Magda Papadaki PhD, former Head of Manufacturing & Innovation, Association of the British Pharmaceutical Industry (ABPI) and current Associate Director, MSD shares her recent presentation at London's Cell & Gene Therapy Congress 2018, “Business Transformation and Partnering Strategies to Accelerate Commercialisation of Cell & Gene Therapies.” The presentation includes key information and insights into: - New Pathways to CGT commercialisation and clinical use - System Readiness: New Pathways & Collaborations - Innovating how we Innovate to Deliver Cures. More information about the 2019 Cell & Gene Therapy Congress can be found here: www.celltherapy-congress.com

1. BUSINESS TRANSFORMATION AND
PARTNERING STRATEGIES TO
ACCELERATE COMMERCIALISATION
OF CELL & GENE THERAPIES
Magda Papadaki, PhD
magda.papadaki@gmail.com
4rth Annual CGT Conference
London, 25&26 Oct 2018

2. Cell and Gene Therapy Products
M.Papadaki - October 2018 2
Unlike Small and Large Molecule drugs, there are no ‘Products’,
but distinct ‘pathways to treatment’ design and delivery
3 Main categories
Plasmid
Delivery vehicle
(e.g. lentivirus, AAV)
Donor
Cells
1. Ex vivo, autologous
CGT product
2. Ex vivo, allogeneic
CGT product
Transduction
Transduction
Cell
Transfection
3. Gene therapy
product
CAR-T product
Gene of
interest
Patient’s own
Cells

3. CGTs State of the market - 2018
■ EU: 500 clinical trials using ATMPs
~ 270 ATMP classifications
~ 250 scientific advice requests
■ EU: 20 MAAs reviewed;
11 approved (3 withdrawn; 1 Suspended )
– ChondroCelect (TiGEnix)
– Glybera (UniQure)
– MACI (Genzyme)
– Provenge (Dendreon)
– Holoclar (Chiesi)
– Imlygic (AMGEN)
– Strimvelis (GSK, San Raffaele)
– Zalmoxis (MolMed)
– Spherox (Co.DON)
– Kymriah (Novartis)
– Yescarta (KITE/Gilead)
M.Papadaki - October 2018 3
■ US – picking up speed
– First 2 CAR-T Therapies approved
– First GT for blindness – (Luxturna, SPARK)
▪ U.S. FDA RMAT Designations:
⁻ Asterias’s AST-OPC1 (spinal cord injury)
⁻ Athersys’s MultiStem (ischemic stroke)
⁻ bluebird bio’s LentiGlobin (sickle cell)
⁻ Cellvation’s CEVA101 (brain injury)
⁻ Humacyte’s Humacyl (hemodialysis)
⁻ Enzyvant’s RVT-802 (DiGeorge
syndrome)
⁻ jCyte’s jCell (retinitis pigmentosa)
⁻ Juno’s JCAR017 (r/r aggressive LBC-NHL)
⁻ Kiadis’s ATIR101 (leukemia)
⁻ Mallinckrodt’s Stratagraft
⁻ Mesoblast’s MPC-150-IM (heart failure)
⁻ Vericel’s ixmyelocel (cardiomyopathy)

4. CAR-Ts: coming of age
M.Papadaki - October 2018 4
ARM, SOTI 2018
■ Unprecedented speed through to CTs and regulatory assessment
■ Unprecedented pace of approval timelines:Aug 2012:
UPenn &
Novartis
Alliance
Dec 2013:
study of 59pts
completed
July 2014:
CTL019 gets
FDA- BD
Dec 2015:
PhII data with
93% CR in
paed BC-ALL
Aug 2017:
FDA firsts
CAR-T
approval
Dec 2014:
IND FDA
application for
Ph I/II
Dec 2015:
gets FDA- BD
for aggressive
NHL
March 2016:
Completes
FDA BLA for
new CAR-T
Oct 2017:
FDA
approval

5. From miracles to a new industry
▪ >1000 products in clinical development
▪ 40 new CGT products expected to launch by 2020
▪ Indications getting crowded: diabetes, oncology, rare:
haemophilia, immunodeficiencies, neurological, other metabolic)
5
M.Papadaki - October 2018
Rare/ultra-rare: Haemophilia,
ADA-SCID, Thalassemia, Sickle Cell
Adoptive T-cell therapies for EBV/CMV,
MSCs for GVHD, CD133+ in cardiac regeneration,
T1-Diabetes, spinal cord injuries, Immuno-oncology

6. 6.2 4.4 2.9
9.8
6.6
4.4
Gene Therapies T-Cell Immunotherapy Non-Oncology Cell
Therapies
2025 Market Sizes, Base and Upper
Product Pricing Ranges
Base Estimate Upper Adjustment
11.8 11.7 7.8
18.7
17.7
11.9
Gene Therapies T-Cell Immunotherapy Non-Oncology Cell
Therapies
2030 Market Sizes, Base and Upper
Product Pricing Ranges
Base Estimate Upper Adjustment
M.Papadaki - October 2018
6
The size of the prize
The global C&G Therapy market forecast
ABPI & PWC market analysis, October 2016
Note: All values calculated in US Dollars, with 5 year average rate used to account for current volatility (1.5 USD: 1 GBP), sum totals rounded to nearest 1bn.
Number of products in the non-oncology cell therapies segment is not shown due to a top-down methodology approach base on overall market rather than individual products
Total: $14bn to $21bn = £9bn to £14bn Total: $31bn to $48bn = £21bn to £32bn
Number of products in each segment
Gene Therapies: 21 T-Cell Immunotherapies: 19
Non-oncology Cell Therapies:
n/a

7. CLINIC
Order  Collection
Leukapheresis
CLINIC
Patient
Scheduling
Reinventing Drug Manufacturing and Supply:
The example of autologous CAR-Ts
M.Papadaki - October 2018 7
MANUFACTURING FACILITY
Cell Processing
and Storage
(Selection, Activation,
Transduction, Expansion)
TRANSPORT TRANSPORT
Distribution
Center
A D Kaiser, et al. Towards a commercial process for the manufacture of genetically modified T cells for therapy. Cancer Gene Therapy (2015)
■ Demand on the rise:
➢ Kymriah: B cell ALL: 20% of 650 or 3000 new pts /pa (UK/US)
■ Supply shortages
➢ Centralized Manufacturing:
■ U Penn, CHOP: only 5 patients/month
■ Seattle Children’s Hospital: 10 batches a month
■ Triage plans in place: sickest patients first
➢ Private Investment: $43m Novartis plant in N. Jersey and
proprietary cell freezing technology
➢ Defining scope and specifications for Centres of Excellence

8. NEW PATHWAYS TO CGT
COMMERCIALIZATION
AND CLINICAL USE

9. The standard R&D model is NOT
fit-for-purpose
■ E2E barriers to product assessment
■ Need for continued monitoring /evidence generation
■ Lack of skilled human capital & cross-disciplinary talent pool
9
CMC
Clinical
assessment
Change in trial
design and
infrastructure
▪ Small Patient
cohorts –
statistical
nightmare
▪ Long-term
efficacy and
Safety
Regulatory
Market Access &
Clinical adoption
High upfront
costs
▪ Technologies still
lacking
▪ Infrastructure
redesign
▪ Standardization
▪ Industrialization
Unavailability of
evidence at the
time of filing:
▪ Need for
frequent re-
assessment
▪ Multiple
sources of data
for long term
clinical B/R
Long-term effects
raise value-based
pricing
▪ Budget Impact
▪ Affordability
▪ Use of RWE
▪ Not capturing
health system
benefits
▪ New pricing
Schemes
Research &
Discovery
Moving
Goalpost
▪ Now @4rth
generation
designs
▪ Vectors
▪ Molecular
Switches

10. Can we make them? Process is the Product
Improving reliability
1. Use of closed systems
2. Control of input cell
material
3. Standardization of
consumables
Process Simplification /
Automation
1. Integrated and closed
system platforms
2. Sampling and IPCs
3. Batch recording capability
Scalability & Cost-
Effectiveness:
1. Production lines in
centralized vs multi-sites
2. Point-of-care device
manufacturing
3. Universal Cell-Therapies
Regulatory Challenges
1. CQAs still unknown
2. Material standardisation
3. Volume limitations
4. Global harmonization
• The lack of bespoke technologies and automation solutions is a huge driver of COGs
• Need for early and continued engagement of scientists/manufacturers and regulators
Each patient batch essentially corresponding to a different product

11. Fachbereich
Facility and Supply Chain Design:
Looking for the Pareto optimum
M.Papadaki - October 2018 11
MAH
Central
cGMP
site
Clinical
site
1. CURRENT
DRUG
PRODUCTION
MODEL
- Limitations:
Scale and shelf-
life
- MIA/IMP & QP
assigned to site
(MAH or CMO
owned)
Mfr
site
Mfr
site
Mfr
site
Clinical
site
Clinical
site
Clinical
site
Clinical
site
Mfr
site
MAH /
Sponsor
2. DECENTRALIZED
ALTERNATIVE: Scale-out to
Multiple sites
- Role of Central Site?
- Requirements for QPs and
MIA/IMP?
Central
Site?
Automated
Manufacturing
in Clinical Site
MAH /
Sponsor
3. OPTIMAL FUTURE SCENARIO:
• MAH/Sponsor provides clinical site with
- validated automated equipment
- standardised materials
- Skills and personnel training
• Sites without MIA/IMP
• Major revisions to current legislation
Automated
Manufacturing
in Clinical Site
Automated
Manufacturing
in Clinical Site
Automated
Manufacturing
in Clinical Site

12. New costing and business models
M.Papadaki - October 2018 12
Treatment areas
Patient monitoring
and recruitment
Transport Tracking
Manufacturing: Flexibility
Reproducibility, scalability
New technologies, GMP,
Change management
storage
Approved
treatment delivery
Clinical trial
portfolio
Agreed Coverage
& Price
The CGT Value Chain is NON SILOED AND NON LINEAR
Business viability and readiness to launch needs prospectively planned strategies
to target the cost inflection points from development through to reimbursement

13. New clinical manufacturing
& in-market supply challenges
M.Papadaki - October 2018 13
Manufacturing Innovation Strategy
- Technical Innovation
- Process development
and economics
- Patient scale and
throughput
- Lifecycle process
management
- Acceptable QC limits
and PACM
Clinical plan and supply
₋ Capacity planning
₋ Manufacturing pilots
(central vs hospital)
₋ Producing for new
types of CT (adaptive)
₋ Managing risk:
Expected vs observed
outputs (ie. CQA)
Market supply and ATMP
Portfolio Management
- Demand prediction
- Optimal batch lifespan
- Supply chain risk points
- Manufacturing
adaptations
- Attainable cost/level of
flexibility
Portfolio SelectionCapacity Planning Production Scheduling
Production economies and Institutional / Clinical readiness need adaptation strategies:
1. Highly patient centric supply
2. Activity based costing & scheduling models

14. Global Regulation of ATMPs in flux:
Ongoing Quality and Licensure updates
■ AT-IMP Guideline - drafting ongoing
■ S&E follow-up / Risk Management
Plan guideline – Revision ongoing
■ Comparability of ATMPs (Q&A) –
ongoing
■ Revised GM Cell Guideline
■ GMP for ATMP –published in
November 2017
■ GLP application through
development – EMA clarification
■ Q&A for minimally manipulated
ATMPs - published
M.Papadaki - October 2018 14
■ New regulatory framework/RMAT
designation
■ Anticipated FDA disease-specific gene
therapy guidances
■ Updated guidances re CMC,
manufacturing
■ Sakigake (Forerunner Initiative)
■ First launch to be in Japan
■ Expedited Approval for ATMPs
(CT & GT)

15. M.Papadaki - October 2018 15
➢Priced at 900K euro once- Germany
➢$100m in development
➢Turned down by CHMP (x4)
➢Time and cost waste: 2yrs and Amsterdam
Therapeutics bankruptcy
Reimbursement, Access and Pricing
➢ 594,000 euros (once?)- money-back guarantee,
staggered payments (AIFA)
➢ Offered only in Milan – EU patients travelling
➢ 15 eligible pts/pa/across EU
➢ SOC: Cost of a donor BMT up to 1 million Euro
➢ Life-long enzyme injections cost 250kE pa
CAR-Ts
Kymryah (>25yrs) at $475K/pp
Yescarta (adults) $373k/pp
* Plus hospitalization and other costs
** 1 month outcomes-based pricing
YES from NICE (£45K per QUALY)
No from NICE (approx. £140k per QUALY)

16. SYSTEM
READINESS:
NEW PATHWAYS &
COLLABORATIONS

17. REGULATORY INNOVATION
Regulators have opened several regulatory
opportunities to evaluate assets in more timely /
iterative manner:
➢ UK with EAMS and AAR
➢ EMA:
– Tools: Accelerated Assessment, Conditional
Marketing Authorization, Compassionate Use
– Novel Development concepts: Adaptive
pathways, for gradual indication expansion
and increasing use of real-world evidence
– EMA-EUNetHTA 3-year plan on joint
assessment focusing on ATMPs
M.Papadaki - October 2018 17
ATMPS: 3/6 in Adaptive
Pathways Pilot Phase 2
➢ 121 applications received >
35 were ATMPs (29%).
➢ 28 PRIME granted > 13
were for ATMPs (46%):
- 12 are GTMPs, 1 CTMP
- 7 Oncology, 4
Haematology,
- 1 Transplantation, 1
Neurology
REGULATION 1394/2007/EC
Legal definition: Not traditional transfusion or transplantation: cells
either manipulated or intended for non-homologous use

18. HG Eichler et al., Clin Pharmacol & Ther, March 2015
LIFECYCLE MANAGEMENT:
Changing the paradigm of treatment evaluation
M.Papadaki - October 2018 18
LIFECYCLE APPROACHTRADITIONAL APPROACH
Key AIM
Focus on Licencing approval Focus on Patient Access, at the outset
Process
Single gated licencing decision Life cycle management approach
Methods
RCTs are the main assessment tool
Use of a much broader Toolkit: biomarkers,
surrogates and health databases.
Penetrance
Aiming at Broad Populations Aiming at Targeted Populations
Access
Goal is Open product utilization Controlled access is essential
Assessment
Main regulatory/reimbursement strategy is
via B/R Prediction
Main regulatory/reimbursement strategy is
via B/R Monitoring
Adaptive approaches allow earlier access in B/R optimized populations, under requirements for
progressive evidence accumulation and stakeholder interaction, across a product’s lifecycle.

19. M.Papadaki - October 2018 19
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/10/WC500237029.pdf
CLINICAL AND
MA ROUTES
FOR ATMPS
Papadaki, M. Adaptation through Collaboration: Developing Novel Platforms
to Advance the Delivery of ATMPs to Patients, Frontiers in Medicine, 2017

20. Plug and Play
20
Utilizing and integrating within the emerging CoEs and Hospital/Clinical environments for
ATMP development, translation and commercialization helps companies secure access to
patients, experts and facilities
These combine several interacting units:
Clinical Centres of Excellence
(Oncology, rare diseases, Autoimmune, CNS, etc)
R&D Units
- Preclinical work
- Development
- Analytical labs
Cell production and
CQ Units
- Cell Preparation
- GMP Processing
- QC facility
- BioBanking
Clinical Evaluation
and Regulatory
Advise
- Patient / Donor
registries
- HE / HTA evidence

21. INNOVATING HOW
WE INNOVATE
TO DELIVER CURES

22. M.Papadaki - October 2018 22
PartnershipsAnd collaborationsa prerequisite forsuccess
New Industry Partnerships
Example, Celgene acquired Juno Therapeutics pipeline of CAR-Ts and TCRS,
and equally GSK span out rare disease units to Orchard Therapeutics.
Focused Diversification
The opportunity to pivot and apply a platform to different therapeutic areas
can help mitigate risk and expand a platform’s commercial potential.
Multi-stakeholder collaboration
Broader collaboration between developers, academic and clinical centers,
patient advocacy groups, payers, and regulators.
Change the external environment and max financing/capital opportunities.
Targeting Innovation Hubs
Link with CGT centers of excellence, through partnerships between
manufacturers, academics, suppliers and health systems
(UK ATTCs, Milan, Berlin, Boston, SF).
1. Business Diversification And Externalization

23. 2. OPERATIONS: Integrated
CGT Product Planning Strategies
1. Improving manufacturing Infrastructure:
▪ Standardization, scalability and productivity
▪ Facility design (patient-side vs centralised)
2. Process Improvement - Impact of expected demand:
▪ More flexible production planning
▪ Impact on selected production mode
3. Accelerated/ Adaptive assessment strategies (Regulatory
and Clinical)
▪ Adaptive pathways / PRIME, EAMS
▪ Small, single-arm, screening-aided clinical trials
4. Early reimbursement consideration and discussions:
▪ Acceptance of long-term B/R evidence on a rolling basis
▪ Value-based pricing and control of patient access
▪ Use of novel payment, risk-sharing schemes (Annuity, pay
for performance, lifetime leasing)
M.Papadaki - October 2018 23

24. 3. HEALTHCARE REFORM:
Preparing Global Health systems
Progressing emerging Adaptive policies and guidelines
Developing new ways of assessing and rewarding innovation, allowing
gradual build-up of evidence and risk-sharing schemes.
Developing specialized clinical trial and administration centers and
services, to address the customization needs & costs and propel use.
Developing real world data systems and policies to address evidence
requirements and build B/R knowledge.
Early and sustained interactions between all healthcare stakeholders, as
well as patients, are paramount to start developing shared knowledge and
align the decision making processes.
Securing development and adoption success for novel treatments I
s as much about the scientific and clinical challenges,
as it is about the readiness of global health-systems and stakeholders.
M.Papadaki - October 2018 24

25. M.Papadaki - October 2018 25
THANK YOU
Magda Papadaki, PhD
Magda.Papadaki@gmail.com