Intercytex Ltd

Intercytex Ltd
Are animal studies always essential?
: An industrial perspective
P l Kemp
Paul
K
London: 18th November 2011
0
ARE ANIMAL STUDIES ALWAYS ESSENTIAL?
Essential for what?
There are several examples of cell-based ATMPs being
approved to enter the clinic without animal testing
However….
NO
There are no examples currently of cell-based ATMPs being
licensed without animal testing
Maybe
1
1
Regenerative Medicine
iPS cells
Stem Cells
Differentiated Cells
– Peripheral- & cord bloodderived progenitor cells
“Functional” Cells
– Progenitor cells, e.g. stem
cells derived fromFactors
various
Matrix
types of human tissues,
embryos; iPSCs
Cell Therapy
– Modified cells (e.g.
engineered T cells)
Tissue Engineering
– Differentiated cells, e.g.
islet cells, cartilage cells,
Products to Regenerate Tissues
or Organs
fibroblasts etc.
Joy Cavagnaro: AccessBio (jcavagnaro@accessbio.com)
2
Joy Cavagnaro: AccessBio (jcavagnaro@accessbio.com)
–Richard Woodfield
–9th Nov 2005
3
Challenges
–New iterations based on
clinical feedback
–Protocol
–Potency assay
–
End points
–
Follow up
–Jurisdictions
Research
Clinical
–Number of sites
–P.I.
–How to ensure supply
C
Company
–How fast to run the
study
O
Operations
ti
•
Batch size
•
Batch
frequency
–Blinding
–How to pay for the study
–How to ship
4
8
Product
Development
Safety
Mechanism of
Action
Product/Process
Improvements
Joy Cavagnaro: AccessBio (jcavagnaro@accessbio.com)
5
Issue
Somatic Cell and Tissue Engineered ATMPs are living human
cell based p
products and will be rapidly
p y rejected
j
by
y all immuno
competent animals
Either
A) Use immuno incompetent animals.
Issues of appropriate inflammatory/ remodeling reaction
O
Or
B) Use animal cell analogue of the human product
Issues of time, expense and relevance
10
Product
Development
6
Apligraf
12
Apligraf
“Apligraf
Apligraf took on an
unusual appearance
compared to the normal
process of skin grafts
whereupon it became
translucent and jelly like
13
7
Apligraf
14
Tissue Engineered remodeling
Implant
In vivo
Healed
Defect
“Integrity”
new host tissue
Failure
Remodeling
Time
8
Tissue Engineered remodeling
Implant
In vivo
Healed
Defect
“
“Integrity”
new host tissue
Healing by
secondary
intent
Remodeling
Time
Failure
Ok for skin but
not for a
construct with
critical physical
function such
as tendon or
heart valve
17
9
Safety
19
10
Testing for safety
Assay
Required Test
MCB
WCB
Sterility (Ph. Eur / USP)
+
+
EOP
+
Mycoplasma (by cell culture and inoculation)
+
+
+
Species identification (by Isoenzyme analysis)
+
+
-
Karyology
+
-
+
Tumourgenicity (by in vivo assay)
+
-
+
Detection of adventitious viruses
+
-
-
Detection of adventitious viruses
-
+
+
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)
+
-
-
Bovine polyoma virus screen (by PCR)
+
-
-
SV-40 screen (by PCR)
+
-
-
Detection and quantification of Retrovirus associated reverse transcriptase activity
+
-
+
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
+
+
+
21
11
22
Mechanism of
Action
12
ICX-TRC
For hair regeneration
24
Hair “loss”
• Hairs are not actuallyy
lost but get
progressively smaller
and less visible
• Beginning with
“terminal hairs”
25
13
• Hairs are not actuallyy
lost but get
progressively smaller
and less visible
26
200-250 terminal hairs cm2 –
full head
• Hairs are not actuallyy
lost but get
progressively smaller
and less visible
100-125 terminal hairs/cm2 –
thinning
• Ending with “vellus
hairs”
0-50
0
50 terminal hairs/cm2 –
bald
27
14
Research and proof
1964
1967
1984
1984
Cohen shows hair induction from transplanted
p
dermal p
papilla.
p
Oliver demonstrates whisker induction using dermal papilla.
Dermal Papilla cells first cultured (human and rat).
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
cells.
–ICX-TRC
ICX-TRC – The Product
–Biopsy
Biopsy
–Critical proprietary step
–Reimplantation
–Cell culture
–Growth
–Dermal Papilla Cells
15
Hair Induction Assay- Nude Mouse model
–Cultured Human Dermal Papilla Cells induce Hair
–A
–B
–Control with
–Cultured DP Cells
–Human Dermal Fibroblasts
16
–Long Term Growth of Hairs Induced
–by Cultured DP Cells
–5 Months
–11 Months
Grafted Cells Form Dermal Papillae in
Induced Hairs
17
ICX-TRC – Mode of action
a) Rejuvenation
b) Follicle neogenesis
34
VAVELTA®
18
Scar Contracture treatment with ICX-RHY
(Vavelta)
–Before Treatment
–Restricted neck movements and painful
Scar Contracture treatment with ICX-RHY
(Vavelta)
–Before treatment
–12 weeks (07/01/08)
–Completely full neck rotation and pain free
19
Joy Cavagnaro: AccessBio (jcavagnaro@accessbio.com)
38
Product/Process
Improvements
20
Conclusions
ƒ A case-by-case approach is needed rather than the
checklist approach that has developed for small
molecule pharmaceuticals.
ƒ Predictive studies needed both to predict possible
clinical safety and outcome as well as predict possible
MAA issues
ƒ Because it isnt a one-size-fits-all process, an effective
dialogue between developer and regulator(s) MUST be
established and maintained
41
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