Cell Therapy Expansion and Challenges in Autoimmune Disease

There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.

In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.

Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.

Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.

1. Health Advances and Parexel
Delivering on Autoimmune
Excitement Will Require Significant
Changes in Cell Therapy Delivery
Presented to
May 30, 2024

2. Health Advances and Parexel ISCT Presentation
May 30, 2024
2
Speaker Introductions
Jamie Pierson
Senior Project Leader, Parexel
•Cell and Gene Therapy Program Lead
•Expertise leading cross-functional teams globally to
deliver high-quality and patient-focused clinical trials and
help bring life-changing treatments to market faster
•Experience across multiple therapeutic areas with
specific interest in pediatric rare disease, neurology, and
oncology
Ned Wydysh, PhD
Vice President, Health Advances
•Co-Leader of the Health Advances Biopharma, Cell
and Gene Therapy, and Oncology Practice
•Expertise in portfolio planning, development, and
commercialization strategy across therapeutic
areas, with specific interest in oncology,
orphan/genetic diseases, CNS, and autoimmune
diseases
•Decision Resources, Analyst in Autoimmune and
Inflammatory Disease Group
•Johns Hopkins University, PhD, Chemistry
•Williams College, BA, Chemistry

3. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Cell therapy development has expanded beyond oncology in recent years as sponsors have
set sights on autoimmune indications.
Indication US Prevalence Select Manufacturers Developing Cell Therapies
SLE & Lupus
Nephritis
~250,000
Myasthenia Gravis ~50,000
Multiple Sclerosis ~900,000
Crohn’s Disease ~1MM
Type-1 Diabetes ~2MM
Rheumatoid
Arthritis
~1.3MM
Note: Not all cell therapies in development for autoimmune indications are CAR-Ts, but also include Tregs, MSCs, and other cell types.
Source: Health Advances analysis, Izmirly 2021 Arthritis Rheumatol, Wallin 2019 Neuro, Myasthenia.org, Xu 2018 J Clin Med, Lewis 2023 Gastro, CDC.
More
Mature
Less
Mature

4. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Autoimmune disorders with
any cell therapy in development*
~5MM
estimated US prevalence
Approved CAR-Ts
for oncology indications
~50,000
addressable
US patients
Autoimmune
disorders
with CAR-Ts in development
~1MM
estimated US prevalence
If these programs are successful, the number of patients eligible to receive cell therapies
could grow from tens of thousands to millions in the near future.
* Includes Type 1 Diabetes
Source: Health Advances analysis, Datamonitor, FDA, company websites.

5. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Delivering on the promise of gene-edited cell therapies for autoimmune disease will require
significant changes in how cell therapy is delivered.
New Manufacturing and Delivery Models
Manufacturing and administration must scale for larger populations
Improved Risk-Benefit Profiles
Cell therapies must meet a safety standard for chronic, non-fatal conditions
Widespread Market Access
Today’s CAR-T prices are a barrier to use in a far broader population
Addressing
Millions More
Autoimmune
Patients will
Require…

6. Health Advances and Parexel ISCT Presentation
May 30, 2024
6
Improved Risk-Benefit Profiles
Cell therapies must meet a safety standard for chronic, non-fatal conditions
Widespread Market Access
Today’s CAR-T prices are a barrier to use in a far broader population
Today, manufacturing and infrastructure bottlenecks limit the uptake of cell
therapies, challenges which will be magnified as indications for these treatments expand.
Delivery Models
Addressing
Millions More
Autoimmune
Patients will
Require…
New Manufacturing and Delivery Models
Manufacturing and administration must scale for larger populations

7. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Only a small fraction of eligible patients receive CAR-Ts today, due in part to
manufacturing capacity limitations for autologous cell therapies.
Addressable versus Treated Auto-T Patients
US, 2017-2023
Note: Addressable patients defined as drug-treated 2L+ DLBCL or 3L+ MM patients.
Source: Health Advances interviews and analysis, Datamonitor, GlobalData, Oribiotech, Medscape.
0
10,000
20,000
30,000
40,000
2017 2018 2019 2020 2021 2022 2023
US DLBCL and MM Patients
Addressable Patients
Auto-T Treated Patients
Currently only ~17%
of eligible patients
receiving auto-Ts
“We have a backlog of
myeloma patients who don’t
have access. We have only
4 manufacturing slots but
~50-60 eligible patients.”
– Dr. Nina Shah, UCSF
Delivery Models

8. Health Advances and Parexel ISCT Presentation
May 30, 2024
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While developers are investing in increased manufacturing capacity and
efficiency, incremental progress will still lag demand as CAR-Ts move to earlier lines.
Source: Health Advances analysis, Gliead company website.
~50% Reduction
Global
~25% Planned Reduction
Global
Kite
Acquisition
2023
2030
✓
✓
✓
Reduce Deviations
Internalize Vector
Reduce Scrap
✓
✓
✓
Increased Volumes
Procurement Efficiencies
Rapid Manufacturing
Automation
Increased Output
Operational Excellence
Cost Per
Therapy
Targeting biologics product gross margin of ~80% in the US by 2030
Delivering Consistent Manufacturing Improvements
Presentation to Investors, March 2024
Delivery Models

9. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Autologous cell therapy administration occurs at specialized transplant centers,
which are concentrated in urban centers and have limited capacity.
Source: Health Advances interviews and analysis, Leerink, HRSA, AHA.
Out of ~6100 US
hospitals…
…there are fewer than
200 HSC transplant
centers…
…of which only ~150
administer auto-Ts
Major US Auto-T Transplant Centers
Illustrative
“We foresee a shift to an infrastructure-
limited market... with a gap between supply
and demand of 2,000 doses per quarter by
2030.” – Leerink 2023
Delivery Models

10. Health Advances and Parexel ISCT Presentation
May 30, 2024
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New Manufacturing and Delivery Models
Manufacturing and administration must scale for larger populations
Widespread Market Access
Today’s CAR-T prices are a barrier to use in a far broader population
The successful expansion of cell therapies into autoimmune disease will require
establishment of an appropriately balanced risk-benefit profile.
Addressing
Millions More
Autoimmune
Patients will
Require…
Risk-Benefit
Profile
Improved Risk-Benefit Profiles
Cell therapies must meet a safety standard for chronic, non-fatal conditions

11. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Both auto- and allo-CAR-Ts in oncology carry the risk of serious complications
such as CRS, which is generally acceptable in this treatment setting.
Safety
Efficacy
Moderate CRS risk
Class-level black
box warning (T-cell
malignancies)
Efficacy
▪70+% response
rates
▪Relatively limited
durability to date
Auto CAR-Ts Allo CAR-Ts
Safety
Moderate CRS risk
Low GvHD risk
Elevated risk of
chrom. abnormalities
✓90+% durable
response rates
Source: Health Advances analysis, BiopharmaDive, ISCT.
Clinical Profile in Oncology
Illustrative
“Risks from CAR-T therapies should be contextualized against other
standard treatment modalities such as chemotherapy and radiotherapy.
These therapies have significantly higher rates of subsequent
malignancies.” – Dr. Bruce Levine, ISCT Past President
Risk-Benefit
Profile

12. Health Advances and Parexel ISCT Presentation
May 30, 2024
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While the safety risks of CAR-Ts may be acceptable in oncology, that will not be
the case in autoimmune disease.
Oncology
Autoimmune
Disease
Disease Severity Fatal Non-Fatal
Treatment Duration Acute Chronic
Risk of Alternative Treatments Higher Lower
Specialist Familiarity w/
Managing Toxicities
Higher Lower
Acceptability of
Lymphodepletion
Higher Lower
Amenable to Current CAR-T
Clinical Profile ✓ 
Source: Health Advances analysis, HCPLive, Shahzad 2021 Blood, Chan 2022 Biomedicines, McCallion 2023 Clin Exp Immuno.
“The risk tolerance in
oncology is better
because patients have
limited time, and
they're willing to take
these therapies. For
autoimmune
patients, that might
not necessarily be
the case.” – Tiffany
Chen, VP Discovery
@ GentiBio
Risk-Benefit
Profile

13. Health Advances and Parexel ISCT Presentation
May 30, 2024
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New Manufacturing and Delivery Models
Manufacturing and administration must scale for larger populations
Improved Risk-Benefit Profiles
Cell therapies must meet a safety standard for chronic, non-fatal conditions
Finally, the broader addressable patient populations in autoimmune diseases
could lead to large budget impacts and increased market access restrictions.
Addressing
Millions More
Autoimmune
Patients will
Require…
Market Access
Widespread Market Access
Today’s CAR-T prices are a barrier to use in a far broader population

14. Health Advances and Parexel ISCT Presentation
May 30, 2024
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In the US, high-priced transformative drugs can struggle to achieve broad
market access due to substantial budget impact on payers.
Market Access
Case Study: Curative Treatments for Hepatitis C
Source: Health Advances interviews and analysis, Henry 2018 J Health Biomed Law, Linas et al 2015 Ann Intern Med.
2013 2014
Sovaldi approved in US
•Improved efficacy, safety
over SOC (90+% cured)
•Favorable ICER
evaluation, even at annual
list price of $84,000
$6.5B USD
Total US Sovaldi budget impact in
2014, incl. $4.5B by Medicare
$310B USD
Theoretical cost to
treat all 3.7MM HCV
patients
$361B USD
Actual spend on all
drugs in 2014 by US
payers
Significant Access
Restrictions Due to
Budget Impact
•Outright coverage denial
•Aggressive prior authorization
•Specialist prescribers only
•Restricted use to liver fibrosis
population

15. Health Advances and Parexel ISCT Presentation
May 30, 2024
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The current price tag for auto-CAR-Ts – partly driven by high COGS – would be
unsustainable if used in large patient populations. Allo-CAR-Ts will face this same challenge.
$1
$10
$100
$1,000
$10,000
$100,000
$1,000,000
mAbs Auto CAR-TsAllo CAR-Ts
Cost per Dose (USD)
Cost of Manufacturing Per Dose
Across biologic modalities
Source: Health Advances interviews and analysis, Farid 2020 MABS, GEN News, Harrison 2019 Cytotherapy, Hernandez 2018 AJMC, Choe 2022 JAMA Network Open, Jenkins 2018 Biochem Eng J, company materials.
~$1,000
$95,000+
$5,000+
Market Access
$0
$100
$200
$300
$400
$500
$600
mAbs Auto CAR-Ts Allo CAR-Ts
Annual List Price (000’s USD)
Annual List Price per Patient
Across biologic modalities
$20K-$120K
$370K+
TBD; may approach
annual cost of auto-Ts
if redosing required

16. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Change will be required for either autologous or allogeneic products to become widely used
in autoimmune disease. Which of these changes occur – and to what extent – will determine
the dominant modality.
Auto-
CAR-Ts
Remain
Dominant
Allo-
CAR-Ts
Prevail
Long-
Term
Current
State
New
Logistical
Models
Sustainable
Pricing
Better
Safety Profiles

17. Health Advances and Parexel ISCT Presentation
May 30, 2024
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A future state where auto-Ts remain dominant will need new infrastructure and access
models, while allo-Ts must have improved duration of efficacy to prevail.
Auto-Ts to be Dominant Cell
Therapy Modality for Autoimmune
Allo-Ts to Prevail over Auto-Ts in
Long-Term
Evolution required for…
Investment in treatment infrastructure,
via expansion of existing CAR-T sites
and/or establishment of dedicated
outpatient centers
Risk sharing between sponsors
and payers (e.g., outcomes-based
agreements) to reduce budget impact
More durable efficacy,
highly favorable safety
profile to overcome the
current shortcomings of
allo-Ts in hematologic
malignancies
For both classes: Improved manufacturing efficiency to limit the
budget impact for payers and improve access for patients

18. Health Advances and Parexel ISCT Presentation
May 30, 2024
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Cell therapy sponsors must start early to ensure their development, manufacturing, access,
and regulatory plans align with the different stakeholder needs for autoimmune therapies.
Keys to Success for Autoimmune Cell Therapy Sponsors
✓Efficacious and safe
✓Broad access across care settings
Patients ✓Sufficient treatment infrastructure
✓Appropriate time-to-treatment
Providers
✓Capture all key clinical outcomes
✓Compelling health economic rationale
Payers ✓Acceptable study design
✓Certified manufacturing facilities
Regulators
Early Clinical Development
Late Clinical
Development
Market Entry

19. Health Advances and Parexel ISCT Presentation
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