January 2022 - Investor Relations | Akouos
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January 2022
Forward Looking Statements This presentation contains “forward-looking statements” and information within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectation about timing and execution of anticipated milestones, including our planned investigational new drug application submissions for AK-OTOF and AK-antiVEGF, initiation of clinical trials, and additional product candidate and target selections; our expectations regarding our internal manufacturing capabilities and external manufacturing supply; our expectations regarding our regulatory strategy; and the geographic expansion of the Resonate™ program. These forward-looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “possible,” “target,” “will,” “would,” and other words and terms of similar meaning. Akouos may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions, and expectations disclosed in these forward-looking statements as a result of various factors, including: our limited operating history; uncertainties inherent in the development of product candidates, including the initiation and completion of nonclinical studies and clinical trials; the timing of and our ability to submit applications for, and to obtain, regulatory approvals of our product candidates; whether results from nonclinical studies will be predictive of results or success of clinical trials; our ability to obtain sufficient cash resources to fund our foreseeable and unforeseeable operating expenses and capital expenditure requirements; our ability to obtain, maintain, and enforce our intellectual property; the impact of the COVID-19 pandemic on our business, results of operations, and financial condition; the potential that our internal manufacturing capabilities and/or external manufacturing supply may experience delays; risks related to competitive programs; and the other risks and uncertainties that are described in the Risk Factors section included in the Company’s most recent Quarterly Report on Form 10-Q, which is on file with the Securities and Exchange Commission, and in other filings that Akouos may make with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this presentation represent Akouos’s views only as of the date made and should not be relied upon as representing its views as of any subsequent date. Except as required by law, Akouos explicitly disclaims any obligation to update any forward-looking statements. 1
Genetic Medicine Platform Focused on Inner Ear Conditions
~466mm people worldwide with disabling hearing loss, including ~34mm children. Over 8,000 children are
High Unmet Need and Opportunity to
born with genetic sensorineural hearing loss every year in the US and Europe. No pharmacologic options are
Create Value
available
Multimodal Precision Genetic Building a platform of proprietary ancestral AAV vectors, a novel delivery approach that is designed to be
Medicine Platform familiar to surgeons, and multimodal tools such as gene transfer, knockdown, and editing
AK-OTOF, a potential gene therapy for OTOF-mediated hearing loss, generated promising nonclinical data and
Potential for Rapid Advancement of
has potential for rapid clinical readout using an objective, clinically accepted efficacy endpoint. Targeting IND
Lead Program, AK-OTOF
submission to FDA in 1H 2022
Disciplined Execution to Support Build AK-antiVEGF, a potential gene therapy for vestibular schwannoma, targeting IND submission to FDA in 2022.
of Pipeline with Potential for AK-CLRN1 product candidate selected. Precision genetic medicines platform also being applied more broadly
Broad Applicability to GJB2-mediated hearing loss, hair cell regeneration, and other inner ear conditions
Established internal infrastructure to manufacture vector for GLP toxicology studies. Partnered with well-
Manufacturing to Support Near- and
established CDMOs to advance cGMP campaigns, for both the AK-OTOF and AK-antiVEGF IND
Long-Term Growth
submissions. Developing internal cGMP manufacturing infrastructure and capabilities
World-Class Management Team with Purposefully assembled team of experts in auditory anatomy and physiology, otopathology, human genetics,
Unique Combination of Expertise inner ear drug delivery, gene therapy, and rare disease drug development and commercialization
2 Abbreviations: AAV = adeno-associated viral; CDMO = contract development and manufacturing organization; cGMP = current good manufacturing practice;
FDA = U.S. Food and Drug Administration; GLP = good laboratory practice; IND = investigational new drug application.; OTOF = human otoferlin gene
Recent Highlights and Upcoming Milestones
• Expanded leadership and capabilities of team
• Targeting IND submission for AK-OTOF in 1H 2022
• Continuing progress toward planned IND submission in 2022 for AK-antiVEGF
• Presenting nonclinical data at Association for Research in Otolaryngology annual conference in February 2022
• Demonstrating broad applicability of platform with earlier pipeline programs and plan to provide an update on progress
in February 2022
• Developing infrastructure and capabilities for internal cGMP manufacturing
3 Abbreviations: ARO = Association for Research in Otolaryngology; ASGCT = American Society of Gene and Cell Therapy; cGMP = current good manufacturing practice;
FDA = U.S. Food and Drug Administration; IND = investigational new drug application.; ODD = Orphan Drug Designation; RPDD = Rare Pediatric Disease Designation.
Experienced Management Team with Otology, Genetic Medicine,
and Rare Disease Drug Development Expertise
Emmanuel Simons, Ph.D., M.B.A. Michael McKenna, M.D.
Founder, Chief Executive Officer Founder, Chief Medical Officer
Jennifer Wellman, M.S. John Connelly, M.B.A.
Chief Operating Officer SVP, Portfolio Strategy, R&D Operations
Karoline Shair, Ph.D., J.D. Sachiyo Minegishi, M.B.A.
Chief Legal Officer Chief Financial Officer
Kathy Reape, M.D. Stacy Price, M.S.
Chief Development Officer Chief Technical Officer
4
CONFIDENTIAL
Deep Pipeline Highlights Broad Applicability of Platform
Product Candidate or Estimated Stage of Development
Development Program Prevalence Next Planned
(Indication) (U.S. and E.U.) Milestone
Discovery Preclinical Phase 1/2 Pivotal
Hair Cells
AK-OTOF
20,000 ▪ IND Submission
(OTOF-Mediated Hearing Loss)
AK-CLRN1
2,000 ▪ Pre-IND Meeting
(Usher Syndrome Type 3A)
Autosomal Dominant Pending Target
Hearing Loss ▪ Target Selection
Selection
Supporting Cells
GJB2
(GJB2-Mediated Hearing Loss) 200,000 ▪ Candidate Selection
Hair Cell Regeneration Pending Target
▪ Target Selection
Selection
Secreted Proteins
AK-antiVEGF
(Vestibular Schwannoma) 200,000 ▪ IND Submission
AAV-Enabled Modalities: Gene Transfer Gene Transfer + Knockdown Therapeutic Protein Expression
5 Abbreviations: GJB2 = human gap junction protein beta 2 gene;
IND = investigational new drug application. OTOF = human otoferlin gene.
How We Hear
1• Sound enters the ear through the external auditory canal of the outer
Spiral Ganglion Cells ear, where it vibrates the ear drum
2• The sound vibrations are then relayed through the middle ear where
Oval Window
Auditory
they articulate with the cochlea at the oval window
3• The cochlea contains a long, coiled, ribbon-like epithelial membrane
Nerve
Ear Drum
that is suspended between two cochlear fluid compartments
4• Sensory cells, called hair cells, sense the movement of fluid and
convert the fluid waves into nerve impulses that are sent along the
Round Window auditory nerve to the brain
Membrane
(RWM)
6 Illustration ©Chris Gralapp
Overview of Genetic Forms of Hearing Loss
• Tens of millions of children with monogenic hearing loss worldwide
• Congenital hearing loss recognized as a potential neurodevelopmental emergency by the American
Academy of Pediatrics
• Some of the most common forms of monogenic deafness affect an estimated 200,000 individuals in
the U.S. and Europe
• No drugs currently approved for the treatment of sensorineural hearing loss
1 of 500 newborns has
disabling hearing loss
Complex Etiology Genetic Causes
(20-40%) (60-80%) Nonsyndromic Syndromic
Autosomal
Nonsyndromic Syndromic Recessive >75 genes >30 genes
(75-80%) (20-25%)
Autosomal
Dominant
>48 >10
Recessive Dominant Mitochondrial
(~80%) (~19%) & X-Linked (~1%)
7 Note: Syndromic hearing loss means, in addition to hearing loss, the individual has other symptoms of medical importance.
References: Sloan-Heggen et al 2016 Hum Genet (2016); Morton et al N Engl J Med.(2006); Sheffield et al Cold Spring Harb Perspect Med.(2019); Kral et al N Engl J Med. (2010); https://www.aap.org/en-us/advocacy-and-policy/aap-health-
initiatives/PEHDIC/Pages/Early-Hearing-Detection-and-Intervention.aspx.
The Anatomy and Biology of the Inner Ear Are Ideal for
One-Time Genetic Medicines
Opportunity to Leverage Learnings from Unique Advantages
Development of Genetic Medicines for the Eye and Brain of the Inner Ear
• Fewer target cells and smaller
delivery volume → less vector
required for meaningful
transgene expression
• Anatomy is fully developed at
birth → more favorable
benefit-risk profile in pediatric
populations
• Enclosed compartments → opportunity for local, targeted delivery
• Reduced immune surveillance → lower impact of neutralizing antibodies
• Non-dividing target cells → potential for one-time delivery to provide life-long benefit
While the unique anatomical challenges of delivering to the inner ear have hindered genetic medicine development for
hearing loss and other inner ear conditions, we believe Akouos is uniquely positioned to overcome these
8
delivery challenges
The Akouos Precision Genetic Medicine Platform
Novel Proprietary Multimodal
Delivery Approach AAV Vector Library Capabilities
Gene transfer targeting loss-of-
function mutations
Gene knockdown or editing
targeting toxic gain-of-function or
dominant negative mutations
Therapeutic protein expression
(e.g., monoclonal antibody)
targeting disease pathways
responsible for non-monogenic
hearing loss
9 Abbreviation: AAV = adeno-associated viral.Novel Delivery Approach Designed to Enable Efficient Access to Target Cells
and Controlled Distribution of Product Candidates Throughout the Cochlea
Uncoiled Cochlea
Vent in Stapes / Oval Window
Injected Fluid Path
Akouos Delivery Device Administered fluid path
in Round Window
Akouos’s novel delivery approach is designed to allow for the safe and effective delivery of product candidates through the round window
membrane
• The surgical approach (transcanal tympanotomy) and venting (stapedotomy) are minimally invasive and routine in standard otologic
practice
Akouos's delivery device, intended to be used as part of a delivery system that also includes a syringe and syringe pump, is designed to
be familiar to otologic surgeons and to deliver product candidates in a fixed volume at a controlled flow rate
• Direct intracochlear administration through the RWM, with venting of the stapes footplate, allows for distribution of product candidates
across the full length of the cochlea
10 Abbreviations: kHZ = kilohertz; RWM = round window membrane.
Illustrations ©Chris Gralapp.Novel Delivery Approach Is Designed to Allow for the Safe and
Effective Delivery of Product Candidates
Key Attributes Akouos’s Novel Delivery Approach
of Delivery Approach Planned for Clinical Use
✓ Transcanal Tympanotomy
A minimally invasive (A standard surgical approach that provides access through the external auditory canal and
surgical approach does not require drilling through mastoid)
Distribution of product candidate ✓ Fenestration of stapes footplate to serve as a vent
along full length of cochlea (Achieved by a standard surgical technique called a stapedotomy)
Direct intracochlear administration
through round window membrane
✓ Akouos Delivery Device
Delivery of product candidate at
fixed volume and fixed rate
✓ Akouos Delivery Device
11AAVAnc80 Exhibits High Transduction Efficiency Compared to
Other AAV Capsids in Nonclinical Studies
AAVAnc80 Transduces Cochlear Hair Cells More Efficiently than Other AAV Capsids1
Capsid AAV1 AAV2 AAV8 AAVAnc80
Dose 21x 3.5x 7x 1x
100 100
80 80
%GFP+ OHCs
%GFP+ IHCs
60 60
40 40
20 20
0 0
Apex
Base
Multiple independent investigations have shown increased hair cell transduction
efficiency of AAVAnc80 relative to other AAV capsids in mouse and non-human primate models
12 References: Landegger LD, et al. Nat Biotechnol. 2017;35(3):280-284. Yoshimura H, et al. Sci Rep. 2018;8(1):2980. Tao Y, et al. Hum Gene Ther. 2018;29(4):492-506. Gu X, et al. Front Cell Neurosci. 2019;13:8.
(1) Images are in apex of cochlea; “green” represents green fluorescent protein and “red “represents phalloidin.
Abbreviations: AAV = adeno-associated viral; AAVAnc = ancestral adeno-associated viral vector; IHCs = inner hair cells; GFP = green fluorescent protein; OHCs = outer hair cells.Multi-Dose Tropism Study in Cynomolgus Macaque Showed
Efficient Inner Hair Cell Transduction at Three Weeks
Percentage of Inner Hair Cells Expressing GFP Three Weeks AAVAnc80-GFP Expression in Cynomolgus Macaque Cochlea Across
Following AdministrationAAVAnc80-eGFP
of an AAVAnc80 Vector Encoding GFP Frequencies and Doses (in vg per Cochlea)1
100
(%)
Cell
80
Hair Cells
Expressing GFP
Transduction
% InnerHair
60
40
Inner
20 Dose
2.4E11 vg
6.0E10 vg
1.5E10 vg
0
0.06 0.5 4 32
Cochlear Frequency
Position (kHz)
75 to 100% of inner hair cells express transgene at 6E10 vg per cochlea in the cynomolgus macaque
13 Reference: Francis, S.P. The Adeno-associated Viral Anc80 Vector Efficiently Transduces Hair Cells in Cynomolgus macaques (M. fascicularis): Development of a Non-Human Primate (NHP) Model for Cochlear Gene Therapy.
Presented at the 22nd Annual American Society of Gene and Cell Therapy Meeting; 2019. (1) In images, “green” represents green fluorescent protein and “red “represents phalloidin.
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; GFP = green fluorescent protein; IHC = inner hair cells; kHz = kilohertz; OHC = outer hair cells; SC = supporting cells; vg = vector genomes.The High Transduction Efficiency of AAVAnc80 Coupled with Local Delivery to the Inner
Ear Compartment Allows for a Dual Vector Approach for Larger Transgenes
Percentage of Inner Hair Cells Expressing Transgene Three
5’ GFP cDNA 3’ GFP cDNA Weeks Following Administration of Dual AAVAnc80 Vectors
5’ GFP cDNA
% IHCs Expressing GFP
3’ GFP cDNA
GFP mRNA
Full-length protein
Cochlear Frequency Position (kHz)
Ability to deliver transgenes that are larger than 5 kilobases in size creates the
potential for broader treatment of inner ear conditions
Reference: Darcy, Y. Use of the Adeno-Associated Viral Anc80 (AAVAnc80) Vector for the Development of Precision Genetic Medicines to Address Hearing Loss.
14
Presented at the 23rd Annual American Society of Gene and Cell Therapy Meeting; 2020.
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; cDNA = complementary DNA; GFP = green fluorescent protein;
h = human; dB = decibels; IHCs = inner hair cells; ITR = inverted terminal repeats; kHz = kilohertz; mRNA = messenger RNA; polyA = polyadenylation tail; SA = splice acceptor; SD = splice donor; vg = vector genome.AAVAnc80 Efficiently Transduces Multiple Cell Types in the Inner Ear
• Conducted nonclinical studies across three
different non-human primate models using GFP as
a reporter gene delivered by AAVAnc80
• AAVAnc80 can efficiently transduce multiple target
cell populations throughout the cochlea in the
primate inner ear
• Pre-existing neutralizing antibodies, even at
relatively high levels in serum, did not inhibit
cochlear cell transduction following intracochlear
AAVAnc80
-GFP
delivery
Negative
Control
15 Reference: Data on File.
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; GFP = green fluorescent protein.Multimodal Capabilities Create Potential to Address a Broad Range
of Monogenic and Non-Monogenic Inner Ear Conditions
Akouos Precision Genetic Medicine Platform
Gene Gene Gene Therapeutic
Transfer Knockdown Editing Protein
Modality Non- Expression
Single Dual Nuclease-
RNA-interference nuclease-
Vector Vector based
based
Hair Cells CLRN1 OTOF Undisclosed autosomal dominant indications
Supporting GJB2
Cells Hair Cell Regeneration
Target
Secreted Vestibular
Proteins Schwannoma
Initial pipeline spans multiple vector-mediated modalities and cochlear targets to potentially address
inner ear conditions affecting hundreds of thousands of individuals in the U.S. and Europe
16 Abbreviations: CLRN1 = human clarin-1 gene; GJB2 = human gap junction protein beta 2 gene; OTOF = human otoferlin gene.AK-OTOF Overview
• AK-OTOF • AK-OTOF encodes otoferlin, a protein that enables the sensory cells of the ear to release
neurotransmitter vesicles, activating auditory neurons
• Prevalence • Estimated 20,000 cases of OTOF-mediated hearing loss in the US and EU
• Treatment of OTOF-mediated hearing loss, a form of sensorineural hearing loss caused by
• Indication mutations in OTOF
• Mutations in OTOF are a major cause of genetic non-syndromic hearing loss
• Delivery Method • Use AAVAnc80 as a delivery vehicle for OTOF
• Administer product candidate directly into the inner ear
• Encodes otoferlin to enable inner hair cells of the cochlea to release neurotransmitter vesicles
• Mechanism of Action to activate auditory neurons in response to sound
• Auditory neurons then carry electronically encoded acoustic information to the brain allowing
us to hear
• Promising nonclinical data generated in translationally relevant mouse models
• Progress and Status • Pre-IND meeting with FDA; executing on agreed IND-enabling nonclinical studies
• Designing a Phase 1/2 trial for AK-OTOF and targeting an IND submission in 1H 2022
• FDA granted ODD and RPDD and European Commission granted ODD for AK-OTOF
17
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; FDA = U.S. Food and Drug Administration; IND = investigational new drug application;
ODD = Orphan Drug Designation; OTOF = human otoferlin gene; RPDD = Rare Pediatric Disease Designation.Dual Vector Delivery of AK-OTOF Led to Restoration of ABR
Thresholds and Durable Auditory Function in Mice
Restoration of ABR Thresholds in Otof Knock-Out Mice Intracochlear Delivery of AK-OTOF Resulted in Significant,
Receiving a Dual AAV Vector Expressing OTOF Long-Term Hearing Restoration in Otof Knock-Out Mice
Otof-/- (n=6)
Click ABR threshold (dB SPL)
Click ABR threshold (dB SPL)
90 100 Untreated Otof-/- (n=5)
80 Wild-Type (n=6 at 1 mo; n=3 at 10 mo)
Otof-/- (5’ alone; n=3)
70 Otof-/- + AAVAnc80-hOTOF (n=3 per group)
80
60
50 Otof-/- (5’ + 3’; n=8) 60
40
Wild-type (n=8) 40
30
20 20
10
0 0
1 4 10 15 25 30 1 mo 3 mo 7 mo 10 mo
Weeks Post-Injection Approximate Age at ABR Test
(Administration at 1 week old)
AK-OTOF utilizes a dual vector approach to restore durable auditory function in knock-out mouse models –
one AAVAnc80 vector carries the 5’ fragment of OTOF and the other AAVAnc80 vector carries the 3’ fragment of OTOF
18 References: Akil et al., PNAS 2019; 116 (10) 4496-4501. Darcy, Y. Use of the Adeno-Associated Viral Anc80 (AAVAnc80) Vector for the Development of Precision Genetic Medicines to Address Hearing Loss.
Presented at the 23rd Annual American Society of Gene and Cell Therapy Meeting; 2020.
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; ABR = auditory brainstem response; dB SPL = decibel sound pressure level; mo = month; OTOF = human otoferlin gene; Otof = mouse otoferlin gene.A Single Dose of AK-OTOF Restored Auditory Function in Otoferlin
Knock-Out (Otof -/-) Mice with Mature Cochleae
Wild-Type Vehicle Control Otoferlin KO + Vehicle Control Otoferlin KO + AAVAnc80-hOTOF
Time re Click Onset (msec) Time re Click Onset (msec) Time re Click Onset (msec)
In a nonclinical study, a single dose of AK-OTOF restored auditory function in mice lacking otoferlin
19 Valero MD. The Adeno-associated Viral Anc80 (AAVAnc80) Vector: Precision Genetic Medicines to Address Hearing Loss. Presented at the 43rd Annual Association for Research in Otolaryngology Mid-Winter Meeting; 2020.
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; dB SPL = decibel sound pressure level; KO = knock-out; msec = millisecond; Otof = mouse otoferlin gene.Planned AK-OTOF Phase 1/2 Clinical Trial
Part A Part B
Dose Escalation Cohort Expansion
Assess: Safety, tolerability, and bioactivity Assess: Safety and effectiveness
Up to 5-year clinical follow-up
• Individuals with OTOF-mediated hearing loss
Key Eligibility • Amenable to surgical delivery and potential for benefit
• May enroll children as young as one year old in the expansion phase (1)
Administration • Administered to trial participants through a single unilateral intracochlear injection
Efficacy Endpoints • Objective and clinically relevant ABR testing and age-appropriate behavioral assessment
• Target IND submission in 1H 2022
Timing • Intend to file the delivery device along with the investigational medicinal product as a combination
product (1)
20 (1) Based on pre-IND meeting with FDA in September 2019. Abbreviations: ABR = auditory brainstem response; FDA = U.S. Food and Drug Administration;
IND = investigational new drug application; OTOF = human otoferlin gene.AK-antiVEGF Overview
• AK-antiVEGF encodes a secreted inhibitor of vascular endothelial growth factor (VEGF) to treat
• AK-antiVEGF vestibular schwannoma
• Prevalence • Estimated to affect approximately 200,000 individuals in the U.S. and E.U.
• Treatment of vestibular schwannoma, a common intracranial tumor
• Indication • Current interventional standard of care consists of surgical resection / removal and/or radiation,
both of which typically result in hearing loss and can be associated with significant morbidity
• Uses AAVAnc80 as a delivery vehicle to achieve local, sustained anti-VEGF protein at tumor site
• Delivery Method • Administer product candidate directly into the inner ear
• Systemic anti-VEGF has been shown to reduce tumor volume and improve hearing in some patients
with vestibular schwannoma
• Mechanism of Action • Local delivery may avoid the systemic side effects of high dose intravenous VEGF inhibitor infusion
and could remove or reduce the need for other interventions
• Computational modelling supports the potential for diffusion of anti-VEGF protein, at or above
reported biologically active levels, to site of tumor
• Progress and Status • An initial NHP study demonstrated long-term, local expression of anti-VEGF protein is robust and
well tolerated
• Pre-IND meeting feedback supports IND submission targeted in 2022
21 Abbreviations: AAVAnc = ancestral adeno-associated viral vector; IND = investigational new drug application;
NHP = non-human primate; VEGF = vascular endothelial growth factor.AK-antiVEGF for the Treatment of Vestibular Schwannoma
Human Data Demonstrate Ability of Systemic VEGF Inhibitor to Improve
Nonclinical Data in NHPs Demonstrate Delivery of AK-antiVEGF is Well-
Hearing and Reduce Tumor Volume in Some Patients with
Tolerated and Results in Potentially Therapeutic Protein Expression
Vestibular Schwannoma
Shifts in ABR thresholds
(relative to baseline ABRs in the same
ear prior to intracochlear
administration are shown at 1, 2, 3,
and 6 months post-intracochlear
administration of an AAVAnc80
vector encoding anti-VEGF. Group
means (±SD) at each timepoint
reflect bilateral measurements in
each NHP on study.
Computational Modeling Supports Feasibility of Diffusion to Tumor Site
AAV-mediated anti-
VEGF protein
secretion in
perilymph
1
Reference: Connelly, J. Demonstration of Tolerability of a Novel Delivery Approach and Secreted Protein Expression Following Intracochlear Delivery of AK-antiVEGF (AAVAnc80-antiVEGF Vector) in Non-Human Primates. Presented at the 24th
22 Annual American Society of Gene and Cell Therapy Meeting; 2021. 1. Range of location of early VS from MRI data (Koen 2020 Otolaryngol Head Neck Surg).
Abbreviations: AAV = adeno-associated viral; AAVAnc = ancestral adeno-associated viral vector; ABR = auditory brainstem response; dB = decibel; IAC = internal auditory canal; kHz = kilohertz; mm = millimeter;
NHP = non-human primate; SD = standard deviation; VEGF = vascular endothelial growth factor.The Resonate™ Program Seeks to Improve Access to Genetic
Testing for Eligible Individuals with Auditory Neuropathy
TM
Akouos is partnering with Blueprint Genetics to provide access to a potential genetic
diagnosis at no cost to eligible individuals, their insurance, or their healthcare
providers
• Today, few individuals with auditory neuropathy receive a • To be eligible for the program, individuals:
genetic diagnosis. A key barrier is the availability and • Can be any age;
accessibility of genetic testing.
• Must have a current or prior clinical diagnosis of bilateral
• A genetic diagnosis for auditory neuropathy: auditory neuropathy, or a medical history consistent with
• Can empower individuals to make informed choices, foster bilateral auditory neuropathy; and
connections with others living with disabling hearing loss, • Must not have a syndromic medical history
and may provide valuable insight into medical management
• Participants in the program have access to the Blueprint
• Could help individuals and their healthcare providers Genetics Comprehensive Hearing Loss and Deafness Panel that
determine potential eligibility for future clinical trials includes more than 230 genes associated with genetic forms of
hearing loss
The program is available in the United States and plans to expand to
additional geographic regions
23Key Advantages to Our Manufacturing Process
Well characterized HEK293 cell suspension
and 250 L bioreactor system
Low dose requirements given small size
and compartmentalized nature of the
inner ear
Exclusive access to ancestral AAV vectors
for inner ear provides opportunity to
optimize production process and secure
additional competitive advantage Targeted delivery and high transduction
efficiency alleviate the need for large scale
production
Clinical-scale and intended commercial-scale manufacturing process for Akouos’s product
candidates, including AK-OTOF, has resulted in multiple successful at-scale batches of
AAVAnc80 vectors
24
Abbreviations: AAV = adeno-associated viral; AAVAnc = ancestral adeno-associated viral vector; HEK293 = human embryonic kidney 293; L = liter.Manufacturing to Support Near- and Long-Term Growth
Expertise in Gene Therapy
• Expertise covers development from vector design through drug product manufacture
and Gene Editing
• Developing scalable manufacturing capabilities, which may allow for significant
control over process development timelines and cost
• Developing internal capabilities to support manufacturing activities through Phase
1/2 clinical trials
Building In-House
• Leveraging single use, disposable, closed system operations aligned to genetic
Research and cGMP medicine platform to promote both flexibility and cost-effectiveness
Manufacturing • Internal analytical and process development
Capabilities • 250-liter single-use bioreactor system using suspension HEK293 cells
• Completed manufacturing of AK-antiVEGF for IND-enabling GLP toxicology study
• Lonza performed manufacturing for pivotal IND-enabling nonclinical studies for the
Agreements with Well- AK-OTOF program
Established CDMOs • Working with multiple third-party manufacturers to advance cGMP campaigns for
both the AK-OTOF and AK-antiVEGF IND submissions
25 Abbreviations: AAV = adeno-associated viral; CDMO = contract development and manufacturing organization; cGMP = current good manufacturing practice;
GLP = good laboratory practice; HEK293 = human embryonic kidney 293; IND = investigational new drug application.Recent Highlights and Upcoming Milestones
• Expanded leadership and capabilities of team
• Targeting IND submission for AK-OTOF in 1H 2022
• Continuing progress toward planned IND submission in 2022 for AK-antiVEGF
• Presenting nonclinical data at Association for Research in Otolaryngology annual conference in February 2022
• Demonstrating broad applicability of platform with earlier pipeline programs and plan to provide an update on progress
in February 2022
• Developing infrastructure and capabilities for internal cGMP manufacturing
26 Abbreviations: ARO = Association for Research in Otolaryngology; ASGCT = American Society of Gene and Cell Therapy; cGMP = current good manufacturing practice;
FDA = U.S. Food and Drug Administration; IND = investigational new drug application.; ODD = Orphan Drug Designation; RPDD = Rare Pediatric Disease Designation.Appendix 27
Venting Supports Distribution of AAVAnc80 Across Length
of Cochlea Following Intracochlear Administration
AAVAnc80-eGFP Efficiently Transduces Inner Hair Cells in Without Venting, AAVAnc80-eGFP Transduction of Inner Hair Cells is
Non-human Primates with Venting of Stapes Footplate Sporadic and Biased to Base of Cochlea in Non-human Primates
% IHCs expressing eGFP
% IHCs expressing eGFP
Cochlear Frequency Position (kHz) Cochlear Frequency Position (kHz)
Dose (vg per cochlea): Dose (vg per cochlea):
Three weeks following intracochlear administration of AAVAnc80-eGFP, average Three weeks following intracochlear administration of AAVAnc80-eGFP at a dose of
transduction per dose group and by cochlear frequency position. Seven NHPs with 4.5E10 vg per cochlea, average transduction by cochlear frequency position. One NHP
venting of the stapes footplate (6 unilateral and 1 bilateral, for a total of 8 ears). with venting and two NHPs without venting of the stapes footplate (all bilateral, 6 ears).
28 There may be potential to overcome this barrier, e.g., through increased dose, larger volume, and/or
slower infusion, but these strategies may not be ideal for clinical development
28 Valero, M. Translation of Potential Genetic Medicines for the Inner Ear. Presented at the 44th Annual MidWinter Meeting of the Association for Research in Otolaryngology; 2021.
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; eGFP = enhanced green fluorescent protein; IHCs = inner hair cells;
kHz = kilohertz; NHP = non-human primate; vg = vector genome.Full-Length Otoferlin Expression Was Only Detected in IHCs
and Well Tolerated in NHP Cochlea
Cochlear micrographs from mid-cochlear region (4 kHz; left panels) and hair cell survival and FLAG positive cell quantification (right
panels) from animals administered vehicle (top panels) or AAVAnc80-FLAG.hOTOF (bottom panels); inner hair cell and outer hair cell
survival was robust in animals expressing FLAG-otoferlin
IHC survival OHC survival FLAG positive IHC
Phalloidin Anti-FLAG 100
Cell counts (%)
80
Vehicle 60
OH
(Animal #3504) C 40
IH
20
C
4 kHz
16
32
1
4
0.25
16
32
1
4
0.25
16
32
1
4
0.25
0
IHC survival OHC survival FLAG positive IHC
100
Cell counts (%)
80
OH
AAVAnc80- C 60
FLAG.hOTOF (Animal IH 40
C
#3507)
20
16
32
16
32
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Andres-Mateos MD. In Vitro and In Vivo Analyses of Dual Vector Otoferlin Expression to Support the Clinical Development of AK-OTOF (AAVAnc80-hOTOF Vector).
29 Presented at the 24th Annual American Society of Gene and Cell Therapy Meeting; 2021.
Abbreviations: h = human; IHC = inner hair cell; kHz = kilohertz; NHP = non-human primate; OHC = outer hair cell.AK-OTOF Administration to Otof Knock-Out Mice Resulted in Durable Expression
of Human Otoferlin Sufficient for Sustained Restoration of Auditory Function
• Otof-/- mice showed durable expression of human otoferlin • Expression of human otoferlin in more than 20% of IHCs results in restoration of
protein in inner hair cells that was detectable by auditory function (click ABR thresholds) to within the range of wild-type
immunohistochemistry 6 months post-administration of (Otof+/+, WT) mice
AK-OTOF
• Click-ABR thresholds at 1, 3, and 6 months were pooled across all doses
16-kHz COCHLEAR MICROGRAPHS (n = 106 Otof-/- mice)
6 MONTHS POST-ADMINISTRATION • The percentage of Otof-/- mouse IHCs expressing otoferlin following
administration of AK-OTOF was computed from confocal image stacks
AK-OTOF (Dose 1X)
(like those on the left), averaged across 8, 16, and 32 kHz frequency
19180: Otof -/-
OHCs
positions, and pooled across 1, 3, and 6 months and across all doses
IHCs
19167: Otof -/-
Vehicle
OHCs
IHCs
Myo7a Phalloidin Otoferlin
Cochlear micrographs represent maximum projections through
confocal image stacks.
30 Hickox, Ann. Durable Recovery of Auditory Function Following Intracochlear Delivery of AK-OTOF (AAVAnc80-hOTOF Vector) in a Translationally Relevant Mouse Model of Otoferlin Gene (OTOF)-mediated
Hearing Loss. Presented at the 24th Annual American Society of Gene and Cell Therapy Meeting; 2021.
Abbreviations: ABR = auditory brain stem response; IHC = inner hair cell; kHz = kilohertz; Myo7a = Myosin VII a; OHC = outer hair cell; Otof = mouse otoferlin gene; WT = wild-type.AK-CLRN1 Overview
• AK-CLRN1 encodes clarin-1, a protein believed to modulate cochlear hair cell
• AK-CLRN1 mechanotransduction and synaptic function, for patients with Usher syndrome type 3A
• Prevalence • Estimated 2,000 cases in the U.S. and E.U.
• Treatment of sensorineural hearing loss due to mutations in CLRN1
• Indication • Mutations of CLRN1 cause syndromic genetic hearing / vision loss, characterized by
progressive sensorineural hearing impairment and progressive vision loss
• Uses AAVAnc80 as a delivery vehicle for CLRN1
• Delivery Method
• Administer product candidate directly into the inner ear
• Mutations in CLRN1 reduce the production and localization of clarin-1 protein to hair cell
membranes
• Mechanism of Action
• AK-CLRN1 is intended to treat hearing loss in patients with Usher syndrome type 3A by
delivery of a healthy copy of CLRN1 to cochlear hair cells
• Published data demonstrate ability of AAV-mediated delivery of mouse clarin-1 to rescue
auditory function in mouse model of Usher syndrome type 3A
• Progress and Status • Additional nonclinical data with AAVAnc80-mediated delivery of human clarin-1 demonstrate
auditory function rescue in mice with mature cochleae
31
• Product candidate selected
Abbreviations: AAVAnc = ancestral adeno-associated viral vector; CLRN1 = human clarin-1 gene.Proof of Concept Data: AAV-Mediated Delivery of Clrn1
Recovered Auditory Function in a Knock-Out Mouse Model
Restoration of Auditory Function in Clrn1 KO Mice Injected at P2-3
• Nonclinical data demonstrated auditory
function preservation in the KO-TgAC1
mouse model, which recapitulates the
auditory phenotype observed in patients
with Usher syndrome type 3A
• AAV delivery of Clrn1 with its endogenous
UTR preserves auditory function at levels
near wildtype animals ABR Waveforms
WT KO-TgAC1 KO-TgAC1 + Clrn1 + UTR
• Early nonclinical data show that AAVAnc80
encoding human clarin-1 can rescue auditory
function in KO-TgAC1 mice with mature
cochleae
32 Reference: Geng, R., et al. Sci Rep 7 2017; 13480.
Abbreviations: AAV = adeno-associated viral; AAVAnc = ancestral adeno-associated viral vector; ABR = auditory brainstem response; Clrn1 = mouse clarin-1 gene;
db SPL = decibel sound pressure level; KO = knock-out; UTR = untranslated region; WT = wild type.You can also read
