A WORLD IN WHICH THE PRIVILEGES OF HEARING AND BALANCE ARE AVAILABLE - TO ALLTM Citi Virtual BioPharma Conference - Decibel Therapeutics
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A WORLD IN WHICH THE
PRIVILEGES OF HEARING AND
BALANCE ARE AVAILABLE
TO ALL
TM
Citi Virtual BioPharma Conference
September 2020
CONFIDENTIAL | 1
Hearing & Balance: Significant Needs, Life-Changing Medicines
Focused Approach: Restore Functional Hair Cells to Inner Ear
Integrated Platform: Single cell genomics, Gene Therapy
Experienced Team: Inner Ear Biology, Drug Hunting
Leading Company
Emerging Field
Sustainable Value Creation: Platform, Pipeline, Intellectual Property
Significant Unmet Needs: Hearing and Balance Disorders
CONFIDENTIAL | 3
Hair Cells in Inner Ear: Key Transducers of Mechanical Signals
Loss of HCs in Cochlea/Vestibule is Major Cause of Hearing & Balance Disorders
Stereocilia
Vestibule / Balance Function Hair cell
Aging and chemical insults cause loss
of functional hair cells in the vestibule
Nerve ending
Cochlea / Hearing Function
Aging, noise, and genetics cause loss
of functional hair cells in the cochlea
CONFIDENTIAL | 4
Decibel Platform: Restoring Hair Cell Functionality
Restoration of Hearing
and Balance
Restoration of Hair Cell
Functionality
Rare Genetic Disorders Common Disorders
Gene Replacement Hair Cell Regeneration
Single-cell Genomics Precision Gene Therapy Inner Ear Expertise
CONFIDENTIAL | 5
Gene Therapy: Ideal Modality For the Ear
Strong parallels to the eye
Ideal Organ Decibel Proprietary Gene Regulatory Elements Manufacturing
Enable Precise Spatial and Temporal Regulation
• Tiny volume, enclosed • ~100x lower product
compartment, high requirement vs systemic
titers
All Hair Cells
• Local delivery, no
systemic exposure
• Access validated Inner Hair Cells
delivery/surgery route
• Immuno-privileged Outer Hair Cells
Systemic Otic
Vestibular >5,000L Process ~200L Process
Supporting Cells scale for scale for
commercial commercial
CONFIDENTIAL | 6
Targeted Delivery of Otic Therapy
Platform links key gene targets to proprietary products
Genomics & Computation Platform Therapeutic Delivery
Epigenome
Gene Therapy:
Proprietary
target/promoter Non-
ATACseq; Cut&Run functional
Transcriptome Therapeutic
Target
scRNAseq; NucSeq
Small Molecule:
Spliceosome Validated Target Restore
Functionality
PacBio IsoSeq
CONFIDENTIAL | 7
Decibel’s Strategies for Restoration of Hair Cell Functionality
Drugs to complement genetic mutations or to regenerate hair cells
Immature
Cochlear Hair Cell
Regeneration Supporting
Cell
Gene Inner
Outer
Hair Cell
Replacement Hair Cell
Vestibular
Regeneration
Type I
Type II Hair Cell
Hair Cell
Supporting
Cell CONFIDENTIAL | 8
Pipeline 2020: Decibel Retains 100% of Commercial Rights
PROGRAM TARGET/MOA TARGET ID/VALIDATION DRUG DISCOVERY CLINICAL TESTING NEXT MILESTONE
Gene Therapy for Congenital Deafness
REGENERON
DB-OTO Otoferlin
Co-development;
IND Q4’21
Decibel
AAV.103 Undisclosed commercializes DC
Regenerative Medicines: Hair Cells
DB-ATO ATOH1/Vestibule IND 1H’22
AAV.RF301 Cochlea DC
Discovery Vestibule/Cochlea DC
Discovery Vestibule/Cochlea DC
Otoprotection
DB-020 Cisplatin Inactivation POC 2021*
*Registrational Trial
2022
Gene Therapy Small Molecule
CONFIDENTIAL | 9
DB-OTO for congenital genetic hearing loss
DB-OTO for Congenital OTOF Deficiency
• Biology: Otoferlin is a calcium sensor at base of inner hair cell
• Patient Phenotype: Profound deafness
• Identification: Newborn testing; OTOF genetic test
• Epidemiology: Estimated US & EU5 prevalence of 9,000 –
36,000; incidence of ~115 – 450 / year
• Treatable OTOF Mutations: Single gene transfer
• DB-OTO: Differentiated vs competition
– Precision gene therapy; proprietary, selective expression
of otoferlin in hair cells
– Clinical strategy leverages unique relationship with
largest characterized patient cohort
C O N F I D E N T I A L | 11Dual AAV.OTOF Delivery Rescues Normal Hearing Sensitivity in
Congenitally Deaf Mice
OTOFQ828X/+ OTOFQ828X/Q828X OTOFQ828X/+ OTOFQ828X/Q828X OTOFQ828X/Q828X Treated
Dual AAV-OTOF Delivery
Expression of OTOF Transgene: Selective expression, robust functional recovery
C O N F I D E N T I A L | 12DB-OTO: Proprietary Regulatory Element Provides Cell-Specific
Expression and Enables Improved Prolonged Efficacy
Durable efficacy in rodents vs ubiquitous Cell-selective dual AAV expression
promoter (competition) in non-human primates
Myo7a
AAV-smCBA-hOTOF Hair Cells (Target) DAPI
Sensitivity
GFP
DB-OTO
Normal Range
Weeks After AAV Injection
Emerging safety data in eye confirms importance of cell-selective transgene expression. Xiong et al (2019) PNAS
C O N F I D E N T I A L | 13DB-OTO Clinical Development
Expedited path through committed partnership with largest characterized OTOF cohort
149 Patients with
Confirmed Biallelic
Timeline To Clinical POC OTOF Mutations
Identified in Spain
2020 2021 2022
CMC, Process, Analytical, Stability, Supply,
Centralized Genetic
Manufacturing Distribution Diagnosis with PI
CTA
GLP Tox IND
Profound Congenital Deafness
Clinical Trials
Patient registry
Natural History Study
Ongoing with Patients
C O N F I D E N T I A L | 14Regenerative Medicines
Vestibule
DB-ATO for Regeneration of Vestibular Hair Cells
F-actin
Atoh1+/+
Atoh1-/-
• Product: DB-ATO is an AAV gene therapeutic; deliver ATOH1
with proprietary support-cell promoter
• Biology: ATOH1 is a bHLH transcription factor expressed in
Myo7a (HC marker) developing hair cells, required for hair cell differentiation
Atoh1-/- • Mechanism: DB-ATO converts supporting cells into hair cells
• Indications: Balance disorders caused by chemicals or age
– Severe Indication: Bilateral Vestibulopathy
– 80% loss of vestibular hair cells; 130K in US, EU5
DB-ATO
– Broad Indication: Age-related balance disorders
SC-specific ATOH1 WPRE polyA
– 15M in US
C O N F I D E N T I A L | 16Vestibule
DB-ATO Robustly Regenerates Type 2 Vestibular Hair Cells In Vivo
Support cell-
selective expression Hair Cell Regeneration w DB-ATO
Control + DB-ATO
Off-target
region Contralateral ear Treated ear
HC marker
Pou4f3 (nucleus)
C57Bl/6 mice
Utricle
6-9 wko males
Pou
Hair
4f3 cells
GFP
• Vestibular hair cells killed w IDPN
Off-target • 14d after IDPN, DB-ATO delivered
region
unilaterally
• 14d after DB-ATO, hair cells were
assessed
Crista
C O N F I D E N T I A L | 17Vestibule
DB-ATO Development Path to IND, Clinical Trials
Efficacy in rodent models Identical tests in humans
Electrophysiology Physiology
VOR VOR
In Vivo DC Q121
Regeneration
IND 1H22
Q4 19
Balance Function Mobility and Vision
C O N F I D E N T I A L | 18Cochlea
Regeneration of Cochlear Outer Hair Cells for Restoration of Hearing
AAV.RF301 Converts IHCs to OHCs
Single-cell genomics defines targets AAV.RF301 Overexpresses RF301 and
to direct outer hair cell fate converts IHCs to OHC fate
Hdac3 1
Kdm4a
Untreated Ear
Mtpn
Htatip2
Dnmt3a
Mlxip
Foxo3 0.8
Foxn3
Prnp
Sall1
Pknox2
Klf9
Rora
Six2 0.6
Trps1
Actn4
Mef2a
Pdcd11
Nfkb1
AAV.RF301
Hlcs
Zfp410
Banp 0.4
Zbtb7b
Esrra
E2f3
Zfp740
Zkscan3
Creb3l1
Ighm 0.2
Zfp324
Arnt
Lig1
Elk3
Zbtb40
Crem
Smarca2
0
Nfatc2
Rest
Nfib
Zfp608
Nfix
Smad7
OHCs
Mafk
Adarb1
RF301
Irf6
Nacc2
Rorb
Bhlhe40
Ikzf2
Jun
Zfp423
Nr3c1
Tppp
Cat
Zfp637
Zfp777
Kmt2a
Nr2f2
Zfp592
Pura
Zfp365
OHC
Transcription factors
Zbtb46
Zfp654
BC005561
Zfp516
Cic
Zhx3
Rxra
Zfp106
Zfp277
Thra
Tmem33
candidates
Zc3h7a
Srrm3
Pds5a
Zbtb4
Ube2k
Ctbp2
Id4
Srebf1
Nfat5
Ddit3
IHCs
Sall3
Mdm2
Prestin
Srebf2
Gtf2i
Prdx5
Smap2
Zbtb7a
Zfp618
Gata3
Irf9
Mef2d
Phalloidin
Taf1
Zfp523
Kdm2a
Abcf2
Zfp398
Zfp638
Hmg20a
Msi2
Nmral1
Tead1
Tead2
H2afy
Irx3
Ezh2
Rfxap
Sox9
Tgif2
Egr4
AAV-RF301 Treated Ear
Egr3
Npas4
Sox11
Fhl2
Prox1
Sox2
Cers2
Gm10093
Dazap1
Dnajc21
Isl1
Ran
Ebf1
Atoh1
Hes6
Rpl35
Rps10
Psma6
Akr1a1
Barhl1
Smarca5
Ruvbl1
U2af1
Gtf2a2
Zfp428
Ssbp3
Zfp326
Nuak1
Pknox1
Cyb5r1
Tceal5
Msra
Hdac3 Cers6
Zmat4 1
Kdm4a Bcl11b
Npdc1
Mtpn Bcl2
Htatip2 Ybx1
Stub1
Dnmt3a Zmat2
Zfp667
Mlxip Yeats4
Foxo3 Tfdp2
Hnrnpa10.8
Foxn3 Tfdp1
Prnp Rbm17
Hmgn3
Sall1 Lhx3
Pknox2 Cers4
Ugp2
Klf9 Bax
Rora Mrps25
H1fx
Six2 Nap1l1 0.6
Trps1 Pax2
Traf4
Actn4 Mcm6
Mef2a Neurod6
Rab2a
Pdcd11 Cd59a
Nfkb1 Ptcd1
Klf7
Hlcs Las1l
Zfp410
Banp
Cdk2ap1
Mycl
Nono
Zfp330
0.4
Zbtb7b Insm1
Esrra Irx2
Id1
E2f3 Id2
Zfp740 Magoh
Nr2f6
Zkscan3 Zbtb20
Creb3l1 Diablo
Gar1 0.2
IHCs expressing the
Ighm Snrpb2
Zfp324 Rps4x
Zmiz1
Arnt Hnrnpc
Lig1 Nr2f1
Rbpj
Elk3 Lsm6
Hmgb2
Zbtb40 Tbpl1
Crem
Smarca2
0
OHC marker, Prestin
Nfatc2
Rest
Nfib
Zfp608
Pseudotime
Nfix
Smad7
Mafk
Adarb1
Irf6
Nacc2
Rorb
Bhlhe40
Ikzf2
Jun
Zfp423
Nr3c1
Tppp C O N F I D E N T I A L | 19
Cat
Zfp637
Zfp777
Kmt2aDB-020 for ototoxicity
DB-020 for Cisplatin Ototoxicity: Clear Path to Value Inflections
POC in ~40 Patients; Single Registration Study “Better than dead? At this point,
I’m wondering…..hearing loss and
DB-020 Provides Broad Protection against Cisplatin-induced this constant tinnitus is life-
changing, far more than having
Hearing Loss cancer.”
• 260k cisplatin patients/year in US/EU5/ Japan
• ~80% adults, >50% children
– permanent hearing loss; tinnitus, hyperacusis, balance loss
• Validated mechanism: sodium thiosulfate inactivates cisplatin;
100% hearing protection in preclinical models
• Office-based injection; proprietary formulation
C O N F I D E N T I A L | 21DB-020 Program: Fast Path to Human POC and Product Registration
2019 2020 2021 2022
I.A. LPO
Phase 1A Phase 1B POC (AU/US) Registration trial
Phase 1A, Human PK, Safety, Phase 1B, Human POC
Tolerability • DB-020 administered 3hrs before
• DB-020 administered locally, cisplatin
feasibly
• Placebo in contralateral ear
• Well tolerated, mild TEAEs, no
auditory findings • IV cisplatin, 21-28d
• Systemic exposure 20x below • Any tumor type
cisplatin efficacy inhibition • Safety, tolerability
• Opportunity for strong audiometric
efficacy signal
C O N F I D E N T I A L | 22Decibel Therapeutics: Leading Company, Emerging Field
• Major opportunities in hearing and balance
• Differentiated precision gene therapy
platform: state-of-art for ear
– Gene replacement
– Regenerative medicines
• Restoration of hair cell functionality: cellular
focus of pathology, validated mechanisms
• Demonstrated drug development and
delivery capabilities for inner ear diseases
C O N F I D E N T I A L | 23You can also read
