Denali Therapeutics Inc. · NASDAQ:DNLI
Denali Therapeutics — Technical Presentation (July 2021)
33 slides from Denali Therapeutics's technical presentation, Jul 25, 2021
Slide 1: Denali Therapeutics Webinar to Present Interim Data from DNL310 Phase 1/2 Hunter Syndrome Patient Study
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
Slide 2: Disclaimers: Forward Looking Statements
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
Slide 3: Introduction
Introduction Ryan Watts, PhD, Chief Executive Officer
Slide 4: Our Purpose: Defeat Degeneration
OUR PURPOSE: DEFEAT DEGENERATION Degeneration creates significant unmet medical need, with few disease-modifying medicines RARE AMYOTROPHIC LATERAL PARKINSON’S ALZHEIMER’S NEURODEGENERATIVE SCLEROSIS (ALS) DISEASE DISEASE DISEASES 4 ©2021 Denali Therapeutics. All rights reserved.
Slide 5: Our Principles: Discovery and Development
OUR PRINCIPLES: DISCOVERY AND DEVELOPMENT DEGENOGENES GENETIC PATHWAY PATIENT IMPACT POTENTIAL ENGINEERING BRAIN DELIVERY Increase the likelihood of success BIOMARKER-DRIVEN to bring effective therapies to DEVELOPMENT patients and families 5 ©2021 Denali Therapeutics. All rights reserved.
Slide 6: Our Development Portfolio
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
Slide 7: Solving the BBB Challenge 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 T
Slide 8: TV Technology Delivers Biotherapeutics to the Brain
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 concentr
Slide 9: TV Potential: Wide Range of Indications and Targets
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 ONCO
Slide 10: DNL310 Ph1/2 Study – Summary of Interim Data
DNL310 PH1/2 STUDY – SUMMARY OF INTERIM DATA Endpoints Measures Phase 1/2 Interim Data Assessment CSF GAGs (primary • Heparan sulfate (HS) • Normalization in all subjects substrate of IDS) • Dermatan sulfate (DS) • Normalization in most subjects CSF Exploratory • GM3 • GM3, GlcCer, BMP reduction con
Slide 11: DNL310 Interim Phase 1/2 Data (MPS II)
DNL310 Interim Phase 1/2 Data (MPS II) Carole Ho, MD, Chief Medical Officer and Head of Development
Slide 12: DNL310: Engineered to Reconstitute IDS Throughout the Body
DNL310: ENGINEERED TO RECONSTITUTE IDS THROUGHOUT THE BODY Enzyme Transport Vehicle (ETV) Systemic delivery Extensive tissue penetration 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 TfR is expressed on a
Slide 13: DNL310 Phase 1/2 Study Design in Pediatric MPS II Patients
DNL310 PHASE 1/2 STUDY DESIGN IN PEDIATRIC MPS II PATIENTS DNLI-E-0002 STUDY OVERVIEW (NCT04251026) DOSING SCHEMA Cohort A (n=5): 5-10 y.o., neuronopathic MPS II SE Open label 6-month study with 18-month safety extension (SE) • DNL310 is administered by weekly IV infusion Study 3 mg/kg 7.5 mg/kg 15
Slide 14: Cohort Status and Demographics of Safety Population
COHORT STATUS AND DEMOGRAPHICS OF SAFETY POPULATION Cohort A (n=5) Cohort B (n=12)* Enrollment status Completed Ongoing Completed 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.
Slide 15: Phase 1/2 Interim Data Outline
PHASE 1/2 INTERIM DATA OUTLINE Cohort A: Safety up to Week 43 Safety Cohort B: Safety up to Week 25 Heparan Sulfate Cohort A (CSF, urine and serum HS): Up to Week 24 (HS)* Cohort B (CSF HS): Up to Week 13 Cohort A (GM3, BMP, GlcCer): Up to Week 24 CSF Lysosomal Biomarkers* Cohort B (GM3): Up to Week
Slide 16: Interim Safety Summary
INTERIM SAFETY SUMMARY SAFETY POPULATION N=17 (COHORT A N=5 AND COHORT B N=12) • 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) STATUS • Cohort B (n=12): 10 continue in th
Slide 17: Total Urine GAGs (Safety Lab)
TOTAL URINE GAGS (SAFETY LAB) SAFETY POPULATION N=17 (COHORT A N=5 AND COHORT B N=12) Cohort A (3 to 30 mg/kg) Cohort B1 (3 mg/kg) Total urine GAG levels were measured by Cohort B2 (7.5 mg/kg) colorimetric assay. Upper 20 limit of normal (ULN) of Cohort B3 (15 mg/kg) total urine GAGs/mmol (mg/mmol C
Slide 18: Serum HS, DS and KS
SERUM HS, DS AND KS BIOMARKER POPULATION N=5 (COHORT A) Serum HS, DS, and KS are increased in MPS II patients * * 3000 * • Non-MPS samples 3.7x 2000 2x from Bhalla et al., Int Keratan sulfate 2.4x J Mol Sci 2020 (ng/mL) • MPS II samples from 1000 NCT04007536 500 300 Bhalla et al., Int J Mol Sci 2020
Slide 19: 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 20: CSF Heparan Sulfate (HS)
CSF HEPARAN SULFATE (HS) BIOMARKER POPULATION N=15 (COHORT A N=5 AND COHORT B N=10) CSF HS is increased in MPS II patients Cohort A – 3 to 303mg/kg Dose: to 30 mg/kg IV weekly * 1200 CSF HS (ng/mL) 1000 10.7x 800 600 Wk 24 mean reduction 90% 400 200 0 BL 5 7 9 13 17 24 Bhalla et al., Int J Mol Sci 2
Slide 21: CSF Dermatan Sulfate (DS)
CSF DERMATAN SULFATE (DS) BIOMARKER POPULATION N=15 (COHORT A N=5 AND COHORT B N=10) CSF DS is increased in MPS II patients Cohort A – 3 to 303mg/kg Dose: to 30 mg/kg IV weekly 600 * 31x CSF DS (ng/mL) 500 Wk 24 mean 400 reduction 75% 300 200 100 0 BL 5 7 9 13 17 24 Bhalla et al., Int J Mol Sci 2020
Slide 22: CSF Gangliosides (GM3)
CSF GANGLIOSIDES (GM3) BIOMARKER POPULATION N=15 (COHORT A N=5 AND COHORT B N=10) GM3 is increased in CSF of MPS II patients Cohort A – 3 to 303mg/kg Dose: to 30 mg/kg IV weekly 12 GM3(d36:1) (ng/mL) GM3(d36:1) (ng/mL) 10 Wk 24 mean reduction 46% 3.7x 8 6 4 2 0 BL 5 7 9 13 17 24 Bhalla et al., Int J
Slide 23: CSF BMP and Glucosylceramide
CSF BMP AND GLUCOSYLCERAMIDE BIOMARKER POPULATION N=5 (COHORT A) BMP is increased in CSF of MPS II patients Cohort A CSF BMP – 3 to 30 mg/kg 1.5 Total di-18:1 BMP Wk 24 mean reduction 48% BMP 1.3x 1 (ng/mL) Bis(monoacyl glycerol)- 0.5 Phosphate 0 BL 5 9 13 24 Bhalla et al., Int J Mol Sci 2020 Study
Slide 24: Serum and CSF Neurofilament (Nf-L)
SERUM AND CSF NEUROFILAMENT (NF-L) BIOMARKER POPULATION N=5 (COHORT A) Serum Nf-L is increased in MPS II MPS II Natural History Study (NCT04007536) Cohort A – 3 to 30 mg/kg 300 300 Wk 24 mean increase 15% Mean increase 94% 7.2x 100 4.5-6mo pre-dose 100 Nf-L (pg/mL) Nf-L (pg/mL) 30 30 SERUM 10 10 1 1
Slide 25: Serum and CSF Neurofilament (Nf-L) and CSF Tau
SERUM AND CSF NEUROFILAMENT (NF-L) AND CSF TAU BIOMARKER POPULATION N=5 (COHORT A) Serum Nf-L is increased in MPS II MPS II Natural History Study (NCT04007536) Cohort A – 3 to 30 mg/kg 300 300 Wk 24 mean increase 15% Mean increase 94% 7.2x 100 4.5-6mo pre-dose 100 Nf-L (pg/mL) Nf-L (pg/mL) 30 30 SER
Slide 26: Progressive Loss of Cognitive Milestones in Hunter Patients
PROGRESSIVE LOSS OF COGNITIVE MILESTONES IN HUNTER PATIENTS Regression . For neuronopathic patients that experience early loss of cognitive milestones, development trajectory demonstrates little to no improvement over time 26 ©2021 Denali Therapeutics. All rights reserved.
Slide 27: Clinician & Parent/Caregiver Global Impression of Change (CGI/PGI-C)
CLINICIAN & PARENT/CAREGIVER GLOBAL IMPRESSION OF CHANGE (CGI/PGI-C) CLINICAL POPULATION N=5 (COHORT A THROUGH WEEK 24) CGI-C PGI-C Worsening Improvement In Cohort A patients (5-10 years old), interim assessment of clinical outcomes suggest improvement in overall MPS II symptoms, cognitive abilities
Slide 28: Clinician & Parent/Caregiver Global Impression of Change (CGI/PGI-C)
CLINICIAN & PARENT/CAREGIVER GLOBAL IMPRESSION OF CHANGE (CGI/PGI-C) CLINICAL POPULATION N=5 (COHORT A THROUGH WEEK 24) CGI-C Excerpts from Comment Field of CGI-C entered by Investigator into database: Worsening • Language much improved, more complex sentences • Now able to hold a pencil • More cons
Slide 29: DNL310 Ph1/2 Study – Summary of Interim Data
DNL310 PH1/2 STUDY – SUMMARY OF INTERIM DATA Endpoints Measures Phase 1/2 Interim Data Assessment CSF GAGs (primary • Heparan sulfate (HS) • Normalization in all subjects substrate of IDS) • Dermatan sulfate (DS) • Normalization in most subjects CSF Exploratory • GM3 • GM3, GlcCer, BMP reduction con
Slide 30: DNL310 MPS II Development Plan
DNL310 MPS II DEVELOPMENT PLAN ü Rapid reductions in CSF heparan sulfate and sustained normalization demonstrate BBB crossing, Cohort A Ages 5-10 y.o. CNS activity and durability of response of DNL310; enhanced peripheral activity also observed Neuronopathic ü Cohort A 6-month data suggest clinical
Slide 31: Conclusion
CONCLUSION Ryan Watts, Ph.D., Chief Executive Officer
Slide 32: Positive 6-Month Data from DNL310 Phase 1/2 Study in MPS II
POSITIVE 6-MONTH DATA FROM DNL310 PHASE 1/2 STUDY IN MPS II KEY RESULTS • Hallmark biomarker “GAG” normalized in Further Validation of cerebrospinal fluid in all patients TV Platform that uses TfR for brain delivery • Global impression scales show improved cognition, behavior, and physical function
Slide 33: Denali
JENALI \ - = ® ME ~ Sa Ss, ’ _
Denali Therapeutics — Technical Presentation (July 2021) on 6ix