ICX-SKN - Connect

Practical experiences of running
Phase I to III Cell Therapy clinical
trials
Getting the product to the patient - right time, right place
and safe to deliver
Loughborough: October 30th 2013
Paul Kemp CEO & CSO Intercytex
1
Practical experiences of running
Phase I to III Cell Therapy clinical
trials
Getting the product to the patient - right time, right place
RIGHT PATIENT and safe to deliver
Loughborough: October 30th 2013
Paul Kemp CEO & CSO Intercytex
2
3
4
5
6
Process Steps
Procurement  Isolation  Expansion 
Assembly  Maturation  Shipping  Application
7
“Commercial off-the-shelf methodologies and tools become
available to ease the development process.”
Procurement  Isolation  Expansion 
Assembly  Maturation  Shipping  Application
• Out sourcing
– Cell Bank Manufacture (HTA license issue)
– Culture Media
– Shipping
8
Testing for safety
Required Test
Assay
MCB
WCB
EOP
Sterility (Ph. Eur / USP)
+
+
+
Mycoplasma (by cell culture and inoculation)
+
+
+
Species identification (by Isoenzyme analysis)
+
+
-
Karyology
+
-
+
Tumourgenicity (by in vivo assay)
+
-
+
+
-
-
-
+
+
+
-
+
+
-
-
Bovine polyoma virus screen (by PCR)
+
-
-
SV-40 screen (by PCR)
+
-
-
+
-
+
+
-
+
+
-
-
+
-
-
+
+
+
Detection of adventitious viruses
28 day (by in vitro assay)
Detection of adventitious viruses
14 day (by in vitro assay)
Detection of adventitious viruses
(by in vivo assay)
Human virus detection (by PCR)
(HIV-1 and 2, HTLV-1 and 2, EBV, HBV, B19, HCMV, HPV, HHV-6, 7 and 8, HCV)
Detection and quantification of Retrovirus associated reverse transcriptase activity
(by RT – PCR)
General virus detection (by TEM)
Bovine screen (by in vitro assay)
(BVDV, REO-3, BAV, BRSV, BP)
In vitro porcine virus screen (by in vitro assay)
(PPV, PAV, TGE and HEV)
Bacteriostasis and fungistasis
9
Some Examples
10
Apligraf
Developed as a potential
replacement for split
thickness autografts for burns
11
1st FDA Approval for chronic wounds 1998
12
13
The Opportunity
VLUs
20,000,000 WW
2,300,000 US
DFUs
8,000,000 WW
1,200,000 US
Pressure ulcers
9,000,000 WW
2,500,000 US
Target Market – Hard to heal ulcers (US Only)
245,000
255,000
* Sources:Independent consultants, company estimates
359,000
14
®
Cyzact
For treatment of chronic leg & foot ulcers
15
15
Product History
• Strongly supported by original investors (JJDC)
in order to compete in the then very visible
chronic wound sector
• Product developed and in clinic within 2 years.
Aim was to have a product that could be
manufactured in one day with low COG and
could be easily shipped, stored and applied
S
• Apligraf and Dermagraft left the market around
the time Cyzact entered clinical studies
• Unlike Apligraf and Dermagraft FDA regulated
ICX-PRO as a Biologic
Standard of care significantly
• Unlike Apligraf and Dermagraft FDA required improved since Apligraf and
Dermagraft trials from Una
cellular control and three arm study
Paste Boot to 4 layer
compression
16
Phase III trial design
•
Double-blind randomised controlled study
•
Three arm study Randomised trial with a ratio of 2:1:1
– 2/4 Active + compression bandaging
– 1/4 Vehicle (Fibrin) + compression bandaging
– 1/4 Compression bandaging (SOC)
•
Inclusion criteria:
– Venous leg ulcer of at least 3 months duration
– Non-responsive to conventional therapy
– Roll-in on four layer compression bandaging (< 30% healing in 1 month)
•
Multicentre – UK, US and Canada
•
Endpoints
– Rate and incidence of closure (MHRA)
– Complete healing at 12 weeks (FDA)
17
Constraints
 Product

Shelf life

Temperature

Manufacturing and release cycles

Lot size
 Supply Chain

Contract Manufacturing Partners (Labelling and Distribution)

Couriers

Sites (locations, operating hours, receiving processes)

Import and Export
 Protocol Constraints

Patient accrual and screening

Randomization and Screening Failures

Subject visit schedules
18
Real World Models – Logistics

The up front planning and coordination work involved
establishing business relationships between;

Intercytex and the Logistics provider

The Logistics provider and the Distribution Center

The Logistics provider and the Clinical Sites
19
Phase III trial DSMB
• DSMB interim analysis (March 2007) 108 patients
– recommended continuing the trial
– Assumptions for control arm too low
– Sample size re-estimation to approx. 390
20
To maximise patient recruitment product was always
available at each of the sites. (Cyzact and fibrin alone)
• Phase III Cyzact trial
– 3 countries
– 62 clinical sites
– >800 subjects screened
– 400 subjects enrolled
– 350 batches produced
– Over 11,000 units manufactured
– 2,000 shipments made
– 10,000 units shipped
21
Cyzact® – Phase III sub-analysis
Year of Informed
consent
Cyzact®+ 4 layer
bandage
4 layer bandage
4 layer + fibrin
2005/2006
26% (22/85)
14% (6/42)
18% (7/40)
22
Cyzact® – Phase III sub-analysis
Year of Informed
consent
Cyzact®+ 4 layer
bandage
4 layer bandage
4 layer + fibrin
2005/2006
26% (22/85)
14% (6/42)
18% (7/40)
2007
24% (18/75)
37% (15/41)
29% (12/42)
23
Cyzact® – Phase III sub-analysis
Year of Informed
consent
Cyzact®+ 4 layer
bandage
4 layer bandage
4 layer + fibrin
2005/2006
26% (22/85)
14% (6/42)
18% (7/40)
2007
24% (18/75)
37% (15/41)
29% (12/42)
2008
44% (16/36)
41% (7/17)
39% (7/18)
24
Cyzact® – Phase III sub-analysis
Year of Informed
consent
Cyzact®+ 4 layer
bandage
4 layer bandage
4 layer + fibrin
2005/2006
26% (22/85)
14% (6/42)
18% (7/40)
2007
24% (18/75)
37% (15/41)
29% (12/42)
2008
44% (16/36)
41% (7/17)
39% (7/18)
% healing cutoff
Cyzact®+ 4 layer
bandage
4 layer bandage
30%
28.5% (56/196)
28% (28/100)
20%
30.9% (39/126)
21.6% (13/60)
10%
30.7% (24/78)
13.1% (5/38)
25
ICX-SKN
Skin graft for acute wounds
26
26
ICX-SKN
Implant
In vivo
Healed
Defect
“Integrity”
new host tissue
Failure
Remodeling
Time
27
ICX-SKN
In vitro
Implant
In vivo
ICX-SKN
“Integrity”
fibroblasts
produce HECM
Healed
Defect
new host tissue
Fibroblasts +
Fibrin
Failure
Failure
Remodeling
Manufacturing
Time
28
ICX-SKN
ICX-SKN: Manufacturing Process
Fibroblasts, Fibrinogen, Thrombin, Media
Maintain in culture
Cell produced Extra-Cellular Matrix
Freeze-dry and gamma irradiate
Stable Extra-Cellular Matrix
Rehydrate and repopulate
ICX-SKN
29
ICX-SKN
ICX-SKN
ICX-SKN – The Product
• Cell-produced human
collagenous matrix
• Human fibroblasts
• To repair “holes” formed by
surgery or trauma
• Phase I size 2cm x 2cm
30
ICX-SKN
ICX-SKN supports attachment and
differentiation of HK
Collagen IV
ICX-SKN + HK
HK
Stratum Corneum
ICX-SKN
Stratum Spinosum
Stratum Granulosum
Stratum Basale
Laminin 5
31
ICX-SKN
ICX-SKN
Larger pieces of ICX-SKN made in the labs
10cm X 10cm
32
ICX-SKN
ICX-SKN - Phase I trial histology
ICX-SKN
SKIN
33
ICX-TRC
For hair regeneration
34
34
ICX-TRC
Scientific Basis
40 Years of Supporting Research and
Proof of Principal
1964- Cohen shows hair induction from transplanted dermal papilla.
1967- Oliver demonstrates whisker induction using dermal papilla.
1984- Dermal Papilla cells first cultured (human and rat).
1984- Jahoda et al show induction of hair growth by (minimally) cultured
dermal papilla cells.
1992- Jahoda and Reynolds demonstrate cultured dermal papilla cell
induction of hair in glabrous skin (rat foot pad).
1996- Yoshizato et al demonstrate long-term culture of hair inductive
dermal papilla cells. Intercytex has exclusive license.
35
ICX-TRC
How ICX-TRC is expected to work
a) Rejuvenation
b) Follicle neogenesis
Stenn et al
36
Phase I: Hair Count Changes
450
180
/ cm2
Count
HairHair
Count
400
160
350
140
AAA
BBB
CCC
JHT
GTC
JBK
ASP
300
120
250
100
200
80
150
60
100
40
week 0
week 6
week 12
week 24
37
Current Licensing system
Eichler et al Nature Clin Pharm & therapeutics Vol 9 p 426 2012
Progressive Translation
Progressive Translation is based on three principles:
•Progressive Licensing: Focus on unmet medical need and orphan products in order
to allow access to the current legislative frameworks already in place of conditional
approvals.
• Progressive Development : A close partnership between client, contract developer
and hospital allowing iterative development of new treatments.
• Progressive Reimbursement: Obtain early reimbursement from a variety of sources
that will both help development finances as well as providing critical marketing
information
To do this, we want to base Cell2Therapy in Manchester infrastructure:
• Use Vavelta/ICX-RHY as exemplar
• Further develop details of system and operations
• Develop collaboration/partnership with “NHS system “
• Develop additional manufacturing capability
• Expand nationally and internationally
39
An Example: ICX-RHY / VAVELTA®
40
ICX-RHY Medical applications: EB
–Epidermis
–Basement Membrane
–Dermis
–Dystrophic EB
41
Results from Patient 1
Right axilla D0
Right axilla D0
Day 0 right parietal
Day 0 right parietal
Right axilla 1month
Right axilla 1month
1 month right
parietalright parietal
1 month
“A couple of months later,
I had fibroblasts injected
into my underarms and
scalp, two very
problematic areas for me.
Having been hospitalised
because of severe
infections in those areas
only a few months before,
I was amazed that within
a few days, the wounds
had started to heal. Over
a year on, the skin is
greatly improved – I’m
still amazed by it!”
42
Results from Patient 14
Day 0
Day
233
“Just after a week of treatment I began to notice improvement in my very large back
wound. Although it hasn't fully healed yet it, it has significantly shrunk in size
and the healed areas around the wound are much stronger now as they do not
blister as they used to and the wound, almost a year on is continuing to heal,
something that it has not done in the last fourteen years.”
43
Key findings
• 354 people with RDEB were assessed at
three EB adult specialist centres
• 23 were screened
• 13 subjects with a total of 91 erosions
entered
• 11 subjects and a total of 29 erosions
randomised at single centre with home
follow-up visits
“Although the optimal dose of fibroblasts and frequency of treatment, as well
as the best delivery modalities are yet to be determined, the study showed
that the initial healing of chronic erosions in RDEB is faster following
intradermal injections of allogeneic fibroblasts”
“The clinical utility could be extended further provided that a less painful
means of intradermal delivery could be achieved”
44
Progressive Translation
• Progressive Licensing: Focus on unmet medical need and orphan products in order
to allow access to the current legislative frameworks already in place of conditional
approvals.
•Orphan designation obtained in EU and US
•Phase II clinical trial completed
•Specials license obtained for Intercytex manufacturing facility
• Progressive Development : A close partnership between client, contract developer
and hospital allowing iterative development of new treatments.
•Biocatalyst grant to Improve shelf life and logistics to enable pharmacy supply
•Working with Cell Therapy Catapult to produce less painful injection system
•Working with MIMIT to examine feasibility of using hollow microneedles
•Working with suppliers on scale-up options
• Progressive Reimbursement: Obtain early reimbursement from a variety of sources
that will both help development finances as well as providing critical marketing
information
•Developed costing models for current system and scale up options
•Obtained full hospital reimbursement to treat first patients under Specials
•Working with charities to examine reimbursement possibilities
45
Cell2Therapy - Contract Progressive Translation
Services
• Mentored
Manufacturing
• Contract
Manufacturing
• Contract Research
and Development
• Contract Translation
46
Intercytex Ltd
• Clinical development of both Autologous and
Allogeneic cell therapy IMPs and Class 2 Medical
devices
• Experience in a number of human cell types and
product formats from injectable suspensions to 3D
constructs
• Experience at shipping cryopreserved, low
temperature and ambient products worldwide
• The first UK team to have manufactured IMP and
operated a Phase III clinical multinational clinical trial
• Submitted numerous regulatory, CTA and IND filings
in the EU and US
47
Intercytex Ltd
• MIA (IMP) and Specials licensed GMP facility
• 83m2 clean room capacity
• 2 independent fully GMP licensed clean room
suites capable of operating up to Grade A (Class
100)
• Grade C space available for closed system
operations
• Controlled rate freezing and cryopreservation
storage
• Dedicated GMP QC laboratory
• 100m2 of process development labs
• GMP compliant Quality Management System
48
UHSM Medipark
Manchester
Enterprise
Zone
49
Thankyou
[email protected]
www.intercytex.com
www.cell2therapy.com
51