AAV Gene Therapies Industry Perspectives on Key Challenges · 2020. 12. 8. · market access...

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




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

9

Agenda

• Background



o Limited Regulatory Guidance & Industry Standards

o Analytical Challenges

o Limited Production Capacity

o Talent Shortage


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



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


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


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


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


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


15

Agenda

• Background






o Talent Shortage


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)


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 …”


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)


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 …”


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


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


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






o Talent Shortage


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


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


“… 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)


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


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


23

HIGH COST

Given the current capacity shortage, trade-offs must be made to secure manufacturing


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)


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


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


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


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


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


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


27

Agenda

• Background






o Talent Shortage


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


“… 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 …”


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


Solutions for bridging the talent gap include hands-on training programs for bioprocessing & CGT,

industry-academia collaborations, and internship or fellowship opportunities


30

Agenda

• Background




31

The AAV gene therapy space has enormous potential for growth and top challenges will no

doubt evolve over time


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

AAV Gene Therapies Industry Perspectives on Key Challenges · 2020. 12. 8. · market access...

Documents

Transcript of AAV Gene Therapies Industry Perspectives on Key Challenges · 2020. 12. 8. · market access...