1
DeciBio Consulting, LLC
10250 Constellation Blvd., Suite #100
Los Angeles, CA 90067
Phone: 310-451-4510
Email: [email protected]
www.decibio.com
AAV Gene Therapies –
Industry Perspectives on Key Challenges
September 22nd, 2020
Presenter
Susan Zhou: [email protected]
The following presentation was presented by DeciBio at the
BioProduction Summit virtual conference with minor adjustments
2
Agenda
• Background
• Pain Points & Challenges
• Challenges Deep Dives & Solutions
• Concluding Thoughts
3
AAV-based gene therapies is a growing field of interest with two approved therapies with
blockbuster sales expectations; a wealth of late-stage clinical programs should act as further
catalysts driving the value of this class
Drug Luxturna Zolgensma
AAV AAV2 AAV9
Indication Retinal DystrophySpinal Muscular Atrophy,
Type 1
Approval Date Dec. 19th, 2017 May 24th, 2019
List Price $425k / eye $2.1M
Sales• $27M (2018)
• $30M (through 3Q’19)• $346M (2H’19)
Peak Sales
Projection- • $2.5B (2025)
Approved and Late-Stage Clinical Assets
Source: DeciBio internal analysis
Indication Notes
• Hemophilia A (AAV5)
• Inserts FVIII gene
• BLA submitted to FDA Dec.
2019
• Bladder Cancer (ND)
• Inserts gene encoding for
IFN α-2b
• Positive Ph3 results with
priority review voucher
• Hemophilia B (AAV5)
• Inserts FIX gene
• All patients in Ph3 dosed as
of Mar. 2020
Approved Therapies Marquee Phase 3 Programs
Additional Phase 3 Programs
Leber’s hereditary optic neuropathy
Choroideremia
Hemophilia A
Hemophilia B
4
Additionally there is a significant amount of commercial activity, with >200 commercial programs
in the pipeline
Source: DeciBio internal analysis
5
DeciBio conducted primary and secondary research to provide an industry-level perspective on
top challenges and associated solutions in AAV gene therapies
Key Questions for Research
What are top CMC, development and production
challenges in AAV gene therapies?
How can we define and (where relevant) quantify
the impact of these challenges?
How might these challenges be addressed in the
near term?
What organizations, companies, and products are
involved?
6
We conducted 15 interviews with stakeholders across various functions and organization types
within the AAV space
Note: * Not an exhaustive list; showing organizations that interviewees work at in order to provide a sense of the diversity of perspectives, but recognizing that opinions are personal to
the interviewees and that interviewees are not speaking on behalf of their organizations nor expressing the views of their organization
Source: DeciBio Interviews
0%
20%
40%
60%
80%
100%
Organization Type Interviewee Function Interviewee Role
n = 15 n = 15 n = 15
Biopharma / Biotech
Other
CMO /
CDMO
Academic / Non-
Profit
Manager
Scientist /
Engineer
Director &
Above
Analytical
Process
CMC / Tech
Ops
Other / General
Interviewee Demographics (% Of Respondents)
7
Agenda
• Background
• Pain Points & Challenges
• Challenges Deep Dives & Solutions
• Concluding Thoughts
8
Top challenges discussed were related to lack of standardization and limited capacity
• Most challenges are related to the relative
nascency of the AAV space and those
created by rapid growth
• Overcoming these challenges could lead to
timeline and cost improvements to AAV
development and commercialization
Top-of-Mind Challenges Among Interviewees - Open-ended Responses* (n=15)
0% 20% 40% 60%
Limitations of current analyticalmethods
Shortage and cost of rawmaterials
Gaps in translating AAV biologyto process and manufacturing
Purification inefficiency andscalability
Lack of standardizationanalytical methods
Limited talent availability
Limited production capacity
Limitations with yield, scalability,potency
Lack of regulatory guidance /industry standards
% of Interviewees
Sta
nd
ard
izatio
n
Cap
acity
Incre
asin
g N
um
be
r o
f M
entio
ns
Note: * Displaying challenges mentioned by >20% of interviewees
Source: DeciBio Interviews and Analysis
This presentation will explore ideas around
possible solutions and opportunities
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Agenda
• Background
• Pain Points & Challenges
• Challenges Deep Dives & Solutions
o Limited Regulatory Guidance & Industry Standards
o Analytical Challenges
o Limited Production Capacity
o Talent Shortage
• Concluding Thoughts
10
Despite the existence of multiple guidance documents and workshops for the gene therapy
space to-date, interviewees noted that the regulatory framework is still a moving target
“… We have been using HEK293T cells, but recently, the
regulatory agencies seem to have been going back and
forth on their guidance on it …”
“… I’ve heard of people going to the agencies to argue for
use of GMP-sourced, IND-ready, or similar high-grade
non-GMP plasmids to presumably cut down on cost and
wait times. It’s a grey area right now …”
“… We’re always hoping for regulatory guidance on bridging
studies but it’s evaluated case by case. You stand
before the agency with a package, and there’s a chance
it’s deemed insufficient, forcing you to go back to the
drawing board and/or do costly bridging studies …”
“… There is limited or no historical regulatory guidance on
some product characteristics …”
Source: DeciBio Interviews, FDA Website
Established guidance would help streamline development
programs, costs, and timelines
Standardization Analytical Capacity Talent
11
Limited regulatory guidance is a chicken and egg problem that may be resolved over time,
but could be accelerated by increased data generation and sharing
Data Generated &
Shared
Revised Regulatory Guidance
Clinical or Commercial
Activity
Process / Technical Improvements
(e.g., via publications, conferences, various
organizations)
Long-term Near-term
Source: DeciBio Interviews and Analysis
Standardization Analytical Capacity Talent
12
“… It’s still relatively early in terms of the development of AAV gene therapies, and
everyone is still working to understand and optimize the process …”
“… As we gather more historical data, I think that these issues will be resolved
over the next 5 years. For example we’ve been doing extra work to understand
stability, and the data has started coming out recently …”
Relative nascency of
the AAV space and
continuous
innovation
Lack of incentives for
sharing innovation
outside of
company silos
A similar issue exists with the development of industry standards; additionally the competitive
nature of the field limits industry-level collaboration and sharing of best practices
Source: DeciBio Interviews
Barriers to Development of Industry Standards and Best Practices
“… Everyone is figuring out their own piece of the puzzle and optimizing their own
processes. Of course you can present the high level at conferences, but what
really matters is all in the details that are not shared …”
“… We all want to see the field succeed, but it’s difficult to do so in a pre-
competitive manner and there aren’t incentives in place …”
“… Getting first to market is so critical, so you have to prioritize getting your process
‘good enough’ to be viable and move your product across the finish line.
There’s not enough time to fully explore or understand the different aspects …”
Pressure to get to
market fast
disincentivizes
exploration
Standardization Analytical Capacity Talent
13
Select Organizations High Level Description Select Initiatives
StandardizationUSP
• Independent, not-for-profit,
nongovernmental pharmacopeia
• Best practices documentary standards
• Reference standards
NIH • National Institutes of Health• Gene therapy “toolbox" for the Therapeutics
for Rare and Neglected Diseases program
Tech innovationNIIMBL
• Public-private partnership with the goal
of advancing innovation in biopharma
manufacturing
• Technology roadmaps
• Technology and workforce development
projects
Bridging
research &
clinic
Odylia Therapeutics
• Pre-competitive consortium and
nonprofit accelerating the development
of gene therapies from lab to clinic
• Support across legal, administrative, clinical
trial, manufacturing, and regulatory
• Negotiated CMO rates and reserved slots
Catapult
• UK initiative to help CG&T organizations
globally translate early stage research
into commercially viable and investable
therapies
• Support across industrialization, regulatory,
clinical development, health economics and
market access
Cross-
stakeholder
collaboration
ARM
• International multi-stakeholder
advocacy organization
• Promotion of legislative, regulatory and
reimbursement initiatives
ASCGT
• Primary professional membership
organization for gene and cell therapy
• Promotion of communication / collaboration
between stakeholders
Multiple organizations are working to create frameworks for standardization and collaboration;
coordination could amplify the impact of these initiatives
Source: Organization Websites and Presentations
Standardization Analytical Capacity Talent
14
Top opportunities / Low
hanging fruitHigh impact, Low feasibility
Low need, high feasibilityUnnecessary
Interviewees perceived the top opportunities for standardization to be that of optimized
production and characterization protocols that could jump start future therapy development
Perceived Impact vs. Near-term Feasibility of Standardizing
of Various Components of AAV Development & Production
Note: *Considering a 3-year timeframe
Source: DeciBio Interviews
Legend: Vector generation
Process / Protocols
(Pre)clinical
Analytical
Plasmid sequences for optimized capsids
Cell lines & cell banks
Pharma/tox and preclinical testing protocols
Upstream protocols
Downstream protocols
Database of safety profiles matched to vector
information
GMP facility set-up options and requirements
Clinical trial protocols
Delivery protocols
Characterization assays and protocols
Library of CQAs
1.0
1.0
Imp
act o
n F
utu
re D
eve
lop
me
nt
Low
Hig
h
Low HighNear-term* FeasibilityLow High
Perceived to be too variable across
programs and indications to realize
benefits of standardization
Processes and protocols that are
sufficiently optimized could jump-start
future therapy development
High impact, but feasibility is limited by
lack of full process understanding for
CQAs and IP considerations for
optimized capsids and cell banks
Standardization Analytical Capacity Talent
15
Agenda
• Background
• Pain Points & Challenges
• Challenges Deep Dives & Solutions
o Limited Regulatory Guidance & Industry Standards
o Analytical Challenges
o Limited Production Capacity
o Talent Shortage
• Concluding Thoughts
16
“… Potency assays are particularly challenging for certain serotypes that don’t
transduce well in vitro, if you’re not looking for specific enzyme activity,
or if the reaction requires other substrates from the in vivo environment…”
Developing
effective potency
assays
Ability to properly
define & separate
heterogeneous
pools
Top analytical pain points and challenges were largely related to limitations of current methods
and validation and standardization (1 of 2)
Source: DeciBio Interviews
Analytical Challenges – Limitations of Current Methods
“… We don’t yet have good tools to pull apart the heterogeneous pool of AAV
particles and understanding what production conditions leads to this
heterogeneity …”
Amount of material
required for
release testing
“… Each batch needs to be released with full panel of testing, and in smaller
production runs, this could use up 40% of the batch …”
“… It’s difficult when you don’t have much material at the end of a run and have
to be really judicious in the studies you’re conducting …”
Standardization Analytical Capacity Talent
17
Comparability
between labs
Difficulties
with qualification
& validation
Defining Critical
Quality Attributes
(CQAs)
“… CQAs are a moving target, particularly when we’re still building our
knowledge of what matters - for example there’s been a lot of talk about
aggregates, and the jury’s still out on the impact of partials …”
“… Everyone’s using their own standards that may not be comparable.
Someone may report 1E13vg and if I do it in my lab, I get 5E12 …”
“… We’ve been working with a top CROs to qualify our assays to go into clinical,
but even assays that performed perfectly fine in our hands, don’t perform the
same in other labs. It’s been an on-going effort for the past year…”
“… As an academic core, we’ve made potency testing the responsibility of the PI
since it’s much too risky to try an import a method from a customer…”
“… For the mAb world a binding assay can work for all, but an AAV potency assay,
you’d need different assays for different constructs …”
Top analytical pain points and challenges were largely related to limitations of current methods
and validation and standardization (2 of 2)
Source: DeciBio Interviews
Analytical Challenges – Validation & Standardization
“… Qualification can take months when there are over 20 assays. Newer
technologies like NGS may also be tricky to interpret and validate …”
Standardization Analytical Capacity Talent
18
Tech for in-line / real-time analytical testing
Improved high-resolution separation techniques
Non-destructive analytical methods
Potency assays that are more physiologically
relevant
1
1
Considering impact and feasibility, interviewees identified in-line or real-time testing and
improved separation techniques as top near-term opportunities
Note: *Considering a 3-year timeframe
Source: DeciBio Interviews
Perceived Impact vs. Near-term Feasibility of Opportunities in Analytical Methods
Low High
Imp
act o
n F
utu
re D
eve
lop
me
nt
Low
Hig
h
Low HighNear-term* FeasibilityLow High
Top opportunities / Low
hanging fruitHigh impact, Low feasibility
Low need, High feasibilityUnnecessary
In-line and miniaturization are
considered more important than
non-destructive methods
Continuous improvements
such as on affinity resins
and ion exchange columns
are being made by key
vendors (e.g., Thermo, GE)
Some feasibility today (e.g.,
pH, viability) but could be
expanded; ideally could be
miniaturized to reduce
consumption of materials
Standardization Analytical Capacity Talent
Particularly impactful for therapies where
enzyme activity is not the desired result; organ
on a chip may play a role but has limitations in
terms of reproducibility and GMP-validation
19
Agenda
• Background
• Pain Points & Challenges
• Challenges Deep Dives & Solutions
o Limited Regulatory Guidance & Industry Standards
o Analytical Challenges
o Limited Production Capacity
o Talent Shortage
• Concluding Thoughts
20
0
10
20
30
40
50
60
70
80
90
100
2015 2016 2017 2018 2019 2020YTD
Phase 3
Phase 2/3
Phase 2
Phase 1/2
Phase 1
Considering the current and forecasted number cell and gene therapy programs in clinical trials,
demand for manufacturing capacity is expected to rapidly outpace supply beyond 2020
Forecasted No. of Ongoing Clinical Trials in CGT
Source: ClinicalTrials.gov, Analysis conducted in 2018 by Joe Rininger and colleagues at Latham Biopharm and published on BioProcess Intl
“… We anticipate that by 2020 we will be receiving more than 200 INDs per year… And by 2025, we predict that the FDA will be approving 10 to 20 cell and gene therapy products a year …”
- Statement from FDA Commissioner Scott Gottlieb, M.D.
and Director of CBER Peter Marks, M.D., Ph.D.,
Anticipated Commercial Activity
Total projected batches
- Assuming continued capacity increase every year in line
with past expansion
Clin
ica
l Activity
Co
mm
erc
ial A
ctivity
Commercialization of gene therapies in indications
with high disease prevalence will place increasing
strain on the capacity shortage, in the case that
production is outsourced to CDMOs
Standardization Analytical Capacity Talent
21
$0
$2
$4
$6
$8
2015 2020 2025E
First in Human Late Clinical
As a result, the cost and wait times for AAV production has grown in recent years (based on
anecdotal accounts) and may be further exacerbated by capacity needed for vaccine production
Source: DeciBio Interviews and Analysis
“… I’ve seen the supply-demand curve push the price to
produce first-in-human material up. The same proposal 5
years ago would now cost you 4x, on top of the wait
times at these top CDMOs …”
- Head of Gene & Cell Therapy, Pharma Consultancy
Estimated AAV Production Costs at CDMOs
(Per Batch, Anecdotal)
Costs of outsourcing production can become prohibitive
to small companies and (ultra)-rare disease indications
0
12
24
36
48
2015 2020 2025E
Estimated Wait Times for Production Slot
Anecdotal
“… Based on my recent experience, even trying to put in a
back-up slot at a CDMO in case there’s an issue with the
batch is a challenge, and we are a large company …”
- Scientist, Large Biopharma
Wait times of >18 months for a production slot can have
significant commercial and patient impact
$M
illio
ns
Mo
nth
s
??
?
Precise impact of COVID
vaccine manufacturing on
capacity is still to be determined
Variable depending on batch
size, additional involvement
with license application,
process validation, etc.
Future capacity availability can be
influenced by multiple factors (e.g.,
capacity expansion, increased
yield, potency, or durability)
Standardization Analytical Capacity Talent
22
Near-term workarounds necessitate the trade-offs between manufacturing options, while in the
long term, technical and platform improvements may lower demands on manufacturing capacity
Source: DeciBio Interviews and Analysis
Long-termMid-termNear-term
Balance Trade-offs Between
Manufacturing OptionsCapacity Expansion
Yield, Scale, Potency
Improvements
Cost
Capability
Capacity
Benefit
vs.
Risk
Technical Improvements
Process / Platform
Improvements
Standardization Analytical Capacity Talent
23
HIGH COST
Given the current capacity shortage, trade-offs must be made to secure manufacturing
Source: DeciBio Interviews and Analysis
Trade-Offs of Manufacturing Options
New entrants
(e.g., biologics
CDMOs)
Internal
Manufacturing
Academic Cores
Top
CDMOs
Incubators
Long-term
CDMO
agreements
LACK OF
CAPACITY(including intentionally
selective / small-scale
organizations)
LACK OF
EXPERIENCE(either perceived
or actual)
Standardization Analytical Capacity Talent
24
Both CDMOs and drug developers realize the benefits of capacity expansion, but there are key
drawbacks related to investing in a still relatively nascent space
Benefits Risks / Drawbacks
Note: * High-level estimates
Source: DeciBio Interviews and Analysis
Cost & Time to Build
and Qualify Suite
• ~$500M and up to 5 years to build
new facility*
• ~$10M and 1 year to retrofit or
repurpose an existing GMP suite*
Talent Shortage• Limited experienced personnel to
staff a facility; More advanced training
than is typical for biologics
Operational Agility &
Quality Control
Turnaround Time
• Benefits to having manufacturing, PD
and AD within one organization
• Full control and oversight over
transfer and day-to-day operations
• Reduce wait times for slots at leading
CDMOs
• Decrease time to market
Resilience from
Manufacturing
Disruption
• Limited reliance on available capacity
at external parties
Business
Opportunity
• Rapidly growing space with high
demand
Expected Facility
Usage & Business
Risk
• For CDMOs: Demand could drop due
to increased production efficiency or
failed programs
• For drug developers: Estimated
usage of a new facility (influenced by
# of programs, # of patients, expected
productivity, expected success of
programs) influence build decisions
For CDMOs – Capacity Expansion
For Drug Developers – Internal Capacity Build
Innovation in manufacturing set-up and operations
may be able to mitigate these risks & drawbacks
Standardization Analytical Capacity Talent
25
Although there is no “one-size-fits-all” solution to de-risking capacity expansion, near-term
approaches may include design of modular and highly efficient and repurpose-able facilities
Source: DeciBio Interviews and Analysis
Considerations
for SolutionsDescriptions Benefits & Drawbacks
Build
Time
Build
Cost
Day-
to-day
Labor
Bus.
Risk
Increasingly
Efficient &
Repurpose-able
Room Layouts
• Facilities can be utilized for
multiple processes / products
• Highly efficient space use for
cleanroom setup
+ Optimizes productivity per room / sq ft
- Strict oversight required for repurposing
and to prevent cross contamination
- Can be labor intensive to repurpose
D D U U
Modular Build
Facilities
• Plug-and-play modules are
built off-site and can be
installed for green and brown
field sites
• Autonomous cleanroom units
without interconnections
+ Lower build time allows decision to build
to be made when there is greater
visibility regarding market demand
+ Build modules off-site to add capacity
without disruption
- Potentially higher cost
D U
No
ChangeD
Standardized,
Pre-approved
Layouts
• Standardized operations,
layout, single use systems,
that can be used across
development and commercial
production
+ Standardization minimizes build and
process transfer time
+ Lowers qualification burden
+ Lowers time to on-board new operators
- Difficult to achieve given state of field
D U D D
Automation• High integration of physical
components
+ Lower personnel requirements
+ Increased productivity
- Difficult to attain in standardized manner
U U D D
Incre
asin
g N
ea
r-te
rm F
ea
sib
ility
Standardization Analytical Capacity Talent
26
Finally in the long term, technical, platform or process improvements may improve scale, yield,
potency, or quality in a way that can significantly alleviate capacity shortage
Source: DeciBio Interviews and Analysis
DownstreamVirus ProductionCell expansion & Transfection
Impro
vem
ents
Technical Improvements
• Adjusting plasmid or helper
virus ratios
• Codon modification /
optimization
• Alternative promoters
Process / Material
Improvements
• Improved transfection reagents
Cell lines
• Insect cell lines
• Producer cell lines or
packaging cell lines with
improved efficiency
Culture
• High density production tanks
• Perfusion culture
• Process / Material
Improvements
• Improved purification methods
(e.g., new resins, monolith
columns)
Impact • Yield
• Potency
• Quality
• Yield
• Scalability
• Quality
• Yield
• Quality
Standardization Analytical Capacity Talent
27
Agenda
• Background
• Pain Points & Challenges
• Challenges Deep Dives & Solutions
o Limited Regulatory Guidance & Industry Standards
o Analytical Challenges
o Limited Production Capacity
o Talent Shortage
• Concluding Thoughts
28
Talent Shortage is expected to gate the growth in number of facilities; Hands-on experience
working with viral vectors in a GMP environment is lacking
• Source: DeciBio Interviews
Interviewee Feedback on Talent Availability Challenges
Source: DeciBio Interviews and Analysis
“… There are too few people with the relevant industry experience of how to
make these therapies on a large scale. The manufacturing and CMC
side of things is so different from doing this at a research scale, at a vector
core or academic institution …”
Experience across
virology, CMC /
GMP, and industry
scale can be rare
Talent gap may
disproportionately
impact small biotech
and academia
“… Coming from the biologics space, oftentimes people have the operational
know-how. In development especially, it’s the theoretical virology
background that is lacking and can really make a difference …”
“… Few people have industry scale experience purifying viral vectors. Even
fewer are GMP trained …”
“… Outside of BTEC’s gene therapy manufacturing course, I haven’t heard of
another hands-on option being offered yet …”
“… I imagine that large biopharma companies may not experience talent
shortage to the same extent as small biotech. Academia may see even
greater challenges in retaining talent …”
“… Roles in the gene therapy space can be more lucrative than mAb or vaccines
at the director level and above, but I think it’s comparable at operator levels …”
Standardization Analytical Capacity Talent
29
Academia and the commercial biologics industry are common feeds for talent in the AAV gene
therapy space; Skill gaps are perceived to be greatest in process and analytical development,
coinciding with the greatest talent demand given that most programs are in early stages
Personnel Background
Academia
(e.g., virology lab)
Biologics Industry / Commercial
(e.g., mAb, vaccine)
Process
Development
Upstream Mod - limited experience with GMP best practices,
scale-up, manufacturing operations
Mod - limited understanding of virology and gene
therapy manufacturing best practicesDownstream
Analytical DevelopmentHigh - need to balance creativity with demands of
developing robust processesMod - some similarities to biologics
Manufacturing OperationsHigh - limited GMP and manufacturing scale
operational experience
Low - significant similarities given personnel are
experienced operating in GMP environment
Quality ControlLow - assuming straightforward takeover from
Analytical Development
Skills Gaps Upon Entry to AAV Space from Academia vs. Biologics Low HighPerceived Skills Gap:
Process Analytical
Source: DeciBio Interviews and Analysis
Solutions for bridging the talent gap include hands-on training programs for bioprocessing & CGT,
industry-academia collaborations, and internship or fellowship opportunities
Standardization Analytical Capacity Talent
30
Agenda
• Background
• Pain Points & Challenges
• Challenges Deep Dives & Solutions
• Concluding Thoughts
31
The AAV gene therapy space has enormous potential for growth and top challenges will no
doubt evolve over time
Source: DeciBio Interviews and Analysis
Top-of-Mind Challenges Across Interviewees
Current Challenges1
Creation of New Challenges2
• Challenges related to standardization, process
understanding, and technology limitations will likely
resolve over time as the space matures
• On the other hand, capacity issues may prove to be
a continuous game of catch-up, and can be
influenced by a multitude of factors
Incre
asin
g N
um
be
r o
f M
entio
ns
• New top challenges will no doubt be introduced as
the field shifts towards incorporation of novel
approaches, greater numbers of commercialized
products, programs focused on systemic
administration, and higher prevalence diseases
Sta
nd
ard
iza
tion
0% 20% 40% 60%
Limitations of current analyticalmethods
Shortage and cost of rawmaterials
Gaps in translating AAV biologyto process and manufacturing
Purification inefficiency andscalability
Lack of standardizationanalytical methods
Limited talent availability
Limited production capacity
Limitations with yield,scalability, potency
Lack of regulatory guidance /industry standards
% of Interviewees
Cap
acity