Denali Therapeutics Webinar to Present Interim Data from DNL310 Phase 1/2 Hunter Syndrome Patient Study Ryan Watts, PhD, CEO Carole Ho, MD, CMO and Head of Development July 25, 2021
Denali Therapeutics Webinar to Present Interim Data from DNL310 Phase 1/2 Hunter Syndrome Patient StudyRyan Watts, PhD, CEOCarole Ho, MD, CMO and Head of DevelopmentJuly 25, 2021
Disclaimers
Forward Looking StatementsThis 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 Denali Therapeutics Inc.’s (“Denali’s”): future results of operations and financial position; business purpose, strategy and plans; planned or future preclinical studies and clinical trials and expectations regarding the results of such studies and trials; plans, timelines, potential of, and expectations related to the DNL310 program including the ongoing Phase 1/2 study and planned future studies, Denali’s TV technology platform, and other programs enabled by Denali’s TV platform; and the timing and likelihood of success of approval and commercialization of DNL310, 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 risk that results from early clinical biomarker studies will not translate to clinical benefit in late clinical studies; the uncertainty that product candidates will receive regulatory approval necessary to be commercialized; the uncertainty that Denali’s clinical products will differentiate from competitor products; 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 25, 2021, and May 5, 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 DataThis 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.
Degeneration creates significant unmet medical need, with few disease-modifying medicines
RARE NEURODEGENERATIVE
DISEASESAMYOTROPHIC LATERAL
SCLEROSIS (ALS)PARKINSON’S
DISEASEALZHEIMER’S
DISEASE
OUR PURPOSE: DEFEAT DEGENERATION
4 ©2021 Denali Therapeutics. All rights reserved.
OUR PRINCIPLES: DISCOVERY AND DEVELOPMENT
5
DEGENOGENESGENETIC PATHWAY
POTENTIAL
ENGINEERING BRAIN DELIVERY
BIOMARKER-DRIVEN DEVELOPMENT
PATIENT IMPACT
Increase the likelihood of success to bring effective therapies to
patients and families
©2021 Denali Therapeutics. All rights reserved.
OUR DEVELOPMENT PORTFOLIO
6
PROGRAM TARGET DRUG CANDIDATE* DISEASE INDICATIONDRUG DEVELOPMENT
PARTNERDrug
Discovery IND-Enabling Early Clinical Late Clinical Approved
LYSOSOMAL FUNCTION PATHWAY
LRRK2 DNL151 Parkinson’s 50/50 US commercial
Iduronate 2-sulfatase DNL310 MPS II (Hunter)
Sulfamidase DNL126 MPS IIIA (Sanfilippo)
PGRN DNL593 Frontotemporal Dementia 50/50 US commercial
GLIAL BIOLOGY PATHWAY
RIPK1 (CNS) DNL788 ALS, MS, Alzheimer’s 50/50 US commercial
TREM2 DNL919 Alzheimer’s 50/50 US commercial
CELLULAR HOMEOSTASIS
EIF2B DNL343 ALS, FTD
OTHER
RIPK1 (Peripheral) DNL758 Inflammatory Diseases, COVID-19 Royalty
Biotherapeutics Small Molecules
15+ programs in Discovery stage (including 5 ETVs, 4 ATVs, 2 OTVs, and 3 small molecules)©2021 Denali Therapeutics. All rights reserved. *Investigational – not approved for treatment
TfR binding TransportVehicle (TV)
Cargo : IDS
7
The Transport Vehicle (TV) is engineered to deliver efficacious concentrations of biotherapeutics to brain cells via receptor mediated transcytosis
SOLVING THE BBB CHALLENGE FOR BRAIN DELIVERY OF BIOTHERAPEUTICS
TargetBrain Cell
Brain EndothelialCell (BBB)
The blood-brain barrier (BBB) is a major obstacle for brain delivery of biotherapeutics
THE BBB CHALLENGE OUR SOLUTION
©2021 Denali Therapeutics. All rights reserved.
BLOOD
BRAIN
Tf
TfR
Tf
TfR
Tf Tf
ATV
endothelial cell membrane
ETV:IDS
TV TECHNOLOGY DELIVERS BIOTHERAPEUTICS TO THE BRAIN
8
TfR
Tf Tf
ATV
endothelial cell membrane
Cortex (cynomolgus monkey)
Published May 27, 2020
Enzyme Transport Vehicle
(ETV)
Antibody Transport Vehicle
(ATV)
IDS KO Mouse Brain
• TV achieves high concentrations and broad distribution of biotherapeutic in brain• TV achieves dose-dependent reduction in brain substrate
©2021 Denali Therapeutics. All rights reserved.
TV POTENTIAL: WIDE RANGE OF INDICATIONS AND TARGETS
9
NEURO-DEGENERATION
LYSOSOMAL STORAGE
DISORDERS
ONCOLOGY
INFECTIOUS DISEASES
NEUROLOGYe.g., pain, epilepsy,
neuropsychiatry, neuromuscular
e.g., AD, PD, ALS, FTD
e.g., Hunter syndrome
e.g., CNS metastases
CURRENT PLATFORMS
POTENTIAL FUTURE PLATFORMS
AntibodiesEnzymes Proteins
Oligos
Gene TherapiesNovel RMT
TargetsOther
Modalities
CURRENTFOCUS
FUTURE OPPORTUNITIES
©2021 Denali Therapeutics. All rights reserved.
DNL310 PH1/2 STUDY – SUMMARY OF INTERIM DATA
CSF GAGs (primary substrate of IDS)
• Heparan sulfate (HS)• Dermatan sulfate (DS)
• Normalization in all subjects• Normalization in most subjects
CSF Exploratory biomarkers of lysosomal function and neuronal structure
• GM3• GlcCer• BMP• Nf-L
• GM3, GlcCer, BMP reduction consistent with improved lysosomal function
• High variability in Nf-L observed pre- and post-treatment
Clinical Global Impression • CGI/PGI-C • Improvement over 24 weeks based on Clinician and Parent reported global impression of change
Urine GAGs • Heparan sulfate• Dermatan sulfate
• Reduction after switching from idursulfase
Serum GAGs• Heparan sulfate• Dermatan sulfate• Keratan sulfate
• Reduction after switching from idursulfase
Endpoints Measures Phase 1/2 Interim Data Assessment
CN
S A
ctiv
ityPe
riphe
ral
Act
ivity
10 ©2021 Denali Therapeutics. All rights reserved.
Safety• AEs• IRRs• Total urine GAGs
• Safety profile with up to 43 weeks of dosing consistent with standard of care enzyme replacement therapy
• Infusion-related reactions most frequently observed adverse eventsSafe
ty
DNL310: ENGINEERED TO RECONSTITUTE IDS THROUGHOUT THE BODY
• 1. Jefferies WA, et al., 1984. 2. Qian ZM, et al., 2002. 3. Bakardjiev AI, 2021. 4. Arguello A, 2021. 5. Ullman JC, et al., 2020. 6. Wang S, et al., 2020. 7. Gammella E, et al., 2017. 8. Carlevaro MF, et al., 1997.
TfR is expressed on all cells of the body, potentially facilitating IDS delivery into tissues such as bone, cartilage, and the heart2,6-8
TfR is highly expressed at the blood-brain barrier, so the transport vehicle is designed to enable DNL310 to cross the blood-brain barrier1-5
Systemic delivery Extensive tissue penetration
DNL310 has the potential to treat neuronopathic and peripheral manifestations of MPS II
Enzyme Transport Vehicle (ETV)
12 ©2021 Denali Therapeutics. All rights reserved.
DNLI-E-0002 STUDY OVERVIEW (NCT04251026) DOSING SCHEMA
Study Design
Open label 6-month study with 18-month safety extension (SE)• DNL310 is administered by weekly IV infusion• n= ~30 patients in 3 cohorts• Dosing in Cohort C and potential dose modifications in Cohort
B will be determined by emerging safety and biomarker results
Key Eligibility
• Treatment naïve or receiving approved IDS for >4 months• IDS-treated patients will be switched to DNL310 without a
washout
Key Endpoints
Primary endpoints (Safety)• Adverse events• Infusion-related reactions (IRRs)• Total urine GAGs
Secondary endpoints• HS (CSF and Urine)• Plasma PK• Anti-drug antibodies (ADA)
Exploratory endpoints• DS (CSF, urine, serum), HS (serum), KS (serum)• Pathway biomarkers (e.g. CSF lysosomal lipids, CSF & Serum
Nf-L)• Cognition, Behavior, and Global Impression
DNL310 PHASE 1/2 STUDY DESIGN IN PEDIATRIC MPS II PATIENTS
Cohort A (n=5): 5-10 y.o., neuronopathic MPS II
TBD
3 mg/kg2 doses
7.5 mg/kg≥ 2 doses
15 mg/kg≥ 4 doses
30 mg/kg< 16 doses
Cohort B2: 7.5 mg/kg x 24 doses
Cohort B3: 15 mg/kg x 24 doses
Cohort B1: 3 mg/kg ≥ 12 doses
30 mg/kgweekly
SE
Cohort B (n≈17): 2-18 y.o., (non-) neuronopathic MPS II SE
15 mg/kgweekly
TBD
Cohort C (n≈8): <4 y.o., neuronopathic MPS II SE
* Dose To Be Determined (TBD)
TBD*
13 ©2021 Denali Therapeutics. All rights reserved.
COHORT STATUS AND DEMOGRAPHICS OF SAFETY POPULATION
Cohort A (n=5) Cohort B (n=12)*Enrollment status Completed OngoingCompleted 6-month study and in safety extension 5 (100%) 2 (16.6%)Age (median) 5-8 years (6 years) 2-12 years (6 years)Neuronopathic 5 (100%) 11 (91.7%)Non-neuronopathic 0 1 (8.3%)IDS-treated patients at enrollment 5 (100%) 12 (100%)Race/Ethnicity (n=17)White 8 (47.1%)Asian 2 (11.8%)Black/African American or Black/African American + White 2 (11.8%)Race not reported, other or unknown 5 (29.3%)Not Hispanic or Latino 12 (70.6%)Hispanic or Latino 4 (23.5%)Ethnicity not reported 1 (5.9%)
*Cohort B patients who received at least 12 weekly doses of DNL310 are included in this interim analysis
14 ©2021 Denali Therapeutics. All rights reserved.
PHASE 1/2 INTERIM DATA OUTLINE
Cohort A (CSF, urine and serum HS): Up to Week 24
Cohort B (CSF HS): Up to Week 13
Cohort A: Safety up to Week 43
Cohort B: Safety up to Week 25
*Biomarker population n=15 (Cohort A n=5, Cohort B n=10);excludes 2 participants without Week 13 CSF available at Week 13 data cut off
Cohort A (GM3, BMP, GlcCer): Up to Week 24
Cohort B (GM3): Up to Week 13
Cohort A: Up to Week 24
Cohort B: Not yet assessed
Cohort A (CGI-C/PGI-C): Up to Week 24
Cohort B: Not yet assessed
CSF Lysosomal Biomarkers*
Serum and CSF Nf-L
Clinical
Safety
Heparan Sulfate (HS)*
15 ©2021 Denali Therapeutics. All rights reserved.
Weekly IV infusions of DNL310 for Cohorts A and B were generally well tolerated at doses of 3 to 30 mg/kg
INTERIM SAFETY SUMMARYSAFETY POPULATION N=17 (COHORT A N=5 AND COHORT B N=12)
STATUS
• All enrolled patients remain in the study with no discontinuations• Cohort A (n=5): All have completed the 6-month study period and have advanced to the safety extension (SE) • Cohort B (n=12): 10 continue in the 6-month study period and 2 have advanced to the SE
• Independent Data Monitoring Committee on July 9, 2021 recommended continuing study without modifications
TEAEs
• All TEAEs were mild or moderate except for 2 severe TEAEs (both IRRs in 1 patient)• Infusion-related reactions (IRRs) were the most common TEAEs, occurring in 71% of patients (12 of 17)
• Majority of patients had mild (n=5) or moderate (n=6) IRRs, 1 patient had severe IRRs (SAEs, detailed below)
• Of the 12 patients with IRRs, 8 required standard interventions to prevent subsequent IRRs (all received standard pre-infusion medications with 2 receiving additional dose and infusion rate reductions)
• Most IRRs to date occurred between Weeks 3 and 6; of the 3 patients who experienced IRRs and have advanced to the SE, most pre-infusion medications have been discontinued
SAEs
• 1 SAE (mild IRR) in 1 patient at Week 4 with hospitalization for overnight observation (previously reported)• 2 SAEs (severe IRRs) in 1 patient met Sampson criteria of anaphylaxis at Weeks 3 and 4, managed with pre-infusion medications, dose and infusion
rate reductions
• Patient remains in the study and has tolerated weekly doses, including dose increases
SAFETY LABS
• There were no notable abnormalities or trends in safety laboratory evaluations except for anemia• 4 patients (2 each in Cohort A and Cohort B3) had TEAEs of anemia, all considered not related to study drug• Anemia was graded mild (n=3) and moderate (n=1) and improved (n=2) or resolved (n=2) despite continued dosing at 15 or 30 mg/kg
16 ©2021 Denali Therapeutics. All rights reserved.
0
5
10
15
20
BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Tota
l Urin
e G
AG
s(m
g/m
mol
Cre
atin
ine)
Study Week
2-3 years
6-7 years10-11 years
Total urine GAG levels were measured by colorimetric assay. Upper limit of normal (ULN) of total urine GAGs/mmol creatinine is age dependent, ranging from 36 mg at ≤1 year to 5.5 mg at ≥14 years. Relevant ULN for each Cohort are represented by gray lines:
Decline in total urine GAGs after switching from idursulfase to DNL310 without a washout period in majority of patients suggests added peripheral activity in all cohorts studied
Cohort A (3 to 30 mg/kg)
Cohort B1 (3 mg/kg)
Cohort B2 (7.5 mg/kg)
Cohort B3 (15 mg/kg)
17 ©2021 Denali Therapeutics. All rights reserved.
TOTAL URINE GAGS (SAFETY LAB)SAFETY POPULATION N=17 (COHORT A N=5 AND COHORT B N=12)
Urine heparan sulfate from Cohort A showed similar results
Decline in serum HS, DS, and KS after switching from idursulfase to DNL310 without a washout periodsuggests added peripheral activity
Normal ranges and non-MPS pediatric controls of serum HS and DS measured by LC-MS/MS clinical assay not yet determined
0100200300400500600700800
BL 5 9 13 24
Seru
m H
S (n
g/m
L)
Study Week
Cohort A Serum HSCohort A Serum HS – 3 to 30 mg/kg
Wk 24 mean reduction 51%
0
200
400
600
800
1000
BL 5 9 13 24
Seru
m D
S (n
g/m
L)
Study Week
Cohort A Serum HSCohort A Serum DS – 3 to 30 mg/kg
0300600900
120015001800
BL 5 9 13 24
Seru
m K
S (n
g/m
L)
Study Week
Cohort A Serum HSCohort A Serum KS – 3 to 30 mg/kg
18 ©2021 Denali Therapeutics. All rights reserved.
Serum HS, DS, and KS are increased in MPS II patients
2.4x
* *
Bhalla et al., Int J Mol Sci 2020
• Non-MPS samples from Bhalla et al., Int J Mol Sci 2020
• MPS II samples from NCT04007536
2x3.7x
Non-MPS MPS II300
3000
1000
2000
500Ker
atan
sul
fate
(n
g/m
L)
*
Wk 24 mean reduction 67%
Wk 24 mean reduction 36%
Non-MPS pediatric controls (0 – 9 years; median age: 5 years) for serum KS are samples from Bhalla et al. 2020
SERUM HS, DS AND KSBIOMARKER POPULATION N=5 (COHORT A)
CLINICAL PHENOTYPE OF MPS AND GAG ACCUMULATION
19
TYPE NAME ENZYME DEFICIENCY GAGMPS I Hurler / Scheie α-L-iduronidase HS, DSMPS II Hunter Iduronate-2-sulfatase HS, DS
MPS IIIA Sanfilippo A Heparan sulfamidase HSMPS IIIB Sanfilippo B N-acetyl-α-D-glucosaminidase HSMPS IIIC Sanfilippo C Acetyl-CoA:α-glucosaminidase HSMPS IIID Sanfilippo D N-acetylglucosamine-6-sulfatase HSMPS IVA Morquio A N-acetylgalactosamine-6-sulfatase KS, CSMPS VI Maroteaux-Lamy N-acetylgalactosamine-4-sulfatase DS, CSMPS VII Sly β-Glucuronidase HS, DS, CSMPS IX Natowicz Hyaluronidase HA
Heparan sulfate is associated with MPS disorders with CNS involvement
Kobayashi et al., Journal of Human Genetics 2019CNS involvement HS= heparan sulfateDS= dermatan sulfateCS= chondroitin sulfateKS= keratan sulfateHA= hyaluronic acid
©2021 Denali Therapeutics. All rights reserved.
0200400600800
10001200
BL 5 7 9 13 17 24
CSF
HS
(ng/
mL)
Study Week
0200400600800
10001200
BL 5 7 9 13 17 24
CSF
HS
(ng/
mL)
Study Week
CSF Heparan Sulfate normalized in all patients after switching from idursulfase to DNL310, with rapid response in 12 patients by Week 7
Preliminary normal range (10th and 90th %ile gray dashed bars) determined using 30 healthy adult CSF samples (age range 18-81 years, median 52 years). Total CSF GAG levels are similar in adults and children (Hendriksz et al., 2015). *One patient in Cohort B1 escalated to higher dose one week before Week 13 CSF collection. Timepoints on x-axis represent intended collection times and may vary by ~1 week in some subjects.
Cohort B2 – 7.5 mg/kg Cohort B3 – 15 mg/kgCohort A – Dose: 3 to 30 mg/kg IV weeklyCohort B1 – 3 mg/kg
Cohort A – Dose: 3 to 30 mg/kg IV weeklyCohort A – 3 to 30 mg/kgCSF HS is increased in MPS II patients
Bhalla et al., Int J Mol Sci 2020
*
10.7x
*
Wk 24 mean reduction 90%
Wk 13 mean reduction 86%
0200400600800
10001200
BL 5 7 9 13 17 24
CSF
HS
(ng/
mL)
Study Week
Wk 13 mean reduction 92%
0200400600800
10001200
BL 5 7 9 13 17 24
CSF
HS
(ng/
mL)
Study Week
Wk 13 mean reduction 92%
20 ©2021 Denali Therapeutics. All rights reserved.
CSF HEPARAN SULFATE (HS)BIOMARKER POPULATION N=15 (COHORT A N=5 AND COHORT B N=10)
0100200300400500600
BL 5 7 9 13 17 24
CSF
DS
(ng/
mL)
Study Week
0100200300400500600
BL 5 7 9 13 17 24
CSF
DS
(ng/
mL)
Study Week
CSF DERMATAN SULFATE (DS)BIOMARKER POPULATION N=15 (COHORT A N=5 AND COHORT B N=10)
CSF Dermatan Sulfate normalized in most patients after switching from idursulfase to DNL310, with rapid response in 12 patients by Week 7
Preliminary normal range (10th and 90th %ile gray dashed bars) determined using 30 healthy adult CSF samples (age range 18-81 years, median 52 years). Total CSF GAG levels are similar in adults and children (Hendriksz et al., 2015). *One patient in Cohort B1 escalated to higher dose one week before Week 13 CSF collection. Timepoints on x-axis represent intended collection times and may vary by ~1 week in some subjects.
Cohort B2 – 7.5 mg/kg Cohort B3 – 15 mg/kgCohort A – Dose: 3 to 30 mg/kg IV weeklyCohort B1 – 3 mg/kg
Cohort A – Dose: 3 to 30 mg/kg IV weeklyCohort A – 3 to 30 mg/kgCSF DS is increased in MPS II patients
Bhalla et al., Int J Mol Sci 2020
*0
100200300400500600
BL 5 7 9 13 17 24
CSF
DS
(ng/
mL)
Study Week
0100200300400500600
BL 5 7 9 13 17 24
CSF
DS
(ng/
mL)
Study Week
*
21 ©2021 Denali Therapeutics. All rights reserved.
Wk 24 mean reduction 75%
Wk 13 mean reduction 62%Wk 13 mean reduction 73% Wk 13 mean reduction 76%
31x
02468
1012
BL 5 7 9 13 17 24GM
3(d3
6:1)
(ng/
mL)
Study Week
02468
1012
BL 5 7 9 13 17 24
GM
3(d3
6:1)
(ng/
mL)
Study Week
02468
1012
BL 5 7 9 13 17 24GM
3(d3
6:1)
(ng/
mL)
Study Week
CSF GANGLIOSIDES (GM3) BIOMARKER POPULATION N=15 (COHORT A N=5 AND COHORT B N=10)
Across Cohorts A and B, 10 of 15 patients achieved normal CSF GM3, including lower dose regimen
Preliminary normal range (10th and 90th %ile gray dashed bars) determined using 17 healthy adult CSF samples (age range 22-50 years, median 27 years)*One patient in Cohort B1 escalated to higher dose one week before Week 13. Timepoints at x-axis represent intended collection times and may vary by ~1 week in some patients.
Cohort B2 – 7.5 mg/kg Cohort B3 – 15 mg/kgCohort A – Dose: 3 to 30 mg/kg IV weeklyCohort B1 – 3 mg/kg
Cohort A – Dose: 3 to 30 mg/kg IV weeklyCohort A – 3 to 30 mg/kgGM3 is increased in CSF of MPS II patients
Bhalla et al., Int J Mol Sci 2020
3.7x
GM
3(d3
6:1)
(ng/
mL)
*
Wk 24 mean reduction 46%
Wk 13 mean reduction 53% Wk 7 mean reduction 45%Wk 7 mean reduction 48%
02468
1012
BL 5 7 9 13 17 24GM
3(d3
6:1)
(ng/
mL)
Study Week
22 ©2021 Denali Therapeutics. All rights reserved.
0
0.5
1
1.5
BL 5 9 13 24
Tota
l di-1
8:1
BM
P(n
g/m
L)
Study Week
0
0.5
1
1.5
BL 5 9 13 24
Glc
Cer
(d18
:1/1
6:0)
(n
g/m
L)
Study Week
GlcCer is increased in CSF of MPS II patients
CSF BMP AND GLUCOSYLCERAMIDEBIOMARKER POPULATION N=5 (COHORT A)
Non-MPS MPS II0.01
0.1
1
10
30
Glu
cosy
lcer
amid
e (n
g/m
L)
*
Non-MPS MPS II0.01
0.1
1
3
Glu
cosy
lcer
amid
e(A
rea
Rat
io)
*
2.4x
Glc
Cer
(ng/
ml)
BMP is increased in CSF of MPS II patients
1.3x
Preliminary normal range (10th, 50th, 90th %ile gray dashed lines) determined using 17 healthy adult CSF samples (age range 22-50 years, median 27 years)
Cohort A CSF GlcCer – 3 to 30 mg/kg
Wk 24 mean reduction 22%
Cohort A CSF BMP – 3 to 30 mg/kg
Wk 24 mean reduction 48%
Reduction of CSF BMP and potential decline of GlcCer at Week 24 consistent with improved lysosomal function
BMPBis(monoacylglycerol)-Phosphate
GlcCerGlucosyl-ceramide
Bhalla et al., Int J Mol Sci 2020
Bhalla et al., Int J Mol Sci 2020
23 ©2021 Denali Therapeutics. All rights reserved.
1
10
100
BL 5 9 13 24
Nf-L
(pg/
mL)
Study Week
300
30
Cohort A – 3 to 30 mg/kg
SERUM AND CSF NEUROFILAMENT (NF-L)BIOMARKER POPULATION N=5 (COHORT A)
Serum Nf-L is increased in MPS II
Bhalla et al., Int J Mol Sci 2020
7.2x
MPS II Natural History Study (NCT04007536)
1
10
100
-50 -40 -30 -20 -10 0
Nf-L
(pg/
mL)
Study Week
300
30
Wk 24 mean increase 15%
Cohort A – 3 to 30 mg/kgCSF Nf-L is increased in MPS II CSF Nf-L Natural History in MPSII Not Available
Bhalla et al., Int J Mol Sci 2020
5.4x
30
300
3000
BL 5 9 13 24
Nf-L
(pg/
mL)
Study Week
Wk 24 mean increase 36%• NCT04007536 longitudinal serum Nf-L data suggesting biological variation
• All 3 patients subsequently enrolled in Cohort A
SERUM
CSF
100
1000
Mean increase 94%4.5-6mo pre-dose
24 ©2021 Denali Therapeutics. All rights reserved.
• Increase in Nf-L, an exploratory biomarker of neuronal structure, observed in limited Natural History Study over 4.5-6 months • Within patient variability in Nf-L levels seen pre- and post-treatment• Utility of Nf-L in MPS II requires further investigation across the field, specifically with additional Natural History data
-24
• Increase in Nf-L, an exploratory biomarker of neuronal structure, observed in limited Natural History Study over 4.5-6 months • Within patient variability in Nf-L levels seen pre- and post-treatment• Utility of Nf-L in MPS II requires further investigation across the field, specifically with additional Natural History data• Biomarker of neuronal structure (Tau) shows no change and near normal levels
1
10
100
BL 5 9 13 24
Nf-L
(pg/
mL)
Study Week
300
30
Cohort A – 3 to 30 mg/kg
SERUM AND CSF NEUROFILAMENT (NF-L) AND CSF TAUBIOMARKER POPULATION N=5 (COHORT A)
Serum Nf-L is increased in MPS II
Bhalla et al., Int J Mol Sci 2020
7.2x
MPS II Natural History Study (NCT04007536)
1
10
100
-50 -40 -30 -20 -10 0
Nf-L
(pg/
mL)
Study Week
300
30
Wk 24 mean increase 15%
Cohort A – 3 to 30 mg/kgCSF Nf-L is increased in MPS II
Bhalla et al., Int J Mol Sci 2020
5.4x
30
300
3000
BL 5 9 13 24
Nf-L
(pg/
mL)
Study Week
Wk 24 mean increase 36%
SERUM
CSF
100
1000
25 ©2021 Denali Therapeutics. All rights reserved.
Cohort A CSF Tau– 3 to 30 mg/kg
Wk 24 mean increase 8%
Mean increase 94%4.5-6mo pre-dose
-24
Preliminary normal range (10-90%ile grey bar) determined using 17 healthy adult CSF samples (22– 50 years; median age: 27 years)
For neuronopathic patients that experience early loss of cognitive milestones, development trajectory demonstrates little to no improvement over time
Regression
26 ©2021 Denali Therapeutics. All rights reserved.
PROGRESSIVE LOSS OF COGNITIVE MILESTONES IN HUNTER PATIENTS
CLINICIAN & PARENT/CAREGIVER GLOBAL IMPRESSION OF CHANGE (CGI/PGI-C)CLINICAL POPULATION N=5 (COHORT A THROUGH WEEK 24)
CGI-C PGI-C
Impr
ovem
ent
Wor
seni
ng
In Cohort A patients (5-10 years old), interim assessment of clinical outcomes suggest improvement in overall MPS II symptoms, cognitive abilities, behavior, and physical abilities as assessed by an expert clinician (CGI-C)
and parent / caregiver (PGI-C)
27 ©2021 Denali Therapeutics. All rights reserved.
CGI-CExcerpts from Comment Field of CGI-C entered by Investigator into database:• Language much improved, more complex
sentences• Now able to hold a pencil• More conscious of conversations
surrounding him• Physical features are much improved• Building much more complex lego towers• Better stick figure drawing• Using new words (tangle, disgusting) and
completes 3- to 4-word sentences• Less aggressive, following directions
Impr
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ngCLINICIAN & PARENT/CAREGIVER GLOBAL IMPRESSION OF CHANGE (CGI/PGI-C)CLINICAL POPULATION N=5 (COHORT A THROUGH WEEK 24)
In Cohort A patients (>5 years old), interim assessment of clinical outcomes suggest improvement in overall MPS II symptoms, cognitive abilities, behavior, and physical abilities as assessed by an expert clinician (CGI-C) and
parent / caregiver (PGI-C)
28 ©2021 Denali Therapeutics. All rights reserved.
DNL310 PH1/2 STUDY – SUMMARY OF INTERIM DATA
CSF GAGs (primary substrate of IDS)
• Heparan sulfate (HS)• Dermatan sulfate (DS)
• Normalization in all subjects• Normalization in most subjects
CSF Exploratory biomarkers of lysosomal function and neuronal structure
• GM3• GlcCer• BMP• Nf-L
• GM3, GlcCer, BMP reduction consistent with improved lysosomal function
• High variability in Nf-L observed pre- and post-treatment
Clinical Global Impression • CGI/PGI-C • Improvement over 24 weeks based on Clinician and Parent reported global impression of change
Urine GAGs • Heparan sulfate• Dermatan sulfate
• Reduction after switching from idursulfase
Serum GAGs• Heparan sulfate• Dermatan sulfate• Keratan sulfate
• Reduction after switching from idursulfase
Endpoints Measures Phase 1/2 Interim Data Assessment
CN
S A
ctiv
ityPe
riphe
ral
Act
ivity
29 ©2021 Denali Therapeutics. All rights reserved.
Safety• AEs• IRRs• Total urine GAGs
• Safety profile with up to 43 weeks of dosing consistent with standard of care enzyme replacement therapy
• Infusion-related reactions most frequently observed adverse eventsSafe
ty
DNL310 MPS II DEVELOPMENT PLAN
Cohort A Ages 5-10 y.o.Neuronopathic
Cohort BAges 2-18 y.o.
Neuronopathic & Non-neuronopathic
Cohort CAges <4 y.o.
Neuronopathic
Designed to further explore clinical endpoints – including behavior and cognition – in an age range for which treatment effects on developmental milestones may have the highest likelihood to be observed
Ph2/3Neuronopathic
Non-neuronpathic
Registrational study designed to demonstrate patient benefit in neuronopathic and non-neuronopathic MPS II
30 ©2021 Denali Therapeutics. All rights reserved.
ü Rapid reductions in CSF heparan sulfate and sustained normalization demonstrate BBB crossing, CNS activity and durability of response of DNL310; enhanced peripheral activity also observed
ü Cohort A 6-month data suggest clinical improvement based on Global Impression of Change scales in children aged 5-10
ü Exploratory biomarker data is consistent with improved lysosomal function
ü Safety profile with up to 43 weeks of dosing is consistent with standard of care ERT
POSITIVE 6-MONTH DATA FROM DNL310 PHASE 1/2 STUDY IN MPS II
• Hallmark biomarker “GAG” normalized in cerebrospinal fluid in all patients
• Global impression scales show improved cognition, behavior, and physical function
• Exploratory lipid biomarkers consistent with improved lysosomal function
• Safety and tolerability profile consistent with current standard of care
KEY RESULTS
Accelerate Development-Initiate Phase 2/3 in 1H 22
Further Validation ofTV Platform
that uses TfR for brain delivery
Build Out ETV Franchisefor lysosomal storage diseases
32 ©2021 Denali Therapeutics. All rights reserved.