3mg/kg
0 4 8 12 1610 20 24
100 DNL310 - 10mg/kg DNL310 - 10mg/kg
Time (hours)
100
10 IgG:IDS IgG:IDS
5
IgG:IDS 1mg/kg IgG:IDS 1mg/kg
1
IgG:IDS 3mg/kg IgG:IDS 3mg/kg
0.1 IgG:IDS
10 10mg/kg IgG:IDS
0 10mg/kg
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (hours) Time (hours) Time (hours)

• ETV:IDS achieves higher serum concentrations compared to IgG:IDS at all doses tested
• IgG:IDS has greater liver uptake compared to ETV:IDS
• ETV:IDS shows superior brain uptake to IgG:IDS
22 ©2021 Denali Therapeutics. All rights reserved.
 ETV:IDS SHOWS ENHANCED DISTRIBUTION INTO NEURONS COMPARED TO IgG:IDS

huIgG (vascular) + Neuronal marker huIgG / NeuN

huIgG (parenchymal) (NeuN) Localization to lysosomes

2.5×104
**

Intraneuronal huIgG signal/

IgG:IDS

neuronal volume (a.u.)

2.0×104

1.5×104

1.0×104

5.0×103

ETV:IDS 0.0

S
:ID

ID
V:
G

ET
Ig
Neocortex, 10 mg/kg, Superimposed summary
stats from 5 animals (solid) consisting of 3
different image volumes from each animal (open).
The 5 means were used to calculate mean ±
SEM; p values: unpaired t test; ** p £ 0.01.

ETV:IDS shows trafficking to target cells in the CNS at a significantly greater rate than IgG:IDS
23 ©2021 Denali Therapeutics. All rights reserved.
 ETV:IDS SHOWS IMPROVED BRAIN AND CSF GAG REDUCTION
COMPARED TO IgG:IDS IN AN MPS II MOUSE MODEL

Liver
Liver Brain
Brain CSF
CSF
50 15 6

40
(D0A0, D0S0, D0a4)

(D0A0, D0S0, D0a4)

(D0A0, D0S0, D0a4)
Total GAGs (ng/µg)

Total GAGs (ng/μg)

Total GAGs (ng/μl)

10 4
30 ** ***
*** ****
**** ****
20 **** ****
**** 2 ****
5
**** ****
10
**** **** **** **** **** ****
0 0 0
dose dose dose
- - 1 3 10 1 3 10 (mg/kg) - - 1 3 10 1 3 10 (mg/kg) - - 1 3 10 1 3 10 (mg/kg)

Vehicle IgG:IDS ETV:IDS Vehicle IgG:IDS ETV:IDS Vehicle IgG:IDS ETV:IDS

TfRmu/hu Ids KO;TfRmu/hu TfRmu/hu Ids KO;TfRmu/hu TfRmu/hu Ids KO;TfRmu/hu

ETV:IDS shows improved, dose-dependent GAG reduction in brain & CSF compared to IgG:IDS

24 ©2021 Denali Therapeutics. All rights reserved.

 SUMMARY OF ETV:IDS COMPARISON TO IgG:IDS
Architecture engagement & affinity to TfR impacts brain uptake, distribution & CNS GAG reduction
BLOOD IgG:IDS ETV:IDS

Brain
Endothelial
Cell (BBB)

Target
Cell

BRAIN
• Improved brain uptake observed for ETV:IDS compared IgG:IDS
• Efficient transport of ETV:IDS across brain vasculature (endothelial cell transcytosis) as compared to
entrapment of IgG:IDS in vasculature (consistent with endothelial trafficking to lysosome)
• Increased brain & CSF GAG reduction with ETV:IDS compared to IgG:IDS
25 ©2021 Denali Therapeutics. All rights reserved.
 EXPANDED ETV PLATFORM DRIVING NEAR-TERM GROWTH
ETV STRATEGY ETV PORTFOLIO
STAGE
PROGRAM INDICATION
Substantial unmet need and opportunity Discovery
IND-
enabling
Early
clinical
Late clinical

• CNS manifestations in 2/3 of LSDs

ETV:IDS
• ETV can treat body and brain with IV (DNL310)
MPS II
administration
ETV:SGSH MPS IIIA

Parkinson’s;
ETV:GBA
Clinical Proof of Concept Achieved Gaucher
• Expanding DNL310 Phase 1/2
ETV:ARSA MLD

ETV:NAGLU MPS IIIB

Path forward
• Expanded portfolio of ETV programs ETV:IDUA MPS I
• Build and grow internal manufacturing
and commercial capabilities
ETV:GAA Pompe

Execute internally with fast-to-market strategy to serve patients and capture full potential of ETV platform
26 ©2021 Denali Therapeutics. All rights reserved.
 TV POTENTIAL: WIDE RANGE OF INDICATIONS AND TARGETS
CURRENT FUTURE
FOCUS OPPORTUNITIES

NEUROLOGY
NEURO- e.g., pain, epilepsy,
DEGENERATION CURRENT PLATFORMS neuropsychiatry,
neuromuscular
e.g., AD, PD, ALS,
FTD
Enzymes Proteins
Antibodies Oligos

Novel RMT Other

Targets Gene Therapies Modalities ONCOLOGY
e.g., CNS metastases
POTENTIAL FUTURE
PLATFORMS

LYSOSOMAL
STORAGE INFECTIOUS
DISORDERS DISEASES
e.g., Hunter syndrome

27 ©2021 Denali Therapeutics. All rights reserved.

 DIVERSE TV PORTFOLIO IN CNS AND BEYOND
ONCOLOGY

ATV:TREM2 PTV:PGRN
PTV:PGRN OTV ATV:HER2
Cortex
150 : Single dose

ATV:BACE1)
: Multi dose

Control)
8 1400 Control IgG (40 mpk)
**** Tras + Per (3+3 mpk)
**** 1200 Tras + Per (10+10 mpk)

Tumor Volume (mm3)

Relative Iba1+ area

6 100 Tras + Per (20+20 mpk)

(% ATV
1000 ATV:tras + ATV:per (3+3 mpk)
/parenchyma

ATV:tras + ATV:per (10+10 mpk)

mRNA (%
800 ATV:tras + ATV:per (20+20 mpk)
4

Malat1 mRNA
600
50
400
2

Malat1
200
ns ns * ****
0 0 0
0 10 20 30 40 50 60
ATV ASO mAb OTV OTV
0m pe

pk pe

0m M2

pk 2
m EM

Days on Study
AT pk

V k
10 soty

m ty

10 RE

BACE1 ASO
p
10 :Iso

10 :TR
T
I

AT

ATV:TREM2 robustly PTV:PGRN rescues lysosomal OTV knocks down gene ATV:HER2 enhances anti-tumor
increases microglia in mice function in GRN KO brain expression in mouse brain activity in xenograft model

28 ©2021 Denali Therapeutics. All rights reserved.

 OUR TV PORTFOLIO Undisclosed targets: LF - Lysosomal Function target; CH - Cellular Homeostasis target

DRUG DRUG DEVELOPMENT

PROGRAM TARGET DISEASE INDICATION PARTNER
CANDIDATE* Drug Discovery IND-Enabling Early Clinical Late Clinical Approved

ETV – Enzyme Transport Vehicle

Iduronate 2-sulfatase DNL310 MPS II (Hunter Syndrome)

Sulfamidase ETV:SGSH MPS IIIA (Sanfilippo Syndrome)

GBA ETV:GBA Parkinson’s, Gaucher

ARSA ETV:ARSA MLD

NAGLU ETV:NAGLU MPS IIIB

IDUA ETV:IDUA MPS I

GAA ETV:GAA Pompe

ATV – Antibody Transport Vehicle

TREM2 DNL919 Alzheimer’s

Abeta ATV:Abeta Alzheimer’s

Tau ATV:Tau Alzheimer’s

Alpha-Synuclein ATV:aSyn Parkinson’s, DLB, MSA

HER2 ATV:HER2 Oncology

PTV – Protein Transport Vehicle

PGRN DNL593 Frontotemporal Dementia

OTV – Oligonucleotide Transport Vehicle

Undisclosed OTV:CH2 Alzheimer’s

Undisclosed OTV:LF3 Parkinson’s

29 Biogen has option rights to 1 additional undisclosed TV enabled program ©2021 Denali Therapeutics. All rights reserved. *Investigational – not approved for treatment
OUR SMALL MOLECULE PROGRAMS
 LRRK2 AS A THERAPEUTIC TARGET FOR PARKINSON’S DISEASE
BROAD THERAPEUTIC POTENTIAL DE-RISKED TARGET

• Genetics indicate that lysosomal dysfunction is central to PD • Human LRRK2 LOF mutants do not have functional
consequences (Whiffin et al, Nature Med 2020)

Number of Genetic Associations

Glial Biology-related Degenogenes
Parkinson’s

and Implicated Genes

Lysosomal Function-related Degenogenes
Disease

Cellular Homeostasis-related Degenogenes

Other Degenogenes

• Inhibition of LRRK2 may be a therapeutically beneficial approach for

both genetic and idiopathic PD • Nine month chronic dosing in nonhuman primates with
did not demonstrate effects on pulmonary function
• DNL151 and are clinical-stage LRRK2 inhibitors that target
both wild-type and mutant forms of LRRK2 with therapeutic potential to • Pulmonary function is unaffected in nonhuman primates
treat LRRK2 and other drivers of lysosomal dysfunction following LRRK2 inhibition (Baptista et al, STM 2020)

• Denali clinical data with DNL151 and supports

tolerability of >70% inhibition at trough for 28 days in healthy
volunteers and patients

31 ©2021 Denali Therapeutics. All rights reserved.

 INHIBITING LRRK2 RESCUES LYSOSOMAL DYSFUNCTION AND DOWNSTREAM
NEURONAL DEGENERATION

GENETICS PATHWAY PATHOLOGY

LRRK2 is a degenogene LRRK2 negatively regulates Lysosomal dysfunction can lead to
lysosomal function neuronal cell loss

BMP ↑

Human genetic variants link LRRK2 to familial Parkinson’s and sporadic Parkinson’s disease risk
Region-specific LRRK2 activation corresponds to lysosomal dysfunction in sporadic Parkinson’s disease

LRRK2 inhibition is a potential therapeutic approach in both LRRK2-mutant and sporadic PD

32 ©2021 Denali Therapeutics. All rights reserved.
 BIIB122/DNL151 ADVANCING INTO LATE-STAGE DEVELOPMENT IN 2021
ROBUST TARGET ENGAGEMENT AND PATHWAY MOVING DNL151 INTO LATE-STAGE STUDIES
ENGAGMENT CLINICAL DATA WITH A GLOBAL STRATEGIC PARTNER

• Over 300 individuals dosed in total with a LRRK2
inhibitor in extensive Phase 1/1b testing
• Safety and tolerability profile support further
development in Parkinson’s patients
• Achieved target engagement and pathway
engagement goals in healthy volunteers and
Parkinson’s patients for both DNL201 and DNL151
• Late-stage development in both LRRK2 mutation
carriers and idiopathic Parkinson’s patients
• Co-development and co-commercialization
agreement with Biogen in August 2020
• $1.025B upfront payment; up to $1.125B
milestones plus profit sharing and royalties

LRRK2 INHIBITOR EARLY-STAGE DEVELOPMENT LRRK2 INHIBITOR LATE-STAGE DEVELOPMENT

DNL201 Phase 1 DNL201 Phase 1b DNL151 Selected DNL151 late-stage study

n=122 (Completed) (n=28) (Completed) favorable profile, LRRK2 Mutation Carriers
Initiate late-stage
including potential for development by
DNL151 Phase 1 DNL151 Phase 1b once daily dosing DNL151 late-stage study
n=184 n=36 end 2021
Idiopathic PD

33 ©2021 Denali Therapeutics. All rights reserved.

 DNL151 PHASE 1/1B SAFETY SUMMARY
• DNL151 was generally well tolerated in healthy volunteers and in patients with Parkinson’s disease
• No serious adverse events were observed in either study
• The majority of healthy volunteers and patients with treatment-emergent adverse events (TEAEs)
experienced mild to moderate TEAEs
• Study discontinuations
– Two healthy volunteers in the Phase 1 study who received 250 mg twice daily and 400 mg twice daily, respectively,
discontinued with symptoms including nausea and headache considered related to study drug
– Two patients in the Phase 1b study discontinued on the first study day
• One patient who received 130 mg once daily experienced severe asymptomatic hypotension, considered by the
investigator as being unrelated to study drug (pre-existing hypotension)
• One patient who received 300 mg once daily experienced mild hypotension and orthostatic hypotension with mild
dizziness
• In all discontinuations, symptoms resolved with discontinuation of therapy
• No clinically meaningful changes in pulmonary or renal function in either study

Treatment with DNL151 for up to 28 days was generally well tolerated and supports plans for
late-stage studies in patients with Parkinson’s disease

34 ©2021 Denali Therapeutics. All rights reserved.

 DNL151 PHASE 1B STUDY: TARGET AND PATHWAY ENGAGEMENT
pS935 pRAB10

LRRK2 Target Engagement LRRK2 Pathway Engagement

BMP ↑ BMP ↑

DNL151 treatment resulted in robust reductions in target (pS935) and pathway (pRab10) biomarkers
in patients with Parkinson’s disease across all dose levels studied
Levels of pS935 measured in whole blood and of pRab10 measured in PBMCs at trough (pre-dose) and at steady state (Day 28)
35 ©2021 Denali Therapeutics. All rights reserved.
 EFFECT OF DNL151 ON A LYSOSOMAL FUNCTION BIOMARKER

BMP 22:6 concentration measured in urine at baseline and steady state

LRRK2 negatively regulates Phase 1 Healthy Volunteers Phase 1b Parkinson’s Patients
lysosomal function

BMP ↑

DNL151 treatment resulted a dose-dependent reduction in BMP 22:6,

providing peripheral evidence supporting improvement of lysosomal function

36 ©2021 Denali Therapeutics. All rights reserved.

 EIF2B AS A THERAPEUTIC TARGET FOR ALS/FTD

GENETICS PATHWAY PATHOLOGY

Degenogenes, including EIF2B, cause ISR leads to aggregation of RNA-binding These harmful aggregates trigger
an integrated stress response (ISR) proteins (e.g. TDP-43) into stress neurodegeneration
granules and harmful aggregates

Integrated Stress Response (ISR) Neuronal Loss (ALS / FTD)

Activating EIF2B can inhibit the ISR pathway and prevent and
reverse the formation of stress granules associated with disease
37 ©2021 Denali Therapeutics. All rights reserved.
 EIF2B ACTIVATOR DNL343 DISSOLVES STRESS GRANULES IN VITRO

ALS patient neurons with TDP-43 pathology

Stress
Granules
TDP-43
expressing
Neuman et al. Science 2006 cells
Protein
aggregates
TDP-43 inclusions are found in >95% of
ALS patients and ~50% of FTD patients1 Stress DNL343

EIF2B activator DNL343 reverses pre-formed

stress granules and TDP-43 inclusions
1Goedert et al. Cold Spring Harbor Perspectives in Medicine, 2012.

38 ©2021 Denali Therapeutics. All rights reserved.

 DNL343 PHASE 1 STUDY TRANSLATIONAL
STUDY OVERVIEW DOSING AND DETAILED DESIGN PHARMACODYNAMICS
WT Mutant
500

WT+Vehicle)
Phase 1 study in healthy

Expression
Gene expression
Type

toto0WT+Vehicle
volunteers Complete cohorts (colored) 400
Planned cohorts
* Cohorts with CSF collection 300
Planned: 88 healthy volunteers,
Population
18-50 years (SAD=48; MAD=40)

Chac1 gene
200

% relative
SD6

(% relative
Chac1
Safety PK (+/- food) 100
• AEs SD5
• Plasma 0
• Safety labs • CSF SD4 MD4* Veh Veh DNL343
• ECGs
SD3 SD3 MD3* 150

(% relative to 0 uM DNL343)
Plasma C24hr by dose
• Vital Signs

CHAC1 gene expression

Key
endpoints • C-SSRS (MAD) SD2 MD2*
100
Key Pathway engagement in PBMCs: SD1 MD1*
endpoints ATF4 protein, CHAC1 gene
expression 50

Exploratory Single dose Food effect Multiple dose

• CSF and plasma metabolomics, N = 8 / cohort N = 8 / cohort N = 10 / cohort 0
lipidomics, and cytokines (6 active : 2 PBO) (6 active : 2 PBO) (8 active : 2 PBO) -12 -10 -8 -6
log10 DNL343 unbound (M)

Dosing of all SAD cohorts completed; Safety, tolerability, PK and PD support further development of DNL343

39 ©2021 Denali Therapeutics. All rights reserved.

 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 ↑

Microglial dysfunction and Necroptosis

metabolic dysregulation

RIPK1 inhibition enables selective modulation of the TNFR1 pathway,

reducing inflammation and necroptosis in the brain
40 ©2021 Denali Therapeutics. All rights reserved.
 DEVELOPING RIPK1 INHIBITORS FOR CNS & INFLAMMATORY DISEASE

DNL788 (CNS-penetrant) DNL758 (peripherally-restricted)

• Phase 1 study* initiated in Dec 2020 • Phase 2 study* in cutaneous lupus

erythematosus (CLE) recruiting patients
• Therapeutic target areas: ALS, AD, MS
• Phase 1b study* in Covid-19 completed;
while the primary endpoint was not met,
DNL758 was found to be generally well
tolerated and did generate positive signals of
relevant biological effect
*Sanofi sponsored studies

41 ©2021 Denali Therapeutics. All rights reserved.

LOOKING AHEAD
 EXPECTED
OUR PLANS: 2021 KEY MILESTONES TIMING
§ DNL310: 3-month data from Cohort A of Phase 1/2 study (WORLD late-breaker) § Completed
ETV:IDS
Hunter Syndrome
§ DNL310: 6-month data from Cohort A of Phase 1/2 study § Mid 2021
§ DNL310: 6-month data from Cohort A+B of Phase 1/2 study § Early 2022

LRRK2
Parkinson’s
§ DNL151: Initiate late-stage clinical development in collaboration with Biogen § Late 2021

EIF2B § DNL343: Phase 1 data in healthy volunteers § Completed

ALS, FTD § DNL343: Initiate Phase 1b study in ALS patients § 2H 2021

RIPK1 § DNL758 (inflammatory diseases): Commence dosing in Phase 2 study in CLE patients* § 1H 2021
CNS and
Peripheral
§ DNL788 (ALS, Alzheimer’s, MS): Phase 1 data in healthy volunteers* § 2H 2021
*Sanofi study

§ Received
ATV:TREM2 § DNL919: Milestone payment from Takeda for initiation of IND-enabling studies
Alzheimer’s
§ Late 2021/
§ DNL919: File IND application or CTA
Early 2022

PTV:PGRN § DNL593: Milestone payment from Takeda for initiation of IND-enabling studies § Received
FTD § DNL593: File IND application or CTA § Late 2021

§ Expand ETV portfolio

TV Platform § Ongoing
§ Expand manufacturing capabilities and continue to build out commercial capabilities
43 ©2021 Denali Therapeutics. All rights reserved.
 DRIVING TO DEFEAT DEGENERATION

DEVELOPING
DISEASE-MODIFYING
THERAPEUTICS FOR PATIENTS

44 ©2021 Denali Therapeutics. All rights reserved.

 LEARN MORE ▶

To learn more about Denali Therapeutics

please visit www.denalitherapeutics.com