Denali Therapeutics Inc. · NASDAQ:DNLI
Denali Therapeutics — Technical Presentation (June 2023)
24 slides from Denali Therapeutics's technical presentation, Jun 20, 2023
Slide 1: Robust Reduction in NfL with DNL310 (ETV:IDS) Treatment in MPS II
Robust Reduction in Neurofilament Light (NfL) with DNL310 (ETV:IDS) Treatment in MPS II (Hunter Syndrome) June 20, 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. Forward-looking statements expressed or implied in this presentation include all statements other than statements of historical fac
Slide 3: Agenda
AGENDA TOPIC SPEAKER Introduction Ryan Watts, PhD Chief Executive Officer Robust Reduction in Neurofilament Light (NfL) with DNL310 Carole Ho, MD (ETV:IDS) Treatment in MPS II (Hunter Syndrome) Chief Medical Officer and Head of Development Closing Remarks Ryan Watts, PhD Chief Executive Officer Ryan
Slide 4: Introduction
Introduction Ryan Watts, PhD, Chief Executive Officer
Slide 5: Our Purpose: Defeat Degeneration
OUR PURPOSE: DEFEAT DEGENERATION RARE NEURODEGENERATIVE AMYOTROPHIC DISEASES LATERAL SCLEROSIS PARKINSON’S ALZHEIMER’S Orphan 15,000+ (US) 1,000,000+ (US) 6,000,000+ (US) on Di sea y Populati se Popula alth tio He n Normal PD Normal AD Significant unmet medical need with few disease-modifying medici
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 Function (PTV:PGRN) Granulin (
Slide 7: 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 8: Further Validation of Transport Vehicle Platform Potential
FURTHER VALIDATION OF TRANSPORT VEHICLE PLATFORM POTENTIAL 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 Oligonucl
Slide 9: Today's News
TODAY’S NEWS • Interim results demonstrate average reduction of 64% (p < 0.001) from baseline in serum NfL after 2 years of dosing with DNL310 in Phase 1/2 study • FDA has recommended assessment of NfL, a marker of neuroaxonal damage, as a possible biomarker in MPS II • Additional interim data from
Slide 10: Robust Reduction in NfL with DNL310 (ETV:IDS) Treatment in MPS II
Robust Reduction in Neurofilament Light (NfL) with DNL310 (ETV:IDS) Treatment in MPS II (Hunter Syndrome) Carole Ho, MD, Chief Medical Officer and Head of Development
Slide 11: Developing a Therapy for MPS II (Hunter Syndrome)
DEVELOPING A THERAPY FOR MPS II (HUNTER SYNDROME) DNL310 (ETV:IDS) is an investigational iduronate-2-sulfatase (IDS) fusion protein engineered to treat both the brain and physical manifestations of mucopolysaccharidosis type II (MPS II) with a single weekly IV infusion Administration by weekly Enzym
Slide 12: DNL310 Therapeutic Hypothesis and Development Strategy
DNL310 THERAPEUTIC HYPOTHESIS AND DEVELOPMENT STRATEGY Replace IDS in Restore Cellular Health Improve Clinical Outcomes periphery and brain (Improve Lysosomal Function and Neuronal Health) Biochemical Correction Cellular Correction Neuronal Correction Brain Clinical Patient ImpactData VABS (adaptive
Slide 13: DNL310 Phase 1/2 Study Design and Interim Analysis Population
DNL310 PHASE 1/2 STUDY DESIGN AND INTERIM ANALYSIS POPULATION • Open-label, 24-week study followed by an open-label extension (NCT04251026) • Approximately 45 participants ≤18 years of age with MPS II • Participants receiving IDS at baseline switch to DNL310 without a washout period COHORTS Primary
Slide 14: Clinical Phenotype of MPS and GAG Accumulation
CLINICAL PHENOTYPE OF MPS AND GAG ACCUMULATION TYPE NAME ENZYME DEFICIENCY GAG MPS I Hurler / Scheie α-L-iduronidase HS, DS MPS II Hunter Iduronate-2-sulfatase HS, DS MPS IIIA Sanfilippo A Heparan sulfamidase HS MPS IIIB Sanfilippo B N-acetyl-α-D-glucosaminidase HS MPS IIIC Sanfilippo C Acetyl-CoA:α
Slide 15: Biomarkers: CSF HS
2023 WORLDSymposiumTM BIOMARKERS: CSF HSa Mean HS reduction Week n from BL, % 24 25 90.6 49 19 90.0 104b 3 91.4 ADA Titer at BL ● Negative ● Positive/low-medium (<1×106) ● Positive/high (> 1×106) Rapid and sustained normalization of CSF HS achieved with DNL310 treatment ADA, anti-drug antibodies. aP
Slide 16: Biomarkers of Lysosomal Function
2023 WORLDSymposiumTM BIOMARKERS OF LYSOSOMAL FUNCTION a a a ADA, anti-drug antibody; BL, baseline; CSF, cerebrospinal fluid; GM, ganglioside; GlcSph, glucosylsphingosine; W, week. aPreliminary GM3 normal range (gray dashed lines indicate 10th and 90th percentiles) determined using CSF samples from
Slide 17: DNL310: Serum NfL in Ph1/2 Participants
DNL310: SERUM NfL IN PH1/2 PARTICIPANTS Week n Mean serum NfL change from BL, % 24 27 +11.9 49 23 -13.5 104 13 -63.8 (**p<0.001) 53.5% mean reduction (p=0.011) in CSF NfL at Week 104 (n=11) Spearman Correlation coefficient is 0.76 for the change from baseline at week 104 between serum NfL & CSF NfL
Slide 18: Neurofilament (NfL): A Marker of Neuroaxonal Damage
NEUROFILAMENT (NfL): A MARKER OF NEUROAXONAL DAMAGE NfL elevation NfL reduction Indication disease vs. non-disease control Therapeutic on treatment FDA approval CLN2a ~50-fold (plasma) cerliponase alfa ~85% (plasma @ 3 yrs) SMA Type 1b ~30-fold (CSF) nusinersen 75% (CSF @ ~ Wk 12) SOD1 ALSc,d ~4-fol
Slide 19: DNL310 (ETV:IDS): Summary of Clinical Assessments in Phase 1/2 Study
2023 WORLDSymposiumTM DNL310 (ETV:IDS): SUMMARY OF CLINICAL ASSESSMENTS IN PHASE 1/2 STUDY VABS-II Raw Score Mean Change From Baseline BSD-III Raw Score Mean Change From Baseline Week 49 BSID Cognitive Raw Score (age equivalent <=42 months, n=11) BSID Cognitive Raw Score (with imputation of KABC)a (
Slide 20: 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) MPS II followed by OLE Design • DNL310
Slide 21: Closing Remarks
Closing Remarks Ryan Watts, PhD, Chief Executive Officer
Slide 22: Summary & Conclusions
SUMMARY & CONCLUSIONS DNL310 (ETV:IDS) DEVELOPMENT • Biochemical: Rapid and sustained normalization of CSF heparan sulfate to normal healthy levels Further Validation of • Cellular: Improvement in lysosomal function TV Platform biomarkers • Neuronal: Robust reduction in NfL • Clinical: Positive chan
Slide 23: 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 24: Q&A
Q&A Denali Therapeutics Inc. 24
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