A Majority-Owned Subsidiary of Fortress Biotech
May 2025
Robust Global IP Portfolio
Targeting $13B Global Cell
Therapy Market
7
In Vitro & In Vivo Proof of
Concept Established in
Multiple Cell Types
2
Clinical Development in Rare
Pediatric Disease & Other
Inflammatory Conditions
6
Results in Proprietary (Off-
the-Shelf) Cell Types with
COGS Reduced by Up to 75%
5
Enhanced Potency Based on
Established Matrices (↑PGO,
↑IDO, ↓TNFα, ↓Tcells)
3
Ability to Use 2-5X Fewer
Cells Than Conventional
(Clinical) Doses
4
Investment Highlights
Novel Bioreactor for Enhancing
Potency of Cellular Therapies
1
Overview
Novel Cellular Therapeutics for Inflammatory Conditions
• Based on Research from University of Texas Health Science Center (Houston)
CEVA-D (Mechano-Transduction Device)
• Shear Stress Up-Regulates Anti-Inflammatory Gene Programs
o Ability to use fewer, more potent cells for any cell therapy
o Substantially reduces COGS (vs. conventional MSCs)
• Proof of Concept Completed In Vitro, In Vivo
o Tested with Adipose, Amniotic Fluid, Bone Marrow
o Mechano-Transduced Cells More Effective at Lower Dose
CEVA101 (Next Gen Cell Product)
• “Off-the-Shelf” Mechano-Transduced MSCs
• Upregulated Anti-Inflammatory Gene Programs
o More Effective @ Substantially Lower Dose
• Initial Indication(s): rGVHD, Crohn’s, ARDS, CHF
Global Stem
Cell Market
Global Stem Cell Therapy Market
Estimated at $11B in 2022,
Expected to Reach $31.5B by 2030
Pharma with Increased Interest In
Stem Cell Therapy Based on
Number and Size of Biotech Deals
Expanding Clinical Applications in
Cardiac, Neurological and
Autoimmune Disorders
Increased Adoption, Growing
Investment in R&D, Favorable
(Global) Regulatory Environment
Development Pipeline
CEVA-101 (Mechano-Transduced Cells) Pre-Clinical Phase 1 Phase 2 Phase 3 Market
Potential
Steroid
-Refractory Pediatric Graft Versus
Host Disease
$2.7B Global
Market in 2023
Crohn’s Disease
$10B Global
Market in 2023
Acute Respiratory Distress Syndrome
$3B Global
Market in 2023
Congestive Heart Failure
Chronic Low Back Pain
Other Inflammatory Conditions
$7B Global
Market in 2023
$10B Global
Market in 2023
>$5B Potential
CEVA-D: Enhanced Potency
Reduces COGS
Enhanced potency based on established matrix
o PGE2 production
o IDO production
o TNFα suppression
o T cell proliferation suppression
Increased potency translates into
o Decreased COGS based on lower dosing requirements
o Potential to expand into other indications
Dosing of MSCs typically in the 2-10 million cells / kilogram range
Data generated to-date demonstrates a 2-5X dose reduction
o Using potency assays of PGE2 production and/or TFNα suppression
COGS of ~US$20,000 per billion cells (or 10M cells per kilogram for 100 kilograms)
o Based on estimated cost of cells from major supplier (Rooster Bio)
o COGS could conservatively be reduced to $4,000 per dose
Children with steroid-refractory acute graft versus host disease (SR-aGVHD)
Treatment Options
o Corticosteroids are first-line therapy for aGVHD
o Only one approved treatment for disease refractory to steroids
o No approved treatment in the US for children under 12 years old
Burden of Illness
o Acute GVHD is a life-threatening complication
o Occurs in ~50% of patients receiving allogeneic bone marrow transplants (BMTs)
o Acute GVHD primarily affects skin, GI tract, and liver
o Steroid-refractory aGVHD is associated with mortality rates as high as 90%
o Significant costs associated with extended hospital stays
Market Opportunity
o More than 30,000 allogeneic BMTs performed globally (>20K US/EU) annually, ~20% pediatric
o >4,000 allogeneic BMTs in children and adolescents in US
o >5,000 allogeneic BMTs in children and adolescents in China
CEVA-101: Proprietary Cell Product
Initial Indication: Refractory Pediatric Acute GvHD
Initial Clinical Design
Inclusion Criteria
o Male and female, ages of 2 months and 17 years
o Confirmed aGVHD following BMT
o Failed to respond to treatment with systemic corticosteroid therapy
o Grades C and D aGVHD involving the skin, liver and/or gastrointestinal (GI) tract OR
o Grade B aGVHD involving the liver and/or GI tract, with or without concomitant skin disease
Number of Patients & Design
o Single Arm (Open Label) Trial in ~20 patients
o Initial Therapy: IV CEVA-101 at dose TBD twice per week, for each of four consecutive weeks
o Continued Therapy: eligible participants to receive add’l once per week infusion for four weeks
▪ Twice per week for four consecutive weeks if aGVHD persists or flares
Endpoints
o Primary Outcome: Overall Response Rate 28 Days after Initiation of Therapy
▪ Complete Response: resolution of aGVHD in all organs
▪ Partial Response: organ improvement of at least one stage w/o worsening of other organs
o Secondary Outcome: Overall Survival at Day 100
CEVA-101: Proprietary Cell Product
Initial Indication: Refractory Pediatric Acute GvHD (cont.)
Proprietary Bioreactor and Novel Cells
Key Data & Technical Details
CEVA-D & CEVA101: Key Publication
Wall Shear Stress (WSS) Stimulates Anti-Inflammatory Mediators
• Promotes Signaling To Suppress TNF-α
• Improves Therapeutic Efficacy of MSCs in Rat Model of TBI
Create a biological enhancement during the manufacturing process
Stem cells start out in embryologic aorta-gonad-mesonephros
Subjected to shear stress that up-regulates specific gene programs
Concept observed for HSCs in Daly Lab
CEVA-D: Rationale
CEVA-D: Conditioned Cells More
Effective @ Lower Dose (published)
% TNF
-α Production
% TNF
-α Production
A Suppression of TNF- α B Dosing for Equivalence of TNF- α Suppression
CEVA-D: Increases PGE
2
Production
3x Increase in PGE
2
Production
• Cells treated for three hours in CEVA-D bioreactor
• PGE
2
: established marker for MSCs efficacy
CEVA-D: Increases PGE
2
and IDO Production
Importance of PGE
2
Expression
Genetically engineered MSCs expressing PGE
2
better suppress microglial M1 polarization
MAPCs suppress GVHD via PGE2 synthesis (Highfill et al, Blood 2009)
0
1
2
3
4
5
6
7
8
9
Ipsilateral Contralateral
Percent CD86+ microglia
Sham
CCI
hAF19
hAF19 EGFP
hAF19 COX2
0
200
400
600
800
1000
1200
PGE2 (pg/ml)
PGE2 (pg/ml)
hAF19
hAF19 EGFP
hAF19 COX2
PGE2 Production M1-type microglia
p=0.05
*
**
Kota et al. (2017) Stem Cells 35:1416-1430
CEVA-101 vs. Static MSC
Data derived using cGMP compliant WJ-derived MSCs
CEVA-D Cells: Potency
RNA-Seq Demonstrates Enhanced Potency of CEVA101 Versus Static Cells
• Log-fold increases in key anti-inflammatory signals
• Confirms published pre-clinical data with cGMP compliant cell line
*PTSG2 is COX2
**TNFAIP8 isTSG6
CEVA-D Cells: Characterization
Sample CD34 CD73 CD90 CD105 CD146
hBM-MSC 5204
(Research Grade
Control) [p3]
0.17 99.99 99.93 99.08 100
RoosterBio hBM-
MSC (GMP Grade
Control) [p4]
0.06 100 99.89 99.72 99.86
RoosterBio hBM-
MSC (CEVA-101)
[p4]
0.11 99.93 99.79 99.58 99.89
Consistent Expression of Key Cell Surface Markers After Mechano-Transduction
o Repeated passages & differentiation often reduce anti-inflammatory potency
CEVA-D: Sterility & Quality Control
Viability
▻ Release Criteria: >70.0%
▻ Lot Average: 90.80%
Endotoxin Testing
▻ Release Criteria: <5.00 EU/mL
▻ Lot Average: <1.00EU
14 Day Sterility Culture
▻ Release Criteria: Negative
▻ Lot Average: Negative
Viable Cell Yield
▻ Release Criteria: >80.0%
CEVA-D: Biology of Mechano-Transduced Cells
Enhanced anti-inflammatory activity (Potency)
o Broad set of gene programs up-regulated
o Gain and loss of function of PGE2 confirms importance
MSC Source Agnostic
Reproduced under cGMP conditions, release
Potency assays linked to outcomes in in vivo models
CEVA-D: Development Status
and Intellectual Property
2D Device: functioning with defined manufacturing process
3D Device: in prototype development phase
All devices and methods backed by robust IP protection
o Methods & Apparatus for Conditioning Cell Populations
o Issued / Allowed: Australia, China, Japan, Russia, US
o Pending: Brazil, Canada, EP, Hong Kong, Israel, Korea
o Earliest Expiration Date: 06/23/2036
o Broadest Claim: An apparatus comprising: an inlet fluid feed plate; a base plate; and a plurality of intermediate plates positioned
between the inlet fluid feed plate and the base plate, wherein each of the plurality of intermediate plates comprises: a first end, a
second end, a first side, and a second side; a distribution channel proximal to the first end; and a gathering channel proximal to the
second end, wherein: the distribution channel extends between the first side and the second side of the intermediate plate; and the
gathering channel extends between the first side and the second side of the intermediate plate.
CEVA-D: Scale Up
Production of Single Dose (CEVA101)
Channel Dimensions: 7.50 x 8.00 x 0.04 cm
o ~⅕ Clinical-scale
o Seeding Density: 60k MSC / cm
2
All parts designed for injection molding
CEVA-D: Manufacturing Work-Flow
CEVA-D: Production Model
Quick Connects
Run 8X per pump
50 million cells @ 25k/cm
2
45 x 10 cm size
CEVA-D: Flow Loop
CEVA-D: Conditioning Schedule
Conditioning Schedule
o Fibronectin Coating: 12 hours
▪ 10 ug/mL
o Seeding: 4 hours
▪ Can optimize for chosen cell line
o Incubation: 15 hours
o Flow Loop: 3 hours
o TrypLE Harvest: 15 minutes
CEVA-D: Process for 2D Production
Injection molding of casing
Laser cutting of plates
Laser welding
Cleaning
Sterilization (gamma, EtO)
Packaging
CEVA-D: 3D Scale-Up
Rather than keeping cells still and moving fluid (2D), the opposite is done for 3D
3D cannot be accomplished with stirrer tank as beads and cells move with fluid
Strategy based on use of magnetic beads with pulsatile current
o Produces cell movement through the fluid
o Generates shear stress in large-volume bioreactor
No moving parts
No cleaning or disinfection (simply discard canister after use)
Programmable shear profiles
CEVA-D: 3D Process Rendering
Magnetic beads (depicted in green) are coated with cells
Spiral current (see blue arrows) creates magnetic field
Magnetic field accelerates movement of beads and produces shear stress
Robust Global IP Portfolio
Targeting $13B Global Cell
Therapy Market
7
In Vitro & In Vivo Proof of
Concept Established in
Multiple Cell Types
2
Clinical Development in Rare
Pediatric Disease & Other
Inflammatory Conditions
6
Results in Proprietary (Off-
the-Shelf) Cell Types with
COGS Reduced by Up to 75%
5
Enhanced Potency Based on
Established Matrices (↑PGO,
↑IDO, ↓TNFα, ↓Tcells)
3
Ability to Use 2-5X Fewer
Cells Than Conventional
(Clinical) Doses
4
Investment Highlights
Novel Bioreactor for Enhancing
Potency of Cellular Therapies
1
