Denali Therapeutics Webinar to Present Interim Data from ...

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.

IntroductionRyan Watts, PhD, Chief Executive Officer

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


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


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


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


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


Endpoints Measures Phase 1/2 Interim Data Assessment

CN

S A

ctiv

ityPe

riphe

ral

Act

ivity


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 Interim Phase 1/2 Data (MPS II)Carole Ho, MD, Chief Medical Officer and Head of Development

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)


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*


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


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)*


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


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)


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


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)

*



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


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


*

10.7x

*



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 (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 A – Dose: 3 to 30 mg/kg IV weeklyCohort A – 3 to 30 mg/kgCSF DS is increased in MPS II patients


*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

*



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 A – Dose: 3 to 30 mg/kg IV weeklyCohort A – 3 to 30 mg/kgGM3 is increased in CSF of MPS II patients


3.7x

GM

3(d3

6:1)

(ng/

mL)

*


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


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


Cohort A CSF BMP – 3 to 30 mg/kg


Reduction of CSF BMP and potential decline of GlcCer at Week 24 consistent with improved lysosomal function

BMPBis(monoacylglycerol)-Phosphate

GlcCerGlucosyl-ceramide




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


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


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


• 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


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


Cohort A – 3 to 30 mg/kgCSF Nf-L is increased in MPS II


5.4x

30

300

3000

BL 5 9 13 24

Nf-L

(pg/

mL)

Study Week


SERUM

CSF

100

1000


Cohort A CSF Tau– 3 to 30 mg/kg


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


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)


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

ovem

ent

Wor

seni

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)


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


Serum GAGs• Heparan sulfate• Dermatan sulfate• Keratan sulfate


Endpoints Measures Phase 1/2 Interim Data Assessment

CN

S A

ctiv

ityPe

riphe

ral

Act

ivity


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


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

CONCLUSIONRyan Watts, Ph.D., Chief Executive Officer

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


Q&A

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Date post:	23-Mar-2022
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