1. Chiesi’s commitment to limbal stem cell deficiency (LSCD) and future directions

2. Chiesi: our values RELIABLE COMPANY FOCUS ON PEOPLE FOCUS ON CUSTOMERS
Ethics
Transparent
Listening
Development
FOCUS ON CUSTOMERS
TEAM SPIRIT
Excellence
Devotion
Cohesion
Collaboration
VALUE GENERATION
EVERY ONE OF US IS CHIESI
Innovation
Entrepreneurship
Sense of belonging
Responsibility

3. Our vision Focus Respiratory Neonatologia Neonatology Rare diseases
High level research and development investment
Respiratory
Knowhow and expertise in product development in the respiratory area is key for growth
Neonatologia
Neonatology
Chiesi aims to offer concrete and effective solutions for perinatal diseases and prematurity syndrome
Rare diseases
Unmet medical needs and social impact of rare diseases are at the core of our work in this area
LSCD is among the areas of interest

4. Research & Development – Facts & Figures
Headcount: 515 (including regulatory affairs)
Investments in 2014: 236 Million of Euro (17,6% on turnover)
30 projects active in R&D*
Neonatologia

5. Corporate Research Centers (R&D Staff)
Parigi
14 staff
Chippenham
12 staff
Frederick 8 staff
PARMA: 361 staff in R&S
Lidingo & Hillerod
16 staff
Neonatologia

6. Chiesi–Holostem collaboration
World class technology 1
The University’s Centre for Regenerative Medicine 2
1394/2007 CE
REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
on advanced therapy medicinal products and amending Directive 2001/83/EC and
Regulation (EC) No 726/2004
New European regulation:
Pharma rules, incl. GMP, apply 3
Regulatory and industrial knowhow
Commercial infrastructure in Europe 4
GMP, good manufacturing practices

7. The first and only EMA-approved stem cell-based medicinal product

8. Holoclar®: production and delivery
1–2 mm2 limbal biopsy
Manufacturing
Transplant
Autologous human corneal epithelium containing stem cells
Production facility
Ophthalmic centre

9. Holoclar® Manufacturing Process
Enzymatic treatment
Freezing
Thawing
GRAFT FOR TRANSPLANTATION
CRYOVIALS
CULTURE ON PLATE
CULTURE ON FIBRIN
LSCs
Certified Feeder layer cell line
DRUG SUBSTANCE
BIOPSY
MONITORED BY >30 INTERNAL PROCESS CONTROLS, PATIENT-SPECIFIC

10. The regulatory process
2008 Defined as advanced therapy medicinal product by ITF
protocol assistance procedures with CAT
2008 Designated orphan medicinal product by COMP
2013 EMA submission
2012 Approval of HOLOCLAR® brand name by NRG
2010 Defined as ‘tissue engineered product, not combined’ by CAT
2014
CHMP positive opinion
2011
Scientific advice procedure with PEI; protocol assistance procedure #3 with CAT; PIP approval by PDCO
2015 Final EC approval (17 February)
CAT, Committee for Advanced Therapies; CHMP, Committee for Medicinal Products for Human Use; COMP, Committee for Orphan Medicinal Products; EC, European Commission; EMA, European Medicines Agency; ITF, Innovation Task Force; LOI, letter of intent; NRG, Name Review Group; PDCO, Paediatric Committee; PEI, Paul-Erlich-Institut; PIP, paediatric investigation plan

11. Comprehensive record of positive Clinical Data over time
HOLOCLAR® Clinical Development Plan
FPFV
January 2016
HLSTM04
N=15
HLSTM01
N=104
Success
72,1%
HLSTM02
N=29
60%
Favourable Safety Profile
HOLOSIGHT
N=100
HOLOCORE
N=65
October 2015

12. HOLOCORE: study design
Phase IV, multinational, open-label, uncontrolled clinical trial
Single arm, with second treatment option after 12 months from the first graft
Efficacy and safety of HOLOCLAR® for restoration of corneal epithelium in patients with LSCD due to ocular burns
Visual acuity post-keratoplasty included in HOLOCORE follow-up
Endpoint at 1 year, follow-up for at least 2–3 years
Combined primary endpoint (CNV and epithelial defect) after first ACLSCT
ACLST, autologous cultivated limbal stem cell transplantation CNV, corneal neovascularisation

13. HOLOCORE project plan
Single administration of HOLOCLAR® with second treatment in case of failure

14. HOLOSIGHT: registry study design
European observational, multinational, multicentre, prospective cohort study
For each patient enrolled:
Start of the observation: day of the corneal biopsy (consent signature)
End of the observation: 5 years after first HOLOCLAR® implant
Patient population: first 100 patients treated with HOLOCLAR® in the routine clinical practice setting who agree to participate in the registry
Follow-up period: 5 years
Setting: 10–25 centres in 10–12 European countries

15. Provides Easy and Supported access to treatment
Holoclar will be delivered to patients in Europe thanks to an integrated and “service-based” logistic business model
Chiesi does not only guarantee to deliver the product but the structure will also ensure all the logistic phases of biopsy taking, manufacturing, shipment of cell tissue and implant

16. HOLOCLAR® Key Values
First EMA-approved product for LSCD due to ocular burns
Revolutionary Product: First stem-cell product approved in EU using Autologous Stem Cells
Comprehensive record of positive Clinical Data over time
Certified High-Quality production standard
Highly labour-intensive product by extremely Qualified personnel
Provides Easy and Supported access to treatment
Proven to be a Cost-Effective alternative to conservative management

17. Before Holoclar® After Holoclar®
Pre-surgery:
Chemical burn, 3years from the accident
No previous surgery
Neovascularization in 4 quadrants with central corneal involvement
1 year post Holoclar implant:
Avascular corneal surface with regular and stable epithelium
Best Corrected Visual Acuity: 0.9

18. The pipeline HOLOCLAR® HoloMO HoloGENE BIOTRACHEA Bio-COMET Endomatrix
Preclinical
Phase I
Phase II
Phase III
Regulatory
Launch
HOLOCLAR®
HoloMO
HoloGENE
BIOTRACHEA
Bio-COMET
Endomatrix

19. The future
Additionally, Chiesi is working with Holostem on a new product: reconstruction of oral mucosa on to the patient’s eye
Will potentially allow treatment of other forms of LSCD (total bilateral and other pathologies such as aniridia)